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Towards Human Exploration of Space: a EUropean Strategy - Roadmap

ROADMAP March2012 1 THESEUS Consortium

Project Coordination and Communication European Science Foundation, France Jean-Claude Worms - Coordinator Nicolas Walter – Project Officer Olivier White - Project Officer (Jan-Sept 2010) Johanne Martinez-Schmitt – Project Administrator Karina Marshall-Bowman - Editorial Support

Work Package 1: Integrated systems physiology Centre National de la Recherche Scientifique - Institut Pluridisciplinaire Hubert Curien (CNRS-IPHC), France Stéphane Blanc – Work Package Leader Iman Monken – Work Package Support

Work Package 2: Psychology and human-machine systems University of Sheffield, UK Bob Hockey – Work Package Leader

Work Package 3: Deutschen Zentrums für Luft- und Raumfahrt (DLR), Germany Günther Reitz - Work Package Leader

Work Package 4: Habitat management Belgian Nuclear Research Centre (SCK•CEN) Natalie Leys – Work Package Leader Felice Mastroleo – Work Package Support

Work Package 5: Health care Institut de Médecine et de Physiologie Spatiales (MEDES), France Bernard - Work Package Leader

Work Package 6: Integration Deutschen Zentrums für Luft- und Raumfahrt (DLR), Germany Rupert Gerzer – Work Package Leader Gerda Horneck – Expert Support

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus:

Cluster 1: Integrated Systems Physiology 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

3 Table of contents

1. Executive Summary 6

2. The Role of Europe in Global Space Exploration 9

2.1. International context and background 9

2.2. Studies on future human exploration of space 10

3. THESEUS Process and Approach 13

3.1. Identification of Key Issues 14

3.2. Identifying areas of common interest 15

4. THESEUS Roadmap: Providing Relevant Orientations for Research 17

4.1. Theme 1. Integrated view of human adaptation to the 18

4.2. Theme 2: Integrated view of countermeasures to multiple stressors 21

4.3. Theme 3: Integrated view of tools and methods 23

4.4. Tying Key Issues to recommendations 24

4.5. Implementing the THESEUS approach 36

5. Relevance to Earth Issues 37

Annex: List of 99 THESEUS Key Issues 43 References 48

4 Contents 1 Executive Summary

Future exploration of the system and beyond will can be defined as high priority disciplinary scientific undoubtedly be a collaborative endeavour of both topics or methodology issues representing challenges humans and robots, enabled by innovation, ingenuity or opportunities for human space exploration, and global cooperation. Physical, psychological and requiring further attention in the future. In identifying technological challenges are inherent to human Key Issues, the THESEUS Expert Groups considered , and become increasingly difficult to the challenges imposed by the demanding understand and overcome with longer-duration space exploration scenario proposed in the first steps missions. Future exploration class missions may last of the THESEUS project, this led the groups to study up to several , exposing to extreme knowledge gaps to be filled and methodological environmental conditions and physical stressors approach required to implement a long duration that could cause major issues in both health and mission to (in the range of 500 days). performance. Currently, some of these issues are showstoppers for human missions to e.g., Mars and To enable research of the recognised key issues, the need to be resolved. To truly enable and allow for THESEUS roadmap has developed a three-themed future endeavours, the approach to space exploration- approach with underlying recommendations: enabling research must be over-hauled.

Besides system-level investigations and studies, a Theme 1: Develop an integrated view of human complete understanding of the integrated response adaptation to the space environment and adaptation to space and planetary surface environments as well as of interactions with the Recommendation 1: Perform a detailed, integrat- spacecraft and between crew members is necessary. ed survey, define and quantify the multiple envi- Once multi-system responses to various stressors ronmental stressors during human space explora- are understood, holistic countermeasures can be tion missions, and assess their potential hazards to developed. Additionally, standardised protocols humans, both individually and in combinations. should be implemented to allow for cross-discipline comparison of data through available databases. Recommendation 2: Perform an integrated survey To implement this essential integrated research and identify interactive human adaptations to the approach, a stable, cross-disciplinary programme complex environments of space exploration in needs to be established at the European level. order to assess the risks to astronauts and develop efficient countermeasures for their mitigation. THESEUS (Towards Human Exploration of Space: a EUropean Strategy) is a Coordination Action funded Recommendation 3: Perform an inventory of by the European Commission seventh Framework personalised exposures and responses to the Programme (FP7). This project aims to provide a complex environments of space exploration cross-cutting, life science-based roadmap for Europe’s with regard to gender-based differences, genetic strategy towards human exploration of space. To disposition and other individual characteristics. achieve its objectives, the project set up 14 Expert Groups (EGs) centred around five main research Recommendation 4: Perform an integrated areas: integrated systems physiology, psychology and risk assessment for human exploration missions human-machine systems, space radiation, habitat combining the risks from exposures to multiple- management and health care. stressor environments, the interactive adaptations to these stressors, and from personalised responses. With inputs from the wider scientific community, This should be the base for quantifying acceptable THESEUS experts identified 99 Key Issues, Key Issues risks for astronauts during exploration missions.

Executive Summary 5 Theme 2: Develop an integrated view of countermeasures to multiple stressors Overall, Europe is currently one of the world leaders in and research. However, a long- Recommendation 5: Mitigation strategies term plan with research prioritisation enabling against certain adverse effects expected from is lacking. The THESEUS roadmap environmental stressors should be implemented proposes implementation of its recommendations in during the planning phase of a space exploration an integrated, phased approach. Such an approach mission, e.g., by designing appropriate habitats, complements fundamental research activities with developing training methods and providing programmes oriented around well-defined goals appropriate countermeasures with the mission and objectives relevant to enabling future human scenarios and timelines. exploration missions and ensuring European competitiveness in future exploration endeavours. Recommendation 6: Develop optimised countermeasure procedures and programmes Overarching Recommendation: that integrate human body functions as well as inter-individual variability, and take into account Structure human exploration-enabling re- the possible interactions between different search around the themes and recommen- dations put forward by THESEUS, using the countermeasures. To achieve this, ground-based phased approach defined by the roadmap analogue facilities need to be developed for exercise. Programmes should be coordina- animal and human studies addressing system-level ted and implemented at the European level questions. and consider direct funding, networking and exchange of knowledge as well as op- Theme 3: Develop an integrated view of tools and timised utilisation of European research in- methods frastructures. In this context, targeted calls and dedicated research solicitation would Recommendation 7: Develop standardised allow medium to long-term consistency in protocols and procedures for studies on integrative the process. human adaptation to the conditions of space during exploration missions and the development From Space to Earth of efficient countermeasures. By and large, issues that humans face during space missions in LEO and beyond have commonalities with Recommendation 8: Set-up a database of issues for individuals on Earth. Key Issues put forward results from ground and space-based integrative by the THESEUS experts are fully relevant to societal human research based on standardised protocols challenges such as ageing, nutrition, civil security and and procedures including the exertion of individual safety as well as sustainable development. countermeasures. A data management and distribution system should be established in It should be emphasised that while some topics coordination with major European stakeholders are already intensively investigated on Earth, space (especially ESA and EC) to make these data exploration provides very specific conditions in accessible to the scientific community. Protocols terms of the environment, technical constraints as should be established for disclosure of anonymous well as opera tional and safety requirements. Theses crew health data to qualified researchers. specificities allow consideration of scientific and technological topics with a different angle, bringing Recommendation 9: Utilise mathematical, added value to many Earth applications. The issue of physical, biological and neurocognitive modelling miniaturisation of diagnostics and health monitoring to understand and anticipate various risks to equipment provides a good example of such added astronauts associated with exploration missions value. and for applying means to reduce them to an acceptable level.

6 Executive Summary THES EU S 2020 2014 THESEUS ROADMAP

THESEUS Roadmap – Articulation of research orientations in the future. The colour range indicates the phasing of a given recommendation – the darker the colour, the more intense activity.

7 2 The Role of Europe in Global Space Exploration

2.1 International context and background

Space exploration requires global collaboration During the same and based on inputs received by to succeed due to its extreme complexity and various stakeholders (including ESF), ESA developed technological challenges. In May 2007, fourteen space- a European long-term strategy for space exploration faring nations agreed on a coordinated approach to [4] focused on four key themes with particular space exploration, the “Global Exploration Strategy” significance for Europe: [1]. The (ESA) and space agencies from four European member states [ASI • The advancement of scientific knowledge: Life and (Italy), BNSC (United Kingdom), CNES (France) and its co-evolution with the planetary environment DLR (Germany)] agreed to take part in this initiative. (main objective as per ESF’s 2007 science-driven This framework for coordination presents a vision for scenario); lunar observatories; life sciences. Innovation and economic development: Applied robotic and human space exploration, focusing on • microgravity research; entrepreneurial activities; destinations within the where humans space services. may one live and work. Robotic exploration will • Support for the European political project: Euro- undoubtedly precede human exploration of the , pean ambitions; the Lisbon strategy; global par- near-Earth and Mars to characterise the tnership. extra-terrestrial environments, assess risks connected • Public constituencies, which recognise the neces- to human missions and identify potential resources sity to engage the general public. to be used for life support and technology purposes. Therefore, space exploration-enabling research must This strategy foresees prolonged human operations in be geared towards both robotic technologies and space, particularly in through utilisation human factors. of the ISS. Through these activities knowledge will be gained on how to sustain human health in space and In 2007 the European Science Foundation (ESF), ways to improve the efficiency and safety of human under the guidance of its European Space Sciences transport and operations in space will be discovered. Committee, was commissioned by ESA to develop a science-driven scenario for space exploration. The Europe has the benefit of being able to rely on the resulting scenario [2-3] acknowledged that the drivers heritage of its past space activities in various scientific for human exploratory missions include science, and technological areas, making them a desirable technology, culture, and economic aspects. Above all, partner in the global space exploration scenario. the search for habitability and, hence, for life beyond Noting that Europe has committed to participate in Earth, has been considered as one of the main international space exploration initiatives, the Space intellectual driving forces in the endeavour to explore Advisory Group (SAG) of the European Commission the Solar System, and the scenario emphasised that recommended that Europe should prepare a exploration without humans lacks an important European vision for space exploration and invest its societal and even scientific interest. Therefore, it key competences in these international efforts [5], was recommended that human spaceflight be [6]. integrated into the European Exploration Programme The need for a European Space Exploration Programme in a synergistic way at all stages of programme is rooted in the European , e.g., in Article development and that the programme focuses on 189 of the TFEU (Treaty of the Functioning of the targets that can ultimately be reached by humans. European Union), which calls for the EU “to support

8 The Role of Europe in Global Space Exploration research and technological development and coordinate discover . It is not only a scientific but also the efforts needed for the exploration and exploitation a political and global endeavour. Space exploration is a of space.” This was further emphasised in the Council driver for innovation, technological development, and Resolution of 29 May, 2009, which “reaffirms the need scientific knowledge which can bring about tangible to assess the possibilities offered by European Union benefits for citizens. It requires a long-term strategic policies to embed space exploration in a wider political vision for tomorrow’s investments and embodies both perspective and, recognising that space exploration has cooperation and competition aspects”. the potential to provide a major impact on innovation, looks forward to the Commission’s proposed High- A further step was made through the “Third Level Political Conference on Space Exploration, on International Conference on Exploration and the First the basis previously agreed in the Space Council, as a High-level International Space Exploration Platform” first step towards the elaboration in due time of a fully- held in Lucca (Italy) in November 2011. Highlighting fledged political vision on “Europe and Exploration” that no single country can afford to explore the Solar encompassing a long-term strategy/roadmap and System in a sustainable way alone, government an international cooperation scheme”. Following this representatives from 28 countries (21 of which were resolution, the Second International Conference on European partners) committed to begin an open Space Exploration in October, 2010, organised under structured, high-level policy dialogue on space the Belgian Presidency of the EU, concluded that exploration at the government-level [7]. “space exploration satisfies the desire of humankind to

2.2 Studies on future human exploration of space

Several studies have been performed regarding technological and system development. The latest research for enabling human exploration of the planning exercise was performed by the International solar system. Notable initiatives include the Global Space Exploration Coordination Group (ISECG – Exploration Roadmap by the International Space established under the auspice of the GES). In its Exploration Coordination Group (ISECG), ESA’s Global Exploration Roadmap [8] endorsed by 12 HUMEX study, NASA’s Roadmap (later space agencies, ISECG defines a long-range human transformed into the Human Research Roadmap) exploration strategy that begins with the ISS and and the US Space Studies Board’s Decadal Survey on then expands human presence throughout the solar Biological and Physical Sciences in Space. Even though system, ultimately leading to human missions to the each study identifies key research areas that must surface of Mars (Fig. 1). Under human exploration be followed to enable human exploration, THESEUS preparatory activities, the roadmap defines takes a more holistic approach by providing a cross- technology areas that need to be further developed, disciplinary, multi-factorial approach to research and such as “human health, life support and habitation countermeasures. systems, improvements in reliability, maintainability, reduced mass and volume, advancements in biomedical Space exploration has several facets, including, for countermeasures, and self-sufficiency with minimal example, the scientific drive to acquire new insights logistics needs as essential for long-duration spaceflight into the emergence of life and the development missions. In addition, advancements in space radiation of the Solar System. It requires a mix of robotic and research are required, including advanced detection and human-related activities and promotes innovative shielding technologies”.

The Role of Europe in Global Space Exploration 9 Global Exploration Roadmap

2011 2020 2030 ISS Research & Technology Demonstrations LEGEND Robotic Mission • Life Support, Human Health, Habitats • Communication and Robotic Technologies Human Mission • International Docking System Standard • Cryo Fluid Management and Transfer

Crew and Cargo Services Commercial/International Low-Earth Orbit Platforms and Missions Two Optional Pathways Guiding Investments Driven by Discovery Moon in Technology, Capabilities, and ISS Utilization and Emerging Technologies

Precursor Moon Next

Lunar Orbital Mission Human Lunar Return

Asteroid Next

EML1 Mission First Human Second Human Near-Earth Asteroids First Mission to Deep Mission Asteroid Mission

Precursor Precursor

Mars Surface

Enabling Exploration Capabilities Deep Space Habitat Advanced In-space Propulsion Multi-purpose Crew Vehicle (MPCV)

Space Exploration Vehicle NGSLV Cryogenic Propulsion Stage

Lander Descent Stage Ascent Stage Next System/ Generation Spacecraft Heavy-

Figure 1. The Global Exploration Roadmap of ISECG (ISECG, 2011).

The Global Exploration Roadmap of ISECG mainly The first European roadmap for space exploration concentrates on flight scenarios and technology explicitly based on life sciences aspects was developments through the coordination of ISECG developed in the 2001 ESA study “HUMEX Study on members. the survivability and adaptation of humans to long- duration exploratory missions” (Fig. 2) [10-14]. The In April 2011, ESA developed five major scenarios for main recommendations of the HUMEX roadmap future human spaceflight and exploration [9]: were: • ISS, robotic precursor missions and technologies, • to largely use the ISS for research and develop- Lunar exploration, ment activities in the fields of space radiation • Deep space operation, health, psychology, physiology and life support • Autonomous capabilities for human transporta- systems; tion and operation in Low Earth Orbit, to make use of robotic precursor missions to ex- Multiple destinations to enable participation in • • plore planetary environments and their habita- multiple international mission scenarios. bility, e.g., in view of radiation protection issues, hazards of planetary environments and in-situ For each scenario, strategic guidance is outlined in view resource utilisation for life support purposes; of ensuring sustained European access to man-tended infrastructures in space, and developing capabilities to • to use terrestrial test-beds and simulation facilities enable and support human missions and operations for understanding human and/or animal respon- in space. In addition, the study determines key activity ses to simulated space parameters and to develop lines, mainly dealing with critical technology to be efficient countermeasures; and developed. Roadmaps developed for the different to develop synergies between space activities and scenarios of this study describe the potential missions • terrestrial technologies and applications. to reach the goals. The THESEUS study intends to contribute to this European strategy by providing For the different flight and test scenarios, each a life sciences oriented roadmap required to field of research, including general health issues, safeguard humans during exploratory missions radiation health, psychology, physiology, and life and to enable successful participation of Europe support systems, was considered separately. Relevant in the envisaged international human spaceflight unresolved issues were identified, and needed and exploration scenarios. research activities were suggested. 10 The Role of Europe in Global Space Exploration In February, 2005, NASA issued the baseline document • Behavioural health and performance of its Bioastronautics Roadmap. This document was • Exploration medical capability intended to list the major risks that crew may face • Human health countermeasures during spaceflight and exploration missions. NASA’s • Space human factors and habitability Bioastronautics Roadmap was intended to guide • Space radiation prioritised research and technology development that, coupled with operational , The 31 identified risks are addressed through more inform: (1) the development of medical standards than 600 research and technology development and policies; (2) the specification of requirements tasks [16]. Similar to the Bioastronautics roadmap, for the human system; and (3) the implementation the Human Research Roadmap (and its associated of medical operations [15]. To this end, the roadmap programme) is continuously evolving and updated describes and justifies a number of risks, with their on a regular basis. context, severity rating, expected countermeasures and prioritised research and technology questions. Another study dedicated to life science aspects of human spaceflight is the recently published “Decadal Following the development of knowledge and Survey on Biological and Physical Sciences in Space” discoveries, this roadmap was regularly updated of the US Space Studies Board’s “Recapturing a Future throughout its lifetime and eventually transformed for Space Exploration: Life and Physical Sciences into the Human Research Roadmap, the backbone of Research for a New Era” [17-18]. This study was based NASA’s Human Research Programme (established in on a request by NASA to achieve the goals of the 2008). As of February 2012, NASA’s Human Research Exploration Initiative: A greater understanding of life Roadmap lists 31 risks clustered around 5 domains: and physical sciences phenomena in microgravity will be

Radiation, Life Support

Radiation

Synergies with terrestrial technology

Radiation, Physiology, Psychology; Life Support Radiation, Physiology, Psychology; Life Support

Figure 2. The roadmap of the HUMEX study for a future European strategy in life sciences-related issues for human exploratory missions (adapted from ESA, 2003).

The Role of Europe in Global Space Exploration 11 required as well as in the partial environments of This Decadal Survey represents the first study to the Moon and Mars. It is one of the goals of this study explicitly mention cross-cutting issues for research to recommend research that enables advancements related to humans in the space environment. It in basic and applied knowledge needed to expand includes horizontal multi- and trans-disciplinary exploration capabilities. Topics that were considered integration as well as a vertical interaction among for space exploration include: basic, preclinical, and clinical scientists to translate • Plant and microbial research to increase funda- fundamental findings into improvements in the health mental knowledge of the gravitational response and well-being of crew members during and after and potentially advance goals for the develop- their missions. It also recognises that an integrated ment of bioregenerative life support; research approach is warranted to address the sum • Behavioural research to mitigate the detrimental effect of a range of physiological and behavioural effects of the spaceflight environment on astro- changes during long-term human spaceflight. This is nauts’ functioning and health; similar to the integrated and holistic approach that • Human and animal biology research to increase THESEUS aims to implement on the European level. basic understanding of the effects of spaceflight on biological systems and to develop critically needed countermeasures to mitigate negative ef- fects of spaceflight on astronauts’ health, safety, and performance; • Translational and applied research in physi- cal sciences that can provide a foundation of knowledge for the development of systems and technologies enabling human and robotic explo- ration [17].

The intent of this Decadal Survey is to lay out steps for developing a portfolio of research that is required for space exploration. Besides developments in technology the following actions were recommended: • Implement an effective countermeasures pro- gramme to attenuate the adverse effects of the space environment on health and performance capabilities of astronauts, a development that will make it possible to conduct prolonged human space exploration missions. • Develop a deeper understanding of the mecha- nistic role of gravity in the regulation of biological systems (e.g., the mechanisms by which micro- gravity triggers the loss of bone or cardiovascular function – an understanding that will provide in- sights for strategies to optimise biological func- tion during spaceflight as well as on Earth (e.g., slowing the loss of bone or cardiovascular func- tion with aging) [18].

12 The Role of Europe in Global Space Exploration 3 THESEUS Process and Approach

3.1 Identification of Key Issues

THESEUS aims to provide a life science-based roadmap all life science domains relevant to human space for Europe’s strategy towards human exploration of exploration ranging from integrated physiology to space. habitat management and health care. THESEUS also aims to identify how research for space exploration THESEUS was initiated in early 2008 with the ambitious can also be relevant to health and societal issues on objective to perform a wide survey of knowledge Earth. gaps that must be filled to enable further human space exploration, in particular beyond LEO, and to To achieve its objectives, the project set up 14 suggest research activities to address these gaps. As disciplinary Expert Groups (EG) clustered around five a horizon scanning initiative, the project cuts across areas of research:

Cluster 2: Psychology and Human-Machine Systems • Group/team processes • Human-machine interface • Skill maintenance Cluster 1: Integrated Systems Physiology • Bones and muscles • Heart, lungs and kidneys • Immunology • Neurophysiology Cluster 3: Space Radiation • Nutrition and metabolism • Radiation dosimetry THESEUS

Cluster 4: Habitat Management • Microbiological quality Cluster 5: Health Care control of the indoor • Space medicine environment in space • Medication in space • Life support: management and regeneration of air, water and food

Each EG involved about ten international experts, Key Issues were identified by the EGs. Key Issues can spanning from Europe, USA, Russia and Japan. Special be defined as high priority disciplinary scientific attention was given to ensure involvement of mem- topics or methodology issues representing chal- bers from ESA topical teams in life sciences, and that lenges or opportunities for human space explora- links with the NASA Human Research Program were tion, requiring further attention in the future. made via participation of US investigators actively involved in this programme. Overall, the THESEUS In identifying Key Issues, the THESEUS Expert Groups Expert Groups involved 123 experts from 23 different considered the challenges imposed by the most de- countries. manding space exploration scenario proposed in the first steps of the THESEUS project, this led the groups The 14 EGs met in April, 2010 to brainstorm the cur- to study knowledge gaps to be filled and methodo- rent state of research in their specific field and iden- logical approach required to implement a long du- tify the main research questions necessary to enable ration mission to Mars (in the range of 500 days). human space exploration. From these workshops, 112

THESEUS Process and Approach 13 While the work performed by the EGs represents the tions. To this end, EGs met in cluster in October, 2010 core of THESEUS, the project also gathered inputs and to review the inputs received from the community comments from the wider scientific community on the consultation, review the Key Issues in detail, and agree identified Key Issues. This was made possible through on the recommendations to be put forward. This step a wide consultation consisting of 14 online question- resulted in the final list of 99 THESEUS Key Issues (see naires open to any interested scientist in the domains Annex 1 for details), further detailed in the five cluster covered by the project. This community consultation reports (published separately) [19-23]. was open for two months (between 15 July and 15 September, 2010), and contributions were received It is important to remember that the THESEUS road- from 169 scientists (of which 149 were not members map presented in this document is fully integrated of any THESEUS EG). Considering the EG membership with the work of the Expert Groups, and the cluster and community participation through the online con- and Expert Group reports form the foundation upon sultation, a total of 272 investigators participated in which it has been built. The roadmap suggests a co- elaborating the EG recommendations and eventually herent way to address issues identified by the THE- to the definition of this roadmap. SEUS experts and is strongly linked with the content of the cluster reports and therefore should not be The third step of the THESEUS project focused on fi- considered independently from these. nalising the Key Issues and associated recommenda-

3.2 Identifying areas of common interest THESEUS considers human exploration-related re- was conducted to confirm, visualise, and provide ad- search from a cross-cutting and integrated perspec- ditional insights into overlaps. To evaluate the degree tive. It is crucial that the findings and outputs from the of interaction across the five clusters and their EGs, EGs are considered in a holistic manner, interlinking the following approach was adopted. First, specific Key Issues and identifying the best way to address keywords were extracted from individual EG reports. them in a coherent and sensible way. Next, metrics were defined to quantify the degree of interaction between Expert Groups. In short, the de- From the list of 99 Key Issues, identification of trans- gree of interaction was proportional to the number disciplinary aspects was an essential step in THESEUS. of common keywords between the two reports. Nor- Although experts dedicated special attention to malisation of that parameter allowed for quantitative identify elements at the boundary between different comparisons of trans-disciplinarity between EGs, re- scientific domains, a more neutral, systematic analysis sulting in the matrices presented in Figure 3.

Continuous interaction between Expert Groups 3−class interaction between Expert Groups 2 11 0.14 11 12 12 1.8 13 0.12 13 1.6 14 14 15 0.1 15 1.4 21 21 1.2 22 0.08 22 1 23 23 Expert Groups Expert Groups 31 0.06 31 0.8 32 32 0.6 41 0.04 41 42 42 0.4 0.02 51 51 0.2 52 52 0 0 11 12 13 14 15 21 22 23 31 32 41 42 51 52 11 12 13 14 15 21 22 23 31 32 41 42 51 52

Care Care Space Habitat Health Space Habitat Health Systems Systems Systems Systems Radiation Radiation Integrated Integrated Physiology Physiology Management Management Psychology and Psychology and Human Machine Human Machine Figure 3. Continuous (left) andExpert discretised Groups interaction matrices (right), showing the degree of interactionExpert between Groups Expert Groups based on colour (lighter colour = more interaction, darker colour = less interaction). For the discretised matrix, 2 thresholds (degree=0.047 and 0.096) were adjusted to split the lognormal distribution of degrees of interaction (white = high, orange = medium, black = low degree of interaction) - EG numbering is provided in annex 1. 14 THESEUS Process and Approach Figure 3 (left) shows the continuous EG interaction the cardiovascular system, immunology, nutritional matrix (the lighter the box, the more interactions). To issues, digestion, infections and sterilisation. enhance the contrast, two thresholds were defined based on the lognormal-like distribution of the • Individual factors degrees of interaction. Three classes resulted from Investigating the mechanisms behind why and how this process: high (white), medium (orange) and individuals respond differently to the conditions of low (black) degrees of interactions. Figure 3 (right) spaceflight by various means (e.g., psychological illustrates the discretised matrix of interaction. From assessments, genetic and medical screening) has been these graphical representations, one can see that the pointed out several times by THESEUS Expert Groups. EG focused on Dosimetry (32) and Life support (42) are This issue is relevant to develop a better understanding the most independent EGs, whereas the EG focused of human adaptation to spaceflight and could also on space medicine (51) interacts with every other be considered in the selection of astronauts and EG. To quantify how much each EG overlapped with crew composition. While it is challenged by ethical another EG, a cumulated degree of interaction was issues, genetic predisposition seems to be a topic of computed. This degree was defined as the sum of the increasing interest. interaction of that EG with every other EG (excluding itself). Figure 4 presents the cumulated degrees of • Molecular and cell biology; genetics interaction of each EG. This theme deals with every aspect of cellular and molecular mechanisms involved in various reactions to stressors at large. It is omnipresent: bones and mus- cles, genetics, immunology, contamination, radiation effects on cells etc. There was no explicit EG to deal with these mechanisms in THESEUS.

• Monitoring and modelling Intelligent, integrated, synchronised monitoring of physiological and psychological systems together with the environment (e.g., radiation, habitat) are mandatory and will be extremely valuable to feed integrated models.

• Integrated countermeasures Countermeasures must be approached in an interdisciplinary manner, firstly, because time is very constrained, and secondly because a Figure 4. Cumulated degree of interaction for each EG. - EG numbering is provided in annex 1. comprehensive approach is much more efficient than the sum of local solutions. All dimensions need to be taken into account. In addition to the ability to visualise interactions across elements in a matrix form, this method also allowed • Radiation effects for the identification of concepts and issues that cut Negative radiation effects represent one of the most across the THESEUS scope, i.e., present an interest for critical showstoppers for long-term spaceflight. a significant part of the THESEUS research domains. Particles from mixed radiation sources are abundant Six of the most transversal concepts are listed below in space, and conventional shielding by thickening by alphabetical order: the habitat is extremely challenging. Active shielding, forecasting events, and determining acceptable doses • Contamination are all important aspects in protecting a crew from This mainly emerges from the Expert Group on danger. Also, understanding the interaction of radiation habitat management and design, but contamination with physiological systems is critical. Monitoring these (microbial and Lunar/Martian material) is also of events is of prime importance as well to feed prediction relevance for integrated physiology issues, including models.

THESEUS Process and Approach 15 4 THESEUS Roadmap: Providing Relevant Orientations for Research

THESEUS EG chairs and rapporteurs met for an inte- a focused, competitive research strategy for solving gration workshop in June 2011 where individual EG targeted risk areas of human health and performance reports and Key Issues were presented and discussed. during space missions. Reaching these goals will not Brainstorming sessions on how to structure the THE- only provide the basis for critical, high quality health SEUS roadmap and properly address EG Key Issues care for crews on-orbit, but it will also result in a wealth were held in plenary and splinter groups. During of physiological, psychological and performance data these sessions, three overarching, trans-disciplinary to evaluate. Examination of these data will undoubt- research orientations were identified: edly yield solutions to medical challenges associated with long-term . The data will also provide Theme 1: Develop an integrated view of human ad- the basis for well-conceived and evidence-based so- aptation to the space environment lutions to such physiological concerns as radiation exposure, immunology, mineral metabolism, protein Theme 2: Develop an integrated view of counter- synthesis, chronobiology, cardiology, and food and measures to multiple stressors nutrition in space as a whole, and also the develop- Theme 3: Develop an integrated view of tools and ment of a new generation of countermeasures for methods both micro and low gravity.

The transition from research on independent func- The THESEUS roadmap is structured around these tions with regard to human responses to the space themes and connects each theme to the output and environment to a more integrated approach requires findings of individual EGs.

4.1 Theme 1. Integrated view of human adaptation to the space environment

Space exploration exposes astronauts to a number complex environments [24]. Additionally, space of inevitable stresses. In response, the human body exploration deals with a small number of members reacts with a variety of symptoms, both physical and of a group, and therefore, a generalisation of human mental. Countermeasures need to be developed responses would not meet the requirements of to mitigate the harmful, long-term effects of these individual astronauts. This fact requires, in addition stressors on astronauts for exploration mission to to the integrative research work, a personalised view even be feasible. of individual responses. These three interconnected research circles of space exploration are shown in To sustain astronauts’ health, well-being and Figure 5, namely competence during exploration missions and after return to Earth, an integrative research programme • the complex interplay of environmental is necessary. This will require an integrated survey stressors, and definition of the multiple stressors associated • integrated human responses, and with human space exploration environments and • astronauts’ individual response. identification of interactive adaptations to these

16 THESEUS Roadmap: Providing Relevant Orientations for Research Environmental stressors

Integrated human responses

Astronaut's individual responses

Figure 5. The 3 research circles of the THESEUS roadmap (Jack in the box scenario)

During exploration missions, humans are confronted • living and working in a habitat with an artificial with a complex interplay of environmental parameters atmosphere, specific habitat micro-flora, speci- fic gravity levels (either microgravity or low gra- and stressors not encountered on Earth. Stressors may vity) altered circadian rhythms, increased levels arise from various sources including: of ionising radiation and physical confinement; • long-term confinement in a spacecraft or habi- • flight dynamics, such as , vibration tat causing problems connected with the isola- and noise during launch and re-entry, as well as tion of a small community. microgravity and changes in circadian rhythms during spaceflight; Table 1 lists the main stressors imposed by spaceflight • as an inhabitable environment and how these impact human body systems. General (space vacuum, the radiation field in space, ex- health is defined as optimal physical and health treme temperature fluctuations) requiring pro- conditions allowing the astronaut to perform tasks tection from its hazardous components to the nominally. Cells marked with a question mark are best extent possible; areas were interactions are not known, thus requiring • inhabitable planetary environments (Moon further investigation. or Mars) with low gravity, an atmosphere not supportive for life or totally absent, intense ra- diation, planetary dust, extreme temperatures, and different daily rhythms;

THESEUS Roadmap: Providing Relevant Orientations for Research 17 Table 1: Impact of spaceflight stressors on crew (+++ high; ++ medium; + low; ? not known; Ø No impact)

STRESSORS factors outside Radiation Nutrition Microflora Remoteness atmosphere) Microgravity Confinement High g during Asteroid, Mars) Asteroid, launch and entry Chronobiological Chronobiological environment (dust, (dust, environment Hypo gravity (Moon, Hypo gravity

Bones and + +++ ? + ? ? + ++ ++ Ø muscles Heart, lung and ++ +++ ? + + +++ + ++ ++ Ø kidney

Immune system ? +++ ? ++ +++ ++ ? ++ ++ ?

Genetic system Ø ? ? +++ ? ? ? ? ? ?

Neurosensory + +++ ? ++ ? ? ++ ? ? ? HUMAN SYSTEMS system

Behaviour + ++ ? ++ ? + +++ ++ +++ +++

General Health ? +++ ? ++ ++ +++ ++ +++ ++ +

While Table 1 provides information on the impact of mune, neurovestibular, genetics, and behaviour. How- individual stressors on crew members, it is crucial to ever, to provide high quality health care to astronauts consider and understand that these parameters do during exploratory missions, which may last months not necessarily act in isolation, but rather, synergistic or even years, an integrated approach is required. This interactions may occur. As an example, an unresolved transition of human research in space from the study issue is the possible interaction of microgravity and of independent physiological, genetic and psycho- radiation on different human physiological and ge- logical functions to an integrated approach requires a netic functions. Radiation and microgravity may also new research strategy. Many impairments and adap- alter other environmental parameters, such as the tations to the spaceflight environment and planetary habitat microflora. habitats pertain to several body functions and are likely to be interdependent. Therefore, such studies of Recommendation 1: Perform a detailed, inte- human adaptations to the stresses occurring during grated survey, define and quantify the multiple envi- exploratory missions require a holistic systems ap- ronmental stressors during human space exploration proach [24]. Only a complete set of data on various missions, and assess their potential hazards to hu- body systems to spaceflight will provide the basis for mans, both individually and in combinations. well-conceived and evidence-based decisions for ap- propriate countermeasures and solutions to medical In the past, most studies on the effects of spaceflight challenges during long-term space exploration mis- on humans have concentrated on specific body sys- sions. tems, such as bone and muscle, cardiovascular, im-

18 THESEUS Roadmap: Providing Relevant Orientations for Research Recommendation 2: Perform an integrated survey responses and the astronaut’s individual response. As and identify interactive human adaptations to the an example, radiation risk assessments are available complex environments of space exploration in order for Low Earth Orbit (LEO) missions [25-26]. The guide- to assess the risks to astronauts and develop efficient lines for radiation protection in LEO missions were de- countermeasures for their mitigation. rived from a postulated ‘acceptable’ risk for late cancer mortality, which was then justified through a compar- In addition to this integrative research approach for ison with mortality rates from ‘normal’ terrestrial occu- identifying interactive responses of the whole human pations. Radiation exposures during previous space- system, a personalised view of individual responses flight activities within the geomagnetic shield, in LEO of astronauts is advisable. There will be only a small and inside the ISS were sufficiently low and no special number of astronauts selected for such long-term actions were necessary to keep within the NCRP lim- exploratory missions, and therefore, their individual its. However, the expected doses during inter-plane- responses to various stressors need to be evaluated. tary exploratory missions are likely to infringe these This also includes determining individual radiation limits unless mass shields are installed, which could exposure for each astronaut during each period of the strain the capacities of the propulsion system, or ac- mission. Another item to be considered is the possible tive (electromagnetic) shielding is shown to be feasi- hormonal-based gender differences in the response ble and consequently -developed. In addition to late to spaceflight, which affect regulation of the central cancer mortality, and this is a decisive difference, the nervous system, bone metabolism or other body possibility that crew members might suffer from early functions. Age and gender based differences can radiation sickness induced by significant solar parti- also be seen in radiation sensitivity. In addition, the cle event irradiation – e.g. during extra-vehicular or possible role of genetic disposition to radiation and extra-habitat activities implies a non-negligible risk other spaceflight stressors needs to be elucidated. for the astronauts [10]. Little work has been done to assess the risks to astronauts from the other inevita- Recommendation 3: Perform an inventory of bly present spaceflight stressors. Here, an integrated personalised exposures and responses to the complex approach is necessary. environments of space exploration with regard to gender based differences, genetic disposition and Recommendation 4: Perform an integrated risk as- other individual characteristics. sessment for human exploration missions combining the risks from exposures to multiple stressor environ- A reliable assessment of human risks during ments, the interactive adaptations to these stressors, exploration missions requires an understanding of and from personalised responses. This should be the the interaction and complex interplay between en- base for quantifying acceptable risks for astronauts vironmental stressors, the integrated human body during exploration missions.

4.2 Theme 2: Integrated view of countermeasures to multiple stressors

To safeguard astronauts’ health, well-being and hypokinesia, and confinement and remoteness during working efficiency, a comprehensive strategy to the mission. On the other hand, countermeasures mitigate various risks is required. On one hand, this need to be developed to mitigate adverse responses concerns qualitative and quantitative strategies to to multiple stressors. Table 2 presents different mitigate environmental stressors such as radiation, types of countermeasures and their efficiency in toxic substances in the habitat atmosphere, the rise compensating the stressors’ effects. of microbiological pathogens, microgravity-induced

THESEUS Roadmap: Providing Relevant Orientations for Research 19 Table 2. Countermeasures effects to mitigate the effects of stressors (+++ high; ++ medium; + low; ? not known; Ø No effect)

STRESSORS Nutrition Radiation Mars) Microgravity Microflora Remoteness Confinement Chronobiology dust, atmosphere) dust, Hypo gravity (Moon, Asteroid, (Moon, Asteroid, Hypo gravity Outside environment (vacuum, (vacuum, Outside environment High g during launch and entry

psychological and skill maintenance + + + Ø Ø Ø + + ++ ++ countermeasures

Shielding Ø Ø Ø +++ Ø Ø Ø Ø + +

Medication + + + + ++ + ++ + + +

exercise countermeasures + +++ ++ Ø ? + + + + +

Nutrition + ++ ++ + + Ø + +++ + + COUNTERMEASURES

Habitat design and safety + ++ ++ +++ +++ ++ +++ + +++ +++

Mission Planning + ++ +++ +++ + + +++ + ++ +++

Several adverse effects from environmental stressors appropriate habitats, developing training methods during space flight can be mitigated through the design and providing appropriate countermeasures with the of an appropriate habitat, e.g., by providing means of mission scenarios and timelines. radiation shielding, developing suitable monitoring and controlling systems for atmospheric pollutants Current exercise countermeasures are mainly and microbiological pathogens, constructing health- targeted towards mitigating harmful responses of optimised countermeasure systems and providing a one specific system of the human body, such as bone human-friendly living area with private areas for each and muscle degradation or . astronaut. Additional mitigation can be achieved by For exploration class missions, a new approach is planning appropriate mission scenarios and timelines, required that considers the benefits of physical and e.g., in order to reduce the chances of exposure pharmacological countermeasures to the whole to solar particle events. This would be one way to human body. In fact, countermeasures targeting implement the best workable practices to assure one stressful response may actually be harmful or that the crew is exposed to a radiation risk that is As counterproductive for another one [27-28]. Suitable Low As Reasonably Achievable (following the ALARA animal and human facilities need to be developed for principle). specially designed experiments that concisely pose and address system-level questions. One such Facility Recommendation 5: Mitigation strategies against may be the newly developed :envihab Facility at DLR certain adverse effects expected from environmental in Cologne. stressors should be implemented during the planning phase of a space exploration mission, e.g., by designing

20 THESEUS Roadmap: Providing Relevant Orientations for Research Table 3. Efficiency of countermeasure on human systems (+++ high, ++ medium, + low, ? not known, Ø No effect)

COUNTERMEASURES Nutrition Shielding Medication Mission planning countermeasures skill maintenance skill maintenance Psychological and Psychological Health care including care Health Habitat design and safety Habitat Exercise countermeasures Exercise

Bones and muscles Ø + ++ +++ ++ ? +++

Heart, lung and kidney Ø + ++ +++ ++ ++ +++

Immune system ? ++ ++ + ++ +++ ++

Genetic system ? +++ ++ ? + ? +++

Neurosensory system ++ ++ ++ + Ø + ++ HUMAN SYSTEMS HUMAN

Behaviour +++ ++ ++ ++ ++ +++ +++

General Health ++ +++ +++ +++ +++ +++ +++

Recommendation 6: Develop optimised counter- between different countermeasures. To achieve this, measure procedures and programmes that integrate ground-based analogue facilities need to be devel- human body functions as well as inter-individual vari- oped for animal and human studies addressing sys- ability, and take into account the possible interactions tem-level questions.

4.3 Theme 3. Integrated view of tools and methods

An integrated research programme on human adap- Recommendation 7: Develop standardised proto- tation to the conditions of space and the develop- cols and procedures for studies on integrative human ment of efficient countermeasures (Themes 1 and adaptation to the conditions of space during explora- 2) requires standardisation of the methods for ex- tion missions and the development of efficient coun- periment design, performance and analyses. Such a termeasures. standardised approach would allow for different ex- periments in space and on the ground to collaborate, In addition to standardising methods for experiment compare results and draw valid conclusions (Fig. 6). design, performance and analyses, the data collected One example could include a series of bed-rest stud- by different teams of researchers should be made ies in which men and women are exposed to exactly available to the scientific community in a compara- the same conditions and countermeasures during the ble and usable form (including their context). Access period of confinement. should also be given to anonymous crew health data, retrospectively and prospectively. For this, protocols

THESEUS Roadmap: Providing Relevant Orientations for Research 21 Research question 1 Research question 1 Research question 1

Standerdised study design

Comprehensive data management

Biological and physical modelling

Figure 6. Scheme of an integrated approach to reach a comprehensive understanding of human responses to the conditions of space exploration and the development of efficient countermeasures (modified from [24]).

would have to be established for disclosure of opera- tory missions, including the radiation field in space, tional performance data to qualified researchers. Max- gravity levels, the habitat design and their possible imum exploitation of currently available resources on interactions. Biology-based modelling will add knowl- Earth and in space, as well as respective databases is edge to a mechanistic understanding of the various mandatory. Examination of these data will provide risks and should be integrated in the design of the ex- the basis for a critical, high quality health care for periments. Mathematical modelling approaches are crews on orbit and will undoubtedly yield solutions currently already being used for the determination of for medical challenges for long-term spaceflights. To space radiation risk in the fields of . Biological efficiently utilise all available resources, a comprehen- modelling is also needed to understand the integrat- sive system of data storage and management must be ed responses of the human body to the complex field set up. This shared database would provide the basis encountered. Studies are needed to transfer small for well-conceived and evidence-based decisions to scale molecular and cellular models into larger multi- physiological concerns such as radiation exposure, scale models, representing the overall response of a immunology, mineral metabolism, protein synthesis, tissue or the whole body. A model-based develop- chronobiology, cardiology, and food and nutrition in ment of technologies is also mandatory for improv- space, taken as a whole as well as for the development ing our understanding of the functioning of closed of a new generation of integrated countermeasures. loops via multiple parameters, as needed for the de- velopment of human life-support systems. Dedicated Recommendation 8: Set-up a database of results multi-physics and multidisciplinary algorithms and from ground and space-based integrative human software tools need to be applied, including models research based on standardised protocols and pro- for thermo-fluid-dynamics, biological processes, hu- cedures including the exertion of countermeasures. man metabolism and respiration, urine and faecal A data management and distribution system should production, motor control, as well as for utilising and be established in coordination with major European exploiting extra-terrestrial resources replenish- stakeholders (especially ESA and EC) to make these ment (ISRU). data accessible to the scientific community. Protocols should be established for disclosure of anonymous Recommendation 9: Utilise mathematical, physi- crew health data to qualified researchers. cal and biological modelling to understand and an- ticipate various risks to astronauts associated with ex- Modelling approaches are needed to simulate the ploration missions and for applying means to reduce complex environments encountered during explora- them to an acceptable level.

22 THESEUS Roadmap: Providing Relevant Orientations for Research 4.4 Tying Key Issues to recommendations

While the THESEUS roadmap addresses overarching evance of recommendations to individual Key Issues research orientations and programmatic implemen- are shown in tables 4 to 8. tation, detailed Key Issues identified by the THESEUS experts represent the building blocks of this strategy. Any of the nine structural recommendations have These Key Issues are numerous (99), and the THESEUS some particular relevance to address at least 1/3 of approach would allow each of them to be addressed the Key Issues, and six of these recommendations are in a comprehensive and rational manner. The rel- relevant to address more than half of the Key Issues.

Table 4: Integrated Systems Physiology - Recommendation’s relevance to Key Issues (+: significant relevance, ++: high relevance)

Theme 2: Theme 1. Integrated Theme 3: Integrated view view of coun- Integrated view of adaptation termeasures of tools and to the space to multiple methods environment stressors

Reco 1: Integrated survey of stressors and impact survey of stressors 1: Integrated Reco surveyadaptations of human interactive 2: Integrated Reco Reco 3: personalised exposures and responses - individual characteristics missions risk assessment for 4: integrated Reco planning phases at 5: CM consideration Reco and programmes 6: optimised CM procedures Reco Reco 7: standard protocols and procedures for the studies on the human adaptation integrative human integrative from of results 8: database Reco physical and biological 9: mathematical, modelling Reco

1.1.1 Sex-based differences + ++ + + + + Musculoskeletal injury (ligament and tendons, 1.1.2 ++ ++ + ++ bone fracture, back pain) 1.1.3 Genetic predisposition ++ + ++ + ++ + 1.1.4 Biomechanics + + ++ + ++ 1.1.5 Radiation ++ ++ + ++ ++ + + + ++ 1.1.6 Ground-based human studies ++ + + ++ + + ++ ++

Bones and Muscles 1.1.7 Ground-based animal studies + ++ + + ++ + ++ 1.1.8 Countermeasures + ++ ++ + ++ What are the inflight alterations in cardiac 1.2.1 ++ + ++ + + + + + structure and function? What is the influence of spaceflight on 1.2.2 ++ ++ + + + structure and function of blood vessels? What level of cardiovascular function loss is acceptable and what type and quantity of 1.2.3 ++ + ++ ++ + + exercise is necessary to ensure that this loss is not exceeded? What are the risks associated with exposure to 1.2.4 ++ ++ ++ + ++ + extraterrestrial dust?

Heart, Lungs and Kidneys Heart, Lungs What are the roles of diet and bone 1.2.5 demineralisation on kidney stone formation + + + + and can we predict the risk of kidney stones?

THESEUS Roadmap: Providing Relevant Orientations for Research 23 Theme 1: Theme 2: Integrated Theme 3: Integrated view of view of coun- Integrated view of adaptation to the termeasures to multiple tools and methods space environment stressors characteristics integrative human adaptation integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 4: integrated risk assessment for missions risk assessment for 4: integrated Reco Reco 1: Integrated survey of stressors and impact survey of stressors 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological 9: mathematical, modelling Reco Reco 3: personalised exposures and responses - individual and responses 3: personalised exposures Reco Reco 2: Integrated surveyadaptations of human interactive 2: Integrated Reco Reco 7: standard protocols and procedures for the studies on for and procedures protocols 7: standard Reco Reco 8: database of results from human integrative space research human integrative from of results 8: database Reco

Identification and quantification of stress factors 1.3.1 + ++ + ++ + + + and their impact on the immune system. Are immune system development, response and 1.3.2 regulation as efficient in space (ISS/Moon/Mars) + ++ + ++ + + + + as on Earth? Consequences of long duration (≥1 year) 1.3.3 + ++ + + + + missions on the degree of immune-suppression. Consequences of “chronic” immune changes 1.3.4 during and after long-duration mission on ++ + ++ + disease. Effect of Lunar or Mars dusts, habitat 1.3.5 environment & other chemicals on immune ++ ++ + ++ + + Immunology performance. Are the observed stress-dependent virus 1.3.6 reactivation patterns linked to cancer + + + + development? Interaction between immune system and other 1.3.7 ++ + ++ + + + + stress-sensitive systems. Definition and testing of (immune targeted) 1.3.8 + ++ ++ + ++ countermeasures. 1.4.1 Impacts of spaceflight on the + ++ + ++

1.4.2 Impacts of spaceflight on sensorimotor + ++ + ++ ++ + + ++ performance Impacts of neurophysiological changes on 1.4.3 spaceflight-induced decrements in neuro- ++ + ++ + + + ++ behavioural performance. Countermeasure strategies to minimize the risks

Neurophysiology 1.4.4 associated with neurophysiological changes + ++ ++ + + during and after g transitions 1.4.5 Developmental neurobiology + + + + +

1.5.1 The in-flight negative energy ++ ++ ++ ++ ++ + + +

1.5.2 Feeding behaviour ++ ++ ++ ++ ++ ++ +

1.5.3 Metabolic stress ++ + ++ ++ + +

1.5.4 Micronutrients deficiency + + +

1.5.5 Alterations of gut microflora + ++ + ++ ++ + +

Nutrition and Metabolism 1.5.6 Hydro-electrolytic imbalance + + +

24 THESEUS Roadmap: Providing Relevant Orientations for Research Table 5: Psychology and human‐machine systems - Recommendation’s relevance to Key Issues (+: significant relevance, ++: high relevance)

Theme 1. Theme 2: Theme 3: Integrated Integrated view of Integrated view of view of tools and adaptation to the countermeasures to methods space environment multiple stressors characteristics integrative human adaptation integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 4: integrated risk assessment for missions for risk assessment 4: integrated Reco Reco 1: Integrated survey of stressors and impact of stressors survey 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological modelling physical 9: mathematical, Reco Reco 3: personalised exposures and responses - individual and responses 3: personalised exposures Reco Reco 2: Integrated survey of human interactive adaptations of human interactive survey 2: Integrated Reco Reco 7: standard protocols and procedures for the studies on for and procedures protocols 7: standard Reco Reco 8: database of results from human integrative space research space human integrative from of results 8: database Reco

Maintenance of team cohesion, wellbeing and 2.1.1 + + ++ ++ + ++ ++ + performance

Impact of reduced communication between 2.1.2 ++ + ++ ++ + ++ ++ + crew and earth

2.1.3 Managing intra-crew differences and conflicts + ++ ++ + + ++

Group/Team Processes Group/Team Integral monitoring of crew and individual 2.1.4 ++ ++ ++ ++ ++ ++ behaviour

2.2.1 Design of human-automation system ++ ++ + ++

Adaptation to support operator state and 2.2.2 ++ ++ + ++ ++ mission goals

Evolving, problem solving and updating during 2.2.3 ++ ++ + ++ missions

2.2.4 Simulation and virtual/augmented reality (SVAR) ++ ++ +

Human-Machine Interface Robots (HRI), agents (HAI) & human-robot-agent 2.2.5 ++ ++ + interaction (HRAI)

Risks for operational effectiveness from 2.3.1 ++ + ++ ++ ++ ++ infrequent or non-use of skills

Need for different training methods for the 2.3.2 acquisition and maintenance of different types ++ + of skill

Use of on-board top-up training to maintain and 2.3.3 + ++ + enhance skills

Protection against effects of stressors on

Skill Maintenance Skill Maintenance 2.3.4 skill learning and effective long-term skilled + ++ + ++ + ++ ++ performance

Management of and work/rest schedules 2.3.5 to prevent skill impairment by sleepiness and ++ ++ ++ + + + + ++

THESEUS Roadmap: Providing Relevant Orientations for Research 25 Table 6: Space Radiation - Recommendation’s relevance to Key Issues (+: significant relevance, ++: high relevance)

Theme 1: Theme 2: Theme 3: Integrated view of Integrated view of Integrated view of adaptation to the countermeasures to tools and methods space environment multiple stressors research characteristics the integrative human adaptation the integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 4: integrated risk assessment for missions for risk assessment 4: integrated Reco Reco 1: Integrated survey of stressors and impact of stressors survey 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological modelling physical 9: mathematical, Reco Reco 8: database of results from human integrative space space human integrative from of results 8: database Reco Reco 3: personalised exposures and responses - individual and responses 3: personalised exposures Reco Reco 2: Integrated survey of human interactive adaptations of human interactive survey 2: Integrated Reco Reco 7: standard protocols and procedures for the studies on for and procedures protocols 7: standard Reco

What is the particle and dose rate dependency 3.1.1 + ++ + ++ + + ++ ++ ++ for acute effects?

How is the sensitivity to acute effects modified 3.1.2 + ++ + ++ + + by the space environment?

What is the effectiveness of GCR at low doses 3.1.3 + ++ + ++ ++ ++ ++ for carcinogenesis?

Is there a risk of CNS damage from low doses 3.1.4 + ++ + ++ + ++ ++ ++ of GCR?

Is there a risk of non-cancer late effects from 3.1.5 + ++ + ++ ++ ++ ++ low doses of GCR?

Is there a risk of hereditary effects from low 3.1.6 ++ + ++ ++ ++ ++ doses of GCR? How will multi-scale mechanistic-based

Space Radiation Effects on Humans Space 3.1.7 modelling of space radiation improve risk + ++ ++ estimates? How can radiation effects be effectively 3.1.8 ++ ++ ++ ++ + ++ mitigated?

Experimental determination of radiation field 3.2.1 ++ ++ ++ ++ parameters

3.2.2 Modelling of radiation environments ++ ++ + ++ ++

3.2.3 forecast ++ ++ ++ +

3.2.4 Transport codes ++ + ++ + ++ ++

3.2.5 Shielding + ++ ++ ++ + Radiation Dosimetry 3.2.6 Individual radiation exposures ++ ++ ++ + + + +

3.2.7 Support to mission planning and operation ++ +

26 THESEUS Roadmap: Providing Relevant Orientations for Research Table 7: Habitat Management - Recommendation’s relevance to Key Issues (+: significant relevance, ++: high relevance)

Theme 1: Theme 2: Theme 3: Integrated view of Integrated view of Integrated view of adaptation to the countermeasures to tools and methods space environment multiple stressors research adaptations - individual characteristics on the integrative human adaptation on the integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 3: personalised exposures and responses and responses 3: personalised exposures Reco Reco 4: integrated risk assessment for missions for risk assessment 4: integrated Reco Reco 2: Integrated survey of human interactive of human interactive survey 2: Integrated Reco Reco 1: Integrated survey of stressors and impact of stressors survey 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological modelling physical 9: mathematical, Reco Reco 8: database of results from human integrative space space human integrative from of results 8: database Reco Reco 7: standard protocols and procedures for the studies for and procedures protocols 7: standard Reco Define correct upper and lower thresholds for 4.1.1 indoor environmental quality control of air, ++ ++ + ++ + + + water, food and surfaces in space habitats Develop efficient materials and methods 4.1.2 to prevent environmental microbial ++ ++ ++ + + contamination in space Develop adequate environmental contamination monitoring (prediction, 4.1.3 detection, identification) systems for use in + ++ + + ++ ++ space Develop materials and methods to mitigate

environment in space environment 4.1.4 environmental microbial contamination and its + ++ ++ + + harmful effects in space Acquire better knowledge on microbial community (microbial ecosystem) dynamics

Microbiological quality control of the indoor Microbiological quality control 4.1.5 and microbial cell evolution over time in ++ + + ++ ++ confined manned habitats in space Develop and adopt common metrics for evaluation of different Life Support System 4.2.1 (LSS) architectures, technologies, and their ++ ++ evolution Develop model-based regenerative Life 4.2.2 Support via a system level approach ++ ++ Further develop Life Support subsystems and 4.2.3 components for long-duration space flight and ++ + + planetary surface mission phases Improve autonomy of LSS via monitoring and 4.2.4 control ++ + Improve LSS robustness, reliability, availability, 4.2.5 maintainability, safety, acceptability in long- + ++ + term integrated operations Screen and develop high performance 4.2.6 materials for LSS ++ Develop and demonstrate capabilities to 4.2.7 exploit resources available on other (In- ++ + Situ Resource Utilization ISRU) for life support Improve LSS architecture to increase

Life Support: management and regeneration of air, water and food water of air, Support:Life and regeneration management 4.2.8 habitability ++ ++

THESEUS Roadmap: Providing Relevant Orientations for Research 27 Table 8: Health Care - Recommendation’s relevance to Key Issues (+: significant relevance, ++: High relevance)

Theme 1: Theme 2: Theme 3: Integrated view of Integrated view of Integrated view of adaptation to the countermeasures to tools and methods space environment multiple stressors research adaptations - individual characteristics on the integrative human adaptation on the integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 3: personalised exposures and responses and responses 3: personalised exposures Reco Reco 4: integrated risk assessment for missions for risk assessment 4: integrated Reco Reco 2: Integrated survey of human interactive of human interactive survey 2: Integrated Reco Reco 1: Integrated survey of stressors and impact of stressors survey 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological modelling physical 9: mathematical, Reco Reco 8: database of results from human integrative space space human integrative from of results 8: database Reco Reco 7: standard protocols and procedures for the studies for and procedures protocols 7: standard Reco

Insufficient control of infectious diseases potentially exacerbated by on-board micro- organism mutations, drug inefficiencies 5.1.1 + + ++ + + ++ and drug resistance - Provide an on-board available means to deal with the risk of infectious disease.

The acute risk to health from radiation exposure, in particular solar flares - Provide 5.1.2 ++ + + + ++ + on-board physical and/or pharmacological countermeasures and/or protection.

Dietary and nutrition-related space flight 5.1.3 disorders and complaints. - Provide on- + + + ++ board countermeasures.

Sub-optimal physical countermeasure hardware for health maintenance. - Identify 5.1.4 + ++ ++ + ++ and provide improved solutions to current bone and muscle loss countermeasures.

Insufficient on-board medical imaging hardware. - Provide on-board means to 5.1.5 + ++ + + maintain medical risks at an acceptable Space Medicine level.

Insufficient on-board smart sensors / smart devices for health monitoring & medical 5.1.6 diagnostics. - Provide on-board means to + ++ + + maintain medical risks at an acceptable level.

Insufficient on-board expert systems / decision support systems for medical 5.1.7 + ++ + diagnostics. - Provide on-board means to maintain medical risk at an acceptable level.

Insufficient on-board drugs for medical/ surgical procedures. - Provide the capability 5.1.8 to offer sufficient drugs and appropriate ++ + procedures to maintain on-board medical risks at an acceptable level.

28 THESEUS Roadmap: Providing Relevant Orientations for Research Theme 1: Theme 2: Theme 3: Integrated view of Integrated view of Integrated view of adaptation to the countermeasures to tools and methods space environment multiple stressors research adaptations - individual characteristics on the integrative human adaptation on the integrative Reco 5: CM consideration at planning phases at 5: CM consideration Reco Reco 3: personalised exposures and responses and responses 3: personalised exposures Reco Reco 4: integrated risk assessment for missions for risk assessment 4: integrated Reco Reco 2: Integrated survey of human interactive of human interactive survey 2: Integrated Reco Reco 1: Integrated survey of stressors and impact of stressors survey 1: Integrated Reco Reco 6: optimised CM procedures and programmes 6: optimised CM procedures Reco Reco 9: mathematical, physical and biological modelling physical 9: mathematical, Reco Reco 8: database of results from human integrative space space human integrative from of results 8: database Reco Reco 7: standard protocols and procedures for the studies for and procedures protocols 7: standard Reco

Insufficient on-board equipment to make sufficient medical procedures available for 5.1.9 appropriate health care delivery. - Provide on- ++ + board capability to maintain medical risks at an acceptable level.

Insufficient on-board surgical techniques and devices (e.g. endoscopic procedures, restraint 5.1.10 systems etc.) - Provide sufficient on-board + ++ + surgical techniques and devices to maintain medical risks at an acceptable level.

Insufficient provision of virtual reality training systems/human patient simulators. - Provide 5.1.11 on-board capability to maintain medical risks at ++ + an acceptable level during human exploration missions.

Lack of provision of appropriate medical curricula for physician astronauts. - Provide capability to achieve and maintain physician skill 5.1.12 sets and knowledge to maintain medical risks at ++ + an “acceptable” level during human exploration

Space Medicine Space missions.

Lack of provision of methods to define the minimum on-board medical infrastructure 5.1.13 needed to maintain medical risks at an ++ + “acceptable” level during human exploration missions.

What triage decisions and medical capability 5.1.14 limitations shall be acceptable during human + + + exploration missions?

What criteria shall be accepted for the medical 5.1.15 selection of astronaut crews for human + ++ + + exploration missions?

What psychological criteria shall be used for the 5.1.16 medical selection of astronaut crews for human + ++ + + exploration missions?

THESEUS Roadmap: Providing Relevant Orientations for Research 29 4.5 Implementing the THESEUS approach

The THESEUS recommendations suggest research allowing mobilisation of the European scientific com- orientations and a programmatic structure that munity around specific topics that would be increas- would properly address the Key Issues and eventually ingly programme-oriented with time. towards filling the current knowledge gaps in the priority topics identified by THESEUS experts. In this context, primary implementation tools are These recommendations have to be considered as European-wide mechanisms offered by the European parts of an overall phased plan, with interdependen- Commission Horizon 2020 programme and the cies and relative importance over the years to come. European Space Agency’s ELIPS (European, Life and Figure 6 illustrates how THESEUS recommendations Physical Sciences in Space) programme. In addition should be integrated in the future research planning to these programmes designed and implemented at the European level (the darker the colour, the more by European organisations, issues put forward intense activity). Following the THESEUS proposed by THESEUS could also be addressed through approach would bring some medium to long-term collaborative research programmes implemented by consistency in an optimised endeavour. Furthermore, consortia of national research organisations. with a clear roadmap ahead, it would foster European research identity in a global context. Besides direct research support, an additional ef- ficient way to address the challenges raised by THE- It is important to note that the THESEUS recommen- SEUS would be to foster and catalyse networking and dations do not substitute blue skies research. Rather, an exchange of knowledge around these challenges. THESEUS complements it by providing a coherent, Such an approach would better structure the Europe- integrated structure that should be implemented an scientific community and create synergies by ad- through targeted calls and research solicitations dressing common complementary research topics.

30 THESEUS Roadmap: Providing Relevant Orientations for Research THES EU S 2020 2014 THESEUS ROADMAP

THESEUS Roadmap – Articulation of research orientations in the future. The colour range indicates the phasing of a given recommendation – the darker the colour, the more intense activity. 31 To investigate the impacts of different elements of Implementing the recommendations of THESEUS the space environment on human health and well- will allow Europe to maintain and expand its role being, independently and combined, integrated as a leader and desired partner in the international experimental studies are required. This includes scenario of space exploration. cellular and animal studies as well as long-term studies with astronauts as experimental subjects. Researchers should also make use of the ISS to the maximum extent possible, as living and working conditions on the ISS and its operations are especially qualified for simulating exploration missions. In addition, planetary probes to the Moon, asteroids and Mars should be used to explore the habitability of their environments and identify potential hazards for astronauts.

Complementary ground-based studies are also Overarching Recommendation: necessary for careful preparation of space experiments, Structure human exploration-ena- detailed analyses of space data, and developing bling research around the themes suitable countermeasures. These include the utilisation and recommendations put forward by of existing and planned infrastructures such as the THESEUS, using the phased approach , :envihab in Cologne, MELiSSA defined by the roadmap exercise. Pro- in Barcelona, confinement facilities in Moskow and grammes should be coordinated and Krasnoïarsk and numerous other facilities. :envihab is implemented at the European level a research facility with a completely new design and and consider direct funding, networ- strategy aimed at studying the whole human and also king and exchange of knowledge as taking in account its interaction with the environment. well as optimised utilisation of Euro- Its aim is also to link space-oriented research with pean research infrastructures. In this terrestrial applications. As the three main challenges context, targeted calls and dedicated to maintain astronauts as healthy high performers are research solicitation would allow me- identical to three main tasks of the future of medicine dium to long-term consistency in the (Prevention – Individualisation – Telecare), :envihab process. will focus on these three tasks and view astronauts as symbols for these tasks in future medicine. Thus, it is not an analogue environment for spaceflight alone, but rather a facility that links space research and terrestrial applications. Although human missions to the Moon, asteroids and Mars are not scheduled in the near future (Fig.1), the interim time of the upcoming 10 years offer the possibility for an in-depth research programme targeting a holistic approach to the responses of the human body to extraterrestrial conditions. This will then allow for a comprehensive risk assessment and development of countermeasures to mitigate risks to acceptable levels. The ALARA principle should be valid for the whole crew during the exploratory mission, thereby guarantying mission success with healthy and efficiently acting astronauts.

32 THESEUS Roadmap: Providing Relevant Orientations for Research 5 Relevance to Earth Issues

By and large, the issues and problems that humans optimising Human-Robot interactions. This field has face during missions in LEO and beyond share many applications on Earth, and it is more likely that commonalities and applications with issues on Earth. space activities will benefit from research performed However, the relative importance of these issues can on Earth than the other way around. vary dramatically. For example, the ability to predict space weather or the reliability of life support systems However, it has to be emphasised that while some are critical issues for exploration missions beyond LEO topics are intensively investigated on Earth, space while also representing opportunities to significantly exploration provides very specific conditions in improve Earth-based systems and operation without terms of environments, technical constraints as immediate risk to loss of life. well as operational and safety requirements. Theses specificities allow consideration of scientific and Following this idea, it must also be acknowledged technological topics with a different angle, eventually that most of the research relevant to considering bringing added value to Earth applications. The THESEUS Key Issues is not performed only in the issue of miniaturisation of diagnostics and health context of space activities. Therefore it is crucial that monitoring equipment provides a good example of space exploration-related research is continuously such added value. linked with and aware of wider research activities and that in addition to spin-offs, potential spin-in The most salient Earth application potentials of space research activities are identified and exploited. This is, exploration-enabling research identified through the for instance, the case for research on improving and THESEUS project are presented below.

5.1 Integrated Systems Physiology

Research on integrated systems physiology aims at of fracture healing and in atrophy due to prolonged maintaining crew health during and after missions hospital stays. and ensuring that crew members are in the required physical condition to perform their tasks. Therefore, Heart, Lungs and Kidneys this area of research is highly relevant to health issues Heart disease is a leading cause of death in the ter- on Earth and is strongly related to current societal restrial population, prompting significant research challenges such as ageing. efforts in the domain. During space flight, a healthy population (astronauts and cosmonauts) experience Bones and Muscles significant and rapid degradation of cardiovascular The strongest translational potential of musculoskel- performance. This provides the potential to utilise etal research for spaceflight is the study of age-re- space-based research to help understand the factors lated osteoporosis and sarcopenia. Although ageing that lead to cardiovascular disease on Earth. and spaceflight may involve changes in morphology and function by fundamentally different cellular and Additionally, many people are exposed to dusty en- molecular pathways, they share a common feature of vironments in the workplace, and particulate matter adaptation to changing levels in strain. Thus, study- in the environment is a known health risk to urban ing musculoskeletal system adaptation to micrograv- populations. Further, many drugs are now delivered ity, and re-adaptation to 1-g parallels the context of in aerosol form, and so a comprehensive understand- age-related atrophy of bone and muscle tissue. Bed ing of the deposition and subsequent clearance of rest studies separate the effect of disuse from those deposited particles is of considerable importance in associated with co-morbidities, both in the context both areas.

Relevance to Earth Issues 33 Immunology Understanding stress-related immune challenges in The altered gravity environments available during space is highly relevant to the understanding of the spaceflight offers an additional platform to study ba- biology of cancer immunology, the balance of inflam- sic neurophysiology of dexterous manipulation (eye mation and endogenous mechanisms to control it, hand coordination), balance and locomotion and ve- and the lack of control (autoimmunity/allergies) in hicle control. Research in these domains can provide young and ageing population on Earth. knowledge that serves to help patients with vestibu- lar, neurological, and motor control problems, as well The functions of the immune system can be affected as the elderly. Knowledge gained from studying the in response to environmental/living conditions, and training and rehabilitation protocols developed for chronic and acute stress conditions can result in a fur- use with astronauts can be transferred directly to pa- ther parallel interaction between the immune system tients with specific lesions or disorders requiring re- and other organ systems. As an example, stress causes training or rehabilitation. neurophysiologic responses and hormone liberation which can modulate inflammation but also promote Nutrition and Metabolism bone resorption. The nutritional questions related to bioastronautics research are very relevant to multiple Earth-based Neurophysiology related health issues. The potential spin-offs are inter- and situational awareness issues esting from a technical point of view and also have are responsible for up to a quarter of all civil aviation great clinical importance. Such spinoffs encompass accidents. Diminished manual flying skills during vis- the increasing burden of modern chronic diseases, ual flight piloting is an increasing problem, especially in which the adoption of sedentary behaviour plays for search and rescue helicopter pilots required to fly a central role (i.e. the metabolic syndrome, insulin with diminished visual cues. A better understanding resistance, dyslipidemia, type 2 diabetes mellitus, of the mechanisms underlying disorientation as well atherosclerosis, etc.). as development of physical aids (e.g., tactile situ- ational awareness system) and countermeasures de- veloped to aid space travellers might also be useful for commercial and military aviation.

5.2 Psychology and Human-Machine Systems

Activities performed in space are set in a very specific rescue situations (e.g. fire-fighting, post-earthquake and peculiar environment: crew members experience rescue operations). Knowledge gained through space continuous confinement, isolation (including exploration is highly relevant to operations in these potential communication delay), a hazardous external specific settings. environment as well as noise, cultural differences and dependency on other crew members. Additionally, Group/Team Processes crew are at the forefront of very costly and complex A defining characteristic of space missions is that endeavours imposing equally complex tasks and humans operate primarily as a team, yet, they procedures. In this very stressful environment, also have individual needs, preferences, skills and performance of astronauts has to be maintained at an personalities. Crews sometimes operate explicitly as appropriate level. teams (with common task goals) and sometimes as separate individuals within a group (with personal Similar environments can be found on Earth, notably goals). These roles, however, can overlap and effective in Antarctic stations but also with oil platforms, inter-personal interactions between crew members nuclear power plants, weather stations, military are critical to overall mission success. units stationed in foreign countries as well as crisis/

34 Relevance to Earth Issues Developing methods and tools to monitor and effective human-automation design will yield benefits maintain team cohesion, well-being and performance for system efficiency and safety in these and other as well as the impact of reduced communication domains. and intra-crew differences and conflict will benefit teams that have to work in stressful and high-risk Skill Maintenance environments on Earth. Research in the field of skill maintenance has a large significance for Earth applications where naturally Human-Machine Interface long breaks occur between situations requiring the Space applications place extraordinary levels of use of specific skills. There is an obvious relevance reliance on technology and may drive advances in for safety critical systems (e.g. nuclear power plants, human-robot and human-agent collaborative work, chemical plants, oil platforms or refineries, hospitals interaction modalities, and concepts for interaction and commercial aviation). Also, there are numerous that involves shared physical proximity and high complex work situations such as in process control criticality applications. operations, the military, aviation, and civil protection services where skills have to be maintained over long Many current and planned work environments on time periods and which may rarely be called upon. Earth involve personnel interacting with increasingly For some situations it may be ethically impossible automated systems. Two examples include the to train staff under real conditions, and therefore programme for transformation of the air traffic trained in real conditions. A particularly relevant management system to accommodate higher levels example is when emergency rescue or disaster teams traffic more efficiently (NextGen in the US and SESAR are required, or in medical emergencies when highly in Europe), and the increasing use of unmanned skilled team members are required, but the situations vehicles and robots by the military. Research on rarely occur.

5.3 Space Radiation

Radiation levels in space pose a major challenge for Radiation Dosimetry human exploration activities and are currently a show- Improved description of the radiation environment stopper for a human mission to Mars. Any knowledge in space, as well as a larger degree of confidence ob- gain in this domain is of high relevance on Earth, es- tained by models and simulations through optimised pecially when considering particle therapy and pro- testing against measurements will have significant val- tection from high dose exposures for individuals and ue for several terrestrial activities such as: i) monitoring electronic systems. and improving the reliability of spacecraft electronics, for example terrestrial and telecommunication Radiation Effects on Humans and navigation systems (GPS, mobile communication, A better understanding of the acute and stochastic ef- Galileo etc.); ii) monitoring aircraft crew exposure; iii) fects of radiation on humans is not only essential to understanding failures rates in aircraft electronics; iv) future human spaceflight, but will also give insights improving hadron therapy and nuclear medicine; iv) into the impact of particle therapy used on Earth. Fur- developing climate models. ther research will determine particle therapy’s impact not only healthy neighbouring tissue but also in the Additionally, proper forecasting of solar events is an context of secondary tumours and non-cancer effects important part of the more general issue of radiation of radiation exposure. source modelling. Possible Earth applications are there- fore very similar to those mentioned for the previous New knowledge in the field of countermeasures could point. These will focus on minimising radiation driven have a potentially high impact on mitigating the side electronic failures, avoiding potential damage to power effects from particle therapies, radiological accidents grids, pipelines, aircraft electronics and navigation, but and terrorism. also on radiation protection for occupational exposure (commercial and military flights, first responders).

Relevance to Earth Issues 35 5.4 Habitat Management

Management of complex systems is a major challenge applications such as treatment of immune-depressed of the 21st century. Process engineering (based patients in hospital. on chemical engineering principles) and systems engineering (based on a hierarchical approach of Life Support: Management and Regeneration of Air, control of interacting subsystems) are the clues Water and Food for modern developments of industrial processes, Today’s major studies on environment issues and whatever the size or functionality. When developing sustainability, e.g., in the field of industrial ecology, and installing a rationale for a specific purpose, such as mainly focus on one requirement at a time (energy life support systems for space applications (especially consumption, water consumption or any other). systems including living organisms), the methodology However, there is a need to approach systems with and approach used will be completely transferable a much more integrated view, taking multiple to other applications. Controllability, modularity requirements into account. Although the key criteria and reliability requirements for life support systems are not necessarily the same for space and Earth are excellent examples of future developments in applications, the methodology and metrics used for modern industrial technology. Applications to any space certainly could be valuable for Earth-based environmental process are straight-forward. systems as well. As life support system complexity (required variety) is currently not known precisely, Microbial Quality Control of the Indoor Environment assessment methods and tooling will surely evolve. in Space Assessment needs and methods have to have a The development of early detection and warning simultaneous and continuous approach with life systems for environmental contamination and support system development and its increasing level pollution has common interests for space and Earth of complexity. This completely matches the methods applications. Such autonomous systems could be of integrating environmental concerns in industrial used to assure healthy environments in housing and developments by finding innovative solutions to working buildings, in hospitals for fast screening of complicated environmental problems, as in the incoming patients (carrier state), for the prevention emerging domain of industrial ecology. of nosocomial infections in public areas and public transport, and in pandemic control in the case of Closed-loop waste water recycling systems could natural catastrophes. Potential medical applications be of interest for applications on boats and cruise are ample, including on-site infection detection and ships, in remote hotels (eco-tourism), remote stations diagnosis. In addition, such systems will be of interest for exploration and/or exploitation of remote areas for continuous quality monitoring of air, water, (e.g. Antarctica, desert…etc.). Derived from the surfaces and products in production facilities in the MELiSSA life support system, there have already food and pharmaceutical industries. been applications regarding grey water treatment for hotel complexes, e.g., The Dutch company IP- In space vehicles, only a ‘simplified’ microbial is currently implementing these applications. community is able to develop (the only source is the Furthermore, grey water treatment can be applied humans, without interaction with plants, soil, animals). to major urban developments, especially new ones, Space research could give a better understanding of laying the path for a more sustainable way of living microbial community dynamics under environmental on Earth. conditions, which could be of interest for more complex Earth communities. A database of indicator organisms for expected/dominant microbial populations in confined habitats is also relevant for indoor environmental air quality control in housing and buildings on Earth in general, or for specific

36 Relevance to Earth Issues 5.5 Health Care

Space Medicine With access to limited medical facilities and Knowledge, experience and technological advances competencies on-board, space medicine requires in the both of these fields are highly relevant to the that significant progress on diagnostic capability provision of medical care in remote and/or isolated (e.g., imaging hardware, smart monitoring devices), conditions (e.g., stations, ships, submarines) and also on the ability to deliver appropriate health and for rescue services through better equipment care and surgery. Miniaturisation, automation and in ambulances. In addition to improving autonomy robotics as well as reliability of equipment and power of some classes of patients, advances in individual efficiency are required to bring appropriate medical health monitoring devices will also provide clear operation capabilities to spacecrafts. Furthermore, it is benefits in preventing diseases or attacks or easing crucial that medical skills are maintained throughout the management of medical emergencies. Further, long-duration missions in order to deal with the advances in telemedicine will provide the opportunity hopefully rare emergencies in the context of a Moon to improve the ability to diagnosis and possibly treat or Mars mission. patients in remote areas on Earth.

Drug Effects Research on the effects of spaceflight conditions (or analogues like bed-rest) on drug treatment, in particular pharmacokinetics, pharmaco-dynamics and side effects, will allow for a better understanding of the parameters that impact drug efficiency, and eventually improve the quality of medication on Earth.

Relevance to Earth Issues 37 Annex : List of 99 THESEUS Key Issues

The 99 Key Issues identified by THESEUS are listed below by cluster; background and full details on these can be found in individual cluster reports [19-23].

Cluster 1: Integrated Systems Physiology

EG1.1: Bones and muscles • Sex-based differences in the preservation of musculoskeletal tissue during space flight • Effects of micro-gravity on musculoskeletal injuries and healing processes (ligaments and tendons, bone fracture, back pain) • Role of genetics in musculoskeletal performance, preposition to injury and overall adaptation to mi- cro-gravity • Biomechanics and impact of partial gravity on the musculoskeletal system • Effects of radiation exposure experienced during space flight on the musculoskeletal system • Ground-based human studies • Ground-based animal studies • Optimise countermeasure efficiency and utilise an integrated physiology approach

EG1.2: Heart, lungs and kidneys • What are the inflight alterations in cardiac structure and function? • What is the influence of spaceflight on structure and function of blood vessels? • What level of cardiovascular function loss is acceptable and what type and quantity of exercise is ne- cessary to ensure that this loss is not exceeded? • What are the risks associated with exposure to extraterrestrial dust? • What are the roles of diet and bone demineralisation on kidney stone formation and can we predict the risk of kidney stones?

EG1.3: Immunology • Identification and quantification of stress factors and their impact on the immune system. • Are immune system development, response and regulation as efficient in space (ISS/Moon/Mars) as on Earth? • Consequences of long duration (≥1 year) missions on the degree of immune-suppression. • Consequences of “chronic” immune changes during and after long-duration mission on disease. • Effect of Lunar or Mars dusts, habitat environment & other chemicals on immune performance. • Are the observed stress-dependent virus reactivation patterns linked to cancer development? • Interaction between immune system and other stress-sensitive systems. • Definition and testing of (immune targeted) countermeasures.

EG1.4: Neurophysiology • Impacts of spaceflight on the senses • Impacts of spaceflight on sensorimotor performance • Impacts of neurophysiological changes on spaceflight-induced decrements in neuro-behavioural per- formance. • Countermeasure strategies to minimise the risks associated with neurophysiological changes during and after g transitions • Understand the role of gravity in the development of the nervous system

EG1.5: Nutrition and metabolism • The in-flight negative energy balance • Feeding behaviour • Metabolic stress • Micronutrients deficiency • Alterations of gut microflora • Hydro-electrolytic imbalance

38 Annex: List of 99 THESEUS Key Issues Cluster 2: Psychology and human‐machine systems

EG2.1: Group/team processes • Maintenance of team cohesion, wellbeing and performance • Impact of reduced communication between crew and earth • Managing intra-crew differences and conflicts • Integral monitoring of crew and individual behaviour

EG2.2: Human-machine interface • Design of human-automation system • Adaptation to support operator state and mission goals • Evolving, problem solving and updating during missions • Simulation and virtual/augmented reality (SVAR) • Robots (HRI), agents (HAI) & human-robot-agent interaction (HRAI)

EG2.3: Skill maintenance • Risks for operational effectiveness from infrequent or non-use of skills • Need for different training methods for the acquisition and maintenance of different types of skill • Use of on-board top-up training to maintain and enhance skills • Protection against effects of stressors on skill learning and effective long-term skilled performance • Management of sleep and work/rest schedules to prevent skill impairment by sleepiness and fatigue Cluster 3: Space Radiation

EG3.1: Space radiation effects on humans • What is the particle and dose rate dependency for acute effects? • How is the sensitivity to acute effects modified by the space environment? • What is the effectiveness of GCR at low doses for carcinogenesis? • Is there a risk of CNS damage from low doses of GCR? • Is there a risk of non-cancer late effects from low doses of GCR? • Is there a risk of hereditary effects from low doses of GCR? • How will multi-scale mechanistic-based modelling of space radiation improve risk estimates? • How can radiation effects be effectively mitigated?

EG3.2: Radiation dosimetry • Experimental determination of radiation field parameters • Modelling of radiation environments • Space weather forecast • Transport codes • Shielding • Individual radiation exposures • Support to mission planning and operation Cluster 4: Habitat Management

EG4.1: Microbiological quality control of the indoor environment in space • Define correct upper and lower thresholds for indoor environmental quality control of air, water, food and surfaces in space habitats • Develop efficient materials and methods to prevent environmental microbial contamination in space • Develop adequate environmental contamination monitoring (prediction, detection, identification) systems for use in space • Develop materials and methods to mitigate environmental microbial contamination and its harmful effects in space • Acquire better knowledge on microbial community (microbial ecosystem) dynamics and microbial cell evolution over time in confined manned habitats in space

Annex: List of 99 THESEUS Key Issues 39 EG4.2: Life Support: management and regeneration of air, water and food • Develop and adopt common metrics for evaluation of different Life Support System (LSS) architectu- res, technologies, and their evolution • Develop model-based regenerative Life Support via a system level approach • Further develop Life Support subsystems and components for long-duration space flight and plane- tary surface mission phases • Improve autonomy of LSS via monitoring and control • Improve LSS robustness, reliability, availability, maintainability, safety, acceptability in long-term inte- grated operations • Screen and develop high performance materials for LSS • Develop and demonstrate capabilities to exploit resources available on other planets (In-Situ Resource Utilisation ISRU) for life support • Improve LSS architecture to increase habitability Cluster 5: Health Care

EG5.1: Space medicine • Insufficient control of infectious diseases potentially exacerbated by on-board micro-organism muta- tions, drug inefficiencies and drug resistance - Provide an on-board available means to deal with the risk of infectious disease. • The acute risk to health from radiation exposure, in particular solar flares - Provide on-board physical and/or pharmacological countermeasures and/or protection. • Dietary and nutrition-related space flight disorders and complaints. - Provide on-board countermeasu- res. • Sub-optimal physical countermeasure hardware for health maintenance. - Identify and provide impro- ved solutions to current bone and muscle loss countermeasures. • Insufficient on-board medical imaging hardware. - Provide on-board means to maintain medical risks at an acceptable level. • Insufficient on-board smart sensors / smart devices for health monitoring & medical diagnostics. - Pro- vide on-board means to maintain medical risks at an acceptable level. • Insufficient on-board expert systems / decision support systems for medical diagnostics. - Provide on- board means to maintain medical risk at an acceptable level. • Insufficient on-board drugs for medical/surgical procedures. - Provide the capability to offer sufficient drugs and appropriate procedures to maintain on-board medical risks at an acceptable level. • Insufficient on-board equipment to make sufficient medical procedures available for appropriate health care delivery. - Provide on-board capability to maintain medical risks at an acceptable level. • Insufficient on-board surgical techniques and devices (e.g. endoscopic procedures, restraint systems etc.) - Provide sufficient on-board surgical techniques and devices to maintain medical risks at an ac- ceptable level. • Insufficient provision of virtual reality training systems/human patient simulators. - Provide on-board capability to maintain medical risks at an acceptable level during human exploration missions. • Lack of provision of appropriate medical curricula for physician astronauts. - Provide capability to achieve and maintain physician skill sets and knowledge to maintain medical risks at an “acceptable” level during human exploration missions. • Lack of provision of methods to define the minimum on-board medical infrastructure needed to main- tain medical risks at an “acceptable” level during human exploration missions. • What triage decisions and medical capability limitations shall be acceptable during human exploration missions? • What criteria shall be accepted for the medical selection of astronaut crews for human exploration missions? • What psychological criteria shall be used for the medical selection of astronaut crews for human ex- ploration missions?

40 Annex: List of 99 THESEUS Key Issues EG5.2: Medication in space • Is there evidence supporting changes in drug efficacy in-flight • Which systems/pathways are operationally important for human spaceflight and why? • What classes of drugs should be studied as a priority to sustain the health and performance of astro- nauts during spaceflight? • Which drugs may have what important unwanted effects? What classes of drugs should be studied to prevent toxicity and risk issues during human spaceflight? What are the important drug interactions that should be avoided? • What pre-flight or in-flight tests should be conducted to avoid or assess possible side effects such as allergic reactions, problems from pharmacogenetics or influences on performance? • What tests should be conducted to assess the possible influences of medication on pre-flight and in- flight performance and sleep quality? • It is important to know whether the pharmacokinetics of various drugs in space is altered. What phar- macokinetic changes in what classes of drugs have the most important clinical impact in space? • What evidence exists of pharmacodynamics changes resulting from posture and physical (in)activity seen in clinical studies (bed ridden patients, sedentary people)? • What models should be used to study pharmacodynamics?

Annex: List of 99 THESEUS Key Issues 41 References

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References 43 Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-00-0 printed in E.U. march 2012

44 45

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Cluster 1: Integrated Physiology - Report

CLUSTER1 March2012 1

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Towards Human Exploration of Space: a EUropean Strategy

Cluster 1: Integrated Systems Physiology - Report

Bone and muscle

Cardiovascular, lungs and kidneys

Immunology

Neurophysiology

Nutrition and metabolism THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low Earth orbit have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus:

Cluster 1: Integrated Systems Physiology Cluster 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space medicine Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

4 Table of Contents

1. Integrated Systems Physiology: Introduction 7

2. Bones and Muscles 10 2.1. Relevance of Research on Bones and Muscles 10 2.1.1. Relevance for space exploration missions 10 2.1.2. Earth benefits and applications 10 2.2. Bones and Muscles – Key Issues 11 2.2.1. Key issue 1: Sex-based differences in the preservation of musculoskeletal tissue during space flight 11 2.2.2. Effects of micro-gravity on musculoskeletal injuries and healing processes (ligaments and tendons, bone fracture, back pain) 15 2.2.3. Key issue 3: Role of genetics in musculoskeletal performance, preposition to injury and overall adaptation to micro-gravity 15 2.2.4. Key issue 4: Biomechanics and impact of partial gravity on the musculoskeletal system 16 2.2.5. Key issue 5: Effects of radiation exposure experienced during space flight on the musculoskeletal system 16 2.2.6. Key issue 6: Ground-based human studies 17 2.2.7. Key issue 7: Ground-based animal studies 18 2.2.8. Key issue 8: Optimise countermeasure efficiency and utilise an integrated physiology approach 19 2.3. Conclusion 21 2.4. References 23

3. Cardiovascular, Lungs and Kidneys 26 3.1. Relevance of Research on the Cardiovascular System, Lungs and Kidneys 26 3.1.1. Relevance for space exploration missions 26 3.1.2. Earth benefits and applications 26 3.2. Cardiovascular, Lungs and Kidneys – Key Issues 26 3.2.1. Key issue 1: What are the in-flight alterations in cardiac structure and function? 26 3.2.2. Key issue 2: What is the influence of spaceflight on structure and function of blood vessels? 28 3.2.3. Key issue 3: What level of cardiovascular function loss is acceptable and what type and quantity of exercise is necessary to ensure that this loss is not exceeded? 28 3.2.4. Key issue 4: What are the risks associated with exposure to extra-terrestrial dust? 29 3.2.5. Key issue 5: What are the roles of diet and bone demineralisation on kidney stone formation and is it possible to predict the risk of kidney stones? 30 3.3. References 31

4. Immunology 34 4.1. Relevance of Research on Immunology 34 4.1.1. Relevance for space exploration missions...... 34 4.1.2. Earth benefits and applications...... 34

5 4.2. Brief Review of Latest Developments 35 4.2.1. Research using isolated cell systems 35 4.2.2. Research using animal experiments: from model organisms to mice 35 4.2.3. Investigations in humans 36 4.3. Immunology – Key Issues...... 37 4.3.1. List of key issues...... 37 4.3.2. Knowledge gaps and research needs...... 37 4.3.3. Proposed investigations and recommendations...... 38 4.3.4. Cross-disciplinary aspects...... 38 4.4. Conclusion 39 4.5. References (other than included in the text) 40

5. Neurophysiology 41 5.1. Relevance of Research on Neurophysiology 41 5.2. Neurophysiology – Key Issues 42 5.2.1. Key issue 1: Impacts of spaceflight on the senses 42 5.2.2. Key issue 2: Impacts of spaceflight on sensorimotor performance 44 5.2.3. Key issue 3: Impacts of neurophysiological changes on spaceflight-induced decrements in neuro-behavioural performance. 45 5.2.4. Key issue 4: Countermeasure strategies to minimise the risks associated with neurophysiological changes during and after G-transitions. 47 5.2.5. Key issue 5: Understand the role of gravity in the development of the nervous system 48 5.3. Conclusion 48 5.4. References 49

6. Nutrition and Metabolism 54 6.1. Relevance of Research on Nutrition and Metabolism 54 6.1.1. Relevance for space exploration missions 54 6.1.2. Earth benefits and applications 55 6.2. Nutrition and Metabolism - Key Issues 55 6.2.1. Key issue 1: In-flight negative energy balance...... 55 6.2.2. Key issue 2: Feeding behaviour...... 56 6.2.3. Key issue 3: Metabolic stress...... 58 6.2.4. Key issue 4: Micronutrients deficiency...... 58 6.2.5. Key issue 5: Alterations of gut microflora...... 59 6.2.6. Key issue 6: Hydro-electrolytic imbalance...... 60 6.3. Conclusion...... 60 6.4. References...... 61

7. Annex: Expert Group Composition 63

6 1 Integrated Systems Physiology

Introduction

The next phase of bioastronautics and human facilitate post-flight readaptation to the terrestrial spaceflight environment. Such basic and upstream research is clearly a pre-requisite for long-term spaceflight, Human bioastronautics programmes have grown interplanetary travel and living on planetary surfaces. from the culmination of 50 years of human spaceflight This objective is far from trivial and priorities have yet experience, including both short- and long-duration to be defined. missions on a variety of platforms. Medical and physiological findings from these missions have Although space medicine has been practiced for more demonstrated that spaceflight has a dramatic impact than half a century, it is quite nascent relative to the on almost all physiological systems including muscle physiological and clinical knowledge and capability atrophy, bone demineralisation, cardiovascular and required for long-term space missions. For example, metabolic dysfunctions, impaired cognitive processes a significant challenge in the evolution of space and reduced immunological competence, and medicine will be to determine how the physiological nutrition/metabolism. These adaptive responses lead adaptation to space may alter the physiopathology to a physiological de-conditioning in space and have the of disease or the manifestation of illness and injury potential to affect crew health and performance both in space. Answers can be found by reviewing the in space and upon return to Earth. In many instances, clinical experience of flight physicians who treated countermeasures have been implemented to mitigate diseases in space, but the strongest approach is to some of the maladaptive changes associated with create an integrated model of the physiopathological space flight, including drugs, nutritional supplements adaptation of multiple organ systems to microgravity. and physical exercise on various workout devices. The exploration of space requires a systematic Although no countermeasures are able to fully understanding of human body, from the molecular mitigate the negative effects of space flight, several to integrated systems levels, as it responds to the have proven to be very effective, allowing crew to live unfamiliar environment of space and microgravity. and work nominally on-orbit. Towards a necessary integrated physiology approach Undoubtedly, significant knowledge has been accumulated on the physiological changes associated This new integrated physiology approach is with the adaptation of humans to short-term undoubtedly necessary for future bioastronautics space flights. Europe scientists have contributed research. Even though it has long been recognised as largely to this knowledge database and acquired an essential scientific approach, for decades research undisputable expertise in basic space physiology has been conducted on individual body systems (e.g. and countermeasures through both spaceflight muscle, bone, cardiovascular system, and nutrition experiments and a strong and complete bed rest researched independently). The limits of such an programme. approach are easily seen through the incomplete success of current countermeasure programmes in Human spaceflight is currently entering the next which scientists focus on specific organ systems and phase of space exploration towards the Moon and symptoms in a piecemeal fashion, rather than using Mars, and with such ambitious goals come inherent a whole body approach. For example, the dual effect medical challenges. Knowledge regarding human of amino acid supplementation which was positive on (mal)adaptation to microgravity is limited to that muscle mass but negative on bone, demonstrates why obtained during 6-month missions, with majority a holistic approach to space adaptation is absolutely of information lying on short-term physiological essential to support future space exploration. changes. Therefore, the primary focuses of the next phase of bioastronautics research will be to further The transition of space research from independent expand knowledge on the effects of long-duration physiological systems to a more rigorous, integrated space flight on crew health and performance, to approach requires a clear, focused, competitive further develop efficient countermeasures and to research strategy for solving targeted risk areas of

Integrated Systems Physiology 7 human health and performance in space. Reaching these goals will not only provide the basis for critical, high quality health care for crews on-orbit but also result in a wealth of physiological data. Examination of this data will certainly yield solutions for significant medical challenges for long-duration space flight and exploration. The data will also provide the basis for well-conceived and evidence-based countermeasures to deal with critical areas of concern including radiation exposure, immunology, mineral metabolism, protein synthesis, chronobiology, cardiology, and food and nutrition in space, for both micro and low gravity.

Considerations of the physiological effects of Lunar and Martian gravity

Another essential research topic that must be considered to enable future planetary exploration is human adaptation not only to weightlessness, but also reduced gravity. The biological effects of long-duration exposure to reduced gravity levels that will be experienced during stays on the Moon (0.16 g) and Mars (0.38 g) are completely unknown. It seems unlikely that the countermeasures developed on-board the International Space Station (ISS) will adequately protect crews on a journey

to Mars and back over a 30-month period, or prevent the effects Figure 1: Changes of various body systems during adaptation to microgravity (Credit: of a long-duration exposure to reduced gravity on the Moon NASA) or Mars. There is therefore a need to obtain basic knowledge on physiological adaptations to reduced gravity levels. Also, new insights could then be used in designing an “integrated countermeasure” for preventing the detrimental effects of weightlessness and/or reduced gravity on the physiological systems of the human body.

The overlooked ground-based applications of bioastronautics

Lastly, it is essential that ground-based applications of bioastronautics are utilised to their fullest potential and communication between researchers is enhanced. For decades, clinicians and physiologists performing research in space have done so separately, unaware of the likely possibility of having very similar research questions and goals. One example includes researchers on aging and chronic diseases, searching for environmental factors that fuel the pandemic of chronic diseases. Although sedentary lifestyle has been highlighted for decades as one of the main factors triggering the development of current chronic diseases such as obesity, insulin resistance, hypertension, muscle disuse, and bone demineralisation, the physiology of physical inactivity has received little attention. Clearly, the causal relationships between sedentary behaviours and the aforementioned diseases are essentially based on epidemiological studies or on the indirect beneficial effects of exercise training. None of these studies provide evidence to support a cause-and- effect relationship, but they indirectly suggest that sedentary behaviours and poor nutrition are the second leading cause

8 Integrated Systems Physiology of death in the USA, right after tobacco, and are major The following sections present the conclusions of contributors to diseases associated with aging. two expert workshops dedicated to the integrated physiology priorities for space exploration, conducted Likewise, certain physiological adaptations to in 2010. The workshops were organised in splinter microgravity stem from an adaptation to physical sessions, focusing on the main physiological functions inactivity, which is exceedingly well simulated in to regroup expertise and draw a clear picture of the ground-based bed rest analogues. In addition to space key questions to address, the latest developments, medicine related questions, bed rest studies are able gaps to fill, and the Earth-based applications. Those to provide unique models to investigate mechanisms splinter sessions were intertwined with plenary by which physical inactivity leads to the development discussion to delineate the foreseen interactions of current societal chronic diseases, and also to test between physiological functions that will require the efficacy of countermeasure programmes in investigations. preventing the development of these diseases. More importantly, because bed rest studies are conducted in healthy subjects that will recover, new therapeutic avenues can be explored.

Finally, the adaptation to reduced loading of the musculo-skeletal system is a major aspect of aging, as well as an adaptation to the space environment. With the new evolving era of proteomics, genomics, researchers can now investigate and try to understand why and how mechanical loading mediates some physiological and biological processes towards “unhealthy” behaviours.

Cluster and expert group objectives

The priorities of research necessary to support future space exploration beyond low Earth orbit present a unique set of issues whose solutions demand an in-depth understanding of whole body integrated physiology and cross-disciplinary work between life scientists, engineers and technologists. The objective of this expert group was to gather interdisciplinary European expertise and create synergies, allowing for an integrated physiology system based on identified research priorities. Due to the necessary holistic approach, those research programmes obviously required the involvement of scientists whose expertise is disseminated across Europe. The specific objectives include:

1. To delineate the priorities of high quality research in physiology needed to support the next phase of space exploration. 2. To define these priorities on a new integrated approach of the deconditioning syndrome based on which a new generation of countermeasures are to be tested in the context of Mars exploration. 3. To better utilise the results of space physiology research and ground-based analogues to strengthen knowledge on the role of sedentary behaviours in the development of current societal chronic diseases.

Integrated Systems Physiology 9 2 Bones and Muscles

2.1. Relevance of Research on Bones and Muscles

2.1.1. Relevance for space exploration missions The knowledge required to develop effective coun- termeasures will derive both from experience in low The musculoskeletal system is central to work, locomo- earth orbit spaceflights of relatively short durations tion, and posture. Maintaining its integrity is essential (<6 month) and from extensive ground based stud- to mission completion as well as to astronaut health ies involving human bed rest models and mechanistic during and after the mission and over the lifespan of animal studies. former fliers. One of the principal obstacles facing the design and implementation of long-duration explora- While maintaining the integrity of the musculoskel- tion class missions is the fact that, without counter- etal system is central to crew health and function, it is measures, all components of the musculoskeletal sys- also important to consider the interaction of the mus- tem adapt to the microgravity environment, and also culoskeletal system with other physiologic systems. incur damage to tissue structure and function due to In order to maximise the large investments made radiation exposure. Notably, bone mass and strength by NASA and ESA in developing and flying exercise are lost (1). Muscle mass is lost and morphology is al- hardware, exercise protocols should be modified to tered, with a loss of muscle strength and endurance also maximise known positive impacts on cognition, (2). Tendon elasticity declines, reducing the power behaviour, and immune function, which have been transmission of muscle contractions. Inter-vertebral established in ground based studies. discs elongate, causing potentially debilitating back pain. Also, many astronauts and cosmonauts have In conclusion, maintaining the integrity of the mus- made multiple flights, further challenging the integ- culoskeletal system is of high importance due to the rity of the musculoskeletal system. known deleterious effects of the spaceflight environ- ment on injury risk and performance, and due to the During an exploration mission, astronauts will have potential benefits of exercise in increasing crew health endure a long-duration spaceflight in weightless- in other physiologic areas. ness, then adapt to live and work in partial gravity, undergo another long-duration spaceflight, and then 2.1.2. Earth benefits and applications finally return to a 1-g environment. In order to func- tion properly, the astronaut’s musculoskeletal system Understanding the effects of spaceflight on the mus- must adapt to each gravitational change. Operating culoskeletal system entails both studies and counter- in a gravitational field with a musculoskeletal system measures that are directly relevant to Earth popula- adapted to microgravity would result in impairment tions, such as the elderly, subjects with muscle wast- of performance due to reduced strength and endur- ing syndromes, or those in prolonged enforced bed ance, increased risk of falling and increased risk of rest. The strongest translational potential of muscu- bone fractures. Also, the process of re-adaptation loskeletal research in the spaceflight context involves itself may increase risk of injury as different muscu- the study of age-related osteoporosis and sarcopenia. loskeletal components may recover at different rates. Although aging and spaceflight may involve changes Thus, to diminish the impairment of performance and in morphology and function by fundamentally differ- risk of injury, it is essential to develop countermeas- ent cellular and molecular pathways, they share the ures that maintain muscle strength and endurance, common feature of adaptation to changing levels of bone mass, and postural balance throughout the strain (3). Thus, studying musculoskeletal system ad- mission. Such countermeasures must be properly de- aptation from microgravity to partial or 1g parallels signed in order to meet their physiologic goals, to be the adaptation needed to function in the context of carried out without an excessive burden of crew time, age-related atrophy of bone and muscle tissue. Fur- and to avoid injury or illness associated with their use. ther, the types of countermeasures required to main-

10 Bones and Muscles tain function in altered gravity environments must take into account preservation of muscle strength, endurance, bone strength and postural balance. Similar approaches are relevant to the prevention of falls and fractures in eld- erly subjects.

Translational potential also exists for technologies such as imaging techniques used to monitor musculoskeletal sta- tus in space. The use of unloading analogues in ground- based research is relevant to patient populations that are subject to prolonged disuse. Bed rest studies allow us to separate the effect of disuse from those associated with co-morbidities, both in the context of fracture healing and in atrophy due to prolonged hospital stays. In summary, research into the musculoskeletal effects of long-duration spaceflight is rich in translational potential in both elderly and other populations affected by disuse atrophy.

2.2. Bones and Muscles – Key Issues

Eight key issues were identified which are relevant to un- derstand the changes in, and to maintaining the health of the musculoskeletal system during spaceflight in order to provide a framework for planning future research. For each identified key issue, the latest developments, knowledge gaps and research needs, proposed investigations and recommendations, as well as trans-disciplinary aspects are presented. Figure 2: ESA astronaut equipped with a bungee harness, exercising on 2.2.1. Key issue 1: Sex-based differences in the preserva- a treadmill on the ISS (Credit: ESA/NASA) tion of musculoskeletal tissue during space flight

Brief review of latest developments Some recent case-study reports of individual male and female astronauts who have spent ~6 months on the ISS have led to the intriguing observation that women, in gen- eral, better preserve their musculoskeletal tissues during missions compared to men (4). However, there are many unanswered questions regarding these observations in- cluding medication use (including estrogen), pre-flight BMDs, exercise countermeasure profiles, etc.

Knowledge gaps and research needs

• While recent bed rest studies involving women have shed new light on the response of women to un- loading and inactivity (5-8), there is still much to be learned. • It is critical to identify the mechanisms for the different

Bones and Muscles 11 patterns of musculoskeletal deconditioning that have been observed in women compared to men. • To date, most women on long-duration missions have inhibited their menstrual cycles through pharmaco- logical intervention. However, this may not be a safe practice for missions to Mars, for example, which may last up to 3-years, and research into this issue is need- ed. • The effects of space radiation in the presence of estro- gen are unknown and require further investigation.

Proposed investigations and recommendations

• There is an urgent need for bed rest studies in which men and women are exposed to exactly the same conditions and countermeasures during the period of confinement. It is possible that data from control sub- jects at NASA’s Flight Analog Research Unit in Galves- ton, TX may already have some appropriate data that could be mined. Similarly, side-by-side animal studies using male and female animals need to be conducted in order to explore sex-based differences at the level of cellular and molecular kinetics. The response of fe- males to simulated and actual unloading in relation to menstrual cycles needs to be studied. • The design of exercise-countermeasure equipment must take differing body dimensions of men and women crewmembers into account. Such equipment must be designed to be adjustable so that women can exercise over a full range of loads and motions without undue hardship.

Figure 3: There are questions regarding sex- Trans-disciplinary aspects based differences in physiological responses to microgravity (Credit: NASA) • Links must be made with the endocrinology research community for joint work on the hormonal basis for sex-differences in response to altered gravity. Also of interest is the regulation of bone and an examination of the role of estrogen and the hypothalamic-pituitary-adrenal axis in homeosta- sis of the musculoskeletal system. • Radiation effects on bone and muscle may also exhibit sex-based differences and these should be examined in collaboration with radiation biologists. • Sex-based differences in nutrition and micro-nutrition interaction and their influence on the musculoskeletal system also need to be studied.

12 Bones and Muscles 2.2.2. Effects of micro-gravity on musculoskeletal • A recent literature review of shoulder injuries at- injuries and healing processes (ligaments and ten- tributed to resistance training (17) has indicated dons, bone fracture, back pain) that predictors of soft tissue injury remain un- known and cited the need for further research in Brief review of latest developments this area.

Information from spaceflight studies on fracture Bone fracture healing may prove to be a useful guide to studies of fracture healing in subjects during extended bed rest • Studies using the hind-limb suspension (HLS) and those with bone loss due to disuse atrophy. Since model of unloading have revealed a contradic- Fibroblasts, muscle cells, and extracellular matrix are tory finding for fracture healing in the rat tibial sensitive to alterations in gravitational forces (9, 10). and femur. Whereas the tibial HLS model shows Sporadic pieces of data from space-flown rats have impaired healing, such was not the case in the shown that the repair process of load-bearing bone femoral HLS model. These changes need to be and may be hindered during acute replicated and explained. exposure to microgravity (11, 12). Furthermore, since • There are indications that HLS affects angiogen- many subjects in bed rest studies experience back esis and vascularity (18, 19). These findings needs pain, results on the management of this condition need to be further examined in relation to the va- may be useful to evaluate the effect of deconditioning lidity of the HLS model for weightlessness. on back pain in a hospital-based population without • A 2002 study (20) reported that skeletal unload- the confounders associated with examining decondi- ing increases adipocyte differentiation concomi- tioning in sick patients. Information from Earth-based tantly with inhibition of osteoblast differentia- studies should inform experiments on the healing of tion. Thus, bone marrow becomes more fatty in ligaments and tendon since unloading is a common unloading. Prolonged exposure to microgravity form of treatment on earth. may potentially lead to profound alteration of skeletal metabolism, perhaps including reduced Ligaments and tendons osteogenic response to exercise. • There is some evidence that immune compro- • There is recent evidence that collagen fibre orien- mise and bacterial virulence increases in the tation in tendons may be altered by microgravity spaceflight environment (21). This may berel- (13, 14). If verified, this may have important im- evant to soft-tissue infection after injury during plications for recovery of soft tissues from long- spaceflight. duration spaceflight. • There is data to support that unloading of the rat Back pain hind-limbs for 3 or 7 weeks inhibits dense fibrous connective tissue wound healing processes (15, • Lower and upper back pain is highly prevalent in 16), suggesting that minimal mechano-transduc- returning crew members. tion may be useful for connective tissue repair. • Recovery from back pain shows persistence of • There is evidence of injury to soft tissues in a bed pain without clear evidence of morphologic rest study which included the level of aggres- change sive resistance exercise that may be necessary to • There are indications that core muscles show maintain bone and muscle during long-duration poor recovery after bed rest missions. • A high rate of injury has been observed in high- Knowledge gaps and research needs intensity exercise in the elderly. Since it is often Ligaments and tendons said that spaceflight mimics aging, this may be a cautionary observation that is relevant to long- • There is a lack of information in general about duration spaceflight. the effects of altered gravity on ligaments and tendons. These tissues have been somewhat ig- nored in favour of studies of bone and muscle.

Bones and Muscles 13 • The enthesis is a common source of problems in by the induction of fractures while in space. sports and orthopedic medicine (22). However, • There is a need to model of different types of frac- information on the response of the enthesis (22) ture fixation. The conventional models (such as to altered gravity is absent from the literature. the classical Einhorn model (24)) are not relevant • What is the effect of particular exercise activity on to human fractures because they require an in- tendons and ligaments? tramedullary rod, which would not be a feasible • What are the predictors of injury to tendons and treatment in space. ligaments? • There are opportunities to use animal models to • Rotator cuff injuries are common in astronauts simulate telemedicine and autonomous medical during training and flight (23). management. These opportunities should be ex- ploited as a complement to human studies. Bone fracture • Currently, it appears that ultrasound is likely to be the major form of medical imaging that will be • The contradictory results in fracture healing of available in space. Research needs to be focused the femur and tibia in hind-limb unloaded ani- on the diagnostic and therapeutic use of ultra- mals needs to be explained. sonic techniques. • Medical management procedures for in-flight fractures need to be elucidated and standard- Back pain ised. • Animal models of conditions leading to back pain Back pain need to be developed in order to understand eti- ologic factors and to test interventions. • The mechanisms of spaceflight-related back pain • In human studies, there is a need to do more cor- need to be elucidated. relative studies between activity, exercise, spine morphology, etc. to gain insight into predictors Proposed investigations and recommendations of back pain. • There is a need for detailed studies of the various Ligaments and tendons tissue compartments (muscles, discs, ligaments, etc.) whose changes are associated with back • There is a need for a comprehensive critical re- pain. view of the literature in the areas of ligament and • A more thorough understanding of the mecha- tendon in spaceflight. Ideally, this could lead to nisms of lower back pain in micro/partial gravity an identification of the key risk factors for injury. needs to be developed. • Little is known about enthesis during space flight and animal studies to address this issue are need- Trans-disciplinary aspects ed. • It would be beneficial to consider the effects of Ligaments and tendons specific countermeasure exercises in key soft tis- sue structures that are at risk of injury. • Bone and muscle have been considered as separate • Research which will safeguard the integrity of the rather than interdependent tissues for much too shoulder in space is urgent. long in spaceflight research, and the anatomical junction between muscle and bone (the enthesis) Bone fracture is an excellent metaphor for their close relation- ship. The gap in knowledge regarding changes • Experiments with rodents in which fractures are in this junction with unloading needs to be filled. induced immediately prior to flight would be in- structive. • The above experiments would be complemented

14 Bones and Muscles Bone fracture 2.2.3. Key issue 3: Role of genetics in musculoskel- etal performance, preposition to injury and overall • Information is emerging regarding changes in adaptation to micro-gravity the vascularisation of bone during fracture heal- ing in the setting of unloading (25). Collaboration Brief review of latest developments with vascular physiologists would be beneficial as these studies move forward. • Genome-wide association studies have identified • Any impairment of immune function could delay specific genes associated with performance and fracture healing and this area needs to be ex- fracture in epidemiologic studies. plored with collaborative research. • Animal models show differences in muscle and • If the spaceflight environment (microgravity and bone phenotypes based on genetic variation radiation) alters hematopoiesis, this may affect the process of fracture healing, as osteoclast pre- Knowledge gaps and research needs cursors derive from the hematopoietic lineage. • Interaction of the spaceflight environment with • At present, there is a dearth of integrated knowl- mesenchymal stem cells may affect the number edge in this area that can be directly applied at and function of osteoblastic cells involved in frac- the human level to activities such as crew mem- ture healing. ber selection with flight-based genetic profiling. • Experimentation on the wide variety of genetical- Back pain ly modified animals has, to date, been confined to 1-g studies. • Back pain has the potential to affect crew -per formance and crew-crew interactions. These ef- Proposed investigations and recommendations fects should be studied with physiotherapists and psychologists with the aim of devising strategies • Detailed family histories of musculoskeletal dis- to minimise mission impact in the event of acute eases, including the incidence of osteoporosis in-flight episodes of back pain. and fractures, should be collected on all crew • Pain affects sleep duration and quality, and re- members and these data should be compared search is needed to examine ways of attenuating with pre- and post-flight measurements of mus- the effects of acute in-flight episodes of back pain culoskeletal status. on sleep. • Better animal facilities are urgently needed on • Back pain has other cascading effects on the the ISS and animal studies with genetically modi- nervous system and these effects require further fied rodents should focus on animals that have elucidation. shown resistance to the loss of musculoskeletal • Exercise compliance in the presence of back pain during 1-g based models of unloading. is likely to be poor and this could lead to an overall deterioration in the crew member’s health. Alter- Trans-disciplinary aspects native exercise prescriptions need to be devised so that crew members can exercise despite acute There is vast potential for overlap in the study of ge- in-flight episodes of back pain. Emphasis may be netic predisposition to changes in the musculoskel- given on the acquisition by the crew of a biome- etal system during spaceflight with all other areas of chanically sound exercising technique when us- health and performance. Work in this area should al- ing exercise apparatuses, an element that may ways be multidisciplinary. have been underestimated as a potential factor merely responsible for initiating lower back pain.

Bones and Muscles 15 2.2.4. Key issue 4: Biomechanics and impact of par- • Simulation of altered gait patterns in partial grav- tial gravity on the musculoskeletal system ity that might lead to injury should be conducted. • Biomechanical analysis of work tasks in partial Brief review of latest developments gravity needs to be conducted. • Biomechanical information on preferred gaits • Recent lunar simulations have indicated that and task requirements is critical for the design of ground reaction forces under simulated EVA load spacesuits and footwear for EVA. conditions are low and unlikely to be osteopro- tective. Trans-disciplinary aspects • Suspension simulations of reduced gravity loco- motor activities are now more readily available. • Coordinated movements require sensorimotor integration which may be altered by prolonged Knowledge gaps and research needs exposure to altered gravity. Collaborative studies with specialists in this area would be beneficial. • Biomechanical modelling techniques have been • Surface activity during Apollo EVAs indicated sig- underutilised for the estimation of whether or nificant metabolic demands and exploration of not various loading scenarios are likely to be os- the cardiovascular consequences of exploration teoprotective in partial gravity. activities are warranted in conjunction with bio- • Lunar exploration through the Apollo programme mechanical studies. showed that preferred gaits on the moon were different from those on earth. Preferred gaits on Mars are not known. 2.2.5. Key issue 5: Effects of radiation exposure ex- • Insight is needed regarding how altered patterns perienced during space flight on the musculoskel- of locomotion in partial-g scenarios may lead to etal system increased risk of injury. • The kinematics and kinetics of simulated con- Brief review of latest developments struction, exploration, and EVA activities are not well-known. Recently published animal studies have shown that • Comprehensive simulations of work tasks in par- exposure to heavy ions simulated galactic sources tial gravity should be conducted to aid in the as- of radiation induce rapid transient osteoclastic bone sessment of fitness for duty after prolonged ex- resorption (26). Studies of cultured osteoblasts have posure to partial gravity and to assess the risk of shown deleterious effects of radiation on osteoblast injury. proliferation and function (27). Other studies have ex- amined the effects of drug and nutritional interven- Proposed investigations and recommendations tions on musculoskeletal status (28, 29) in the simu- lated space environment of hindlimb unloading and • Acceleration Monitoring Units (AMUs) should be radiation exposure. added to spacesuits and space footwear in order to monitor motion during actual and simulated Knowledge gaps and research needs activity. • Ground-based suspension models offer consider- The full extent of the space radiation risk to bone is able possibility for simulation of locomotor and not yet known, and the cellular and molecular path- other activities (such as jumping, work tasks, etc.) ways require continued delineation, although good and these approaches should be exploited. initial progress has been made. The effect of space • Musculoskeletal modelling techniques ought radiation on muscle function is also not yet under- to be refined to generate validated loading esti- stood. Knowledge is lacking regarding the efficacy of mates of structures that are at risk for bone loss preventive or restorative therapies and the extent and (such as the proximal femur). mechanisms underlying recovery of lost function.

16 Bones and Muscles Proposed investigations and recommendations tirely different doses and types of radiation. However, information gained from mechanistic studies may Definition of the risk posed by the space radiation en- shed light on potential cellular and molecular path- vironment on musculoskeletal tissues requires contin- ways by which bone and muscle may be affected in uation of current animal studies establishing cellular the clinical radiation therapy setting. and molecular pathways to bone loss, and extending these studies to examine effects on muscle as well. 2.2.6. Key issue 6: Ground-based human studies These mechanistic studies should involve different radiation types, and examine effects in the context of Ground-based human studies are relevant to all mis- microgravity as simulated by the hindlimb unloading sion types, but are especially important for simulation model (30). These mechanistic studies should also de- of long-duration exploration missions. These stud- fine the ability of radiation damaged musculoskeletal ies are required to overcome the main drawbacks tissues to recover function, and further animal studies of space-based research, which generally have low should begin to assess the effect of countermeasure sample sizes and uncontrolled experimental condi- approaches to radiation induced bone and muscle tions. Human studies of sufficient sample size, with loss, including anti-resorptive therapies for bone, and carefully controlled conditions, are essential to obtain anti-oxidants for bone and muscle. pre-flight baselines and correctly evaluate the effec- tiveness of various countermeasures. Such examina- Trans-disciplinary aspects tions may eventually have to take place in one-year missions to the ISS, as yearlong bed rest studies are Understanding the effect on musculoskeletal tissues considered to be neither ethical nor practical. and function of exposure to space radiation will re- quire a multidisciplinary approach integrating infor- Brief review of latest developments mation from the central nervous (CNS), immune and vascular systems, as well as the hematopoetic (27) Recent bed rest studies have demonstrated the abil- and mesenchymal niches in the bone marrow. Inves- ity of countermeasure approaches to attenuate dis- tigations of radiation effects should take into account use bone loss. These include high intensity resistance the CNS, as it is of primary interest as a target of space exercise (31, 32), resistive vibration (33, 34), and also radiation and is the source of input to skeletal muscle pharmacologic interventions (alendronate and pa- as well as the recipient of sensory information. Recent midronate) (8, 12, 35-37). studies have also pointed to the role of the CNS in regulating both the formation and resorption arms of Knowledge gaps and research needs bone remodelling. Exercise protocols have not yet been optimised in There is extensive literature on the immune response regards to time efficiency, and there is still relatively to radiation exposure. Radiation exposure is also little information about the molecular mechanisms known to affect angiogenesis, a key element of the of the countermeasure action on bone and muscle skeletal muscle and bone repair. Finally, radiation is (38). For techniques such as vibration, it is still not known to impact the progenitor cells of the mesen- known if the effect derives from muscle contraction chymal and hematopoietic niche. Osteoblastic and or impact forces (39, 40). Although studies have dem- muscle satellite cells derive from the same lineage, onstrated positive effects of aerobic exercise on brain and osteoclasts derive from hematopoietic mono- and immune function on Earth populations, there cytes. Thus space radiation exposure may affect the is little knowledge of these relationships in a space- reparative and remodelling functions of bone and flight setting. With respect to pharmaceutical treat- muscle tissue. ment, there is a lack of information on dose-response relationships and on synergies between exercise and On Earth, the closest clinical analogy to space radia- anti-resorptive treatment. Because of bisphospho- tion is clinical radiation therapy, which involves en- nate side effects, there is a need to explore alternative

Bones and Muscles 17 anti-resorptive treatments that are newly available, such as denosumab.

Proposed investigations and recommendations

Continued research with larger sample sizes and control- led conditions will be required to optimise exercise pro- tocols for efficacy and time efficiency. Achieving this goal will require further studies to elaborate the mechanisms of countermeasure effectiveness in bone and muscle. The amount of crew time required for exercise protocols, and the expense devoted to design and placement of the equipment justify efforts in determining the efficacy of- ex ercise for protecting other physiologic systems from the effects of spaceflight, such as brain (behaviour/cognition/ performance) and immune systems. For pharmacologic interventions, dose response studies are required, and new pharmaceuticals should eventually be tested, such as denosumab, which may provide fewer side effects than bisphophonates. Finally, there is a need to examine how exercise and drug treatment can operate synergistically.

Trans-disciplinary aspects Figure 4: Bed rest studies are frequently used as spaceflight analogues for physiology research Exercise is inherently multidisciplinary, integrating cardio- (Credit: ESA/Vista S.T.I.) vascular, skeletal-muscle and skeletal physiology. Future investigations will require collaborations with neurophysi- ologists and cognition/behaviour specialists as well as im- mune and nutrition researchers.

Ground-based studies are highly translational in that they can be used to model long-term bed rest without the con- founding effects of comorbidities. Additionally, prolonged bed rest is a useful clinical paradigm for the study of insulin resistance.

2.2.7. Key issue 7: Ground-based animal studies

Although animal research with hindlimb unloading mod- els has the limitation of imperfect mapping of animal mod- els to humans and hindlimb unloading to microgravity, ground-based animal studies continue to be a high prior- ity. Ground-based animal studies are relevant to all mis- sion types but are especially important for simulation of long-duration exploration missions. These studies provide mechanistic information that is otherwise impossible to obtain in humans, notably the interaction of radiation with disuse and the healing of fractures and wounds in general in radiation and microgravity environments. Animal stud-

18 Bones and Muscles ies also offer the advantages of large sample sizes, as Trans-disciplinary aspects well as the ability to carry out gender studies and ma- nipulate estrogen status. Further, by use of transgenic The studies described above involve interactions be- animals it is possible to understand the effect of ma- tween multiple disciplines. These include interactions nipulating key genes, as exemplified by the myostatin between musculoskeletal sciences and radiobiology, knockout mouse (41). genetics, immunology, neural and vascular studies.

Animal studies in simulated microgravity provide Brief review of latest developments mechanistic information about disuse osteopenia and sarcopenia, and allow for studies of genetic ma- Recent studies using rodent models and accelerator nipulations in these disease areas. They also allow for facilities have discovered high bone loss and deterio- mechanistic information about the interaction of dif- ration of bone structure associated with exposure to ferent physiologic systems in these disease areas and radiation fields simulating deep space. The high bone others. loss has been attributed to a rapid transient activation of osteoclasts. Other studies have yielded conflicting 2.2.8. Key issue 8: Optimise countermeasure ef- results of fracture healing with hindlimb unloading, ficiency and utilise an integrated physiology ap- with open tibial fractures demonstrating delayed proach healing compared to loaded controls, but with femo- ral fractures showing the opposite tendency. Other Brief review of latest developments developments have included preparation of new fa- cilities for ISS, including the Italian Mouse Drawer, and Recent results indicate that exercise is effective for at- the ESA Mice in Space Facility. tenuating muscle and bone loss in long-term bed rest (5, 6, 8). Initial results from a bed rest study led by Cav- Knowledge gaps and research needs anagh indicate that specific protocols tailored to each subject that replace that subject’s 1g loading attenu- Conflicting results from hindlimb unloading models ates bone loss. Amelioration of bone loss and muscle point to the need to fly fractured to atrophy has also been observed with similar results derive conclusive information regarding micrograv- observed for resistive vibration countermeasures (33, ity and fracture healing. The discovery of powerful 42). It has been also demonstrated that mechanical space radiation effects on bone points to the need to stimulation of the plantar foot surface attenuates systematically explore radiation interaction with skel- unloading-induced muscle atrophy both in humans etal muscle. Animal studies are also needed to study (43, 44) and rats (45, 46). Other advances include the musculoskeletal effects of radiation and microgravity development of new multifunctional exercise devices induced alterations of neural function and vasculari- suited for exploration class spacecraft, as well as a sation/angiogenesis. growing volume of data on subjects that exercised with second generation treadmills and resistive ex- Proposed investigations and recommendations ercise devices on the ISS. Treadmill countermeasure exercise on the ISS has also been recently shown to Activation of the American animal facility is of high elicit less force under the feet than similar exercise on priority for increasing sample sizes necessary for earth, suggesting that restraining loads from the sub- mechanistic studies. Unfortunately, there are no cur- ject load devices (SLDs) are inadequate (47). rent plans to fly such a facility. High scientific priority should be given to investigations of space radiation Knowledge gaps and research needs and skeletal muscle, and in particular, to the interac- tion of radiation with fracture healing and wound While bed rest studies have indicated the value for re- healing in general. sistance and resistive vibration exercise in attenuation of bone and muscle loss, there are significant gaps in determining how such countermeasures should be

Bones and Muscles 19 applied, as well as the effectiveness of nutritional and phar- macologic interventions with and without exercise. Infor- mation is lacking on the efficacy of intermittent timing of exercise bouts, on gender differences in exercise counter- measure efficacy, as well as the efficacy of exercise for pro- tecting other physiologic systems, such the immune sys- tem and brain. Although a flight study of alendronate for prevention of bone loss is underway, the information on this and other bisphosphonates is incomplete, and there will be an eventual need to investigate therapies such as denosumab, which may offer anti-resorptive capability without the gastrointestinal side effects of alendronate. Lastly, there is a lack of information in spaceflight and bed rest scenarios using a combination of countermeasure ap- proaches, such as timed nutritional-exercise countermeas- ures, combined exercise and anti-resorptive treatment, and the use of anti-oxidants to combat both radiation and dis- use.

Proposed investigations and recommendations

Exercise countermeasure efficacy should be evaluated in side by side gender comparisons. Attention should also be given to testing exercise approaches that combine re- sistance exercises with balance and proprioception. Novel analogue environments such as EnviHab should be utilised to determine the protective effect of exercise on brain and immune function when exercise is carried out in isolation environments. Studies should be carried out that combine

Figure 5: NASA Astronaut Steve Lindsey using nutritional and pharmacologic approaches with exercise to the advanced Resistive Exercise Device (aRED), determine if there are synergistic effects. Finally, exercise providing high loads to weight-bearing bones studies in transgenic rodent models should be carried out (Credit: NASA) to better elucidate the mechanisms of exercise efficacy.

Trans-disciplinary aspects

Finding the optimal exercise protocol and/or the correct combination of exercise and nutritional/pharmacologic countermeasures will require a multidisciplinary approach, integrating information from the musculoskeletal, sensori- motor, neuro-behavioural, radiation biology and immunol- ogy fields.

Countermeasure studies are highly relevant to health on Earth in that they are developing countermeasures that ad- dress both bone loss and muscle loss as well as balance/fall risk, two factors that underlie the vast public health prob- lem of fractures in the elderly.

20 Bones and Muscles 2.3. Conclusion

Overall, eight key issues have been identified in the tered gravity has received some attention in the past field of muscle and bone research in space, including but much remains unknown, particularly on Mars sex-based differences, musculoskeletal injury, genetic where no empirical evidence is available and few sim- predisposition, biomechanics, radiation, ground- ulations have been conducted. Knowledge of typical based human studies, ground-based animal studies, locomotive patterns is also important for the design and countermeasures. of habitats where increased vertical movement dur- ing gait and enhanced vertical jumping ability will Much still remains unknown about the response of require additional headroom. Biomechanical insights women to altered gravity. While this is not surprising into typical exploration work tasks are important for given that women crew members have represented task scheduling, suit design, and injury prevention. less than 20% of all astronauts to date, there is a com- pelling need to address sex-based disparity in infor- The environment of deep space involves exposure mation and research. to galactic and solar that are largely de- flected by the Earth’s . Recent studies Injury to musculoskeletal tissues during spaceflight have indicated that exposure to this radiation may has the potential to be mission-critical. Many situa- play an important role in bone loss, however the ef- tions can be envisaged in which crew members will fect on muscle is not yet known. Thus, a mechanistic be unable to carry out important, and in some cases understanding of radiation-induced bone loss, based life preserving, manoeuvres because of musculoskel- on realistic simulations of the space environment, is etal injury. Bone fracture has, appropriately, been the essential to understanding the magnitude of the risks focus of most prior spaceflight injury research, but involved and to development of countermeasures. even in this area much remains to be learned and con- While there is some evidence that radiation disrupts tradictory findings need to be explained. However, muscle tissue at the fibre level, the state of knowl- injury to ligaments and tendons, which are very com- edge is much less advanced than it is for bone, and mon in terrestrial workplace and sports settings, are development of the field is of high priority. This work also likely to occur during long-duration spaceflight will be highly interdisciplinary and is likely to produce in the future and very little research to data has ad- knowledge that will be of value to the study of other dress mechanisms for healing in altered gravity. The physiologic systems. potential for varying rates of recovery of muscle, ten- dons, ligaments, and bones from injury upon return to Continued investment in human bed rest and other Earth presents significant challenges to post-flight re- ground studies is essential due to the sample sizes habilitation. Back injuries have also proven to be one and controlled conditions available to obtain infor- of the most common complaints of returning crew mation that can serve as a rational basis for selection members to date, and it is critical that a better under- and optimisation of countermeasure (both in terms standing of its etiology and treatment be achieved. of efficacy for protecting the musculoskeletal system, and for determination and optimisation for protective At some point in the future, it is likely that pre-flight effects on other physiologic systems). investigations will identify genetic predisposition for bone and muscle loss in altered gravity and this may Expanded investment in ground-based animal stud- become part of the selection matrix for potential crew ies is required to generate mechanistic information members. However, such methods are currently not to serve as the basis for the development of coun- available and the focus of activity must remain on ani- termeasures to microgravity and the radiation envi- mal studies. ronment of space. The ability to model radiation and fracture healing effects are two key aspects of animal Biomechanical issues are also important for under- studies that address major spaceflight risks, but which standing a number of aspects of long-duration space- cannot be ethically studied in humans. Further devel- flight. Locomotion during EVA on a surface with al opment of flight-based animal facilities is essential

Bones and Muscles 21 for exploitation of the unique features animal models can offer.

Lastly, the development of effective, time-efficient and comprehensive musculoskeletal countermeas- ures are essential to mission success, since integrity of musculoskeletal tissues and function is indispensable to optimal performance and injury avoidance on par- tial gravity surfaces. This will inevitably be a long-term effort and much work still needs to be done in order to clarify sex-based differences and to test combina- tion countermeasure approaches.

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Bones and Muscles 25 3 Cardiovascular, Lungs and Kidneys

3.1. Relevance of Research on the Cardiovascular System, Lungs and Kidneys

3.1.1. Relevance for space exploration missions in a healthy population (astronauts and cosmonauts), providing the potential to understand the factors that Ensuring adequate cardiovascular health in the astro- lead to cardiovascular disease here on Earth. Many naut and cosmonaut population is a critical aspect of workers are exposed to dusty environments in the long-duration space travel. Experience on the ISS has workplace and particulate matter in the environment shown that missions greater than 6 months in dura- is a known health risk to urban populations. Further, tion, even with substantial amounts of exercise, will many drugs are now delivered in aerosol form, and have significant effects and degradations in cardiovas- so a comprehensive understanding of the deposition cular function in the form of orthostatic intolerance and subsequent clearance of deposited particles is of and a lower level of cardiac performance. In long-du- considerable importance in both areas. Developing a ration exploration-class missions, (e.g. a 6 month lu- more complete understanding of the role of diet and nar stay or a visit to a near-Earth object) crew must be other effects in the development of kidney stones able to function adequately in a hypo-gravity or zero stands to improve the health and reduce the suffering gravity environment, and then be able to return safely of a large percentage of the Earth population. to Earth. On a very long-duration mission, such as a mission to Mars, crew members must be able to func- 3.2. Cardiovascular, Lungs and Kidneys – Key Issues tion on the Martian surface after long periods in zero gravity, and then return to Earth after an even longer The expert group on cardiovascular, kidneys and lung zero gravity exposure. Several key areas remain un- functions delineated five key issues of importance for known or poorly defined to ensure the crew’s ability future exploration. to succeed in these missions at this time. The issues identified here all have the potential to se- In such exploration class missions, crews will be ex- riously impair a successful exploration-class mission, posed to extraterrestrial dusts which will inevitably and to a lesser extent, spaceflight in low earth orbit. be transported into the habitats, and these dusts are They are considered high priority research targets by thought to have a high potential of being toxic. These the Expert Group. fine dusts will be inhaled, and in the low gravity en- vironment, will be transported deeper into the lung 3.2.1. Key issue 1: What are the in-flight alterations where they will likely remain for extended periods of in cardiac structure and function? time, which will likely enhance their toxicity. Relevance for space exploration missions Changes in blood chemistry brought about by space- flight including blood volume reductions, potential Cardiovascular deconditioning has always been ob- dietary effects, and increased calcium resulting from served after spaceflight and ground simulations (bed bone demineralisation all have the potential to in- rest, water immersion). This poses a threat to astro- crease the risk of developing kidney stones. With the nauts upon arrival to the Moon and Mars, and after development of kidney stones come significant risks return to Earth. to overall mission success and thus prevention is a critical issue. Earth benefits and applications

3.1.2. Earth benefits and applications Similar problems occur in patients after prolonged bed rest due to trauma surgery and other conditions forc- Heart disease is a leading cause of death in the ter- ing the patient to stay bedridden for extended periods restrial population. Space travel results in significant of time. and rapid degradation of cardiovascular performance

26 Cardiovascular, Lungs and Kidneys Brief review of latest developments

The optimal countermeasure is yet to be defined but planned developments include and vari- ous exercise modes.

Knowledge gaps and research needs

The effects of prolonged space flight on myocardial mass, intrinsic contractility, myocardial compliance and auto- nomic neuro-regulation are currently unknown. Further, the interaction with peripheral circulation is complex and it is not known whether cardiac changes observed thus far are primarily cardiac or are due to secondary to changes in the peripheral circulation. [Also see following Key Issue].

Proposed investigations and recommendations

• Dynamic responses of cardiac function to exercise/ orthostatic tests simulating different phases of Moon and Mars exploration missions. • Bed rest simulations of relevant durations, and dry im- Figure 6: Lunar dust stuck to the astronaut’s mersion simulations (up to 2 weeks) spacesuit will inevitably be transferred into the • Cardiac muscle structure by advanced echocardiogra- space habitat (Credit: NASA) phy. • Simultaneous monitoring of 1) cardiac function (car- diac output), 2) 24-h blood pressure, 3) sympathetic nervous activity, 4) concentrations of vasoac- tive hormones (vasopressin, catecholamines, natriu- retic peptides and renin-angiotensin-aldosterone). • Monitoring of cardiovascular function during lower body negative pressure and dynamic exercise. • Develop tolerable 24h blood pressure monitoring.

As a justification for the more complex 24 h arterial blood pressure recording, as compared to single-point measure- ments, the latter are considered to be much less repre- sentative for the state of the subject and can be subject to emotional influences from the procedure itself (white coat hypertension).

Trans-disciplinary aspects

• Thermoregulation changes in microgravity, and may impact both metabolic and cardiovascular control. • Radiation may interact with cardiovascular degrada- tion/ repair processes. • Mental stress and sleep disorders are likely to influ- ence cardiovascular health.

Cardiovascular, Lungs and Kidneys 27 3.2.2. Key issue 2: What is the influence of space- ma concentrations of vasoactive hormones (va- flight on structure and function of blood vessels? sopressor and natriuretic vasodilatory substanc- es), as well as the distribution of cardiac output to Relevance for space exploration missions different vascular beds. • Evaluate the effects of simulated low gravity on Orthostatic intolerance is frequently found after structure and function of blood vessels, utilising spaceflight and bed rest simulations, and may bea bed rest and other analogues such as dry immer- hazard to the astronaut and/or to other aspects of sion. mission success including activities on the surfaces of Moon and Mars. Trans-disciplinary aspects

Earth benefits and applications The interaction between muscle and peripheral ves- sels should be considered in the design of experi- Orthostatic intolerance is frequently observed in pa- ments and countermeasures. tients after bed rest, during circumstances that re- duce blood volume, and with the use of certain medi- 3.2.3. Key issue 3: What level of cardiovascular func- cations. tion loss is acceptable and what type and quantity of exercise is necessary to ensure that this loss is not Brief review of latest developments exceeded?

Orthostatic intolerance has a multifactorial causation Relevance for space exploration missions including reduced blood volume and attenuated con- striction of resistance vessels. Recent results implicate Countermeasures aimed at maintaining the full ca- central-nervous processing and/or alpha adrenergic pacity of astronauts have a significant cost in terms receptor dysfunction in post-flight orthostatic intoler- of mass, energy and time. However, it may not always ance. be necessary to maintain this full capacity in order to complete a safe and successful space mission, and Knowledge gaps and research needs there may be an acceptable degree of decondition- ing. • The effects of long-term weightlessness on the structure of the arterial resistance vessels and to Earth benefits and applications what degree it counteracts the development of hypertension is currently unknown. Effective methods can also be used to prevent cardio- • It is currently unknown why the paradox exists vascular deconditioning or improve rehabilitation of that in space, sympathetic nervous activity is patients on Earth. Also, more effective methods can augmented while the arterial resistance vessels be used on the ground to regain good health in sed- are dilated. This has implications for understand- entary populations and to maintain a good health sta- ing the role of gravity in the development of hy- tus in aging populations. pertension. • Currently, nothing is known about the influence Brief review of latest developments of space environment on the mechanotransduc- tion signals and their influence on endothelial Neither resistive nor aerobic exercise alone is ade- functions. [Also see previous Key Issue] quate to prevent deconditioning in spaceflight. The current exercise prescription used in ISS does not en- Proposed investigations and recommendations tirely prevent deconditioning.

• To simultaneously monitor cardiac output, blood pressure, sympathetic nervous activity, and plas-

28 Cardiovascular, Lungs and Kidneys Knowledge gaps and research needs

• What is the requirement for cardiovascular perform- ance upon arrival at the Moon or Mars? • What are the appropriate exercise prescriptions re- quired to achieve such performance? • How can the level of deconditioning that is acceptable to crews who must be rehabilitated upon return to Earth be determined?

Proposed investigations and recommendations

• On Earth, comparison studies of LBNP/exercise and /exercise countermeasures focused on ef- fectiveness on cardiovascular, muscular, bone and neurovestibular systems are suggested. • Different kinds and duration of exercises must be tested to determine the adequate amount of exercise needed. Short-term, middle-term and long-term bed rest studies are required.

Trans-disciplinary aspects

Countermeasures against cardiovascular degradation could/should be combined with countermeasures against

musculoskeletal degradation. Figure 7: Lunar dust is covered in a glassy coat- ing that can either be smooth or jagged (Credit: 3.2.4. Key issue 4: What are the risks associated with ex- Larry Taylor posure to extra-terrestrial dust?

Relevance for space exploration missions In exploration class missions, crews will be exposed to extraterrestrial dusts which will inevitably be transport- ed into the habitats, and these dusts may potentially be highly toxic. These fine dusts can easily be inhaled, and in a low gravity environment, the particles will be transported deeper into the lung where they will likely remain for ex- tended periods of time. This will likely enhance their toxicity.

Earth benefits and applications

Many workers are exposed to dusty work environments and particulate matter in the environment is a known health risk to urban populations. Further, many drugs are now delivered in aerosol form, and therefore a compre- hensive understanding of the deposition and subsequent clearance of deposited particles is of considerable impor- tance in both areas.

Cardiovascular, Lungs and Kidneys 29 Brief review of latest developments reported from the US and Russian space programmes. A calculus in the urinary system could have significant The European Space Agency (ESA) has plans for un- health consequences for an astronaut and could also manned missions to define the physical and chemical have a negative impact on the mission as a whole. properties of lunar dust in the South Polar Region. Earth benefits and applications Knowledge gaps and research needs A better insight into the factors that cause an in- • Size distribution, toxicity and physical properties creased risk for renal stone formation in astronauts is of the dust likely to benefit many individuals on the ground that • The spatial pattern of particle deposition in micro suffer from renal stones or an increased likelihood and low gravity is unknown. of suffering from renal stones. Apart from being ex- • Lung clearance rates in micro and low gravity are tremely painful renal stones may also lead to compli- unknown. Past and on-going studies suppose cations such as infections and hydronephrosis. clearance rates in low gravity are identical to 1G. • Individual variation in airway tree geometry Brief review of latest developments might be a major determinant of particle deposi- tion and subsequent clearance. Ingestion of sufficient amounts of fluids and of potas- sium citrate in astronauts has been shown to counter- Proposed investigations and recommendations act changes in urinary composition that are known to favour renal stone formation. • Studies of toxicity of lunar dust and its passiva- tion rate performed either in-situ (would require Knowledge gaps and research needs unmanned lunar surface exploration) or on Earth using samples collected from future lunar mis- • Can regimes other than fluid and potassium cit- sions and stored in appropriate condition to rate ingestion mitigate renal stone formation? maintain their “freshly fractured” properties. • Can potassium citrate ingestion increase the risk • Study the effects of micro and low gravity on the for brushite stones? clearance rate. This will require access to human • How does renal stone formation relate to bone suborbital or orbital flights. loss during very long space missions? • Scintigraphic and/or fluorescent imaging studies of aerosol deposition and subsequent clearance Proposed investigations and recommendations in the lung either in humans or in an animal model with a focus on the alterations in both deposition • Further studies should be performed of the and clearance that result from reduced gravity. mechanisms for renal stone formation during the post-flight period. Trans-disciplinary aspects • Improved methods to identify the risks for renal stones at the time of selection should be devel- Radiation may interact with pulmonary degradation/ oped, since present routines have proven inad- repair processes. equate. • Improved methods to suppress bone atrophy 3.2.5. Key issue 5: What are the roles of diet and bone should be developed. demineralisation on kidney stone formation and is it possible to predict the risk of kidney stones? Trans-disciplinary aspects

Relevance for space exploration missions The interactions between kidney stone formation and nutrition must be considered, and a close coordina- Despite the fact that astronauts are pre-screened dur- tion with programmes to prevent bone atrophy ap- ing selection to be non-kidney stone formers, a signif- pears necessary. icant number of events with renal stones have been

30 Cardiovascular, Lungs and Kidneys 3.3. References

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Cardiovascular, Lungs and Kidneys 33 4 Immunology

4.1. Relevance of Research on Immunology

Relevance for space exploration missions human system. From fundamental to clinical Immu- nology, the link between organ systems and immune Spaceflight is a unique stress model, impacted con- responses can be addressed thanks to the emerging sistently or intermittently by a myriad of stresses in- knowledge and methodology in Biomedicine to di- cluding psychosocial and physical stressors, high G- agnose immune changes from human blood. From forces at the time of launch and landing, increased clinical investigations in the healthy and the sick, the radiation, sleep deprivation, microgravity, and nutri- lifesaving importance of adequate immunity at the tional factors. This multitude of factors has profound switch between the host and the environment was immune modulatory effects on humans and animals never clear before. and can lead to immune suppression with compro- mised defences against infections. Data have shown Besides controlling infections and eliminating germs, that spaceflight conditions and/or analogues affect immunologic responses are also capable of eliminat- lymphoid organs, peripheral blood leukocyte sub- ing non-functional or dysfunctional tissue-cells, e.g. sets, the functions of immune cells and the number of tumour cells. However, failure to establish adequate bone marrow-derived colony-forming units. immune responses and to distinguish between “self” and “non-self” can result in autoimmune diseases (e.g. Additionally, changes in microbial growth character- rheumatoid arthritis), acute and life threatening infec- istics and pathogenicity during spaceflight have been tions, and overwhelming systemic immune responses observed for several microorganisms (bacteria can (e.g. septicemia) or the development of cancer over more readily proliferate in space). Thus, opportuni- time. Changes to this endogenous balance of the im- ties for microbes to establish foci of infection are en- mune and other organ systems – the so called home- hanced because space travel stimulates their growth ostasis- due to psychological or environmental factors and has a negative impact on immune functions. Fur- (“stressors”) can impact this finely balanced, endo-, thermore, antibiotics are less effective in space and para- and autocrine controlled immune function, re- microbial pathogenicity and virulence are enhanced sulting in immune dysfunction and disease. The un- under real and simulated microgravity. derstanding of these deregulations together with ap- propriate tools can help space travellers as much as Consequently, alterations and weakening of the im- people on Earth. mune system has the potential to be a serious clini- cal risk and represents an area that should be consid- Three specific aspects have been identified by the -ex ered more thoroughly to ensure long-term survival pert group as being highly relevant to life on Earth: in space stations and sustainable habitation on the Moon or any planet (i.e. Mars). The possible adverse • Understanding stress related immune challenges events could each have an immediate impact on mis- in space and the knowledge drawn from it is high- sion objectives. ly relevant to the understanding of the biology of cancer immunology, the balance of Inflammation 4.1.2. Earth benefits and applications and endogenous mechanisms to control it or the lack of control (Autoimmunity/Allergies) in the Immunology is an emerging field of research in which young and ageing population on Earth. an international approach is used to gather more • The translational aspect in highly relevant (e.g. of knowledge on how the immune system is webbed technological developments for space considered in the pathology and clinical appearance of disease, as a highly attractive spin-off, or for the monitor- from it cellular function to an orchestrated, distinctly ing of immune and health conditions in minute balanced action of immune functions in the complex amounts of blood or even non-invasively).

34 Immunology The functions of the immune system can be affected in re- sponse to environmental / living conditions (e.g. chronic and acute stress conditions can result in a further parallel interaction between the immune system and other organ systems). As an example, stress causes neurophysiologic responses and hormone liberation which can modulate in- flammation but also promote bone resorption. These and other cross-interactions are also likely to occur with met- abolic /nutritional changes as well as sedentary life style and aging. These interactions, despite their broad impor- tance for public health and prevention of disease, are not yet acknowledged.

4.2. Brief Review of Latest Developments

4.2.1. Research using isolated cell systems

It has been shown that activation of T cells is strongly im- paired when subjected to the stresses associated with µG (Cogoli et al., Science, 1984, 225, 228-230). Despite impor- tant findings on cells proliferation and communication, the pathophysiological cellular pathways and complex molecular mechanisms remain to be investigated. For now and on the basis of current data and recent publications, it can be concluded that the conditions of microgravity are affecting and impairing the communication between cells Figure 8: During Extra Vehicular Activities of the immune system and can results in the alteration of (EVAs), astronauts are subject to many environ- intracellular signalling pathways. “Gravi-sensitive“ signal mental stressors (Credit: NASA) transduction elements were found in several different cell compartments. These were found on the cell surface (such as the IL-2 and the interleukin-2 receptor which is critical in the regulation of the T-cell proliferation and differentia- tion), in the cytoplasma (e.g. protein kinase C enzyme fam- ily controlling function of other intracellular proteins) and in the nucleus (e.g. genes regulating cellular processes of the cells´ proliferation and differentiation). However, the key molecular mechanism(s) of how microgravity affects cells´ signalling are still unknown (summarised from Ullrich O., Huber K., Lang K., Cell Commun Signal. 2008; 6: 9.).

4.2.2. Research using animal experiments: from model organisms to mice

Following the general observations on stress responses, as described by Hans Selye more than half a century ago, it was shown in mice flown on a 13-day mission to space that the murine spleen and thymus masses were significantly reduced as well as the number of splenic leukocytes when they were compared to mice that were kept as ground

Immunology 35 controls under similar housing conditions. In addi- tionnaires based emotional stress monitoring, to as- tion, the responses of immune cells when challenged tronauts exposed to space flight. These investigations ex vivo with bacterial peptides were reduced. The in man ranged from very acute gravitational stress same observation was made when these cells were challenges (e.g. during parabolic flight) to short (in the activated through T-cell receptor dependent path- range of one to two weeks) and long (4-7 months) ISS ways. This modulation of distinct immune answers increments. These studies revealed that space flight indicates increased immunosuppresive mechanisms conditions induce a significant modulation of the hu- [Baqai FP, Gridley DS, Slater JM, Luo-Owen X, Stodieck man immune responsiveness. These alterations range LS, Ferguson V, Chapes SK, Pecaut MJ; J Appl Physiol. from an alert state of primed innate immune cell after 2009 Jun;106(6):1935-42.]. Other studies showed that acute gravitational stress to a decrease of phagocytes, T cell distribution, function, as well as gene expres- NK, T-lymphocytes functional activity and also in their sion pattern were also significantly affected when altered capacity to produce important cell signalling more complex organisms, such as mice, are subjected molecules (such as cytokines) after returning from the to the stressful conditions of space flight. space mission.

Along with these observations it is interesting to Moreover, tests using peripheral leukocyte subsets note that space flight induces significant changes in show that the early T cell activation and the intracel- mRNA expression in the thymus, especially in genes lular or secreted cytokine pattern indicate a Th1

36 Immunology 4.3. Immunology – Key Issues

4.3.1. List of key issues 4.3.2. Knowledge gaps and research needs

The Expert Group identified eight key issues as im- • In the light of future manned spaceflight for ex- portant aspects to be considered in the future: ploration, extension of the ISS Increments for (some) ISS astronauts/cosmonauts to one year or • Identification and quantification of stress factors longer has been considered by all EG members and their impact on the immune system of very high importance (and was confirmed by • Are immune system development, response and the majority of investigators participating to the regulation as efficient in space (ISS/Moon/Mars) online consultation to be of high or very high im- as on Earth? portance) to answer immune related questions • Consequences of long-duration (≥1 year) mis- for future, extended space missions to the Moon sions on the degree of immune-suppression and Mars. • Consequences of “chronic” immune changes on • The methodological needs to achieve this goal disease during and after long-duration missions include the development of in-flight hardware to • Effects of Lunar or Mars dusts, habitat environ- perform easy-to-handle assays and minimal/non- ment & other chemicals on immune perform- invasive exams to monitor immune and haemo- ance static changes. This was considered to be of very • Are the observed stress-dependent virus reacti- high importance by the EG as well as by 90% of vation patterns linked to cancer development? the consulted specialists. • Interaction between the immune system and • To achieve a higher relevance of the data gath- other stress-sensitive systems (neuro-physiolog- ered, especially for critical investigations, a need ical and others) of i) redundant repeating (at least twice) of in- • Definition and testing of (immune targeted) flight experiments and ii) some standardisation countermeasures of experiment design, methods, assays etc. is re- quested. Both points were considered of high or In order to understand and track the footprint of very high importance by >90% of the scientists space exploration on the human immune system and that were consulted. its interactions with other organ entities, it appears • Before going to space, test and control experi- crucial that these key issues are addressed through ments should be performed using the full scale an appropriate technical and structural framework. In of Earth-bound models that can adequately sim- this context, three interlinked approaches are highly ulate specific spaceflight conditions. 50% of the recommended: respondents considered this point as very highly relevant and 40% as highly relevant. • Pathophysiological cellular pathways and com- • For space and Earth, the establishment of a bank plex molecular mechanisms need to be consid- of tissue and plasma samples available to the sci- ered using isolated cell systems. entific community was defined by the majority of • Implementation of animal experiments (e.g. mice) EG members and external experts (>90%) to be would produce further data, allowing investiga- very important to extract maximal information tions on the complex systemic compromise of as well as to re-analyse samples when new tools the immune system after exposure to multiple become available. stressors during space flight • Taking advantage of health data files from ISS • Finally, investigations in man have to be per- crewmembers, with retrospective and prospec- formed in a coordinated way to better approach tive access, is necessary in order to estimate the consequences of multi-factorial effects of clinically relevant changes of health in regard to physical stressors and emotional stress induced immune alterations (crew data would be anony- by space flight. mous). E.g. stress-dependent virus reactivation

Immunology 37 patterns linked to cancer development and conse- quences of “chronic” immune changes during and af- ter long-duration space missions on disease develop- ment.

4.3.3. Proposed investigations and recommendations

• The immune system is a target and a sensor of change in the environmental conditions (“stressors”) affecting the human system as a whole. Therefore, only inter- disciplinary approaches can help to understand (im- mune-) homeostasis and how immune functions are affected through other organ systems, under the con- ditions of acute or chronic stress in space and on Earth, respectively. • Multidisciplinary approaches should include the full- scale use of available methods from in-vitro to ex- perimental in-vivo (rodents or other animal models, knock-out models also in space) conditions, as well as clinical and space related earth-bound studies (also for countermeasure development). This will further

Figure 9: ESA’s Programme aims to pre- enhance the understanding and interaction of the im- pare Europe to play a key role in the future hu- mune system response and regulation with other or- man exploration of the solar system. Using the gan systems at the cellular and molecular level. ISS as a test bed/analogue for a Martian mission • There is a need to standardise methodologies used for has been proposed as a necessary research plat- immune research as well as the consideration to do re- form for many domains. (Credits: ESA - P. Carril) dundant experiments. • The establishment of an international biological sam- ple archive (from space crew members) is recom- mended. • Provision of access to anonymous health data from crew members, retrospectively and prospectively, is recommended. • There is a need to diagnose immune changes in minute amounts of blood through new non-invasively technologies, a benefit for both space and Earth.

4.3.4. Cross-disciplinary aspects

The immune system is one of the largest and most wide- spread “organs” with hormonal and neuronal control. More- over, antigenic patterns as well as metabolic factors define immune answers and regulate immunity, respectively.

This understanding shows that the immune system is strongly linked with almost every organ homeostasis and can be affected together with other systems upon stress challenges (e.g.: Stress-> stress hormones which can mod- ulate both immune responses as well as e.g. catabolic,

38 Immunology stress permissive bone turnover). Moreover, immune • Habitat environment and design (e.g. oxygen responses are susceptible to exercise and nutritionals level, changes of psychic stress in respective factors as well as environmental factors like radiation, more comfortable habitat) and the microbial load and the oxygen tension in the • Health: prevention, diagnosis and therapy habitat. • Radiation (immune dysfunction)

Therefore, there are manifold, non-selective interac- The immune system can also be affected directly or tions with other fields and topics: indirectly by countermeasures:

• Bone, muscle, kidney • Direct affect countermeasures: e.g. vaccination • Neurophysiology, cognitive performance (boost), pharmacological approaches • Nutrition • Indirect affect countermeasures: Nutrition, exer- • Exercise, cardiovascular & lung cise, psychosocial procedures etc.

4.4. Conclusion Appropriate functioning of the immune system is a In conclusion, the Expert Group “Immunology” rec- critical factor to maintain crew health. Therefore, it is ommends acknowledgement of the abovementioned crucial to understand the biology of immune modu- key recommendations and also, in the light of extend- lation under stress conditions in order to re-estab- ed human exploration mission, to take more advan- lish immune homeostasis under such conditions. To tage of the ISS by increasing the increment duration achieve this goal, maximum exploitation of currently for two to three ISS crew members to 12 months or available resources on Earth and in space, as well as longer and investigate immune changes under these respective databases, is mandatory. This also applies conditions. to testing under conditions in space which are similar to a manned exploration space mission to Mars.

Immunology 39 4.5. References (other than included in the text)

Bascove M, Huin-Schohn C, Guéguinou N, Tschirhart E, Frippiat JP. Spaceflight-associated changes in immu- noglobulin VH gene expression in the amphibian Pleurodeles waltl. FASEB J. 2009 May;23(5):1607-15.

Boonyaratanakornkit JB, Cogoli A, Li CF, Schopper T, Pippia P, Galleri G, et al. Key gravity-sensitive signaling pathways drive T cell activation. Faseb J 2005;19(14):2020-2.

Boxio R, Dournon C, Frippiat JP. Effects of a long-term spaceflight on immunoglobulin heavy chains of the urodele amphibian Pleurodeles waltl. J Appl Physiol. 2005 Mar;98(3):905-10

Choukèr A (Ed.), Stress Challenges and Immunity in Space. Springer 2011 (in press)

Choukèr A, Thiel M, Lukashev D, Ward JM, Kaufmann I, Apasov S, Sitkovsky MV, Ohta A. Critical role of hypoxia and A2A adenosine receptors in liver tissue-protecting physiological anti-inflammatory pathway. J Mol Med. 2008 Mar-Apr;14(3-4):116-23.

Crucian B, Sams C. Immune system dysregulation during spaceflight: clinical risk for exploration-class missions. J Leukoc Biol 2009;86(5):1017-8.

de Quervain DJ, Aerni A, Schelling G, Roozendaal B. Glucocorticoids and the regulation of memory in health and disease. Front Neuroendocrinol. 2009 Aug; 30(3):358-70.

Gueguinou N, Huin-Schohn C, Bascove M, Bueb JL, Tschirhart E, Legrand-Frossi C, Frippiat JP. Could spaceflight- associated immune system weakening preclude the expansion of human presence beyond Earth’s orbit? J Leu- koc Biol 2009;86(5):1027-38

Gridley DS, Slater JM, Luo-Owen X, Rizvi A, Chapes SK, Stodieck LS, et al. Spaceflight effects on T lymphocyte distribution, function and gene expression. J Appl Physiol 2009;106(1):194-202.

Kaufmann I, Feuerecker M, Salam A, Schelling G, Thiel M, Choukèr A. Adenosine A2A receptor modulates the oxidative stress response of primed polymorphonuclear leukocytes after parabolic flight. Hum Immunol 2011 (in press).

Meehan RT, Neale LS, Kraus ET, Stuart CA, Smith ML, Cintron NM, et al. Alteration in human mononuclear leuco- cytes following space flight. Immunology 1992;76(3):491-7.

Pierson DL, Stowe RP, Phillips TM, Lugg DJ, Mehta SK. Epstein-Barr virus shedding by astronauts during space flight. Brain Behav Immun 2005;19(3):235-42.

Roozendaal B, McEwen BS, Chattarji S. Stress, memory and the amygdala. Nat Rev Neurosci. 2009 Jun;10(6):423- 33

Thiel M, Choukèr A, Ohta A, Jackson E, Caldwell C, Smith P, Lukashev D, Bittmann I, Sitkovsky MV. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung in- jury. PLoS Biol. 2005 Jun;3(6)

Sonnenfeld G, Foster M, Morton D, Bailliard F, Fowler NA, Hakenewerth AM, et al. Spaceflight and development of immune responses. J Appl Physiol 1998;85(4):1429-33.

40 Immunology 5 Neurophysiology

5.1. Relevance of Research on Neurophysiology

Neurological responses to the spaceflight environment challenge the performance of crewmembers at critical times during spaceflight missions. Operational perform- ance may be impaired by spatial disorientation, perceptual illusions, disequilibrium, motion sickness, and altered sen- sorimotor control, all of which are triggered by g-transitions and persist for some time after the neurological systems adapt to the new gravitational (or gravito-inertial) loading. These neurological changes may have adverse effects on crew cognition, spatial orientation, control of vehicles and other complex systems, and dexterous manipulation skills. While crewmembers eventually adapt to new gravitational environments (e.g., microgravity), subsequent transitions back to the old environment (e.g., 1-g) or to a new environ- ment (e.g., 1/6-g on the Moon or 3/8-g on Mars) will cause a new disruptions to these systems, impairing perform- ance until readaptation (or new adaptation) has occurred. Following such transitions, crewmembers may be un- able to accomplish certain entry, landing, and post-flight physical activities, including spatial cognition, vehicle control, maintaining balance and locomotion, and dexter- ous manipulation. Current methods of pre-flight training and post-flight rehabilitation have not been optimised to Figure 10: The spacecraft landing (Cred- minimise the functional impacts of these natural adaptive it: NASA) responses during g-transitions or to restore environment- appropriate sensorimotor functions after g-transitions.

While humans have sensory organs that specifically de- tect changes in the and forces acting on our bodies, there are no specific gravity receptors. Instead, the direction and strength of the gravity (or gravito-inertial) vector are deduced from the central integration of infor- mation from many types of sensory receptors distributed throughout our bodies, including visual, proprioceptive, haptic, and vestibular receptors. Nevertheless, the mor- phology and physiology of motor systems have evolved such that the repertoire of movement paradigms enabled survival by accommodating the physical properties of the environment, including gravity. This has resulted in many highly integrated motor control mechanisms that are clearly designed to function in a 1-g environment. One means of understanding how these control mechanisms function is to investigate their routine accommodations

Neurophysiology 41 of daily function when the gravitational environment recognised and better understood. Therefore, critical has changed. questions should be investigated regarding the func- tioning of gravity-sensing receptors, motor systems, Changes in sensorimotor functions resulting from spatial orientation and cognition in both normal and changes in gravitational loading also appear to play altered gravity. An integrative approach should be a role in muscle atrophy, cardiovascular decondition- employed to address these questions. Also, the effects ing, and cognitive deficits, such as poor concentra- of space radiation on the central nervous system need tion, short-term memory loss, and alteration in spatial to be better understood, as the potential for damage representations, known to occur during spaceflight. to neural structures controlling critical life functions Changes in sensorimotor functions are probably not and/or adaptive responses is unknown, and methods the only factors influencing these other flight-asso- for detecting and protecting or repairing such dam- ciated changes, but their contributions should be age are poorly understood.

5.2. Neurophysiology – Key Issues

Five key issues have been identified as space neu- Earth benefits and applications rophysiology research priorities over the next 10-15 years. Each of these important topics is briefly intro- Spatial disorientation and situational awareness is- duced and motivated. Then, relevance for exploration, sues are responsible for up to a quarter of all civil avia- earth benefits, proposed investigations, and trans- tion accidents. Diminished manual flying skills during disciplinary aspects are described. Cross-disciplinary visual flight rules piloting is an increasing problem, elements and potential Earth applications share dif- especially for search and rescue helicopter pilots re- ferent key issues and span over other Expert Groups. quired to fly with diminished visual cues. Physical aids (e.g., tactile situational awareness system) and coun- 5.2.1. Key issue 1: Impacts of spaceflight on the termeasures developed to aid space travellers might senses also be useful for commercial and military aviation.

Changes in gravity have been shown to alter the As graviception plays a critical role in spatial orienta- structure and/or performance of various sensory sys- tion as well as control of balance, locomo- tems (e.g. vestibular, proprioceptive, tactile, olfactory, tion, and dexterous manipulation (see next key issue), baroreceptors, etc.) as well as basic asso- space neurophysiology research will better define ciated with these systems (e.g. graviception, spatial the mechanisms underlying the fundamental role of orientation, self-motion, etc.). However, details and gravity in motor control. It should also help to better mechanisms of these changes during and after g- understand the interplay between nervous system transitions have not yet been clearly elucidated. function and functioning of the cardiovascular and muscular systems as well as some of the cognitive as- Relevance for space exploration missions pects of behavioural performance.

• Altered sensory or perceptual functions can lead Knowledge gaps and research needs to performance decrements (see below), spatial disorientation, or altered situational awareness • While the effects of sustained 0-g on some senso- during critical vehicle control operations that may ry and perceptual functions have been well stud- seriously endanger the mission and the crew. ied, little is known about the effects of sustained • Space flight induced changes in sensory and per- hypo-g (0

42 Neurophysiology about the transient effects on these functions fol- • What structural changes occur in neurological lowing shifts from 1-g to hypo-g (and vice versa). systems (e.g., end organs, cerebellum, brain stem, • Furthermore, little is known about what hap- cortex, spinal cord, etc.) when gravity is altered? pens to sensory and perceptual functions during Are there any long-term health or performance g-transitions (e.g., during launch or entry, where consequences associated with these structural gravito-inertial forces can vary over by 2-3 g or changes? more during periods of 10-30 minutes) from any starting g-level to any finishing g-level. Proposed investigations and recommendations • In addition, while Central nervous system (CNS) responses to repeated g-transitions associated • The relationships between g-level and sensa- with repeated space missions (months to years tions/perceptions must be quantified. What are between missions) have shown some tendencies the g-thresholds for different sensations and per- toward dual-adaptation (e.g., response severi- ceptions? ties decrease as number of missions increases), • The time courses associated with adaptive re- the responses to significant g-level changes with sponses of the sensory and perceptual systems shorter recovery times between (e.g., during in- following launch into space (transition from 1-g termittent artificial gravity exposures every few to 0-g) should be quantified. hours to days) are unknown. How much time is • The time courses associated with adaptive re- required for significant adaptive responses to sponses of the sensory and perceptual systems manifest themselves during/after g-transitions, following transition between 0-g and hypo-g (or and what effects are driven by subsequent g- vice versa) should be quantified. transitions during/after this time period? • The time courses associated with adaptive re- • Sustained hypo-g fields cannot be created on sponses of the sensory and perceptual systems Earth, but sustained hyper-g (g>1) fields can be in rapidly changing gravitational environments created easily using rotating habitats. Can transi- should be investigated (e.g. in rooms rotating at tions between hyper-g and 1-g be used as a valid variable rates). experimental model for examining neurophysio- • Alterations in sensory and perceptual systems logical responses to transitions between 1-g and during launch and entry should be examined. hypo-g? • The effects of pharmaceutical countermeasures • What are the potential effects of radiation on (e.g., ) on sensory and perceptual sensory and perceptual functions? Are they pre- systems should be studied in non-terrestrial en- dictable? What countermeasures can be used to vironments. detect and/or minimise these effects? What reha- • Evaluate the effects of Extra Vehicular Activities bilitation protocols can be used to aid recovery (EVAs) on sensory and perceptual functions by from these effects? performing experiments during scheduled EVAs. • Artificial gravity created by rotating all or part of • Investigate the causes and effects of reported in- a space vehicle might prove to be an efficient, ef- flight changes of on visual percep- fective multi-system countermeasure, but the un- tion and performance. usual force environment created by the rotation • Investigate changes in audition, smell, and (i.e., g-gradients, Coriolis forces, and cross-cou- during microgravity. pled angular accelerations) will likely affect sen- • Examine the use of (commercial) suborbital flights sory and perceptual functions. The magnitudes, as a suitable platform for the study of transient re- time courses, reversibility, and consequences of sponses to changing g-levels. these effects are largely unknown. • Test subjects in prolonged hyper-gravity induced • The effects of Extra Vehicular Activities on sensory by aircraft or long-radius . and perceptual functions have not been studied. • Study subjects that have accumulated significant • The effects of pharmaceutical countermeasures parabolic experience (i.e., many parabolas). (e.g., promethazine) on sensory and perceptual • Study effects of radiation on neurological func- functions have not been studied in any non-ter- tion in ground-based accelerator facilities. restrial environment.

Neurophysiology 43 • Place an animal centrifuge in space to study struc- or exercise/sport/athletic activities, etc. tural changes in the nervous system, and effects of sustained hypo-g exposure. Earth benefits and applications • Place a human centrifuge in space to address is- sues regarding operations under g-level transi- The altered gravity environments available during tions, g-gradients, hypo-g, flight simulator train- spaceflight offer platforms to study the basic neuro- ing, and adaptation to altered gravity. physiology of dexterous manipulation (eye hand co- ordination), balance and locomotion, and vehicle con- Trans-disciplinary aspects trol, providing knowledge that serves to help patients with vestibular, neurological, and motor control prob- Strong links have to be emphasised with issues relat- lems as well as the elderly. Knowledge gained from ed to radiation in space (Cluster 3). studying the training and rehabilitation protocols The longer a crew member is exposed to the radiation developed for use with astronauts can be transferred environment of space, the more likely it is that some directly to patients with specific lesions or disorders high energy particle will cause significant damage requiring retraining or rehabilitation. Finally, math- to a critical CNS neuron/structure that could lead to ematical models developed in the context of a space permanent, functionally relevant structural changes. environment could shed light on mechanisms that What are the potential effects of radiation on neu- can’t be observed on Earth (0-g is a model of hypo- rologic functions? Are they predictable? What coun- activity, which is common in elderly populations). termeasures can be used to detect and/or minimise these effects? What rehabilitation protocols can be Knowledge gaps and research needs used to aid recovery from these effects? • The inaccessibility of operational performance 5.2.2. Key issue 2: Impacts of spaceflight on data by the scientific community complicates the sensorimotor performance study of the relationships between physiologi- cal changes and operational performance dec- Changes in gravity have been shown to alter senso- rements (e.g., piloting performance, emergency rimotor control (e.g., goal-directed eye, hand, head, egress, manual control, etc.). limb, or body movements, eye-head coordination, • No experiments have been performed during Ex- dexterous manipulation, postural control, and loco- tra Vehicular Activities (see Issue 1, above). motive control). However, details and mechanisms of • Three-dimensional changes in eye movements these changes during and after g transitions have not have not been tested during spaceflight (e.g., the yet been clearly elucidated, nor have their functional/ targets for smooth pursuit and move- operational significance. ments have only been tested using a fronto-par- allel screen), and therefore, control of vergence Relevance for space exploration missions movements, in particular, are poorly understood. • What ranges of radius and angular velocity are Altered sensorimotor control performance during required for intermittent artificial gravity to critical mission activities may seriously endanger benefit the sensorimotor systems, as well as the mission objectives, mission equipment, or the crew. heart, bone, muscle, and cardiovascular systems? Furthermore, altered sensorimotor control perform- Are supplemental (concurrent) exercise coun- ance during typical activities of daily living after re- termeasures required to optimise this putative turn from space missions may seriously endanger countermeasure? crew, their friends, or their families. These activities • What ranges of radius and angular velocity are include: controlling space vehicles (e.g., launch, en- required for continuous artificial gravity (rotat- try, landing, rendezvous, docking, etc.), ground-based ing vehicle) to appropriately stimulate the load/ vehicles (e.g., rovers, automobiles, watercraft, aircraft, acceleration receptors while minimising the Co- etc.), or remote manipulators (e.g., robotic arms), per- riolis forces and cross-coupled angular velocity forming Extra Vehicular Activities, emergency egress, side effects?

44 Neurophysiology Few mathematical models exist to describe sensory 5.2.3. Key issue 3: Impacts of neurophysiological motor adaptive responses, especially to altered grav- changes on spaceflight-induced decrements in ity. neuro-behavioural performance.

Proposed investigations and recommendations Changes in gravity have been observed to decrease work capacity, vigilance, cognition, motivation, and • Protocols should be established for disclosure other aspects of neuro-behavioural performance. of operational performance data to qualified re- However, details and mechanisms of these changes, searchers. Developing closer partnerships among especially the role that altered senses and percep- the scientific, operations, and training communi- tions might play during and after g transitions, have ties might be the best way to achieve this. not yet been clearly elucidated. • As most of the issues associated with altered sensory or perceptual functions could lead to Relevance for space exploration missions decreased sensorimotor performance, all of the recommendations under Issue 1 also apply to • The consequences of altered work capacity, vigi- this Issue. lance, cognition, and motivation during space- • Measure three-dimensional con- flight could range from decreased crew efficiency trol performance during space flight. to loss of mission and crew. • Perform ground-based and in-flight artificial grav- • Current countermeasures against motion sick- ity experiments to determine the optimal radii ness during and after flight present unacceptable and angular velocities to promote multi-system risks to crewmembers and may be inappropriate (including vestibular-sensorimotor) protection for exploration missions. from space flight adaptation issues. • Install a flight-simulator in space (centrifuge Earth benefits and applications based, if possible) to correlate landing perform- ance with in flight training. New information from spaceflight studies on the fun- • Develop mathematical models with an explicit damental mechanisms of spatial orientation percep- dependence on gravity to simulate sensorimotor tion of slopes, depths, and heights may aid architects responses to changed gravity. in optimising the design of habitats and affordances for the elderly or for those with neurological deficits. Trans-disciplinary aspects Knowledge gaps and research needs Overarching aspects with links to many scientific dis- ciplines are clearly evident. The inaccessibility of oper- • The incidence and severity of mission-related op- ational performance data to the scientific community erational performance decrements are unknown, complicates the study of relationships between physi- except in a few publicly observed examples. The ological changes and performance decrements (e.g., inaccessibility of operational performance data by piloting performance, emergency egress, manual the scientific community complicates the study control, etc.) during critical mission phases. Protocols of the relationships between neurophysiological should be established for disclosure of operational changes and neuro-behavioural decrements. performance data to qualified researchers. Develop- • Mechanisms of decreased or off-nominal per- ing closer partnerships among the scientific, opera- formance during mission critical operational tions, and training communities might be the best tasks (e.g. vehicle control) are unknown. While way to achieve this. Furthermore, setting up a shared links between vestibular dysfunction and cogni- database and recording past experimental data sets tive deficits have been established on Earth, no and information on their contexts could be very valu- such links have been sought in space research. able to enhance the usability of previous data (e.g. • The effects of ground-based and in-flight train- challenge the low-N problem in space research). ing regimens on neuro-behavioural decrements have not been well studied.

Neurophysiology 45 • Effective motion sickness countermeasures hav- Motivation and vigilance ing minimal effects on neuro-behavioural or sen- sorimotor function are currently unknown. • How do changes in gravitational stimulation of vestibular receptors and/or symptoms of motion Proposed investigations and recommendations sickness affect crew motivation and vigilance? What training methods or medications could be • Protocols should be established for disclosure of used to reduce these effects? neuro-behavioural performance data to quali- • How do medications used to relieve symptoms of fied researchers. This might be best achieved by motion sickness affect motivation and vigilance? developing closer partnerships and integration What alternative medications could be used to of the scientific, medical, and behavioural com- reduce these effects? munities. • Studies should be performed to elucidate the Sleep and circadian rhythms time course and severity of spaceflight-induced cognitive deficits (e.g., Sopite syndrome (drowsi- There is a growing body of evidence suggesting that ness), space fog, aka “mental ” or “space chronic sleep loss, which has been reported to oc- stupids”), focusing on the role of neurophysiolog- cur commonly during spaceflight, is associated with ical changes. neurodegenerative, endocrinological, immunologic, • The effects of ground-based and in-flight train- affective, and cognitive/memory, and motor perform- ing regimens on neuro-behavioural decrements ance deficits. The mechanisms of in-flight sleep loss should be studied. are not well understood. Many factors may play a role, • Effective motion sickness countermeasures hav- including light conditions, psychological issues, and ing minimal effects on neuro-behavioural or sen- vestibular stimulation by gravito-inertial forces. What sorimotor function should be sought. is the relative importance of these factors? How do changes in gravitational stimulation of vestibular re- Trans-disciplinary aspects ceptors affect ? What training meth- ods or medications could be used to minimise these Links are clearly evident with psychology, human-ma- effects? chine systems, and health care. In addition, 5 trans- disciplinary aspects need to be highlighted: Spatial, geographic, and situational awareness

Cognitive function How does loss of the fundamental spatial orientation reference provided by gravity affect spatial process- • How do changes in gravitational stimulation of ing? What affects does this have on spatial, geograph- vestibular receptors affect cognitive function? ic, and/or situational awareness? What training meth- What training methods can be used to reduce ods or physical aids could be used to minimise these these effects? effects? • How do medications used to relieve symptoms of motion sickness affect cognitive function? What Performance alternative medications could be used to reduce these effects? How do changes in sensorimotor control associated • Cognitive function comprises several tasks such with altered gravito-inertial force fields affect crew as attending, selecting, decision making, recog- performance of operational tasks? What training nising, imitating and remembering that involve methods, physical aids, medications, or countermeas- different parts of the brain. To fully assess the ef- ures could be used to minimise these effects? fects of spaceflight on cognitive function and to How do changes in cognition, motivation, vigilance, better characterise the transient spaceflight phe- or spatial processing further complicate perform- nomenon sometimes referred to as the “space ance? What training methods, physical aids, medica- stupids,” each of these cognitive function tasks tions, or countermeasures could be used to minimise needs to be assessed individually with specific these effects? tests.

46 Neurophysiology Previous work has suggested that similar neural sub- • The effects of pre-habilitation (pre-flight training) strates are involved in movement execution, obser- or other countermeasures on performance dur- vation, and motor imagery, and that the same laws ing these phases have not been evaluated. of movement control apply to these processes. How could non-invasive mental imagination and/or ob- Proposed investigations and recommendations servation be used to aid crewmembers in efficiently learning and achieving specific physical tasks in al- • Protocols should be established for disclosure of tered gravity? operational and neuro-behavioural performance data to qualified researchers. This might be best 5.2.4. Key issue 4: Countermeasure strategies to achieved by developing closer partnerships and minimise the risks associated with neurophysi- integration of the scientific, medical, and behav- ological changes during and after G-transitions. ioural communities. • Studies of crew neurophysiological responses Relevance for space exploration missions and performance should be conducted during and immediately after launch/insertion and en- Crewmembers are called upon to perform some of try/landing. the riskiest tasks associated with spaceflight missions • The effectiveness of operational training proto- during and after g transitions, which also happen to cols and recency should be studied. be the times of greatest environmental effects on the • Pre-habilitation or other countermeasures ap- neurological system during a mission. As noted above proaches designed specifically for these phases in Issues 1-3, altered sensations and perceptions, sen- should be studied. sorimotor performance, or cognition during these critical mission phases could seriously endanger the Trans-disciplinary aspects mission and the crew. Links with integrated physiology (especially musculo- Earth benefits and applications skeletal system and cardiovascular, lungs and kidney) are highlighted in addition to: The adaptation and training processes used by astro- nauts to cope successfully with the environmental Loss of motor tone changes associated with g-transitions during long- duration spaceflight missions may provide insight How do changes in gravitational stimulation of ves- into rehabilitation in patients with specific CNS im- tibular and/or peripheral load receptors affect tonic pairments and vice versa. spinal-motor activation of anti-gravity muscles? What role does this play in muscle atrophy and/or (indirect- Knowledge gaps and research needs ly) bone loss? What role does it play in post-flight or- thostatic function? What countermeasures should be • The inaccessibility of operational performance used to minimise these effects? data to the scientific community complicates the study of the relationships between physiological Vestibular control of cardiovascular regulation changes and performance decrements (e.g., pi- loting performance, emergency egress, manual What role do vestibular afferents play in the autonom- control, etc.) during these critical mission phases. ic regulation of myocardial contractility, vascular tone, • Only limited research data has been collected dur- plasma volume, and other aspects of cardiovascular ing g-transitions to and from space platforms. regulation? How do changes in gravitational stimu- • The effectiveness of operational crew training lation of vestibular receptors affect cardiovascular paradigms and training recency on crew per- regulation? What countermeasures should be used to formance during these phases has not been sys- minimise these effects? tematically evaluated.

Neurophysiology 47 5.2.5. Key issue 5: Understand the role of gravity in being born and developing without gravity, allowing the development of the nervous system the fundamental study of the influence of gravity on development. What is the influence of gravity (or its Relevance for space exploration missions apparent absence) on development? For example, is there a critical period for development of anti-grav- Gravity is a fundamental environmental force that has itational reflexes, similar to the critical period for de- shaped the evolution of species on Earth. The role of velopment of vision? Are there synaptic or structural gravity in nervous system development is poorly un- changes in an organism after being in space for long derstood though because it is not possible to remove periods of time? this omnipresent stimulus for more than brief periods on Earth. Spaceflight offers unique opportunities to Knowledge gaps and research needs study neurological development in the absence of gravity, which could provide important insights to The role of gravity in nervous system development terrestrial developmental neurobiologists. In the fu- should be further investigated. ture, exploration missions will possibly require very long transit times and an inhabitation period on the Proposed investigations and recommendations extraterrestrial body requiring multiple serial genera- tions of space travellers. While developmental neuro- • Study the neurobiological development of gen- biology is rather a fundamental field of research, this erations of small animal species born and raised endeavour will require deep understanding of the in the microgravity environment. effects of human gestation and development in non- • Place an animal centrifuge in space to study the terrestrial gravitational environments.. neurobiological development of generations of small animal species born and raised in the hypo- Earth benefits and applications gravity environments.

Space provides a unique platform to observe consecu- tive generations of animals (and eventually humans),

5.3. Conclusion

The human nervous system has evolved to respond to skills into novel environments. However, only space gravitational cues. On Earth, the presence of gravity- flight studies can examine the nervous system re- mediated inputs from an ensemble of somatic recep- sponses to reduced gravity. Thus, we conclude that a tors sensitive to force and acceleration generate a series of basic and operational scientific experiments gravitational reference frame from which spatial ori- into the neurophysiological responses to space flight entation is deduced and movements can be planned are required to enable the next steps in human explo- and executed. Changes in this fundamental refer- ration of space. ence signal caused by spaceflight or other sustained gravito-inertial force fields cause transient disruptions in performance until the central integration func- tions can adapt to the altered reference stimuli. Crew health, safety, performance, and, eventually, mission success, can only be assured after effective counter- measures are developed to optimise the adaptation to new gravito-inertial environments. However, such countermeasures cannot be developed without un- derstanding the fundamental mechanisms underly- ing the adaptive processes involved. Many ground- based studies address learning and transfer of motor

48 Neurophysiology 5.4. References

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Neurophysiology 53 6 Nutrition and Metabolism

6.1. Relevance of Research on Nutrition and Metabolism 6.1.1. Relevance for space exploration missions

Nutrition plays several key roles during space flights, from the basic nutritive intake to maintain the organism in good health to the beneficial psychosocial aspects related to meals. Because nutrition is the source of energy, the pre- cursors for synthesising the functional body units (cells and their core constituents, the macromolecules proteins, DNA, RNA, cells, etc.), and the numerous co-factors, such as mi- cronutrients, to support enzyme activity and detoxification/ repair mechanisms, nutrition is central to the functioning of the body. Conversely, poor nutrition can compromise many of the physiological systems, and also mood and perform- ance.

On the other hand, nutrition is also likely to play a key role in counteracting the negative effects of space flight (e.g., ra- Figure 11: Fresh fruit is a special treat on the diation, immune deficits, oxidative stress, bone and muscle ISS (Credit: ESA/NASA) loss). As mission duration increases, any dietary/nutritional deficiencies will become progressively more important. It is therefore critical that astronauts are adequately nourished (quantitatively and qualitatively) during missions. It is also important to note that problems of nutritional origin are of- ten treatable by simply providing the appropriate nutrients.

Of particular concern for long-duration missions is the ina- bility to maintain energy balance (1-4). Energy requirements during space flight are similar to those on the ground (1; 5), yet astronauts often consume less food than needed to cov- er their energy expenditure (1-3), inducing negative energy balance and body mass loss. While such energy deficits are physiologically tolerable for short-term missions because of the availability of body fat stores, a chronic negative en- ergy balance becomes a significant detrimental issue jeop- ardising health and performance for long-term missions (2). The causes of energy imbalance are, however not fully understood. A pre-requisite to advising astronauts on how to maintain energy balance is to know what the energy re- quirements are. It is also important to include the additional energy costs of any exercise counter-measures used when determining astronaut energy needs, especially in the light of recent data suggesting that microgravity itself removes one of the central components involved in energy balance regulation (Audrey 2010).

54 Nutrition and Metabolism Required energy, macronutrients, micronutrients and mood and behaviour and psychosocial cohesion be- vitamins need to be evaluated for long-term missions, tween the crewmembers. and nutrition countermeasures need to be tested. 6.1. Relevance of Research on This is especially important for micronutrient metabo- 6.1.2. Earth benefits and applications Nutrition and Metabolism lisms that receive very little attention in the context of space flight. The nutritional questions related to bioastronautics research are very relevant to multiple ground-based Bed rest is an appropriate ground-based model for related health issues. The potential spin-offs are both most systems and particularly for nutrition related interesting from technical point of view and are of matters. For a Mars mission, there are technological great clinical importance. Such spinoffs encompass challenges of providing a variety of palatable and the increasing burden of modern chronic diseases, nutritious foods, and ideally, some fresh foods. This in which the adoption of sedentary behaviour plays is important not only for the obvious nutritive role a central role (i.e. the metabolic syndrome, insulin of maintaining crew health, but also for the psycho- resistance, dyslipidemia, type 2 diabetes mellitus, logical aspects. Nutritional shortcomings can affect atherosclerosis, etc.).

6.2. Nutrition and Metabolism - Key Issues

Within the nutrition Expert Group, 6 key issues related ing nutritional status in space. This would be of tre- to exploration have been identified as space research mendous interest to multiple groups on the ground, priorities in nutrition field. Each of these topics is including the military, physicians working with obese briefly introduced. Then, relevance to space explora- patients, and hospital doctors dealing with patients tion, Earth benefits, knowledge gaps, proposed inves- who are for one reason or another unable to eat nor- tigations, and trans-disciplinary aspects are described. mally. Malnutrition amongst hospitalised patients Cross-disciplinary elements and potential Earth appli- remains a critical problem today. It contributes to cations share different key issues and span over other increased morbidity, mortality, increased time in the Expert Groups. hospital, and hence, the overall cost of health care.

6.2.1. Key issue 1: In-flight negative energy balance Brief review of latest developments

As stated above, a negative energy balance is a fre- A new generation of accelerometer-like devices has quent finding during spaceflight. been developed for studies on Earth that are capa- ble of defining the energy-time budget of humans Relevance for space exploration missions and wild animals. These devices, coupled with other methods and instruments (i.e. cardiofrequencemetry, • If sustained over the duration of spaceflights fore- heat flow gauge, etc.) for measuring physical activity seen for planetary exploration, the negative en- pattern and energy expenditure, may give an accu- ergy balance will likely jeopardise the survival of rate estimation of total energy expenditure in free- the crew members and the mission. living conditions. The recently developed bioimped- • A chronic negative energy balance will affect ance spectroscopy systems accurately measure and health performance (muscle, cardio-vascular determine changes in body composition and thus function), mood and behaviour, which will en- energy balance changes over time. These instruments danger the mission and the crew. are likely to provide critical information on the astro- naut’s energy budget during missions of varying du- Earth benefits and applications ration in relation to the different intensities of exercise prescribed as countermeasures. They need, however, Managing energy balance for an astronaut requires robust calibration on the ground prior to use during the development of an accurate system for monitor- flight.

Nutrition and Metabolism 55 6

Knowledge gaps and research needs capacity of muscle more efficiently than equiva- lent supplementation divided over the day. This • The lack of an accurate method to assess in real should be tested as a potential countermeasure. time the changes in energy balance precludes the monitoring of the nutritional status of the in- Trans-disciplinary aspects dividual astronauts. Energy balance status needs to be assessed every other week in other to apply Because energy allocation is a central necessity for efficient counteractive protocols. any physiological function, overarching aspects link • The system should not be confounded by chang- energy balance regulation to all scientific disciplines. es in body composition (e.g. fluid shifts, elec- trolyte changes) or by physical activity patterns On the ground, consequences associated with long- (duration and intensity) or in the rate of energy term energy imbalance include alterations in mood, expenditure and should not be disturbed by mi- performances (6; 7), stress regulation, bone and mus- crogravity environment. cle mass (2; 6-8), cardiovascular function and immu- • The instruments should allow a non-invasive nology (9-12). Some of these consequences also give measurement of energy status and be cost-effec- strong insights regarding the implication of energy tive. alterations in several well-described adaptations to space flights. For example, Muslim army pilots un- Proposed investigations and recommendations dergoing the 1-month partial fast of Ramadan lost weight in a comparable amount to astronauts and • To validate protocols testing different method- show deterioration in their cardiovascular capacity ologies to detect early changes in energy status. that closely mimic what is described as the space- • The validation of these methodologies, which related cardiovascular deconditioning syndrome. include bioimpedance spectroscopy and the Similarly, data collected from both bed rest and space latest generation of 3-axial accelerometry and flights demonstrate that a state of negative energy heart rate, should be held against a gold stand- balance negatively impact the spaceflight-induced ard method such as the doubly labelled water muscle atrophy. method. This is needed in flight to assess the instruments precision and accuracy in detecting Lastly, the development of exercise countermeasure changes in body composition and total energy protocols should be clearly revised in close associa- expenditure. tion with nutritionists. A common goal should be that • The validation of these instruments in-flight is nutritional guidelines and energy prescriptions work clearly a crucial prerequisite to planetary explora- together to maintain a stable energy balance over the tion. period of the space mission (2; 13). • To counteract negative energy balance, food sciences-derived and/or psychological strategies 6.2.2. Key issue 2: Feeding behaviour should be developed to stimulate astronaut’s ap- petite. Part of the problem linked to the negative energy • The consumption of high-energy drinks, classi- balance is a deregulation of eating behaviour during cally used in sports medicine, should be tested as spaceflight. It was consistently shown that astronauts a countermeasure. eat on average 30% less than pre-flight consump- • Some studies have demonstrated the beneficial tion (2). As eating behaviour is a complex, regulated effects of amino acid supplements on muscle process involving energy expenditure itself, gut en- anabolism, however, those results have recently docrinology and enteral nervous systems, adipose been challenged. Further studies need to be per- tissue and numerous other protagonists known and formed to come to conclusions on that important likely unknown, the expert group considered it as a question. A parallel approach that requires atten- self-standing key issue. tion is the use of the chrononutrition. Chrononu- trition has been shown to increase the anabolic

56 Nutrition and Metabolism Relevance for space exploration missions

Understanding the factors that affect feeding behaviour during in a microgravity environment would help manage the energy balance and the maintenance of the general health of the crew members. It is likely that mood and so- cial interactions will also be positively impacted by such control.

Earth benefits and applications

The benefits on Earth are the same than those explained previously for key issue 1.

Brief review of latest developments

Much still remains unknown regarding the regulation of food intake on Earth by humans and animals, and it is a direct factor involved in several pathologies (obesity, ano- rexia, type 2 diabetes mellitus). However, several biomark- ers for satiety and satiation are now available. Combining those with imaging techniques on Earth could provide critical information on how the above mentioned environ- mental factors, independently or combined, affect food intake regulation.

Figure 12: Astronauts sharing a meal on the Knowledge gaps and research needs ISS (Credit: ESA/NASA)

• What elements of the space environment (hypobaric/ hypoxia situations, hypercapnia, stressful situations, motion sickness) affect the regulation of food intake? • What is the impact of exercise countermeasure on feeding behaviour? Is the impact level related to the exercise training protocol (intensity, duration, volume, type of exercise, etc.)? • The interaction between exercises of different inten- sities, hypobaric/hypoxia situations, and hypercapnia environment has to be tightly investigated on feeding behaviour and appetite regulation of astronauts.

Proposed investigations and recommendations

• Investigations on the impact of the different elements of the space environment, independently and com- bined, on feeding behaviour is recommended. • Several facilities exist that could allow experiments to separate out the influence of different environmental factors observed in space on feeding behaviour regu- lation. These include the Concordia station, the ISS

Nutrition and Metabolism 57 itself, and submarines. There is clearly a dearth of debate on the actual causes and subsequent devel- inflight and ground-based data on this topic. opment of metabolic stress. • On the other side of the problem, an improve- ment in palatability of the items proposed by the Knowledge gaps and research needs industries need to be given more at- tention. • In the context of spaceflight, an unresolved issue is the functional consequence of insulin resist- Trans-disciplinary aspects ance. • The interaction between the different protago- Feeding behaviour regulation is one of the two big nists involved in the metabolic stress i.e. insulin components of the energy balance equation (key is- resistance, low grade inflammation, shift in the sue 1), and therefore it shares the same trans-discipli- fuel mix oxidised and oxidative stress has to be nary aspects. It is also related to the problem of habi- determined. tat management since the food industry will have to take into account the impact of food and meals on Proposed investigations and recommendations feeding behaviour. • Fundamental research has to be conducted dur- Because food plays a strong psychosocial role and ing bed rest studies and basic clinical science pro- can help to enhance the cohesion between the crew tocols. members, nutrition and feeding behaviour will have • Overall, more data on the metabolic responses to to be taken in account by the psychological issues re- (long-duration) space flight is needed so it can be lated to space flights as well. integrated with ground-based spaceflight ana- logue studies. 6.2.3. Key issue 3: Metabolic stress • Ground-based studies have shown that in some cases, metabolic stress can be alleviated with ma- Relevance for space exploration missions cronutrients and micronutrients supplementa- tion. Further work is required here, especially to The metabolic stress (high cortisol, hyperinsulinemia, understand the underlying mechanisms. shift in substrate use towards glucose, oxidative stress and low grade inflammation) observed during space- Trans-disciplinary aspects flight will certainly pose problems during exploration as a large body of data in clinical nutrition shows that There is a growing body of evidence suggesting oxi- it is a strong predictor of type 2 diabetes and cardio- dative stress and low-grade inflammation play a caus- vascular diseases (14-17). al role in muscle disuse atrophy (18; 19). Furthermore, the development of insulin resistance seems to pre- Earth benefits and applications clude the decrease of resistance to fatigue, which sug- gests that it may directly impact performances. Those Metabolic stress studies are of direct interest to the aspects strongly need to be considered in these dif- growing prevalence of chronic diseases on Earth in ferent areas. which physical inactivity, as during space flight, plays a causative role. This concerns insulin resistance and 6.2.4. Key issue 4: Micronutrients deficiency lipotoxicity, Type 2 Diabetes, obesity, metabolic syn- drome, cardiovascular risks, muscle function and Prolonged micronutrient deficiency is clearly associ- bone health. ated on the ground with numerous functional altera- tions. Those aspects have been overlooked in bio- Brief review of latest developments astronautics research.

While there is an extensive body of data available from recent clinical nutrition research, there is much

58 Nutrition and Metabolism Relevance for space exploration missions Proposed investigations and recommendations

In the context of planetary exploration, a clear evalu- • Long-duration bed rest studies, fundamental sci- ation of the micronutrient status during long term ence, and of course studies during actual space- spaceflight is required to maintain health, and more flight to collect data are the best ways to investi- specifically, to maintain muscle and bone mass, insu- gate this key issue. lin sensitivity, to reduce oxidative stress and lipotoxic- • If needed, targeted micronutrient supple- ity. Recent data shows that in the general population, mentation (e.g. resveratrol, creatine, omega-3 fatty specific micronutrient deficits can leads to moderate acids etc.) should be evaluated as a potential coun- cognitive impairment that obviously need to avoided termeasure in tightly controlled experiments on during spaceflight. The corollary is that micronutri- ground. ents may mitigate to some extent the deleterious consequences of radiation and other related space- Trans-disciplinary aspects flight deconditioning syndromes. Because micronutrients are involved in intermediary Earth benefits and applications metabolism, regulation of insulin sensitivity, the con- trol of oxidative stress and lipotoxicity, which impact Research on micronutrient requirements will likely bone and muscle mass as well as muscle perform- foster strategies to maintain bone and muscle mass, ances and cognition, an appropriate micronutrients to control sensitivity to insulin effects, oxidative stress intake is crucial for the functioning in space. and lipotoxicity in bed-resting ill patients, sedentary and elderly people. It may also help to better face 6.2.5. Key issue 5: Alterations of gut microflora malnutrition problems in some countries. Perturbation in gut microflora is an understudied area Brief review of latest developments on the ground that is becoming increasingly impor- tant (20; 21). Alterations in the gut microflora may Many ground-based studies have well documented affect nutrient absorption, impact on gut secreting the importance of avoiding micronutrient deficien- peptides and thus metabolism and food intake as well cies. Further studies showed that supplementation in as immune status (22-25). micronutrient may be efficient in activating pathways leading to oxidative defence, oxidative metabolism Relevance for space exploration missions and low inflammation. If gut microflora is altered during spaceflight, this Knowledge gaps and research needs will impact energy intake and assimilation, and thus energy balance, but it will also affect intermediary • So far, the status of general micronutrients (vi- metabolism and the immune system. Altogether, the tamins, minerals) during space flight has been maintenance of gut microflora is important for the poorly investigated, especially during long-term general health of the crew members. missions. • In the area of nutritional supplementation in mi- Earth benefits and applications cronutrients, the primary open question is the applicability of population based ground data. Studies conducted in the new domain of gut microflo- • A major gap is whether targeted specific micro- ra and the impact of physical inactivity on gut micro- nutrients (e.g. reservatrol, creatine, omega-3 fatty flora regulation might open new ways to understand acids) might prove to have unique benefits dur- diseases such as obesity, in which sedentary behav- ing spaceflight. iours were suggested to be causative of weight gain.

Nutrition and Metabolism 59 Brief review of latest developments space environment would negatively impact the health of the crew members and thus jeopardise the Molecular biology tools are now available to easily as- success of the mission. sess changes in gut microflora. Earth benefits and applications Knowledge gaps and research needs Research on hydro-electrolytic balance will also have • So far, the effect of microgravity on the gut mi- strong benefits on Earth since similar alterations of croflora, bacteria diversity, etc., has not been in- hydro-electrolytic balance observed in micrograv- vestigated. ity conditions are observed during exercise, altitude • The critical need is for relevant data. challenges, anorexia, and adaptation to high-protein diet. Proposed investigations and recommendations Brief review of latest developments • Bed rest, fundamental science, and of course studies during actual spaceflight are the best di- No recent data is available, especially for long-term rection to investigate this key issue. missions. • Prebiotics/ Probiotics supplementation might prove to be an efficient countermeasure. Knowledge gaps and research needs

Trans-disciplinary aspects The long-term hydro-electrolytic adaptations to space flight are unknown. Because alterations of gut microflora will likely impact energy balance regulation and intermediary metabo- Proposed investigations and recommendations lism, this issue is related to all the physiological sys- tems. • Hydration and mineral supplements are the more potent countermeasure to test and apply. 6.2.6. Key issue 6: Hydro-electrolytic imbalance • Spaceflight studies are the only option to investi- gate such adaptations. The maintenance of hydro-electrolytic balance is re- quired to maintain whole body physiological home- Trans-disciplinary aspects ostasis and to optimise performance. Hydro-electrolytic alterations could directly impact Relevance for space exploration missions the renal function and vascular systems, and also indi- rectly impact the musculoskeletal system. Alterations of the hydro-electrolytic balance by the

6.3. Conclusion

In past bioastronautics research, nutrition has not space in regards to both energy balance and regula- been a high priority given the relative short duration of tion of the energy substrate (fuel mix) oxidation. flights. However, with the International Space Station now completed and the potential of future long-term Finally, investigations on functional adaptations to missions (e.g. Moon, Mars), the interest in nutrition as actual or simulated microgravity need to include nu- a countermeasure has increased dramatically. Indeed, trition as an important variable in interpreting the ob- an increasing body of data shows a direct relationship served results. Controlling nutrition as a variable was between nutrition and the deleterious adaptations to often over-looked in the past.

60 Nutrition and Metabolism 6.4. References

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62 Nutrition and Metabolism 5 Annex: Expert Group Composition

Integrated Systems Physiology cluster coordinator:

Stéphane Blanc CNRS - Institut Pluridisciplinaire Hubert Curien, France

Bone and Muscle – Expert Group Members:

Peter R. Cavanagh ( Chair workshop 2) University of Washington, USA Thomas Lang (Rapporteur workshop 2) University of California, San Francisco, USA Jack JWA Van Loon (Chair workshop 1) Free University Amsterdam, The Netherlands Susan Bloomfield (Rapporteur workshop 1) Texas A&M University, USA Laurence Vico University of St. Etienne, France Angele Chopard CNRS, Nice, France Joern Rittweger DLR, Germany Antonios Kyparos Aristotle University of Thessaloniki, Greece Dieter Blottner DLR, Germany Ilkka Vuori Tampere, Finland Rupert Gerzer DLR, Germany

Cardiovascular, Lungs and Kidneys – Expert Group Members:

Dag Linnarsson (Chair) Karolinska Institutet, Stockholm, Sweden Iman Momken (Rapporteur) University of Strasbourg, France André Aubert Katholieke Universiteit Leuven, Belgium Irina Larina Institute for Biomedical Problems, Russia Kim Prisk University of California, San Diego, USA

Immunology – Expert Group Members:

Alexander Choukèr (Chair) Hospital of the University of Munich, Germany Jean-Pol Frippiat (Rapporteur) Université Henri Poincaré, France Dominique Quervain University of Base, Switzerland Nicola Montano University of Milan, Italy Daniela Grimm Aarhus University, Denmark Siegfried Praun V&F Medical, Austria Benno Roozendaal University Medical Center Groningen, Netherlands Gustav Schelling Ludwig-Maximilians-University of Munich, Germany Oliver Ullrich University of Zurich, Zurich, Switzerland Manfred Thiel University of Heidelberg, Mannheim, Germany

Annex: Expert Group Composition 63 Neurophysiology – Expert Group Members:

William Paloski (Chair) University of Houston, USA Olivier White (Rapporteur) Université de Bourgogne, France Floris Wuyts (Rapporteur) University of Antwerp, Belgium Gilles Clément International Space University, France Jacques-Olivier Fortrat Université d’Angers, France Anne Pavy-LeTraon CHU de Toulouse, France Jean-Louis Thonnard Université catholique de Louvain, Belgium

Nutrition and Metabolism– Expert Group Members:

Peter T. Stein (Chair workshop 1) University of New Jersey, USA Audrey Bergouignan (Rapporteur) University of Strasbourg, France & University of Denver, USA Stephane Blanc University of Strasbourg, France Veronique Coxam Centre de Recherche en Nutrition Humaine d’Auvergne, France Donal O’Gorman (Chair workshop 2) Dublin City University, Ireland Martina Heer Profil Institute for Metabolic Research & University of Bonn, Germany

64 Annex: Expert Group Composition Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-01-7 printed in E.U. march 2012

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Cluster 2: Psychology and Human‐Machine Systems - Report

CLUSTER2 March2012 1

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Towards Human Exploration of Space: a EUropean Strategy

Cluster 2: Psychology and Human‐Machine Systems - Report

Group/Team Processes

Human-Machine Interface

Skill Maintenance THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low Earth orbit have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development .

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus: Cluster 1: Integrated Systems Physiology Cluster 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space medicine Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

4 Table of Contents

1. Group/Team Processes...... 6 1.1. Introduction...... 6 1.2. Group/Team Processes - Key Issues...... 7 1.2.1. Key Issue 1: Maintenance of team cohesion, wellbeing and performance...... 7 1.2.2. Key Issue 2: Impact of reduced communication between crew and Earth...... 10 1.2.3. Key Issue 3: Managing intra-crew differences and conflicts...... 13 1.2.4. Key Issue 4: Integral monitoring of crew and individual behaviour...... 16 1.3. Conclusions...... 18 1.4. References...... 19

2. Human-Machine Interface...... 22 2.1. Introduction...... 22 2.2. Human-Machine Interface - Key Issues...... 22 2.2.1. Key Issue 1: Design of human-automation system...... 22 2.2.2. Key Issue 2: Adaptation to support operator state and mission goals...... 25 2.2.3. Key Issue 3: Evolving, problem solving and updating during missions...... 28 2.2.4. Key Issue 4: Simulation and virtual/augmented reality (SVAR)...... 30 2.2.5. Key Issue 5: Robots (HRI), agents (HAI) & human-robot-agent interaction (HRAI)...... 33 2.3. Conclusions...... 36 2.4. References...... 36

3. Skill Maintenance...... 39 3.1. Introduction...... 39 3.2. Skill Maintenance - Key Issues...... 40 3.2.1. Key Issue 1: Risks for operational effectiveness from infrequent or non-use of skills...... 40 3.2.2. Key Issue 2: Need for different training methods for the acquisition and maintenance of different types of skill...... 41 3.2.3. Key Issue 3: Use of on-board top-up training to maintain and enhance skills...... 44 3.2.4. Key Issue 4: Protection against effects of stressors on skill learning and effective long-term skilled performance...... 46 3.2.5. Key Issue 5: Management of sleep and work/rest schedules to prevent skill impairment by sleepiness and fatigue...... 48 3.3. Conclusions...... 50 3.4. References...... 51

4. Annex: Expert Group Composition...... 54

5 1 Group/Team Processes

1.1. Introduction One of the defining characteristics of space missions Expert Group on ‘group/team processes’ was directed is that humans operate primarily as a team, yet, they at managing the potential problems associated with also have individual needs, preferences, skills and this intrinsic dilemma. Although this is a very general personalities. Crews sometimes operate explicitly as issue that has long been at the forefront of human teams (with common task goals) and sometimes as space research, many problems remain unresolved. separate individuals within a group (with personal In addition, it is likely that the demands of extended goals). These roles, however, can overlap and effective voyages will make them of even greater relevance to inter-personal interactions between crew members are mission success. critical to overall mission success. The concern of the

Figure 1: Astronauts from and STS-127 crews having a group meal on the International Space Station (Credit: ESA/NASA)

Almost all aspects of team and group processes are a journey to Mars. Very little is known about how considered important for future research activities, such delays can affect communication - not only though a number of distinctive aspects can be with ground control but with family members - or its highlighted. A central issue is the impact of team impact on the wellbeing of crewmembers. One likely cohesion on individual wellbeing and performance. consequence is that the astronauts will be obliged by While negative emotions and reduced goal orientation default to take on an increased level of autonomy in are inevitable as a part of everyday interactions, such decision making. states can strongly interfere with mission goals. A much better understanding of such effects is required Another theme is the development of robust in order to develop procedures for optimising the systems to support team cognition - the shared use maintenance of effective performance. A specific of tasks and information by the whole crew, rather problem is the implication of reduced reliance on than individuals. A widespread complication is the mission control, necessitated by the greatly increased knock-on effects of group interactions on individual lag in space-ground-space communications during psychological health, which in turn has implications

6 Group/Team Processes for team level functioning. At present, there are a number of proposed tools for psychological monitoring and support, sometimes designed to be embedded within the human- machine interface However, the scientific database for such countermeasures remains relatively weak. There is a need to develop effective support tools for the psychological support of crew members, monitoring and responding to both interpersonal conflicts and individual stress reactions. As with the requirement of countermeasures for skill maintenance, there is a need for procedures aimed not only at in-flight support, but also for ground-based training. In all, a total of four broad key issues were identified as worthy of attention by the Expert group.

1.2. Group/Team Processes– Key Issues

1.2.1. Key Issue 1: Maintenance of team cohesion, wellbeing and performance

Relevance for long-duration missions

A major concern for extended missions is the stability of per- formance and well-being of astronauts, which is likely to be threatened by the extreme physical, social and psychologi- cal conditions, with reduced communication, monotony and boredom, as well as the loss of a direct visual contact with the Earth (Kanas & Manzey, 2008), which may undermine estab- lished systems of values and behavioural norms. These condi- tions can give rise to loneliness and loss of mission-oriented motivation (e.g., Van Baarsen et al., 2009). Crew members with a good interpersonal network tend to accomplish more than Figure 2: Japan Aerospace Exploration Agency people with smaller networks, even if the latter think they are (JAXA) astronaut photographs the Earth from a window in the Cupola of the psychologically well adapted. Ground-based research (Kara- International Space Station. It is thought that sek & Theorell, 1990) has demonstrated that high social sup- loss of visual contact with the Earth during port and good communication among team members may a voyage to Mars, may lead to significant decrease the negative impact of individual strain, buffering behavioural issues (credit: ESA/NASA) the effects on team effectiveness.

Case studies, interviews and surveys suggest that crew co- hesion could play a critical role in maintaining performance and well-being during spaceflight. This is especially impor- tant during long-duration expeditionary missions, where the crewmembers will function autonomously and depend on each other for support and safety. Interpersonal tension and group cohesion has been studied under normal terrestrial conditions, in space analogue environments (Sandal et al. 1995, Sandal 2000, Kanas et al., 2010), and during LEO space missions, but more work is warranted in preparation for mis-

Group/Team Processes 7 sions to Mars and/or asteroids. Also, more research is There are currently no studies relating cohesion to needed to determine which contextual factors (such performance during space flight, though Kanas et al. as social support), interpersonal skills and personal (2007) found that the cohesion of ISS crew increased characteristics (such as coping style and self-efficacy) with a more supportive commander. Most evidence best support psychosocial adaptation during long- regarding the relation between cohesion and per- duration missions. formance comes from non-space domains, in particu- lar from military and civil aviation research findings. Earth benefits and applications In aviation, various reports have estimated that crew errors contribute to 65-70% of serious accidents (Wal- There are many applications; e.g., to group conflict ters & Sumwalt, 2000). Accident and ‘mishap’ reports research; personnel operating under isolated condi- note a lack of communication and coordination, and tions; peace-keeping forces; weather stations, military poor decision making as significant causes of - per units stationed in foreign countries, industrial teams, formance failure. Meta-analysis across studies from and personnel stationed for prolonged periods in different domains (Muller & Copper, 1994; Thompson, remote areas. In addition, knowledge on the impact 2002; Beal et al., 2003) show that cohesion enhances of cohesion on performance would benefit all work performance, especially in real (vs. ad hoc) and small groups where the effective interaction of individuals teams. in teams is required to produce products and serv- ices. A variety of dependent variables have been used to assess the effects of changes in team cohesion: per- Brief review of latest developments formance outcomes (both individual and team), be- havioural health, job satisfaction, readiness to perform In terms of loneliness, preliminary results in the and absence of discipline problems. Beal et al. (2003) Mars105 simulation mission suggest that long-lasting demonstrated that the impact of poor cohesion on isolation may increase feelings of loneliness and aban- performance was larger when the work required more donment. This may have a detrimental effect on cog- collaboration. In a meta-analysis of 67 ground-based nitive performance (Van Baarsen et al., 2009), however studies, Gully et al. (2002) noted that team perform- loneliness may also have a positive effect, supporting ance is affected by individuals’ generalised beliefs adaptation to isolation and confinement. Earth-based about team capabilities. Extreme negative attitudes studies relating the purpose and meaningfulness of and interpersonal conflicts will degrade team cohe- life to wellbeing, sociability, and group-oriented ef- sion. In contrast, moderate amounts of disagreement fectiveness (e.g., Lazarus & Delongis, 1983; Harlow, on how to perform a task may enhance performance Newcomb & Bentler, 1986; Zika & Chamberlain, 1992) because team members may correct each other’s may also be significant for adaptation to confinement perceptions, offer alternatives or argue about how and isolation in space (Van Baarsen, 2011). Although to solve a problem (Mannix & Neale, 2005). Although major breakdowns are unlikely, problems such as there is little direct evidence that poor cohesion in loss of motivation, failures to cope effectively, and teams leads to major performance errors and failure reduced team cohesion and self-confidence may re- to meet the demands of the mission, it is likely that duce effective involvement in both mission and team failure to maintain an adequate level of cohesion may goals. For example, Kass & Kass (2001) have demon- results in sub-optimal performance. strated the importance of management of emotions and building of supportive and constructive relations Knowledge gaps and research needs between crewmembers during confinement. Poor team cohesion, as indicated by breakdowns in coor- More research is needed to determine which contex- dination, exchange of resources and information, and tual factors (such as social support, loneliness or bore- role conflicts have been mentioned as contributing to dom), interpersonal skills, and personal characteristics both the Challenger and Columbia shuttle accidents (such as coping style and self-efficacy) best support (Launius, 2004). psychosocial adaptation during long-duration mis- sions (see also; Solodilova-Whiteley, 2007; Suedfeld,

8 Group/Team Processes 2010; Whiteley & Bogatyreva, 2008; Van Barsen et al., in separate training sessions instead of joint sessions. 2009). Little is known about the optimal strategies A drawback of this approach is that the team cannot to maintain resilience and team performance during develop team cohesion, although emergency train- space missions. Central aspects include confidence, ing is done in a few sessions where the six crewmem- motivation, focus, and stress management. External bers are required to train together. When teams are motivation and self-determined motivation has been not able to train together as a group, it is even more studied in sport and work environments and show important that they receive the same behavioural different results over time on performance and men- training; using similar case studies, situations and tal health. role-plays create a common culture and language for all personnel involved in the programme. The re- The effects of stress on team decision making are also inforcement of behavioural skills during technical receiving more attention given the critical tasks un- training can increase the possibility that team skills dertaken by military and industrial teams in hazard- are properly used during all critical technical activities ous environments. Although astronauts often engage (Kanas & Manzey, 2008). in expeditionary training activities to promote team cohesion, there is little evidence regarding the type Proposed investigations and recommendations and method that are most effective to promote team performance for long-duration missions (Schmidt et These knowledge gaps may be addressed by examin- al., 2008). While persons and teams who have been ing interpersonal tension and crew cohesion through- trained and are highly motivated are expected to out LEO or lunar missions and isolating the major fac- be more resilient to stress (physical, emotional, and tors (e.g., time effects, stressors, personality conflicts) managerial) and performance degradation, there is that have a negative impact on them. Such studies still limited evidence on the personal characteristics may form the basis for the development of counter- that can predict who is more likely to adapt effectively measures to prevent the negative impact of team to the psychosocial demands of long-term missions dysfunction and conflicts on performance, individual (Kanas & Manzey, 2008). Studies that examined astro- health, and even safety. Opportunities to conduct re- nauts during MIR operations suggest that there ap- search in this area have recently improved, with the pears to be a limit to how long a person can adapt to wider implementation of simulator-based training for a stressor. Although astronauts are capable of adapt- emergency decision-making team and cockpit crews. ing for 6 months in orbit, MIR participants developed However, little is known about the transfer of team symptoms of fatigue, irritability and minor disorders skills learned during pre-flight training to new, stress- of attention and memory. On the other hand, there is ful environments. also research on personnel operating in isolated and confined settings that indicate that psychological re- actions in a time-limited situation change in a similar manner, independent of the actual duration.

Space organisations have learned a great deal dur- ing the past decades from a variety of spaceflight operations. However, new technologies and changes in organisation continually impose new challenges on training programmes. In ISS operations, working procedures had to be adapted to multi-cultural teams who were working in different time zones, at distant locations, and for different organisations. Differences Figure 3: ESA astronaut Frank de Winne and NASA in working habits, values and attitudes, which were astronaut work controls together at the not aligned and often incompatible, reduced the ef- Canadaarm2 workstation to unberth the HTV ficiency of these teams. Logistics and organisational constraints have resulted in the development of skills

Group/Team Processes 9 More research is needed on the following aspects: cal and psychiatric emergencies, and coping with interpersonal problems with little support, not only • What are the (mission-related) factors that deter- from personnel in mission control, but also from their mine the ability of crewmembers to bond and families and friends. This will have far-reaching conse- work together during extended periods? quences for the way crewmembers will work and live • How can crew dysfunctions be prevented or miti- together. For example, they may displace in-group gated during the course of the mission, especially tension to people on the outside, such as their fami- long-duration missions beyond the Earth-Moon lies or mission control personnel, and ‘groupthink’ environment? may occur which could lead to a loss of individual responsibility for decision-making. Strategies need to Empirical knowledge in these areas should result in be developed for the effective management of com- the development of the following countermeasures: munication, despite time delays. For example, one • Training programmes for multicultural crews that speaker might have to propose a set of alternative are applicable across agencies and national cul- responses to his questions that the other can select tures (for example, NASA Behavioral Health and from in making their response. Performance Training) • Programmes for joint training between flight and The enforced increase in autonomy with delayed mission control crews for optimal communication communication also has major implications for crew and prevention of inter-crew tension during mis- performance; the crew being required to take increas- sions ing levels of responsibility for decisions, including in- • Monitoring programmes for crews to facilitate teractions with technology that have a default setting self-regulatory behaviour and to identify and for automatic control. Crew performance depends not deal with team dysfunctions during flight. These only on the knowledge, skills and processing capacity programmes should combine stress and team of the individual team members, but also on team- training to maintain cohesion, team cognition, level factors (team cognition, quality of the commu- motivation, and effective coping with stress nication, coordination of activities, cooperation) and extra-role performance—the willingness to attend to Trans-disciplinary aspects and care about other crew members. The effectiveness of these team processes is facilitated when crewmem- No clear links with other disciplines were identified by bers share similar mental models. These encapsulate the Expert Group. the knowledge structures teams possess about team member functions and the task environment (Cannon- 1.2.2. Key Issue 2: Impact of reduced communica- Bowers, Salas, & Converse, 1993). Teams draw on their tion between crew and Earth shared mental models to coordinate and adapt their actions to changing demands of the work and other Relevance for long-duration missions team members, enabling the crew to adopt an implic- it mode of coordination and to reduce costs of task In planning for a space mission to Mars or an asteroid, management (Entin & Serfaty, 1999). Team cognition crewmembers will be far away from home, and there provides the glue that binds together the individual will be up to a 40 min or longer delay in the two-way mental models, allowing them to engage effectively communication with Earth, having major implications and safely in crew level coordinated actions through for both social and operational aspects of crew behav- access to a shared understanding of the task and how iour. Because of the delay, normal real-time methods it needs to be managed. This is a critical limiting fac- of communication are not possible, and mission con- tor when crew performance is challenged by threats trol will be able to exert less control over the planning from system failure, time pressure, high workload, or and behaviour of the crew. Therefore, crewmembers by interpersonal conflicts and tension. must adapt to the increase in autonomy. They will need to be responsible for planning their work and The requirement to take on a higher level of autonomy leisure time activities, dealing with on-board medi- is likely to disturb both stabilised individual models

10 Group/Team Processes and the shared model (team cognition), since crewmem- bers will have to incorporate these changes and differ- ences between individuals in how they will do this is likely. Such differences may be due to personality, cultural norms or space agency organisational factors (Boyd et al., 2009). However, this may ultimately lead to a higher level of team cognition that is more effective and resilient under stress and task disturbances. While a certain level of autonomy will be built into the design of the human-computer inter- face, it will also be forced onto the crew by default because of the reduced and delayed communication with mission control. A relevant issue is whether it would be better to provide a higher level of autonomy (i.e., an opportunity rather than an obligation) from the start of the mission, so that crewmembers do not feel that it is forced upon them by default, only when support is no longer available.

Earth benefits and applications

Studying the effects of reduced and delayed communica- tion is relevant to many terrestrial contexts where changes in autonomy are relevant, particularly in environments where people will have limited communications with the outside (e.g., military units, crisis/rescue situations, Ant- arctic overwintering). Understanding the impact on team cognition will benefit teams that have to work in high-risk environments, including safety critical industries, military, police, fire fighters and rescue workers.

Brief review of latest developments Figure 4: NASA Extreme Environment Mission Operations (NEEMO) simulates deep space ex- Few studies have been carried out in space simulation or ploration on the ocean floor (credit: NASA) analogue environments on the effects of increased au- tonomy and delayed communication. Crewmembers par- ticipating in simulation studies were found to respond very positively to the introduction of higher autonomy (Sandal, 2010). However, further research needs to be done in the space environment, possibly using the ISS as a platform, to test the effects of communication delays on crew and ground behaviour and performance.

One study done on Earth demonstrated that crewmem- bers can learn to adapt to this situation and still accom- plish mission goals (Kanas et al., 2010). This involved three space simulation settings: NEEMO missions using the Aquarius submersible, the Haughton-Mars Project in a cra- ter in northern Canada, and the pilot phase of the Mars 500 Programme, where a crew of six individual were isolated in a Mars simulator in Moscow for 105 days. High autonomy

Group/Team Processes 11 periods were those where crewmembers planned unexpected situations; crises involving equipment, or much of their work schedule, while low autonomy the medical and psychological well-being of a com- periods required them to work under the direction promised crewmember). Much more also needs to be of mission control. In the NEEMO and Mars 500 pilot known about the best ways of maintaining the rela- study, a delayed communication of up to 40 min was tionship between crewmembers and their families included in the high autonomy conditions. Based on and friends; how the crew micro-culture develops and questionnaire responses, results suggested that high affects team work, both positively and negatively; and work autonomy was well received by the crews, mis- the factors that determine the displacement of crew sion goals were accomplished, and there were no ad- tension to outside personnel on the ground (Kanas et verse effects. While providing a valuable test of the al., 2007). impact of increased autonomy on wellbeing, Kanas et al. (2010) did not, however, make any measurement On a limited scale, issues of crew cognition have been of crew cognition or performance across the different examined in military settings, and occasionally in conditions. spaceflight simulation, but there has been no direct research during space missions, either during flight Maintaining and promoting team cognition has been activities or in distributed teams involving mission shown to play a major role in preventing performance control or surface-orbital interactions (e.g., during a degradation in teams (Salas, Cooke & Rosen, 2008), MARS mission). Even less is known about the way that from simple cross training (to becoming familiar with changes in autonomy affect either mental models or each other’s roles) to Crew Resource Management team cognition, or how such changes interact with (CRM) training (Kanki, Helmreich & Anca, 2010), which non-work factors such as loss of motivation and with- routinely includes shared cognition and team coordi- in-team conflict. Sandal et al. (2010) found that intro- nation of actions. So far, there is no direct research on ducing greater autonomy during a space simulation training in relation to the need to manage changes study was perceived as highly positive by crew mem- in autonomy, and no relevant data for space environ- bers, since frustration associated with outside factors ments. (including Mission Control) was reduced. However, at the same time, individual differences between crew- Knowledge gaps and research needs members became more salient as a source of tension. The value of team training has also been demon- It is clear that there is little direct understanding of strated by many studies, again mainly in aviation and the impact of reduced and delayed communication military contexts (Salas, Cooke & Rosen, 2008), from on crew-ground relationships or crew functioning, simple cross training (to become familiar with each nor of the more specific effect of increase in required other’s roles) to Crew Resource management (CRM) autonomy. training (Helmreich & Merritt 1998), which routinely includes shared cognition and team coordination of The crew-ground relationship has been studied under actions. So far, there is no direct research on training normal terrestrial conditions, space analogue environ- in relation to the need to manage changes in auton- ments and LEO, but more knowledge is necessary to omy. prepare for longer missions. Little is known about how crew and ground personnel build a shared situation- Proposed investigations and recommendations al awareness of the mission and how it affects both crew and ground control performance. A particular To address these issues, two broad sets of questions issue concerns developing ways for mission control need to be examined under conditions of space or to participate in mission critical events under condi- simulated space conditions: tions of reduced communication. Although increased • Research is required on the effects of restricted crew autonomy will be necessary, the involvement of and/or delayed communication on relationships mission control (in providing expertise and feedback) between individual crewmembers, and also is still desirable for crews to function effectively in with (a) monitoring personnel in mission con- extreme situations (e.g., dealing with dangerous and trol, and (b) families crewmembers. This should

12 Group/Team Processes also examine possible new ways of optimising but also with the dynamics of inter-crew relation- communication and strategies of compensat- ships. However, identifying the ideal crew composi- ing for the restrictive and delayed communica- tion is a complex issue that has been so far studied tion with family and friends. This research should on a limited scale only. Given the large diversity of deal with a variety of two-way communication individual differences (personality, experience, cul- delays, from a few seconds to the 40 minutes tural and organisational background), every crew is or more that will characterise expeditionary unique and will behave differently, and it will be an missions to Mars and asteroids in deep space. all but impossible task to test all possible contribut- Further work is required in space-relevant envi- ing factors and their interactions. In addition, particu- ronments on the best ways to build and main- larly for long-duration missions, crews are likely to be tain team cognition, and the impact of changes selected partly on pragmatic grounds: for example, 3 in autonomy. This needs to examine the impact male-female couples for a six-person crew. Therefore, of changes in autonomy and communication it seems more efficient and practical to focus on train- changes on crew performance, and also on both ing techniques and other countermeasures that will individual mental models and team cognition. It help crew members to deal with their differences in should consider transitions in autonomy in both attitudes, personality and cultural background. directions (increases and decreases), as well as comparing changes in autonomy as a (forced) re- Earth benefits and applications quirement or as an (optional) opportunity. Finally, there is a need to develop training programmes A better understanding of the factors increasing in- that can help both crewmembers and mission terpersonal tension and decreasing the cohesion of control personnel in dealing with delayed com- space crews working under isolated conditions can munication problems. be used to ameliorate problems on Earth in a variety of work and social groups. In addition, space research Trans-disciplinary aspects related to cultural differences has great impact on in- ternational relations on Earth, where groups of indi- There are links with several of the issues related to viduals from different cultural backgrounds, nations, human-machine interface and skill maintenance. and organisational environments must interact to- When considering Human-Machine Interface, the gether around common goals and activities. primary links are with the design of the interface and adaptation of the user interface during the mission. Brief review of latest developments Considering skill maintenance issues, there is a gen- eral relevance of research on training and skill man- As of yet, no studies have been done that relate co- agement at the group level, but the clearest links are hesion directly to performance during space flight, with the provision of on-board training facilities. although Kanas et al. (2007) found that the cohesion of an ISS crew was greater when the commander was 1.2.3. Key Issue 3: Managing intra-crew differences supportive. Case studies, interviews, and surveys pro- and conflicts vide evidence that suggests that team cohesion plays a critical role in maintaining performance and well- Relevance for long-duration missions being during spaceflight. For example, poor team co- hesion, as indicated by breakdowns in coordination, A major source of potential problems for long-du- exchange of resources and information, and role con- ration missions is the development of tensions and flicts, have been mentioned as contributing to both conflicts between crewmembers. Low levels of in- the Challenger and Columbia shuttle accidents (Lau- terpersonal compatibility between crew members nius, 2004). is regarded to be an important determinant of psy- chosocial problems and interpersonal conflicts, sug- There is also little direct evidence for the role of crew gesting that crew selection should concern itself not composition in the effectiveness of teams. To study only with the qualities of individual crewmembers, the impact of diversity on team cohesion and long-

Group/Team Processes 13 term performance, a distinction needs be made between surface-level (i.e., age, gender, and ethnicity) and deep-level diversity (e.g., attitudes, beliefs, cultural background). Har- rison et al. (1998) found that the effects on team cohesion of surface-level diversity increased, whereas the effects of deep-level diversity increased when crew members got to know each other better. Similarity between members in at- titudes appears to facilitate communication and reduce the effects of role conflict. The impact of deep-level diversity may be reduced by providing training and incentives to manage interpersonal conflicts. When teams have ample time to train together and receive instructions on how to deal with differences in attitudes, the effects of interpersonal conflicts can be reduced.

Crew members inhabit several roles, not only as members of an international crew on a space mission, but as mem- bers of a nation, an organisation, and a profession; they also differ in their experience with spaceflight. In several recent space simulation studies (Kanas et al., 2010; Sandal, 2004; Tomi, 2001), cultural differences were found to play a role in many of the personal conflicts that took place either within the crews or between the crews and ground control. Besides language and cultural factors, the crew members mentioned the following aspects: attitude towards the mission, technol- Figure 5: ESA astronauts Paolo Nespoli (left) ogies, research practices, gender relations, and communica- and Roberto Vittori shake hands inside the tion style. According to the crew members, an interpersonal ATV-2 (Credits: ESA/NASA) training programme including both the crew and ground control could have been prevented or reduced these prob- lems. In a series of studies on-orbit with much larger samples, Kanas and colleagues (Boyd et al., 2009; Kanas et al., 2007) compared Russian and US astronauts, and mission-support personnel, in terms of mood and group interactions over time. Compared to the US personnel, the Russians experi- enced less pressure on the job; more tension/anxiety during ISS missions; and more direction, support, and self-discovery during MIR-missions. A recent study by Tomi et al. (in press) involving a total 75 astronauts and 106 ground personnel. The participants worked for one of the space organisations involved in the ISS programme. Poor communication due to misperceptions, misunderstandings, language problems, and differences in work style were among the most often mentioned challenges of the 25 multi-national space crews investigated.

The above problems mentioned reflect differences in policy between the space organisations with regard to selection, work organisation and rewards. For example, NASA astro- nauts receive a fixed salary and bonuses, whereas the salary

14 Group/Team Processes of the Russian astronauts depends on the work ac- whether they are also valid in analogue environments complished. Also, the Russian space programme uti- and during spaceflight. It also should be examined lises fewer written procedures and relies more on ex- which countermeasures can reduce the effects. The pert opinion. One of the unknown aspects of long-du- focus of the research should be on managing the ration missions is how behavioural norms and values effects of deep-level diversity, since they tend to in- adhered to by crew members may change after a long crease during long-term missions. period of isolation and confinement. Crew members may displace in-group tension onto people on the Proposed investigations and recommendations outside, such as their families or mission control per- sonnel (Kanas et al., 2007), while ‘groupthink’ leads to • In general, more research needs to be done on the a loss of individual responsibility for decision making. factors that determine the way in which changes in crew micro-culture develop, which may result Knowledge gaps and research needs in a displacement of crew tension to Earth-based personnel (for example in the form of group- Although differences between crew members are a think). There is a need to know how such changes major consideration to ensure high levels of interper- can be prevented or managed, should they occur sonal compatibility, only limited research has been during a mission; done on the impact of crew diversity on team work in • Existing knowledge on the impact of different space or analogue settings. Some evidence exists to crew composition factors on performance and suggest that personality characteristics are relevant well-being needs to be clarified by a meta-analysis for effective teamwork in small groups, but this has of all studies performed in different isolated and hardly been tested in analogue or space environments. confined environments. This method overcomes Relevant factors include personality characteristics, the problem of reduced statistical power associ- crew size, gender balance and cultural background ated with the typically small sample sizes of space (Kanki, 2009). During space missions, it is important studies. Combining the results from a group of that crewmembers work together cohesively with a studies allows for more reliable conclusions. For minimum of interpersonal tension. Factors disrupt- example, the crew characteristics (e.g., personal- ing crew cohesion need to be identified, and coun- ity, gender, number and culture) collected during termeasures employed to decrease tension and allow the studies at the Concordia polar station could crew members to perform mission tasks and interact be related to performance, well-being, and con- appropriately with each other. On the other hand, it flicts; is possible that cohesiveness can be too high (Sandal, • More attention should be paid to the prevention Bye & Van de Vijver, 2010), since it may reduce the of accidents in space by having (more) debrief- willingness of crew members to voice minority disa- ings and group discussions on aspects topics greements or concerns—the phenomenon known as such as miscommunication and organisational “groupthink”. This is especially important during long- problems. To ensure that crew members, mis- duration missions, where crewmembers depend on sion control and other personnel involved are not each other even more for support and safety. More afraid to communicate their concerns, an open research is needed to determine which contextual learning culture should be promoted able to fos- factors (such as social support), interpersonal skills, ter safety and involvement. This requires that is- and personal characteristics (such as coping style and sues are discussed in workshops as part of team self-efficacy) best support psychosocial adaptation training programmes of astronauts and mission during long-duration missions (see also Whiteley & control personnel; Bogatyreva, 2008; Solodilova-Whiteley, 2007). • Extended training programmes should be devel- oped to train the crew on how to handle these dif- Since it is likely that future crews will be multi-nation- ferences, not only during the training pre-flight, al (and multi-cultural), team diversity needs more at- but also during the flight. Refreshment courses tention. Since most findings have been obtained in may be given to remind the crew of the impor- ground-based studies, more work is needed to show tance of these issues. This could also be part of

Group/Team Processes 15 debriefings and group discussions that are sched- Brief review of latest developments uled regularly. This will improve the self-regulato- ry power of the crew, which is especially in par- Using an ethological perspective, Tafforin and Gerebt- ticular important when the support of mission zoff (2010) showed that changes in movement, pos- control is limited due to communication delays. ture and social relationships could be captured using video analyses of everyday events, and analysed auto- Trans-disciplinary aspects matically to reveal individual differences in adaptation to microgravity. Such methods are being developed No clear links with other disciplines were identified by in current experimental protocols simulating future the Expert Group. interplanetary missions, with an emphasis on Lunar stay and Mars, as part of EuroMoonMars campaigns at 1.2.4. Key Issue 4: Integral monitoring of crew and the Mars Desert Research Station (MDRS) in Utah-USA individual behaviour (REF) and for the Mars-500 study. In this very-long term simulation, video recordings of daily life activ- Relevance for long-duration missions ity and collective tasks are performed in coordina- tion with psychological questionnaires and a wireless Crewmembers have to adapt to a constrained and group structure monitoring system (WLGS-tool). In hostile environment characterised by both physical addition, new virtual-reality 3D training tools help as- (e.g., microgravity, cramped conditions) and psycho- tronauts to learn techniques and pre-flight strategies logical stressors. These factors are likely to affect group they can apply in space, and have been used to moni- dynamics and the effectiveness of cognitive and mo- tor different aspects of neurobehavioural and social tor skills, both at the individual level and at the team performance in long-term spaceflight simulations (De level. Particularly in time-stressed, high-workload task la Torre et al., 2010). environments, team performance is critically depend- ent on team members acting in reliable and predicta- Knowledge gaps and research needs ble ways. In the case of interactions with automation, performance is also dependent on efficient coupling Although the effects of physical and psychological between crewmembers and technology. Although stressors have been studied in a wide range of isola- specific effects have been examined in a number of tion and confinement simulations of short- and me- studies, little is known about their interactions, and dium-duration (e.g., ISEMSI, EXEMSI, HUBES, SFINCSS, how effects may change over time with increased MARS105, Concordia) there have been few system- exposure. Appropriate methods to detect and assess atic studies of their impact and interactions over ex- the occurrence of risky behaviours have to be devel- tended time periods, or in space. One exception has oped. This requires an system, built into the been the work of Kanas and his colleagues, who have on-board systems, designed to monitor and assess examined crewmember interactions and the crew- changes at all levels (overt actions, cognitive, physi- ground relationship during a series of Mir and ISS ological) in individuals and also on a group level. missions and attempted to relate a number of issues to the stressful conditions in space (Boyd et al., 2009; Earth benefits and applications Kanas et al., 2007). A number of different monitoring methods have been used during simulation studies, Development of monitoring methods will have major but their relative effectiveness has not been validated. value for all situations where personnel are operating Although the effectiveness of several indicators has in isolated, high risk settings, with a high inter-depend- been examined in space-related studies, no attempt ence between team-members (e.g., military units, oil has been done to combine and compare these data platforms, remote weather stations, polar outposts), in a meta-analysis. The limited exchange between as well as for organisations and workplaces that de- researchers originating from different disciplines has pend on well-functioning teams for productivity. inhibited a global analysis of inter-disciplinary data (medical, physiological, psychological, psychiatric,

16 Group/Team Processes sociological, ethological, and ethological data (Tafforin & Gerebtzoff, 2010). An integral monitoring system is needed to be able to signal or detect critical changes in health or behaviour during space flights that endanger the comple- tion of the mission. The goal of the system is to provide information that may be used to secure the completion of the flight and to mitigate the effects of inappropriate or unwanted behaviour. The data collected should provide indicators that can be used to regulate behaviour, either by giving feedback to the individual, to the crew, or to mission control. Procedures should be developed to decide who is getting what information. This information may also be used as a basis for making decisions about possible inter- ventions to regulate behaviour or improve mental health and well-being. Very little is known about the potential chronic after-effects of extended missions (for example Figure 6: The crew of the Mars500 isolation depression, post-traumatic stress symptoms). study was locked in a simulated space station for 520 days at the Institute of Biomedical Prob- Proposed investigations and recommendations lems in Moscow • An integral monitoring system should be developed, based on a broad set of indicators associated with dif- ferent analytic disciplines, covering cognitive, emo- tional, physiological, and behavioural aspects of the functioning of the crewmembers, both as individuals and as part of the crew. The large amount of data col- lected during analogue studies (e.g., Mars 105 or Mars 500) offers a unique opportunity to compare the effec- tiveness of different assessment methods and to select the most critical indicators, using a meta-analysis to identify the most reliable measures. These indicators should signal or predict changes in thinking, meaning, emotions, and physiological states that are critical for maintaining (crew) performance, or mental health and team cohesion. They may be based on a combination of parameters, which may originate from different dis- ciplines. • The validity and usability of this integral monitoring should be tested in analogue environments and in ISS or space environments. The research should focus on the changes in : psychological and neurobehavioural aspects of mental health; individual motivation and well-being; Individual and group psychological re- sponse to unexpected and threatening events; objec- tive and subjective assessment of crew interactions, cohesion, conflicts and group structure dynamic. • Other relevant areas for research on monitoring in- clude the advantages and disadvantages of develop- ing self-testing tools, in addition to centralised compu-

Group/Team Processes 17 ter-based systems, and how such information is best used. For example, how should the data be commu- nicated to crew members? Should it be used for inter- vention? And if so, how? Who would be allowed to see the data, and who has the authority to make decisions based on it? As with any new tool, programmes of ef- fective training will also need to be explored.

Trans-disciplinary aspects

A monitoring system of this kind would need to be inte- grated with other monitoring initiatives relevant to Hu- man-Machine Interface and skill maintenance issues. A sin- gle monitoring and support system is envisaged that could be used flexibly for all human interactions with both others and the technical systems.

1.3. Conclusions

The overall conclusion of the EG on “group/team process- es” is that there is a need for a focused examination of the issues related to team and group processes in extended space operations. While much is already known from pre- vious work, it would be a mistake to apply this knowledge too readily to the unique challenge of a mission to Mars. The potential problems associated with intra-group con- flicts, loneliness, disrupted connections with Earth, and ob- ligatory autonomy in managing operational systems need to be carefully managed. In general, crews need to be sup- ported more effectively in both their mission-related ac- tivities and the pursuit of their personal goals.

Specific topics identified were:

• Maintenance of team cohesion, wellbeing and per- formance • Impact of reduced communication between crew and Earth • Managing intra-crew differences and conflicts • Integral monitoring of crew and individual behaviour

Research facilities within the European Community are well equipped to address such problems. There are also many potential Earth benefits from such work, especially in any work context that depends on effective teamwork in dangerous or stressful environments.

18 Group/Team Processes 1.4. References

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Group/Team Processes 21 2 Human-Machine Interface

2.1 Introduction

Research on the design of the human-machine inter- ticular problem is that the ways in which crewmem- face is fundamental to the overall success of any space bers interact with the automation may change during mission, determining the nature of crew interactions a mission, and through practical experience, virtually with the many technical and robotic systems involved nothing is known about how system design can ac- in effective and safe progress. In terms of the wider commodate such adjustments. There are also other technical state of the art, this is a highly developed more specific issues, including: the nature of human area, especially in industrial automation and aviation. interaction with robots, the use of virtual and aug- Yet, while applications to space missions have been mented reality in simulation training and support; the very successful, the greatly extended missions envis- use of EVA wearable computers to monitor changing aged for future human space exploration will require operator state in relation to mission goals, and the use a step change in sophistication and refinement to al- of adaptive function allocation strategies to manage low increased collaboration and trust between human changing relationships between crew and computer and automation components of the human-machine systems. Much more still needs to be known about system team. In particular, the proliferation of auto- the design of decision support systems and dialogue mation and robotics may present major problems for control, and the general problem of how best to crew members, both in monitoring the state of the promote the high degree of collaboration required. system and in making necessary interventions. While many of the technological elements are already in place for these developments, there is currently This is the most general issue identified by the Expert a lack of firm understanding of how to optimise the Group focused on Human-Machine Interfaces, requir- partnership between crew members and automation ing fundamental research on the design of robust technology, and how to allow for context-driven - automation for human-machine cooperation. A par- ibility of optimisation.

2.2. Human-Machine Interface - Key Issues

2.2.1. Key Issue 1: Design of human-automation Relevance for long-duration missions system Future space missions will involve automated sub- use of virtual and augmented reality in simulation systems with relatively high levels of autonomy and training and support; the use of EVA wearable com- authority (Hoffman & Richter, 2003). Automated sys- puters to monitor changing operator state in relation tems can be designed at different levels of authority to mission goals, and the use of adaptive function al- for task completion—between fully manual and fully location strategies to manage changing relationships automated—and different components of informa- between crew and computer systems. Much more still tion processing that are supported—from perception needs to be known about the design of decision sup- through decision making to action (Parasuraman, port systems and dialogue control, and the general Sheridan, & Wickens, 2000). For automated systems to problem of how best to promote the high degree of be used effectively and safely by crewmembers, they collaboration required. While many of the technologi- will need to be designed by taking human capabili- cal elements are already in place for these develop- ties and limitations into account (Parasuraman & Ri- ments, there is currently a lack of firm understanding ley, 1997; Lee & Seppelt, 2009). Human-automation of how to optimise the partnership between crew system design refers not to the design of interfaces members and automation technology, and how to al- between the crew and automated systems, but to the low for context-driven flexibility of optimisation. functionality of automation and to task allocation be- tween humans and automation.

22 Human-Machine Interface Human-automation function allocation is an old topic (SA)—if for no other reason than with diverse proposed solutions, beginning with now that the automation is managing some portion of the outdated methods such as the ‘Fitts List’ of the 1950’s tasks. The threshold at which the workload-SA trade- to current concepts such as adjustable autonomy off occurs for space missions needs to be identified. (Dorais et al., 1998) and delegation approaches to hu- Also, what degree of loss of SA due to high degrees man-automation interaction (Miller & Parasuraman, of automation is tolerable before safety is compro- 2007). However, many unique aspects of space mis- mised? sions, such as their long duration and delayed or little communication between the crew and ground con- Because of the length, complexity, small crew size, trol, require that additional approaches to function al- and limited availability of ground control support of location be identified and evaluated to allow for effi- long-duration space flight, automation will be nec- cient coordination between humans and automation. essary for successful mission completion. A variety Even if existing approaches to function allocation are of such systems, such as life-support systems, deci- found to be relevant, they need to be validated in the sion aiding and planning tools, planetary rovers and context of automated systems to be used in future other robots, etc., will be critical to the performance planned space missions. of crew in executing space missions safely and effi- ciently (Dorais et al., 1998). Such systems will need to Human-automation interaction protocols and meth- be designed so that they operate cooperatively with odologies will need to be specified and evaluated the crew and support rather than hinder their mission throughout the stages of system design. Particular at- effectiveness. Automation designed without concern tention will need to be paid to supporting crewmem- for human capabilities and limitations can result in ber handling of off-nominal or critical, unexpected serious degradation in system performance. For ex- events, i.e. ensuring sufficient crew situation aware- ample, certain automation designs can reduce crew ness to handle the problem. Trust is a key aspect of SA and not provide opportunities for maintenance effective use of automated systems by humans. The of cognitive skills. When unexpected events occur, or human-automation system design should allow for in instances of system malfunction, the crew’s SA will accurate trust between the extremes of distrust and need to be adequate enough to diagnose the prob- unconditional trust, and for trust that is appropriate lem and their manual skills sufficiently well preserved to the use of automation in specific contexts (Lee & to allow for effective resolution. Poorly designed au- Seppelt, 2009). Because of the planned use of rov- tomation can lead to problems that can compromise ers and other robots in space missions, human-robot safety and, in the extreme, lead to accidents. Human- trust also needs examination. Methods to repair loss automation system design based on well-established of trust following system failure in the context of human factors principles is therefore essential for the evolving, long-duration missions need to be better success of long-duration space missions. understood. Trust maintenance and repair involves not only interaction between the crew and their auto- Earth benefits and applications mated systems, but also between ground control and the mission crew. Many current and planned work environments on Earth involve personnel interacting with increasingly As the degree of successful, effective automation of highly automated systems. Two examples include the a system increases, due either to a higher level of al- programme for transformation of the air traffic man- location to machine (vs. human) control or to great- agement system to accommodate higher levels traffic er autonomy for decision making and action, crew more efficiently (NextGen in the US and SESAR in Eu- workload decreases (Wickens et al., 2010), although rope), and the increasing use of unmanned vehicles sometimes the load may only shift to other cognitive and robots by the military. Research on effective hu- demands (Parasuraman & Riley, 1997). At the same man-automation design will yield benefits for system time, increased automation can lead to a decrease in efficiency and safety in these and other domains.

Human-Machine Interface 23 Brief review of latest developments Proposed investigations and recommendations

Current knowledge on human-automation system A methodology for human-automation system de- design has been drawn from empirical studies, field- sign specific to long-duration space missions needs to work, and accident analyses. The combined evidence be identified, tested, and verified. Potential investiga- from these sources has shown that automation tions might target (but should not be limited to): changes cognitive demands on the human operator • Research on how specific automation designs in- and imposes new challenges for coordination (Lee & fluence crew trust, workload, and situation aware- Seppelt, 2009; Parasuraman & Riley, 1997). At the same ness in simulations of mission-relevant scenarios. time, automation impacts crew workload, trust, and • Studies should examine several aspects of auto- situation awareness, in both beneficial and negative mated systems that are relevant to space missions, ways. The challenge is to identify automation designs from low-level sensors and automated actuators that retain the benefits while minimising the costs. At to decision aids and semi-autonomous robots. least three major approaches have been identified for • Since all possible factors influencing human-auto- reaching this goal, (1) levels/stages of automation, (2) mation interaction in human-in-the-loop studies adaptive automation or adjustable autonomy, and (3) cannot be examined, computational modelling delegation approaches. Evidence for the efficacy of studies should be conducted to examine how these approaches in comparison to “static” automa- such factors act individually and in interaction to tion has been provided in studies of automation as influence system performance. applied in air traffic control and human-robot interac- • Strategies should be explored for combining pre- tion (Parasuraman et al., 2000; Miller & Parasuraman, dictive cognitive models whose predictions can 2007). be tested in follow-up human-in-the-loop experi- ments. The benefits and costs of specific automa- Knowledge gaps and research needs tion approaches, e.g., delegation-based adapta- tion, should be tested as part of the verification Designing automated systems to support crew per- process. formance in the specific context of long-duration • The resulting knowledge base should be used to space missions is an important research need. Several identify relevant dimensions and levels for func- taxonomies and frameworks for human-automation tion allocation strategies under different opera- interaction design have been put forward. However, tional conditions and circumstances. current knowledge on human-automation system de- • Also needing examination are requirements for sign is drawn mainly from experience with automated terrestrial simulators to serve the needs of long- systems in such domains as aviation and process con- term space mission research. trol, and the degree to which these can be extended • The research plan should be systematic and pro- to and are applicable to space missions is not known. grammatic, beginning with ground-based simu- The many unique aspects of space flight require that lations of progressively more complex scenarios, new approaches be identified and evaluated for effi- progressing to flight experiments during LEO, cient coordination between humans and automation. moon, or Mars missions. In particular, the differential benefits and limitations of adjustable autonomy and delegation approaches Trans-disciplinary aspects need to be identified. Space mission automation must support crew performance in both routine and mis- There are strong links with issues related to skill main- sion critical conditions, elicit calibrated levels of trust, tenance. High levels of autonomy can lead to atrophy and optimise crew workload and situation awareness of perceptual and cognitive skills that may need to so that crew members have sufficient resources to be exercised by crewmembers when the automation respond effectively to unexpected events. Even the fails or does not provide optimal solutions in a par- definitions of objectives such as “safety” may need ticular context. Good human-automation system de- to be rethought for long-term space missions, where sign, as well as approaches to function allocation such system shut down may be impossible and even stable as adaptive automation, can reduce skill loss. states may need to last for months.

24 Human-Machine Interface Also, considering team/group processes, the system de- sign needs to consider not only interactions between indi- vidual humans and automation but also between multiple humans/groups interacting with individual automated sys- tems, or machine mediated human-human interactions, or within and between teams processes/interactions (e.g. surface and orbit teams). Automated systems and their in- terfaces may also be designed for monitoring physical and mental wellbeing.

2.2.2. Key Issue 2: Adaptation to support operator state and mission goals

Relevance for long-duration missions

The state of the operator is an integral part of the effective human-machine system. Major departures from optimal operator functional state (OFS) may significantly compro- mise mission goals, though such effects may be masked by compensatory recruitment of effort, which protects performance in the short term at the cost of an underlying impairment. There is a need for HMI design to incorporate a system for monitoring of physiological and cognitive changes in OFS, as a basis for adaptive automation and de- cision support.

Adaptive and adaptable HMI design has increasingly been considered in complex systems design as a possible so- lution for keeping operators in control; this holds for the Figure 7: An artist’s conception of a possible short and long run. This enables operators to respond ef- Moon base, with robots and humans (Credit: fectively in unforeseen situations. However, it would be ESA) necessary to improve HMI design to enable the operator to serve as a link in fail-safe principles. The question remains how HMI design can be developed in order to balance the human requirements for active engagement with those of mission goals and safety? An important aspect in this is to investigate the strength and weaknesses of the assess- ment of adaptation mechanisms, establish who has access to the resulting data, and the ability to override the adap- tation that results. The trust in the system is influenced by the sensor intelligence and reliability. The relevance for long-duration missions is considered to be large. This holds both for missions in the nearer regions (LEO, moon) and long distance missions (Mars). An impor- tant aspect, however, that relatively increases the impor- tance of this work for long distance missions is the impos- sibility to elicit support from ground personnel via radio communications in missions to Mars. Otherwise most of the issues of complexity, interaction and adaptation are

Human-Machine Interface 25 present in the other long-duration missions as well. Di Rienzo et al. (2008) studied adaptation to micro- The problem of enhancing adaptation for enhanced gravity reflected in changes of blood pressure, heart operator support involves a number of related top- rate and baroreflex sensitivity (BRS). There are some ics: defining the optimal operator functional state; studies on adaptive designs for task interfaces using monitoring the physiological and psychological state real-time EEG with applications in transport industry, of individuals and teams; monitoring system per- experimental implementation in a US Army study on formance, e.g., for errors; detecting, identifying, and unmanned aerial vehicle operators (i.e. Gunn et al., predicting critical situations/mission situations; de- 2005; Freeman et al., 2004) veloping criteria for OFS breakdown; maintenance of trust in automation; possibilities for adaptive support Knowledge gaps and research needs and task allocation; HMI design to incorporate adap- tive and adaptable support; closing the loop by using There is a strong evidence base in lab research for the feedback, either informational or by biofeedback. effects of OFS changes, but almost nothing is known from space studies. A major growth point is the devel- Earth benefits and applications opment of methods for real-time monitoring of physi- ological measures and estimating state changes. At The relevance for Earth applications is large, in par- present studies are restricted to separate fields (e.g., ticular for aspects such as long-duration interactions EEG, cardiovascular) which make estimations quite with adaptive systems, learning and growing, adapta- crude and incomplete. Furthermore, it is insufficiently tion to attitude, and real-time user support. Specific known in specific working situations what the main applications include: applications in health, rehabili- causes are of detected changes (e.g. task complexity, tation and assistive devices; design of human-cen- time pressure, stress related to crew or ground control tred task and interaction interfaces in safety critical interactions etc.) More sensitive measures for iden- systems: process control operations, transportation, tification and prediction of smaller state changes are manufacturing; Training systems in various fields from likely to be required. Also, know more needs to be health to control systems in hazardous environments. known about the background and impact of subtle An essential point is that management of most critical state changes. systems in the mentioned areas would benefit from a user state assessment. Additionally, the consistency and reliability of indi- vidual state change characteristics need far more at- Brief review of latest developments tention. There is an opportunity and need to monitor and detect psychological state changes, and there are Kanas & Manzey (2008) summarised important as- preliminary techniques available to do so, but little is pects of physiological (i.e. cardiovascular, sensory- known about effective HMI adaptations or interven- motor, muscular) and psychological adaptation in tions, especially in work contexts. space, including empirical findings in this area in their important book on space psychology and psychia- Therefore, questions include defining valid and relia- try. Miller & Parasuraman (2007) designed a method ble state predictors (physiological, performance, self- enabling human-like, flexible supervisory control via assessment), methods for detecting and predicting delegation to automation. Flexibility in human-adapt- high risk states, and developing adequate mitigation able automation can provide important benefits, in- strategies (by early detection and prevention, or by cluding improved situation awareness, more accurate adaptive task changes). The main question is how can automation usage, more balanced mental workload, HMI design be developed in order to balance the hu- increased user acceptance, and improved overall per- man requirements for active engagement with those formance. Little is known about the cardiovascular of mission goals and safety? effects of mental workload in space, but there are a couple of essential studies on the working of auto- Currently available studies refer to potential (general) nomic neural functions and the baroreflex in space. solutions for adaptive HMI interface design and some

26 Human-Machine Interface adaptation mechanisms, but these approaches are Studies of adaptive and adaptable human-machine rather limited for individual task support due to lack task and interaction interfaces often refer to either of criteria and valid, sufficiently sensitive predictors, generalised (design for all) or individualised (design and tend to focus on larger state changes and shorter for single, individual operator) design solutions, while time periods than may be required for adaptation in the first aspect has got far more attention than the long-duration missions; this holds both for estimation second. There is a strong need to investigate conse- of state changes and task adaptation. Where applica- quences of human performance and related state tions are available, (1) their reliability for identification changes of individual task adaptation based on (indi- and prediction of shifts in states is sometimes limited, vidual) detected state changes. Relevant aspects in- (2) they exhibit limited sensitivity and diagnostics for clude the examinations of the short/long-term effects the detection of state changes, (3) their suitability for of task adaptation and feedback (since psychophysi- use outside the lab is limited, and (4) their ability to ological monitoring of operator state will include bio- transfer/use across different mission scenarios, task feedback) on overall system performance. situations is unknown. Suggested research topics include but are not limited There is some knowledge on discrete shifts in inter- to: face and task design between normal and abnormal situations, however, effects of human-centred design • Identify the performance effects of adaptive opti- of transitions between tasks interfaces remain un- misation on non-optimal situations (e.g., is there clear. There is limited knowledge of effects of adap- an automation complacency effect with adaptive tation dynamics on human information processing, automation?) criteria and predictors for adaptation, information • Identify the performance and psychological ef- requirement for safe and efficient operation. Knowl- fects of providing user feedback on different edge is especially limited with regard to long-term types and applications of interface or automation effects/applications, domain and situation specific adaptations critical states, mitigation strategies, lack of real-time • Identify whether and how adverse psychological estimates of state changes during prolonged working (e.g., depression) and/or social (e.g., group antipa- conditions and (many) repeated working days. Ad- thy and non-cohesion) states can be reliably de- aptation of interfaces in normal situations is reason- tected, and what (if any) system adaptations can ably well-known, but costs when unexpected situa- prove effective in combating them. tions and events occur have not systematically been • Usability and well-suitedness of adaptivity and explored. So, more knowledge has to be gained on adaptable interfaces / systems in safety critical the use of adaptive and adaptable interfaces in safety and unexpected situations critical and unexpected situations. Trans-disciplinary aspects Proposed investigations and recommendations There are links with issues related to skill maintenance The broad aim is to be able to identify consistent indi- in terms of using adaptation to encourage mainte- vidual patterns of psychophysiological change with con- nance of skills or training and psychophysiological tinued exposure to natural stress conditions and relate monitoring of skill maintenance (performance). HMI these to control errors and performance breakdown. can also foster team social relationships and/ or effec- There is a need to carry out systematic studies of com- tive collaboration plex H-M task under a fully representative range of ISS living and working conditions and operations; this in- Crew members have a central role in OFS breakdown, cludes both regular testing over several months to grasp and in identifying critical situations; OFS may refer to individual response characteristics and their stability. neurophysiological state assessments.

Human-Machine Interface 27 2.2.3. Key Issue 3: Evolving, problem solving and updating during missions

Relevance for long-duration missions

The sheer duration of a Mars mission, combined with likeli- hood of encountering unanticipated circumstances and con- ditions, make it very likely that system functions and com- ponents, software, as well as human policy and operational procedures, will all evolve and be updated. These updates could be in response to problems and hardware and software failures or to novel opportunities and upgrades, and might be either optional or unavoidable. They could be initiated and developed by the crew, by ground control, by subsystem de- velopers and contractors or even through autonomous ma- chine learning approaches. Few modern software systems go through two-year lifecycles without patches and upgrades in practice today, and current ISS and Shuttle practice involves extensive review and adaptation of most non-critical proce- dures to the current state and operations of the vehicle and crew before they are exercised. But it is unclear how such redesign, evaluation and problem solving should be imple- mented. Who should do the revising (flight crew, ground control, or autonomous machines in either location) under what circumstances? How can crew be kept appraised of revi- sions, especially when/if they are not involved directly? How can newly-acquired behaviours (especially if autonomously learned or developed by the crew) be validated before being adopted? How can equipment and systems (for validation, crew training, etc.) best support such change?

How to make such changes and to validate and verify them is a major research challenge. How can operators (whether crew or ground) be trained in the revisions? How can the “transfer of training” problem (inaccurate generalisation or carry over from old learning) be avoided? And the problem of communi- cation changes within the crew, and between crew and mis- sion control—avoiding “cross shift transfer” problem where changes made by one team or “shift” are not communicated adequately to the next shift, while simultaneously avoiding Figure 8: ISS Mission Control room at NASA the workload problems occurring around cross-team hand- Johnson Space Center (Credit: NASA) offs. Crewmembers will need to be able to understand the ef- fect of change on the full range of systems and procedures, and to be able to obtain support for (recording of) collabo- ration in innovative problem solving technology—related to “design rationale capture” in engineering and software design. There are also bound to be changes in trust at all levels (hu- man-machine, crew-ground and human-human) that have to be managed effectively.

28 Human-Machine Interface As mission duration increases, the likelihood and the Knowledge gaps and research needs need for significant innovation, revision and evolution of systems and processes increases. The same is large- While the above characterisation of recent develop- ly true for mission complexity—and for mission nov- ments in this field shows reasonable progress, limited elty. The inability to replace failed hardware systems knowledge exists on the effects of adapting task con- places an added burden which will likely mandate texts, procedures and HMI design on long term task innovative solutions and “workarounds”. Traditional performance; essentially no knowledge exists about engineering approaches wherein a complex system the optimal rate or magnitude of changes (i.e., soft- is fully designed and thoroughly tested a priori and ware releases) and manners of notification and their then left unchanged during use, might be feasible effects on human awareness and performance. Effec- for short duration, bounded-scope missions, but are tive design rationale capture, especially in high pres- already not adhered to in practice in most complex sure/workload settings among groups using primarily real-world systems such as aviation and process con- verbal communication, remains an unsolved problem. trol and (with ISS) space. Of course, complex software Nothing is known about these functions in the space systems (e.g., Microsoft Office) used in everyday life context, though anecdotal evidence exists, especially undergo upgrades and repairs, sometimes multiple from ISS operations, where sustained operations have times in a day, and though this process can hardly be necessitated known changes to procedures and prob- said to be seamless, transparent or overly safe. ably changes to software after initial installation as well. Earth benefits and applications Proposed investigations and recommendations As noted above, the problem of managing changes to systems, software and practices is already a com- A process of initial identification of analogous Earth ponent of most complex Earth systems and tech- environments (e.g., complex process control, military nologies—with transportation, process control, and command and control at the battalion or division lev- military systems being prime examples. While these el, long-term event management, space mission man- systems arguably do not experience the problems of agement) and collection/review of effective practices managing, supporting and disseminating changes in for problem solving and capturing and disseminating as severe a form as a long-duration space mission will, of modifications is proposed. A subsequent or concur- they will likely benefit from any advances in research rent review of the somewhat extensive collaborative or supporting system design made by a space pro- problem solving and collaboration support tool litera- gramme. ture to identify best practices with relevance to space mission conditions is also recommended. These stud- Brief review of latest developments ies should be followed by laboratory studies of (1) vari- ous collaboration environments, group structures and Currently, collaborative problem solving research is support tools on effective collaboration and problem nascent, with some good work on processes used by solving as well as rationale capture, (2) effects of vari- complex design and engineering teams and on col- ous forms and contents of rationale capture on sub- laborative problem solving teams such as military sequent performance using/accessing the rationales, command, NGO disaster relief, fire-fighters, etc. There and (3) effects of various change notification methods is extensive research on tools to support collabora- and rates on task performance—all with emphasis on tion in design and engineering, and various attempts space mission tasks and contexts. While not all such to develop rationale capture tools (primarily in soft- studies need to involve highly trained experts, crea- ware design teams). Anecdotal evidence from com- tive problem solving environments and high stress/ plex process control and shift work exists—including tempo operations, at least some of them should. documentation of effects of changes on subsequent Eventual migration to long duration studies, ideally in shifts and best-practices for maintaining knowledge naturalistic environments (including high stress and of changes. Good work is emerging on change detec- tempo). Note that investigation of solutions/meth- tion at the user-interface level in Human Factors. ods in space, while desirable, is considered less critical

Human-Machine Interface 29 for this topic because (it is felt) adequate knowledge and future mission scenarios. SVAR can be useful in could be elicited from ground-based analogue stud- operations, training and leisure, e.g. remote control ies for reasonable design for space missions. interfaces in virtual reality for distant robot opera- tions in reality, augmented reality display for navi- Potential investigations might target (but should not gation or safety information in real-time, and leisure be limited to): simulation environments to alleviate sensory depri- vation in space. Central to SVAR is the effective and • Systematic exploration of the effects of frequent efficient support of multi-sensory human information small vs. rare but large modifications of an auto- processing at different stages, i.e. by sharpening and mation and/or user-interface system on task per- extending perception, by improving decision making formance through previews and ‘what if’ scenarios, and by test- • The effects of various protocols for participation ing action implementation for validation of new tools and notification of changes on task performance and procedures. Though SVAR can represent all sys- (e.g., simple notification vs. sign off vs. explicit tem components such as materials, tools, procedures, accept/reject decisions vs. user-initiated change functionalities, and their interactions, feedback about requests) potential gaps between SVAR and reality may be re- • The effects of time lag on group collaboration quired. The high impact of SVAR on long-term space (crew + ground) with special emphasis on creativ- explorations is due to the capacity and flexibility of ity, problem solving, and error/problem detection SVAR in a broad range of applications and for a com- and avoidance. prehensive diversity of tasks. Evidence can already be gained from applications on Earth (e.g., industrial, Trans-disciplinary aspects medical, military operations) and in relation to space (e.g., primarily with regard to training and remote There are links with issues related to group and team control applications). processes: cross-team and cross-shift communica- tion (of changes); team collaboration and consensus Carefully designed according to human information on change/behaviour - How should agreements be processing requirements, SVAR has the potential to made on how a system should appear/behave? What convey solutions or serve as a countermeasure for are the limits of individual adaptation vs. group ex- several unique aspects of space missions, far beyond pectation? space applications currently available. SVAR can po- tentially compensate for: the alleviation of sensory There are also clear links with skill maintenance as- deprivation by providing rich stimulation across all pects: notification of change, rehearsal, training; stages of information processing for all phases, loca- transfer of training problems (and their detection). tions and tasks of the mission; the inability for direct human-machine interaction due to distant, extreme 2.2.4. Key Issue 4: Simulation and virtual/augment- or hazardous environments by facilitating emulation, ed reality (SVAR) ‘what if’ scenario simulation, and remote control; the information complexity in decision-making processes Relevance for long-duration missions during safety-critical mission scenarios by assisting through SVAR functionalities for information repre- By representing approximations of real and imaginary sentation; unforeseen or emerging circumstances in world work and leisure environments, simulation, vir- the course of the mission by adapting SVAR to new or tual and augmented reality (SVAR) provides a tool for future situations; the limitations in safe-guards or fail- and a design methodology of multi-modal interac- safe components during long-duration remote/ iso- tion in human-machine systems. SVAR should serve lated system operations by SVAR support for verifica- an enrichment of system components and function- tion and validation of changes during the mission; the alities already available and provide a complement or lack of opportunities for on-the-job training in una- extension through new components and functionali- vailable or unforeseen environments during the long- ties suitable to improve human performance in actual term mission by augmenting environments or virtu-

30 Human-Machine Interface ally enriching environments; the limited diversity of social interactions due to small crews during long-term missions by Earth working and living scenarios and functionalities; the lack of privacy by using SVAR to enable individualised pursue of interests.

Specific issues are the need for modelling of environments for different mission stages (pre-flight, flight, post-flight), mission requirements (remote control, verification and val- idation of updates, skill maintenance), and mission charac- teristics (nominal and off-nominal, long-duration, confine- ment) for effective and efficient use in SVAR; design and evaluation of SVAR human-machine interfaces, to facilitate dynamic interaction of multi-sensory human information processing for unique mission characteristics; feedback de- sign for appropriate representation of gaps between SVAR and reality; methodologies for assessment and prediction of SVAR fidelity, immersion and presence for appropriate support of human performance; support for mission cycle (including re-adaptation to earth) Figure 9: Astronaut Rick Mastracchio uses vir- tual reality equipment to practice tasks he will Earth benefits and applications perform in space, and virtually interacts with ISS equipment (Credit: NASA) Research on SVAR in long-term space exploration is of high relevance for Earth applications: (1) Envisaged SVAR research is required to build on-Earth applications and therefore will also expand methodologies and function- alities already available (e.g., allow for time-lagged remote control using virtual reality, augment human-machine interaction by ‘invisible’ information on friction or weight, and maintain operator skills through training in SVAR); (2) Required SVAR research needs to address unique aspects of space explorations also relevant for operations under isolated or extreme conditions on Earth (e.g., underwater, arctic, desert, mines) or hazardous operations (e.g., as in some industrial, medical, or military settings); (3) Future research should allow SVAR to further advance from a visu- alisation and demonstration tool to a long-duration, mul- ti-sensation interaction tool in enriched work and leisure situations and to a design and evaluation methodology for effective human information processing support during all stages of the product life cycle.

Brief review of latest developments

Latest developments indicate SVAR improvements in at least four different areas: (1) The SVAR technology itself (e.g., higher display resolution, wider range of sensitivity of haptic devices); (2) the use of SVAR as edutainment en-

Human-Machine Interface 31 vironment and in marketing (e.g., training, gaming, environments. Knowledge is also limited about ap- entertaining, advertising); (3) the use of SVAR as a propriate feedback design, as regards feedback dur- methodology for systems design (e.g., usability stud- ing human-machine interactions as well as feedback ies, verification and validation of design solutions, about limitations stemming from SVAR being only an accident prevention and product safety); and (4) the approximation of the real world. application of SVAR as a tool or complement in hu- man-machine interaction settings during enriched Since most existing application research refers to short work and leisure activities. Recent SVAR research also term uses lasting a working day at best, nothing is resulted in suitable solutions for SVAR space applica- known about long-term effects and about long-term tions (e.g., remote virtual control of distant robot and applications relevant e.g. for space missions. Conse- virtual reality pre-flight training). Therefore, research quently, less is known about regimes or procedures activities in Earth and space applications will provide to serve appropriate adaptation and re-adaptation a sound basis for future challenges of long-term space for switches between SVAR and reality. The available mission. knowledge is also limited on use of SVAR for training, retraining, and retention, especially as regards long- Knowledge gaps and research needs term duration applications.

Current knowledge suggests that virtual and mixed Proposed investigations and recommendations realities are useful as human-machine interfaces, for human machine interface design applications and for Based on the knowledge available and knowledge training. Simulated environments have already suc- gaps identified potential investigations might target cessfully been used in different areas of application (but should not be limited to) the following issues: for design representation, for formative evaluation studies, for prospective system design and for train- • Investigate how multi-sensory interactions in hu- ing purposes. However, several knowledge gaps have man information processing across different stag- been identified for better use of SVAR in space appli- es for different work and leisure scenarios affect cations, with the potential to also improve SVAR suit- SVAR support for human performance and devel- ability for Earth applications. op suitable measures for analysis and diagnosis. • Examine how to diagnose and how to predict Less knowledge is available about its effective inte- the appropriate level of simulation fidelity, level gration as a human-machine interaction interface of immersion or feeling of presence for specified including the different means SVAR may serve (e.g., work and leisure scenarios for frequent use of methodology, tool, complement). This is partly be due SVAR during long-duration missions. to current limitations to effectively support all stages • Investigate human performance effects of long- in information processing in virtual and augmented term and long-duration SVAR applications and simulation environments; beginning with the simula- effects of switches between SVAR and the real tion of a broader range of modes of sensation, each in world. Develop recommendations and coun- its dynamic variation and across multiple modes also termeasures that will effectively avoid negative in its interactions. consequences (e.g., fatigue, human information processing impairments, disorientation, mistrust, Although there is already a lot of research on simula- simulator-sickness) and supports human per- tion fidelity, immersion, and presence, it remains un- formance (in work and leisure activities). clear what level of each would be suitable for what • Because augmented and virtual reality at best will applications or purposes and how to reliably assess be a simulation of the world, determine how to de- sensitive level differences during use of SVAR. Further sign feedback on reality gaps (virtual reality to reality improvements are required as regards realistic illu- deviation) for optimal human performance support mination design and workarounds for limitations in • Determine whether and how SVAR procedures transfer of physical / virtual objects from and to virtual may be used to recall earth-like environments

32 Human-Machine Interface during long-term missions, to expand a subjec- exterior space walks for repairs or observations) and tive sense of space or sense of habitat variation, agents (which can organise and “bundle” the intelli- to compensate for long-term confinement, and to gence and situation awareness required to manage support skill maintenance and group processes. and perform complex functions). Insofar as robots • Study how and when human-automation system and/or agents are intentionally anthropomorphised design, software and hardware changes during in their design and in their use by the crew, they may the mission and human-robot/agent interaction have the ability to help relieve social monotony, en- can be supported by use of SVAR (c.f. Key Issues gender loyalty and trust, and provide a “face” around 1, 3 and 5) which to organise automation functions. This social • Identify required qualities of modalities for hu- aspect implies that HRI/HAI may be useful to influ- man information processing for relevant scenar- ence moods in individuals and teams. Finally, in ex- ios (earth, LEO, moon, Mars, ground/ crew inside/ treme circumstances, robots and agents may be able outside shuttle) and fill the quality and / or mo- to operate and continue at least portions of the mis- dality gaps sion when humans cannot. • Investigate new procedures to address more mo- dalities including variations in intensity, type and Robots are familiar to science fiction readers every- over time where as physical agents that have an autonomous • Investigate how to best enable and support hu- capability to execute tasks with some dynamic deci- man-centred design at early stages of product sion-making ability and authority, ideally as instructed development; better grasp of abnormal situa- by or for the service of a human supervisor. Agents, as tions by simulation (what if when scenarios) (c.f. the term is used here, may be thought of as “software Key Issues 1 and 5) robots” or “softbots”—software-only systems which are otherwise like robots- with the autonomous capa- Trans-disciplinary aspects bility to execute tasks with dynamic decision making authority under the supervision of a human, but to do Virtual and mixed realities are useful for training and so without having a physical presence of their own. HMI design applications; what would be the appropri- Both robots and agents maybe be “personified” and/ ate interaction between training and HMI and group/ or anthropomorphic in an appearance, but they do team processes? SVAR may serve as a tool for team and not need to be—and the benefits or consequences group processes management and skill maintenance of personification in design and in use are a hotly de- issues, especially training operational procedures, bated topic in the field. serving skill maintenance, mitigate micro-cultural dif- ferences, but use of VR may increase sense of isolation. Robots and agents are starting to play increasingly Augmented reality displays may serve monitoring of important roles in mission systems technology dur- life support information. ing the mission and pre- and post missions (see es- pecially NASA and GE’s Robonaut2, http://robonaut. 2.2.5. Key Issue 5: Robots (HRI), agents (HAI) & hu- jsc.nasa.gov/default.asp, delivered to the ISS on STS- man-robot-agent interaction (HRAI) 133 in February 2011. During long-duration missions it will be critical for crew members to be able to train Relevance for long-duration missions for, work and interact effectively with these ‘new crew members’ in operational environment and during lei- Due primarily to increased communication lags, long- sure activities. There is little systematic research on duration deep-space missions will require increased the development of the dynamics of the relationship, autonomy on the part of the crew with decreased or on the development of cooperation and communi- ground support (cf. Key Issue 1 above). One way in cation between the crew and ‘new crew members’ (i.e. which increased autonomy can be achieved is through robots and agents), and almost nothing under actual increased use of robots (which can deliver the extra space conditions—though again, the Robonaut2 de- “pair of hands” required in many situations and can ployment will begin to change this. In addition there go where humans can’t go, or go as safely—such as are significant questions about the capabilities, level

Human-Machine Interface 33 of autonomy and division of labour that will be appropriate for robots/agents to occupy in a future mission (c.f. Key Issue 1 on Human-Automation System Design).

There are some major questions surrounding the extensive use of robots and agents in space missions. How can humans feel safe and develop trust during interaction with robots and agents? Can efficient and safe means of communication and cooperation between the crew, ground, robots and agents be designed? What are the advantages and disadvantages of personification? How does working alongside robots and agents affect a person/crew’s self-reliance? How can robots and agents learn from observation and their interactions with humans? Are they able to develop something like a sense of self-awareness and responsibility? How can robots and agents be used to support leisure activities?

Earth benefits and applications

Robots have been in practical use in Earth applications for almost 60 years. The current explosion of new robotic tech- nologies and applications is testament to their on-going and increasing relevance. Robots have been used in manufactur- ing and industrial processes for decades and tele-operated drones have been used in exploration and maintenance for nearly as long. Recent innovations are increasingly targeting robotic applications for applications in hospitals and care- Figure 10: ESA astronaut Paolo Nespoli fa- giving (e.g., medication delivery and even bathing) as well miliarises himself with Robonaut 2, who was as military applications including armed reconnaissance, launched to the International Space Station on bomb disposal and medical evacuation. Viable software February 24th, 2011 (Credit: NASA) agents have an even broader range of applications, especial- ly if they are defined as decision making or aiding software packages apart from personifications. The field is develop- ing rapidly and will almost certainly continue to do so with or without added investment and focus on space applica- tions. As noted below, however, space applications place extraordinary levels of reliance on technology and may drive advances in human-robot and human-agent collaborative work, interaction modalities, and concepts for interaction that involves shared physical proximity and high criticality applications. This, in turn, would have benefits for similar Earth applications—ranging from military to healthcare.

Brief review of latest developments

A range of emerging applications are described in the previ- ous section. Of course, robotic probes have a long history of use in space exploration, most famously the recent Mars rov-

34 Human-Machine Interface ers and the asteroid and comet explorer. While clubs and robotic helpers. There is a need for a sys- there are certainly advancements in the size, weight, tematic research on the development of dynamics range of motion, battery life and control precision as- and trustful relationships between the people, robots sociated with robotic technologies, and the logic and and agents over long periods of time in safety critical processing power associated with agent technolo- environment. There is a call for to understand how to gies, of most interest to this sub-group are advances develop safe cooperation and reliable communica- in human interaction with robots and agents. While tion between the crew and ‘new crew members’ (i.e. there are long-standing research efforts in speech un- robots and agents) with the focus on the use of these derstanding and generation, it seems fair to say that technologies under actual space conditions to enable there are significant improvements in these areas and, joint human-robot-agent exploration missions. specifically, in their use in interactions with robots and agents to perform work and leisure activities in Proposed investigations and recommendations recent years. Other modalities of input to robots and agents are being researched and are slowly making Since so much work is on-going in terrestrial applica- their way toward commercial products and work envi- tions of HRI and HAI, work in this area should begin ronments as well, including gesture and sketch recog- with a detailed analysis of space-specific needs, fol- nition, facial expressions and bio-metric cues for use lowed by a thorough review of existing and on-going as neurophysiological cues. Similarly, increasing work work for applicable lessons learned. This should lead is on-going in establishing protocols for robots which to a more specific identification of those studies and work in the same physical environment with humans, developments that are needed for space applications both in terms of exhibited modalities of behaviour that are not being filled by existing research lines. In (e.g., robot and agent facial expressions, non-verbal particular, a review of current real-world operations in gaze and linguistically synchronised gestures and military and emergency operations, hospitals, etc. for kinesics, posture and gait). Recent studies (e.g., Bick- lessons learned and concepts of operations, followed more, 2010) are showing that there are circumstances by efforts to project these results to space applica- (e.g., discussing medical protocols) in which some us- tions, followed by analogue and space-based studies ers prefer working with agents to other humans. Of to validate the understanding and concepts. The early course, most of this work is being performed in terres- investigations would focus on development of con- trial labour and leisure environments; comparatively cepts, systematic research approaches and method- little is focused specifically on space. Specific excep- ology to first study how humans react to and commu- tions include Bluethman et al., (2003) and Jones and nicate with robots and agents in laboratory settings; Rock (2002). followed by studies of more complex interactions in diverse and collaborative routine work environment Knowledge gaps and research needs and extended to safety-critical and unexpected sce- narios. There is a small amount of data, both from industrial and space research applications about human-robot Potential investigations might include (but should and human-agent interaction. However, there are not be limited to): an ever-increasing number of studies in Earth appli- cation, such as military and healthcare, which share • comparing effects of a range of personification some similar parameters/conditions to long-duration alternatives on human performance in space- space missions, e.g. reliance and dependence on relevant tasks (in lab or earth-based simulation equipment for survival, development of trust over environments); long-period of time. Despite the field of industrial ro- • developing a set of guidelines for the preferred botics, which has existed in industry for half a century, modalities of interaction/communication (speech, the understanding of issues over an extended period gesture, joystick, etc.) for a range of space condi- of time in actual use of robots and agents in every- tions and tasks; day life is only in its infancy, e.g. automated, aware • developing protocols for division of authority and and interactive homes/restaurants/sports and leisure resource usage.

Human-Machine Interface 35 Initial applications will need to be tested in similar- Trans-disciplinary aspects to-space extreme environments, such as military, medical and nuclear domains, e.g. battle conditions, Robots and agents may be used in monitoring and surgical theatres, oilrigs, deep-sea, disaster relief op- maintaining crew health (use of life shirts, encour- eration. Finally, improved concepts of robots and agement of exercise – robots and agents as personal agents as crew members, their communication and trainers); and crew individual and group psychologi- cooperation skills will then need to be tested in sup- cal well-being. Also, robots and agents have a role to port of LEO and Moon missions (pre/post and during play in training and skill maintenance; as mediators in missions), before these technologies are imbedded in group dynamic processes; and in exercise manage- long-duration missions. ment to support compensation for bone and muscle loss.

2.3. Conclusions

The general conclusion of the Expert Group on ‘hu- • Evolving, problem solving and updating during man-machine interface’ is that much more work is missions needed to design and implement effective human- • Simulation and virtual/augmented reality (SVAR) machine systems for use in long-distance space ex- • Robots (HRI), agents (HAI) & human-robot-agent ploration. Although much of the technology and interaction (HRAI) methodology is already well developed, exploration missions impose unique demands on both human European capability is considerable in these areas, operators and automation. In particular, research and with research activity already at a high level. Such development need to focus on designing systems work is expected to have extensive benefits for Earth- that accommodate the need for flexible and adaptive related problems, notably in work environments in- use of automation. Specific themes identified were: volving interaction with highly automated systems, • Design of human-automation system such as process control, transportation and medicine, • Adaptation to support operator state and mis- and the increasing potential of virtual reality and ro- sion goals bots for many Earth applications.

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38 Human-Machine Interface 3 Skill Maintenance

3.1 Introduction

One of the major problems for the involvement of humans in the management of complex mission tasks is the need to maintain necessary levels of operational skills during pro- longed missions. Such issues have not previously been iden- tified as a special source of problems for humans in space, but this is a serious oversight. Maintaining essential skills un- der long-duration conditions is made even more difficult by the necessary provision of high levels of automation, so that crew intervention may often be required only when faults occur with automatic control systems, or when infrequently scheduled manual sequences need to be activated. Specific concerns lie in the need to carry out unscheduled medical interventions or emergency operational trimming proce- dures, which—by definition—are rarely practised. Here, as with other less critical situations, there is a need not only for in-flight top-up training, but also effective computer-based support tools, integrated with relevant systems.

The key research needs identified by the Expert Group on ‘skill maintenance’ are for the development of effective tools and training procedures, for both individual crewmembers and the crew as a team, and for both ground-based prepa- ration (e.g., simulation training) and on-going in-flight sup- port (refresher or top-up training). However, research on the design of effective training and skill support has generally been piecemeal and fragmented. Training for performance of complex tasks needs to be flexible enough to facilitate Figure 11: Andrè Kuipers inside a Soyuz TMA the effective transfer of acquired skills to unusual operation- simulator during a training session at the al conditions (unexpected events, novel problems, emer- Gagarin Cosmonaut Training Centre in Russia gencies). There is also a need to develop countermeasures (Credits: ESA - S. Corvaja, 2010) against the temporary loss of skill under compromised op- erator functional states associated with the presence of en- vironmental stressors, fatigue, sleep disruption, monotony and boredom, all of which can lead to impaired decision making and operational performance. While the knowledge base for such problems is already well developed on Earth, little is known about the impact of the extreme conditions of long space missions. Effective control of disturbances of operator state—essential for long-duration space explora- tion--will require modelling of performance on an individual level, e.g. by collecting extensive baseline data on individual crew members before and during missions.

Skill Maintenance 39 3.2. Skill Maintenance - Key Issues

3.2.1.Key Issue 1: Risks for operational effectiveness evance for safety critical systems. There are numerous from infrequent or non-use of skills complex work situations such as in process control operations, the military, aviation, and civil protection Relevance for long-duration missions services where skills have to be maintained over long time periods and which may rarely be called upon. For One of the major problems for the involvement of hu- some situations it may be ethically impossible to train mans in the management of complex mission tasks is staff under real conditions. A particularly apposite ex- the need to maintain necessary levels of operational ample is when emergency rescue or disaster teams skills during prolonged journeys. This problem is of are required, or in medical emergencies, when highly increasing importance the longer missions become, skilled team members are obviously required but the and are a major risk for interplanetary travel. One rea- situations rarely occur. son is the (necessary) provision of high levels of au- tomation, so that crew intervention is required only Brief review of latest developments when faults occur with automatic control or when infrequent scheduled manual sequences need to be While there are numerous findings in the literature activated. Other activities may be required only occa- about skills and skill acquisition, research on the dete- sionally, or during specific phases of the mission (e.g., rioration and retention of (particularly complex) skills hand controlled docking of a space craft) while oth- are less prevalent, confined largely to tasks with high ers (catching free floating objects with a robot arm, visuomotor challenges, such as those associated with telemetrically controlling a rover and its specific tools aviation. Few researchers have analysed cognitive for surface exploration) are fundamental to mission tasks involving complex decision-making or problem goals. Because of the threat posed by skill neglect solving (e.g., Sauer, Hockey & Wastell, 2000). Farr (1987) there may be a need for skill maintenance support to provides a good overview of older work, but little has be designed as part of an on-board application. been added since. In terrestrial medical research an analogous problem has been investigated, that of the From another point of view the maintenance and maintenance of resuscitation skills in medical environ- training tools of mission important skills provide an ments. This requires both manual and cognitive skills. approach for monitoring and diagnostic analysis of The results demonstrate the primary vulnerability of the state and workability of the astronaut but could the cognitive components in that complex skills may be extended to monitoring of crew cooperation and decay within three months (Kaczorowski, Levitt, Ham- crew performance. Real tasks, including work sample mond, Outerbridge, Grad, Rothma & Graves, 1998). tests are accepted by the crew and do not tend to be rejected by them even after numerous repetitions. For relatively simple skills the typical finding, as dem- But further research and development is required to onstrated by Manzey (1998) for simple tracking, is for identify valid and reliable monitoring methods. Cur- no obvious deterioration over a long period of space rently plans for such monitoring are not incorporated flight. The only known study of long-term retention into the technically oriented development phase of of complex skill in space was conducted by Salnitski, training systems. An effective skill updating system Myasnikov, Bobrov and Shevchenko (1999), and in- is also required for long-term space exploration mis- volved the manual docking of a spacecraft on a space sions. station. The manual control of a spacecraft represents a very difficult task, requiring the simultaneous con- Earth benefits and applications trol of actions in six degrees of freedom, a situation never experienced under terrestrial conditions. The Skill maintenance has a large significance for Earth task primarily challenges complex cognitive proc- applications with naturally long breaks between epi- esses, and cannot be reduced to a simple sensorimo- sodes requiring skill utilisation. There is an obvious rel- tor coordination task. It involves three dimensional

40 Skill Maintenance perception of own position and movement from a Proposed investigations and recommendations 2d-screen; decision making about possible pathways; Proposed studies include: complex (6df)-control of 6 independent engines for turns around own axes and moves in space; limita- • Development of skill maintenance and training tions in fuel consumption; but no marked time con- systems (inventing new techniques and technolo- straints. Both US astronauts and Russian cosmonauts gies) with embedded monitoring of performance described the manual docking of a spacecraft as a and psychophysiological state for strain assess- very exciting and emotionally challenging task. ment; embedded testing of fundamental cogni- tive skills. A primary objective to start with is to be The practical relevance of the topic is evidenced by able to identify how and when performance and the research of Salnitski and his colleagues (Salnit- operator functional state are being compromised ski et al, 1999; Salnitski, Dudukin & Johannes, 2001). by infrequent or non-use of skills. This will enable The docking procedure is trained only on simulators the appropriate monitoring of performance asso- and rarely practiced in real-life situations. Even with ciated with the introduction of diagnostic meth- well-trained cosmonauts, the reliability of these skills ods to alert operators of the need for additional decreases without practice after a period of more training; than three months on a space flight. Hand control- • Systematic investigation of performance of a led docking is required only if the automatic docking range of skills over a long period (2 years), to al- system fails due to a technical fault in the sensor sys- low the identification of possible differential de- tems (measures of distance, relatively speed etc.) or if terioration of different types of skill over time; a transport spacecraft (Progress) has to be re-docked • Comparison of maintenance and learning under to an alternate docking port to vacate the previous standard Earth conditions and in ICE and space port for the approaching Shuttle. Finally, in most in- environments. This will be necessary because of stances of manual docking, the astronaut is perform- the interaction between learning, performance ing this operation in reality for the first and only time. and the space environment, for example in terms It is obvious that a high level of psychological strain of the effects of adaptation to microgravity, bone may play a critical role in such a situation. The crashed and muscle changes over time. docking during the MIR23-Mission (Ellis, 2000) is an unfortunate example of what can go wrong. Salnitski Trans-disciplinary aspects et al. (2001) developed a common concept for evalu- ating the reliability of an operator’s skill. Besides tak- The embedding of training and monitoring methods ing into account all indicators of docking quality, the into the operational system will need to be designed assessment of the psychophysiological state during in relation to several of the issues related to human- the docking manoeuvre plays an important role for machine interfaces. the prediction of the expected real docking success. 3.2.2. Key Issue 2: Need for different training meth- Knowledge gaps and research needs ods for the acquisition and maintenance of different types of skill While there is an extensive terrestrial empirical base for skill acquisition, as well as for forgetting in simple Relevance for long-duration missions tasks, very little is known about the pattern of skill loss with disuse for more complex tasks. There is only Long transfer phases between Earth and other plan- limited knowledge of methods for monitoring and as- ets require the crew to maintain knowledge and skills sessing potential skill deterioration for different types that typically are acquired and trained pre-flight on of skills. Also, very little is known about the rates and Earth but will only be needed at the destination of the level of skill loss for task knowledge and procedures flight. In addition, with longer space flights there is an that are shared between members of teams or crews. increased probability that crew members have to re- Finally, almost nothing is known about patterns of act to unforeseen incidents in which the trained skills skill learning and deterioration in space missions.

Skill Maintenance 41 need to be flexible applied. High-performance skills vary in their dependence on different cognitive, perceptual and motor components, and are thought to benefit from spe- cific training regimes. Even for skills that are superficially similar (e.g., those used by process operators to manage chemical plants or transport systems) there are variations in the dependency on rules/procedures or knowledge/real- time decision making. Training methods vary in a number of ways (e.g., specific/general skills, whole/part skills, use of feedback, and spacing of practice). From the point of view of preserving these different kinds of skill under the stress and low practice condition of extended missions it would be advantageous to examine the relative effectiveness of different strategies for the range of skill types experienced during missions – not only during acquisition but for later use.

Figure 12: ESA astronaut Frank De Winne trains In addition, the tasks which have to be performed by the inside the Cupola module mock-up in the Mul- crew members may be distinguished in terms of their sta- ti-use Remote Manipulator Development Facil- tus as part of planned activities, differing in frequency of ity (Credit: ESA/NASA) implementation and time until first requirement. For exam- ple, while the skills for performing the tasks during take-off are implemented at the beginning of the journey to Mars (meaning a smaller retention interval), skills relevant to landing manoeuvres on Mars are needed at the earliest 6-8 months after the take-off (a very large retention interval). In addition to these tasks, for which it is possible to esti- mate when they have to be performed, other skills have to be implemented unexpectedly; e.g. trouble shooting in the case of a technical problem or medical emergency. Both conditions of skill application are relevant to consider in the proposed research and need to be addressed differ- ently; e.g., in terms of just-in-time training for predictable skill applications with long retention intervals and other forms of training for addressing the unexpected trouble- shooting applications.

Earth benefits and applications

Many high reliability organisations such as nuclear power plants, chemical plants, oil platforms or refineries, hospi- tals or commercial aviation, are characterised by highly specialised production departments which have to oper- ate on a highly dependent (reliable) level. Whether or not they actually perform reliably is demonstrated in non-nor- mal or abnormal situations which are either (a) technical problems that arise and need to be addressed by the hu- man operator (troubleshooting) or (b) important/danger- ous and infrequent events, such as the shut down every

42 Skill Maintenance five years of a plant for a general technical inspection. Knowledge gaps and research needs Within the time period before the infrequent event, skills are likely to degrade through long periods of Kanas and Manzey (2008) refer to training that pre- non-use and the extensive use of highly automated pares astronauts for coping with the psychological processes. This means that for Earth applications, the demands of space flight, also called non-technical unexpected and immediate skill application as well as skill. But there exists only limited knowledge of the the infrequent use of special skills is also relevant, but following: how training approaches affect the way just-in-time training might be easier to conduct. of maintaining different skills; effective sequencing, spacing and composition of training methods; effec- Brief review of latest developments tive retrieval practice; advantages and disadvantages of training of flexible vs. specialised skills; the effect of Generally it is assumed that training methods vary in the training of general versus specific problem solv- their effectiveness in a number of ways (e.g., specific/ ing procedures; how training of one skill saves train- general training, whole/part task training, quality and ing and rehearsal time of another (and how much it quantity of feedback, spacing of practice; Pashler, depends on there being shared aspect of both tasks); Rohrer, Cepeda & Carpenter, 2007; Schmidt & Bjork, use of recall and recognition cues, such procedural 1992), but there are a small number of isolated stud- aids and decision aids, or online help systems, re- ies directly addressing skill learning, retention, and hearsal techniques, etc.; the extent to which skills relearning (e.g. Arthur et al., 2007; Ginzburg & Dar-El, and skill maintenance can be allocated among crew 2000), or very long intervals of non-use (Pashler et al., members, or whether every crew member needs to 2007; Shute & Gawlick, 1995). be trained to meet predefined performance criteria in order to build up shared knowledge and skill redun- A comprehensive analysis by Arthur et al. (1998; ex- dancy within the group. tended by Leonard, 2007) showed that skill reten- tion depends on the nature of task (physical, natural, Proposed investigations and recommendations speed-based versus cognitive, artificial, accuracy- based) as well as the conditions of retrieval. Addition- High-performance skills vary in their dependence ally, research by Pashler et al. (2007) and by Roediger on different cognitive, perceptual and motor com- and Karpicke (2006) shows that skill maintenance can ponents, and are known to benefit from specific be positively affected by retrieval practice. But so far training regimes. Even for skills that are superficially only relatively simple tasks have been investigated, similar (e.g., those used by process operators to man- such as learning word pairs, mathematical problem age chemical plants or transport systems) there are solving, perceptual categorisation learning, or fact variations in the dependency on rules/procedures learning (e.g. Pashler et al., 2007). These are obviously or knowledge/real-time decision making. Therefore, parts of the complex skills needed for longer space the major need is for a formal analysis of which skills flights, but have not so far been investigated in com- are required after a period of non-use, and how long bination. these practice gaps are for different activities. These skills and their associated periods of non-use may Current research on process control (Burkolter, Kluge, then be ranked in terms of the duration of their pe- Sauer & Ritzmann, 2010; Kluge, Sauer, Burkolter & Ritz- riod of non-use, and investigated in combination with mann, 2010) shows that training methods differential- a cognitive task analysis to systematically investigate ly affect task components after 12 weeks of non-use. the pattern and extent of forgetting. Practising routine drills, for example, supports the use of procedural knowledge within closed loop tasks, leading to fewer decrements in performing fixed se- quences for reacting to a technical problem. However, skills in stabilising a technical system manually (using system knowledge or open loop control) were not af- fected by different training methods.

Skill Maintenance 43 Based on such findings, investigations (training- ex Relevance for long-duration missions periments including pre-flight training and assess- ment on the ISS) are needed of the effectiveness of Many mission relevant skills are trained only on simu- different training approaches: lators prior to a real space flight (e.g., docking train- ing). In professional aviation the use of full scale or • evaluation of advantages and disadvantages of part task simulators is a standard, but this is not pos- part-task training, whole task training, emphasis sible as an on-board application. The need to develop shift training, procedural training; training capabilities and platforms that can be imple- • the spacing and most effective forms of retrieval mented on board and enable training and refresh- practice for different types of complex cognitive ment of skills, tasks and procedures is an important and psychomotor skills, including comparison of challenge for long-duration space missions and is different training schedules and spacing; made possible by contemporary developments in • possible advantages of over-training (beyond the use of virtual reality technology for skill training nominal 100% criteria of performance) in pro- (Gopher et al 2010). It is equally relevant to a large tecting skills against decrement with non-use. variety of long duration, high demand and rich tech- nology tasks performed on earth. All of them have in From the point of view of preserving these different common the need to acquire and maintain high com- kinds of skill, under the stress and low practice condi- petency in a wide and diversified set of skills, inter- tions of extended missions, it would be advantageous act with and be comfortable in the operation of ad- to examine the relative effectiveness of different strat- vanced engineering systems, cope with dynamically egies across the full range of skill types experienced changing demands and respond to emergency and during missions. low frequency events. It is also the case that in space missions as well as in many of these tasks errors are Trans-disciplinary aspects costly, hence there is a low tolerance for errors (e.g. flight control, nuclear power plant control rooms, sub- The Expert Group did not identified obvious overlaps marines, etc.). The challenge is to develop modules with other topics. and formats of training that can be incorporated on board and be accessed during and along with mission 3.2.3. Key Issue 3: Use of on-board top-up training performance. The present age of sophisticated, high- to maintain and enhance skills powered, computer- and AI-supported operational systems, makes it possible and desirable to include One way of overcoming the impairment of skills with an accompanying integrated training module in the disuse or lack of operational practice is to provide sup- basic design configuration of the system. Such a train- plementary (top-up) training, but there are currently ing and simulation module will enable crew to move no accepted criteria for deciding how best to achieve readily between training and operational modes in this. Different perceptual motor competencies, cogni- system operation. This mode may enable the techno- tive and executive control skills, and even individuals, logical age re-instantiation of the “on the job training” may require different schedules and types of refresh- concept. It should be recognised that a prime instiga- ment. Specific questions refer to the timing, inten- tor for the development of separate task simulators sity and design of refreshment training in relation to and training environment was the limited ability to the skill – how specific or varied it is in use, and how conduct training on the real system much it is constrained by environmental input. A sec- ond issue concerns on-board implementation; how Earth benefits and applications can training platforms and refreshment procedures be designed into the system, using either integrated There would be benefits for a variety of industries, in learning modules or self-managed, off-line tools? terms of workability, maintenance of proficiency, and the retraining of professionals (continuing profession- al development).

44 Skill Maintenance Brief review of latest developments

With the advancement of computer technology simulators becoming more hybrid and dynamic systems, visual field and audition have become increasingly driven and gener- ated by computers. Contemporary developments in sen- sors and display capabilities and the exponential increase in computation speed and storage capacity led the way to the development of multimodal virtual environments. In these environments, the operator is immersed, experiencing multimodal sensations and interacting with virtual objects including other humans (Riva 2006, Sanchez-Vives, Slater, 2005). Vision and audition have routinely been included the study and design of simulators. The new important addition is the inclusion of haptics—the ability to feel and exercise force, touch, texture and kinematic sensations. Haptic tech- nology is developing rapidly and haptic interfaces are now being incorporated into many virtual worlds. It is reasonable to expect that the multimodal, virtual reality platforms will dominate the next generation of training simulators. An ex- ample for this development is the current collaborative skills project of the EC 6th Framework Programme on multimodal Interfaces for capturing and transfer of skills (Avizzano 2008; Avizzano et al, 2010; Gopher et al. 2010; Ruffaldi et al, 2010). Figure 13: ESA astronaut The goal is to design, develop and validate training systems uses virtual reality hardware in the Space Vehi- where haptic technologies are introduced in the interaction cle Mockup facility at the Johnson Space Cent- with the training virtual scenarios; in this, the paradigm of er to rehearse duties he will perform on the ISS knowledge acquisition plays a central role. (Credit: ESA/NASA)

In this context specific (complex) tasks have been identified suitable to become the focus of training scenarios based on the application of robotics and virtual environments tech- nologies. These tasks belong to different application do- mains – sport and entertainment, surgery and rehabilitation, industrial maintenance and assembly – and specific training scenarios and demonstrators have been associated to such domains.

Knowledge gaps and research needs

Training simulations, virtual reality, computer based trainers and training environments have all have been developed to serve task and systems but have not been constructed as an added integral component of the operational system to combine operation and training and enable on the job training. Performer training and system operation have been developed independently and analysed separately. Training is conducted in a separate environment, in preparation for operational performance (e.g. Kaiser, & Schroeder, 2003). The

Skill Maintenance 45 main argument here is that with the long-duration 3.2.4. Key Issue 4: Protection against effects of stres- space missions and the present state of technology, it sors on skill learning and effective long-term skilled is possible and necessary to include “on the job train- performance ing” together with the operational system design. It is anticipated that such an approach will be beneficial Relevance for long-duration missions for both operational effectiveness and skill training and reduce their costs. The effective performance of skills can be threatened by compromised operator functional states, such as Proposed investigations and recommendations those produced by the need to combat stressors. Such states are intrinsic to space missions, induced by the A number of fundamental sets of studies are required extreme physical environment, isolation and confine- to develop this area to the point where it can be use- ment, danger and the requirement to maintain mis- ful for space exploration, particularly for dynamic, sion goals under all situations. Effects of stress states high demand tasks, where there is a high degree of are not always obvious because of the typical opera- uncertainty and variability in details of the task pro- tion of an adaptive strategy which protects primary file, and low tolerance to error. In many tasks of this goals through increased effort, but there are likely to type forgetting of skills is exacerbated by the long- be hidden costs which can compromise safety mar- time intervals between the recurrence and repeated gins. In addition, stressors such as noise or threat have use of some task segments, emphasising the need for been found to make learning more specific and rigid, continuing training that can be readily available and with reduced flexibility for responding under unfamil- easily accessed: iar circumstances.

• There is a sufficient level of technology and AI Earth benefits and applications capability on board to justify and support the incorporation of skill training modules. A major The terrestrial applications of the proposed research research goal is to develop formal methods of are many and varied. There is a massive potential ap- achieving these aims within the normal operation plication to stress management; coaching/learning and conduct of the mission. Research needs to be environments; specific healthcare and medical sys- carried out on how to embed training modes, sce- tems; the training of medical skills for disaster situa- narios and options, within and in support of each tions; and operator support in safety critical systems. main system and operational segment. In terms of the advantages of developing appropri- • A major programme of work is required on opti- ate countermeasures there is potential application to mal ways of using virtual and augmented reality work in extreme stress environments, with appropri- capabilities to support complex skills. Methods ate application to stress management, emergency/ need to be established for determining how and terrorist measures, accident management, and es- what performance measures and comparison for- cape training. mats should be added for performance, both on the real system and in the training environment Brief review of latest developments (analogous to transfer of training studies). This would allow the evaluation of learning progress There is widespread knowledge about the short-term as well as possible deterioration in competence. effects of stressors across a range of well-learned skills. However, very little is known about the effects of such Trans-disciplinary aspects stressors on skill acquisition and the long-term main- tenance of skills, for both Earth and for space simu- Provision of on-board training has a direct relevance lation; almost no knowledge of performance under for the management of communication delays and stress in space; and limited knowledge of methods changes in crew cognition. to protect crew members against stress effects. Kanas and Manzey (2008) identified various factors that have

46 Skill Maintenance Environmental factors Individual state factors Psychosocial factors Noise Sleep deprivation Isolation Radiation Disturbance of sleep patterns Confinement Microgravity Fatigue Social interaction Vibration Health and well-being Communications Light/dark cycle Physiological adaptation Boredom/monotony Task demands Psychological adaptation

Table 1. Potential threats to skill maintenance in space missions the potential to cause performance impairments dur- exhibit a ‘graceful degradation’ (Navon & Gopher, ing space flight (see Table 1). 1979), rather than a catastrophic collapse.

However, the outcomes of a huge amount of experi- An important question for space flight is whether mental work on the effects of various stressors on crew members can be trained to deal more effec- single-task performance suggest that degradation of tively with stress states, and reduce the threat to op- simple tasks is unlikely to be observed under normal erational skills. In other words, are there any effective conditions. This is especially so with highly trained countermeasures against impairment under stress? personnel. Impairments of task performance are only An approach known as stress exposure training (SET) likely to be observed under complex multiple-task sit- has been proposed as a training intervention to re- uations or in unpredictable conditions such as emer- duce anxiety and improve performance under stress gencies, although dual-task performance (tracking (Driskell & Johnston, 1998). SET involves instruction in and a reaction time task) was unimpaired in the high- the likely impact of stressors, and allows the practise ly trained astronauts (n=6) tested in the 16-day NASA of task skills under conditions that are increasingly Neurolab mission (Fowler, Bock & Comfort, 2000). In similar to those expected in operational situations. terms of research conducted in space and analogue SET has proved effective in protecting operators by environments there is little evidence of disruption on preparing them for performing under stress (e.g., a range of single tasks, other than for some relatively Driskell, Johnston & Salas, 2001). However, it is pos- short-lasting decrements in tracking and dual-task sible that training skills and preparing operators to performance in the early stages of a flight (Kanas & perform under stress may require specific knowledge Manzey, 2008; Manzey, Lorenz & Polyakov, 1998). Ad- of the situations and tasks likely to be faced by them aptation to the new environment appears to erode in space, which may not always be possible. these effects. Knowledge gaps and research needs Primary-task performance has been described as be- ing protected under ‘normal’ circumstances, particu- Creating real or simulated emergencies in labora- larly in laboratory-based situations (e.g. Hockey, 1997; tory situations is not easy and it is often impossible Kahneman, 1973). This has been found to be true to predict the nature of potential natural emergencies of tasks based on classical industrial activities, such accurately. Although there is a wide literature on the as vigilance (monitoring and inspection activities), effects of single stressors on certain types of perform- tracking (manual control of all kinds) and sequential ance, these tend to be limited to relatively low levels responding (underlying the kind of complex percep- of stress and few studies have examined the effects tual motor skills found in many office tasks). Where of multiple stressors on performance and state out- decrements are found, they are usually not serious, comes. More evidence is also needed on the efficacy have minimal practical implications, and are actively of SET from lab-based studies and military/industrial/ managed. In general, the management of perform- healthcare applications. There is currently no knowl- ance under stress and high demand may be said to edge of effects in space or space simulations.

Skill Maintenance 47 Very little is known about the transfer of skills learned 3.2.5. Key Issue 5: Management of sleep and work/ during simulation training to their use in new stress- rest schedules to prevent skill impairment by sleepi- ful environments. Despite the considerable body of ness and fatigue. research on the effects of environmental stressors on performance, there is little of direct relevance to this Relevance for long-duration missions question. Space flight presents particular challenges for sleep Proposed investigations and recommendations and a number of studies have indicated that sleep is The main recommendations are: impaired by suboptimal work/rest schedules, unsuita- ble temporal light patterns, noise, stress, microgravity • that a systematic investigation should be con- and other factors. Sleep disruption, circadian resyn- ducted of the effects of a combination of stressors chronisation, and the resulting fatigue and sleepiness on a range of skills on Earth and in low Earth or- will, in turn, impair the performance of operational bit. In order for this programme of research to be skills. The occurrence of such disruptions can make effective it will be important that an appropriate the crew dysfunctional in one or two days. Mainte- methodology is developed for studying skill dec- nance of effective sleep is thus a key goal for extend- rement in relation to performance and the costs ed space missions. of managing performance. This will require a multi-measurement approach, in which perform- Earth benefits and applications ance and changes in operator functional state are monitored in relation to the manipulation of mul- Risk management related to fatigue, sleep and circa- tiple stressors; dian disruption is relevant to all areas where human • In terms of the development of appropriate coun- performance, and particularly the guarantee of a cer- termeasures, studies need to be conducted to tain level of performance, is critical. Medical applica- evaluate the effects of stress exposure training tions, nuclear plant management and the transport (SET) for different applications and environmen- industry are among the most obvious applications, tal situations. A study using the ISS would provide but also shift work and other irregular working re- an ecologically valid environment, with initial SET gimes in non-risk related places. Fatigue and sleepi- training on Earth (with control group receiving ness may seem like topics which have already been dummy training). The study would examine the investigated extensively, however, in terms of coun- transfer of SET training during the preliminary termeasures, there is a serious lack of research sup- Earth phase (between different kinds of stressors porting evidence based applications. Another impor- and tasks), then during ISS mission, and during tant benefit for Earth application is the contribution follow-up back on Earth. A suitable sample size to the measurement of fatigue and fatigue-like states. would need to be built up from several cohorts. It This is highly relevant for clinical research on chronic is important that such a study has many relevant diseases, where fatigue is the main symptom affect- outcome measures. It will be necessary to dem- ing quality of life, such as cancer, chronic fatigue, mul- onstrate both the effects of stress and the effec- tiple sclerosis and others. These affections could also tiveness of SET. benefit from the countermeasures identified to be relevant for space flight. Trans-disciplinary aspects Brief review of latest developments Training for stress management has a clear link with that for crew cognition and would best be treated as While sleep loss and circadian influences are known part of the same pre-mission programme. to have remarkably strong effects on alertness and behavioural efficiency, relatively few studies have demonstrated such effects on real-life performance.

48 Skill Maintenance This is a problem because laboratory results cannot be read- ily generalised to operational environments. However, a number of studies have shown that poor or shortened sleep is a predictor of fatal accidents at work, and that accident risk is considerably increased by irregular work hours (Åkerstedt, 2002).

Spaceflight research indicates that the overall quantity and quality of sleep in astronauts is markedly reduced in com- parison to terrestrial sleep (NASA, 2008). Sleep structure changes are variable, with generally more awakenings and intra-sleep wakefulness, and sometimes a decrease in Slow- wave sleep (SWS) during the flight (Frost, Shumate, Salamy & Booher, 1976; Gundel, Polyakov & Zulley, 1997; Dijk, Neri, Wyatt, Ronda, Rie, & Ritz-De Cecco, 2001). Sleep disturbances in space depend on a combination of factors such as mission Figure 14: Sleeping cabins on-board the ISS imperatives, confinement, promiscuity, noise, workload, the are built into the floor, walls and ceiling, pro- loss of stable circadian zeitgebers and circadian misalign- viding astronauts with privacy and a fixed ment. For example, workplace stress, fatigue and sleep dep- place to sleep (Credit: ESA/NASA) rivation were identified by NASA as contributory factors in the Mir-Progress collision (Ellis, 2000).

A number of countermeasures have been implemented in order to improve sleep comfort, including carefully timed bright light exposure (Fucci, Gardner, Hanifin, Jasser, Byrne, Gerner et al., 2005). Current research mainly focuses on ac- tigraphy-data driven scheduling tools: for example, splitting sleep and implement napping strategies under conditions where continuous night rest may not be compatible with operational requirements (Mollicone, Van Dongen, Rogers & Dinges, 2008). An additional promising method is physical activity, which is regarded as a standard non-pharmacolog- ical intervention for sleep disorders (Hauri, 1993). Exercise is particularly effective when other zeitgebers (notably the light-dark cycle) are missing, as will be the case during a long-duration exploration flight. Indeed, the observed de- crease in SWS during space missions (Gundel et al, 1997; Dijk et al, 2001) has been attributed to reduced physical activity during spaceflight, and thus a reduced influence of sleep homeostatic processes. Biofeedback can also be used as a self-regulation method of sleep management (through con- trol of relevant physiological systems: cardiac activity, respi- ration, muscle tone or cortical activity (Egner and Gruzelier, 2004).

Knowledge gaps and research needs

While a great deal is known about sleep and its performance effects in terrestrial environments, relatively little is known

Skill Maintenance 49 on how sleep is affected by long space missions, and valid way because of their multidimensionality. what effects these may have on skill use in such situ- A major goal is to try to model their impact on ations. Research needs can thus be summarised as performance; follows: (1) detailed physiological assessment of sleep • More effective countermeasures or combinations during spaceflight, with clear identification and diag- of interventions need to be identified. These al- nosis of sleep impairments; (2) Impact of sleep and cir- ready include sleep scheduling (including nap- cadian disruption on skill maintenance during space- ping and split-sleep strategies), exercise regimen, flight/confinement; (3) modelling and prediction of biofeedback, phototherapy, nutrition and drugs. performance decrements due to sleep impairment, Effects of countermeasures should be assessed, circadian disruption and demanding work schedules; to issue recommendations with regard to the ad- (4) a better understanding of fatigue – in particular the equate combination to be applied during long- joint effects of fatigue from sleep disruption and from duration space mission. Such studies need to be mental and physical work – with clear predictions of carried out in ISS or ICE settings, which share the its impact on performance; (5) a focussed search for relevant features of sleep discomfort, isolation, more effective countermeasures. confinement and circadian disruption.

Proposed investigations and recommendations Transdisciplinary aspects

• The impact of sleep and circadian disruption on There are evident links with integrative physiology – skill maintenance needs to be fully understood these should be explored further (exercise as counter- and carefully quantified. This implies a need for measure => bone loss and amyotrophy, cardiovascu- measurement tools. Fatigue and skill mainte- lar deconditioning). There is also a link with HMI issues nance are concepts intuitively grasped by every- and habitat – design of mission environment (both body, and yet hard to measure in an ecologically hardware and software).

3.3. Conclusions

The broad conclusion from the Expert Group is that • Use of on-board top-up training to maintain the problem of skill maintenance should be recog- and enhance skills nised as a major focus for space-related research on • Protection against effects of stressors on skill human behaviour. This area has been overlooked learning and effective long-term skilled -per in previous human space programmes, though it formance is likely to have a major role in the success of very • Management of sleep and work/rest schedules long-duration missions. Maintaining operational to prevent skill impairment by sleepiness and skills requires both a better understanding of how fatigue to develop effective training and methods of pro- viding on-board refreshment of skills. A third focus A high level of European capability exists in all these for research is to understand and manage the threat areas, though it is at present not focussed on space from environmental stressors, fatigue and sleep dis- issues. The potential benefits for Earth activities turbances. are almost unlimited, since the programme would ensure better learning, retention and utilisation of Specific topics identified for further research were: complex skills, and a greater resilience of human performance under conditions of threat and stress. • Risks for operational effectiveness from infre- quent or non-use of skills • Need for different training methods for the ac- quisition and maintenance of different types of skill

50 Skill Maintenance 3.4. References

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Skill Maintenance 53 4 Annex: Expert Group Composition

Psychology and human‐machine systems cluster coordinator:

Bob Hockey University of Sheffield, UK

Group/Team Processes – Expert Group Members:

Tony Gaillard (Chair) TNO Human Factors Institute, NL Gro Sandal (Rapporteur) University of Bergen, Norway Gabriel De la Torre University of Cadiz, Spain Fabio Ferlazzo University of Rome la Sapienza, Italy Rhona Flin University of Aberdeen, UK Nick Kanas University of San Francisco, USA Elisabeth Rosnet INSERM, Paris, France Christine le Scanff University of Paris-South, France Carole Tafforin Ethospace, Toulouse, France Berna Van Barsen FU Amsterdam, NL

Human-Machine Interface - Expert Groups Members:

Chris Miller (Chair) SIFT, Minneapolis, USA Peter Nickel (Rapporteur) IOSH, Sankt Augustin, Germany Francesco Di Nocera U of Rome la Sapienza, Italy Ben Mulder U of Groningen, NL Mark Neerincx TNO, NL Raja Parasuraman George Mason U, Washington, USA Iya Whiteley IACE, UK

Skill Maintenance Expert Groups Members:

Andy Tattersall (Chair) Liverpool JMU, UK Bernd Johannes (Rapporteur) DLR Cologne, Germany Torbjörn Åkerstedt Karolinska Hospital Stockholm, Sweden Enrico Thales Alenia Space, Italy Danny Gopher Technion-Israeli Institute of Technology Annette Kluge U Duisburg-Essen, Germany Dietrich Manzey TU Berlin, Germany Nathalie Pattyn VUB Brussels, Belgium.

54 Annex: Expert Group Composition Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-02-4 printed in E.U. march 2012

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Cluster 3: Space Radiation - Report

CLUSTER3 March2012 1

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Towards Human Exploration of Space: a EUropean Strategy

Cluster 3: Space Radiation - Report

Radiation Effects on Humans Radiation Dosimetry THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low Earth orbit have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus:

Cluster 1: Integrated Systems Physiology Cluster 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space medicine Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

4 Table of Contents

1. Radiation Effects on Humans...... 5 1.1. Introduction...... 6 1.2. Key Issues...... 7 1.2.1. Key Issue 1: What is the particle and dose rate dependency for acute effects?...... 7 1.2.2. Key Issue 2: How is the sensitivity to acute effects modified by the space environment?...... 7 1.2.3. Key Issue 3: What is the effectiveness of GCR at low doses for carcinogenesis?...... 8 1.2.4. Key Issue 4: Is there a risk of CNS damage from low doses of GCR?...... 9 1.2.5. Key issue 5: Is there a risk of non-cancer late effects from low doses of GCR?...... 10 1.2.6. Key Issue 6: Is there a risk of hereditary effects from low doses of GCR?...... 11 1.2.7. Key Issue 7: How will multi-scale mechanistic-based modelling of space radiation improve risk estimates?...... 12 1.2.8. Key Issue 8: How can radiation effects be effectively mitigated?...... 12 1.3. Conclusion...... 13 1.4. References...... 15

2. Radiation Dosimetry...... 19 2.1. Introduction...... 19 2.2. Key Issues...... 20 2.2.1. Key Issue 1: Experimental determination of radiation field parameters...... 20 2.2.2. Key Issue 2: Modelling of radiation environments...... 22 2.2.3. Key Issue 3: Space weather forecast...... 23 2.2.4. Key Issue 4: Transport codes...... 25 2.2.5. Key issue 5: Shielding...... 26 2.2.6. Key Issue 6: Individual radiation exposures...... 28 2.2.7. Key Issue 7: Support to mission planning and operation...... 30 2.3. Conclusion...... 31 2.4. References...... 32

3. Annex: Composition of Expert Groups...... 38

5 1 Radiation Effects on Humans

1.1 Introduction

Cosmic radiation is considered the main health hazard Reducing the uncertainty of the risk estimates is for human exploration and colonisation of the solar clearly the main research priority. Effective counter- system. Radiation risk is characterised by a high un- measure design can only become possible once the certainty and lack of simple countermeasures. Most of uncertainty of risk estimates is reduced. the uncertainty on space radiation risk is associated with the poor knowledge of biological effects of cos- The priorities of research that are necessary to sup- mic rays. In particular, gaps in knowledge are mostly port foreseen space travel and planetary exploration related to: represent a unique set of problems whose solution • Relative Biological Effectiveness (RBE) factors of demands an in-depth understanding of the whole energetic heavy ions for late effects, both cancer human body and cross-disciplinary work between life and non-cancer; scientists, engineers and technologists. All the neces- • Dose and dose-rate reduction effectiveness fac- sary expertise has been acquired by European scien- tors (DDREFs); tists during the past decades. In the context of the • Errors in human data including statistics, dosim- THESEUS project, the objective of this Expert Group etry and transfer between populations in applica- was to gather this European expertise to create syner- tion to space radiation risks; gies, facilitating an integrated approach on emerged • Effects of exposure to the mixed high- and low- research priorities. Because of the necessary holistic LET space radiation field; approach, those research programmes obviously re- • Shape of the dose-response curve at low doses quired the involvement of scientists whose expertise for charged particles; is disseminated across Europe.

Interaction of radiation damage with other space en- The following section reports the conclusions of the vironment stressors, particularly microgravity. ‘Radiation Effects on Humans’ Expert Group. This The main biological effects associated with exposure group met during two Expert Workshops in 2010. The to cosmic radiation are: workshops were organised sessions aimed at consid- • Carcinogenesis; ering the key questions to address, the latest devel- • Late degenerative tissue effects; opments, the gaps to fill and the Earth-based applica- • Acute effects; tions. • Hereditary effects.

Currently, cancer dominates risk estimates and dose limits are primarily constrained by cancer mortality risk. However, non-cancer effects are becoming an in- creasing source of concern. They can be again divided into: • Acute and late damage to the central nervous sys- tem (CNS); • Cataract formation; • Cardiovascular diseases including coronary heart disease and stroke; • Digestive and respiratory diseases; • Accelerated senescence leading to endocrine and immune system dysfunction.

6 Radiation Effects on Humans 1.2 Group/Team Processes– Key Issues

1.2.1. Key Issue 1: What is the particle and dose rate and helium ions at different energies. Furthermore, dependency for acute effects? the inter-individual variability for acute effects should be studied in mechanistic detail. Relevance for space exploration missions Proposed investigations and recommendations One of the unknown aspects of long-duration space • Reviewing data from proton and heavy ion missions is the influence of different spaceflight therapy; parameters on the occurrence of acute radiation • Performing mechanistic in-vitro and 3D human effects. Crewmembers may be exposed to different tissue models as well as animal experiments in doses and qualities of radiation, threatening life accelerators; quality and individual survivability, thereby disrupting • Performing energy and dose rate dependent mission success. studies in accelerators; • Providing an adequate infrastructure such as Earth benefits and applications access to accelerator facilities, low dose rate radiation sources, mixed radiation fields, and The main applications are in the fields of medical animal facilities. treatments in terms of normal tissue damage in particle therapy and protection from high-dose exposures in Trans-disciplinary aspects nuclear accidents or radiological terrorism. This issue is linked to radiation dosimetry and Brief review of latest developments immunology aspects for the impact of acute exposure on immune system and health care for radio-protective Recent experiments at the NASA Space Radiation drugs. Laboratory (Brookhaven National Laboratory, NY, USA) show that protons at low dose rate (around 10 1.2.2. Key Issue 2: How is the sensitivity to acute mGy/min) are less effective than at high dose rate. effects modified by the space environment? This sparing effect, similar to what would be expected for X-rays, should be considered in assessing the acute Relevance for space exploration missions risk, as many solar particle events (SPEs) deliver doses at dose rates below 10 mGy/min. For cancer treatments with high and moderate doses from X-rays, protons and heavy ions (carbon) Knowledge gaps and research needs under terrestrial conditions, the occurrence of acute radiation effects has been seen. However, only little The different phases of acute radiation syndrome or nothing is known on the possible contribution of have been studied in humans in radiation-accident spaceflight factors other than radiation. Interaction of related cases, therapy-related cases and animal space environment (e.g. microgravity) and radiation is experiments under normal terrestrial conditions. a possible risk for long-term human space missions. Little is known on the occurrence of the prodomal syndrome (which can be relevant especially for long- Earth benefits and applications term missions outside the magnetic shield of Earth) dependent on the special conditions of the space General applications to ground-based radiation environment. More needs to be known on the dose research concern the interaction of radiation with (fluence) and dose rate dependency for the prodomal various stressors. syndromes and other acute tissue effects for protons

Radiation Effects on Humans 7 Brief review of latest developments 1.2.3. Key Issue 3: What is the effectiveness of GCR at low doses for carcinogenesis? There is increasing evidence that acute effects from protons are modulated by the immune system and Relevance for space exploration missions this can affect the colonisation of the gastrointestinal tract by bacteria. This stresses the importance of Exposure of astronauts to galactic cosmic radiation measuring of acute radiation effects in realistic space (GCR) is a continuous threat for spaceflight missions. environment conditions where the immune system is During long-term missions, doses can be reached that impaired. have been reported to be relevant for carcinogenesis and other stochastic radiation effects. Accordingly, Knowledge gaps and research needs the contribution from galactic cosmic-ray exposure to late effects, such as carcinogenesis, has to be known The interaction of radiation with other spaceflight to assess the risk for astronauts and other space factors is currently under study for systemic biological travellers. responses related to the prodomal syndrome. However, little is known on the impact on acute Earth benefits and applications radiosensitivity of the following factors: immune status, influence of multiple stressors in the space General applications for Earth primarily include environment, nutrition, physical exercise protocols, ground-based radiation protection, and research pre-existing motion sickness, sleep deprivation and for medical applications of radiation in the fields of biorhythm disturbances, high oxygen concentrations radiation-induced secondary tumours after particle and altered body fluid distribution. Age and gender therapy. influence should also be considered. Brief review of latest developments Proposed investigations and recommendations Recent results in animal models have demonstrated • Spaceflight experiments with animals exposed to that the RBE for hematopoietic cancers is lower than high doses from an on-board radiation source; for solid tumours. NASA is now recommending two • Animal experiments at accelerators using different RBE values for leukaemia and solid cancers. simulated microgravity and/or other space factors; Knowledge gaps and research needs • Structuring investigations in a hypothesis-driven manner and appropriate design to generate Data on radiation carcinogenesis have been obtained statistically significant results; from animal experiments and from survivors of the • Providing adequate infrastructure such as access atomic bomb explosions in Hiroshima and Nagasaki. to spaceflight animal cabinets, access to artificial These data are mostly obtained for sparsely ionising on-board radiation sources and access to ground- radiation and only limited data exists for densely based accelerator facilities equipped with ionising radiation qualities. The main general question microgravity simulation devices. is the shape of the dose-response relationship for different radiation qualities and different dose rates. Trans-disciplinary aspects Among others, the following questions have to be answered for understanding stochastic radiation Similar to Key Issue 1, this issue is mostly related to effects: what is the dependency on space radiation radiation dosimetry, immunology and medication in quality; do differences in mechanisms (e.g., latency) space, but habitat management is also of interest as from high- versus low-LET exist; can biomarkers of the exposure conditions depend on the life support cancer risk be validated for astronauts; what is the system. contribution of individual sensitivity and (epi-)genetic

8 Radiation Effects on Humans predisposition to cancer induction and progression; what is the contribution of spaceflight environment parameters; do single particle traversals in cells affect cellular late effects; what are the track structure characteristics for determining effectiveness, and what is the role of non-targeted effects in carcinogenesis?

Proposed investigations and recommendations

• Accelerator experiments using innovative biological systems to model radiation-related endpoints relevant for carcinogenesis; • Investigations of biomarkers in astronauts; • Mechanistic experiments with genetically modified cell or animal models; • Particle microbeam facilities and access to ground- based accelerator facilities are needed for the suggested experiments. For verification of data obtained under terrestrial conditions, access to spaceflight platforms will be necessary.

Figure 1: An artist’s concept of DNA battered Trans-disciplinary aspects by galactic cosmic rays (Credit: OBPR). The link to radiation dosimetry is obviously very important, but a strong interaction with integrated physiology aspects is also necessary, considering that the dose-response curves for carcinogenesis are organ-specific.

1.2.4. Key Issue 4: Is there a risk of CNS damage from low doses of GCR?

Relevance for space exploration missions

Central nervous system (CNS) damage in astronauts from radiation may be a critical point for mission success, as changes in behaviour and/or individual stress response may result in critical situations. Results from animal experiments demonstrate the impact of even low doses from high-LET radiation on performance and premature ageing. Accordingly, the contribution from galactic cosmic-ray exposure to CNS damage has to be known for risk assessment in astronauts and other space travellers.

Earth benefits and applications

Late effects in patients treated for brain diseases with particles. Reactive radical species are linked to radiation- induced CNS damage. Since the same mechanism has been

Radiation Effects on Humans 9 postulated to modulate Alzheimer and Parkinson’s 1.2.5. Key issue 5: Is there a risk of non-cancer late disease, this provides a mechanistic linkage to these effects from low doses of GCR? common neurological disorders. Relevance for space exploration missions Brief review of latest developments Currently, little is known on non-cancer late effects in Although behavioural experiments are still unclear, astronauts after radiation exposure. So far, radiation- much progress has been made in the mechanisms, induced cataracts are best understood, where most particularly in measuring the effects of radiation on data are derived for terrestrial radiation and some brain stem cells. Tissue models are particularly useful data are obtained with astronauts. Less is known on to this goal. Most of the data point to a strong effect non-cancer effects in other organs or tissues. of reactive oxygen species (ROS) and inflammation in the hippocampus. Earth benefits and applications

Knowledge gaps and research needs More research in this area could produce better knowledge of non-cancer effects and their relevance The following questions have to be answered to for radiation protection and particle therapy on understand space radiation-induced CNS damage: Earth. can behavioural changes occur as consequence of single heavy ion traversals; what is the molecular basis Brief review of latest developments of radiation induced neurological damage; is there a role of ROS in CNS damage; do long-term effects exist The epidemiological studies are still unable to provide for CNS; what are the sensitive structures and/or cell information at doses below 0.5 Gy for cardiovascular types in the brain; is there a contribution of multiple disease. It has been suggested that one possible stressors during spaceflight with regard to radiation- biological mechanism is damage to endothelial induced CNS damage? cells and subsequent induction of an inflammatory response. Proposed investigations and recommendations Knowledge gaps and research needs • A thorough review of normal tissue complications in patients with brain tumours and/or other The main general question is the shape of the dose- diseases treated with X-rays, protons or heavy response relationship for different radiation qualities ions would be the first approach for performing and different dose rates. Burning questions in this meta-analysis of the corresponding human data; field are: why are heavy ions highly efficient in cataract • Meta-analysis data should be verified with induction; is there a threshold for different non- accelerator experiments using animals and cancer late effects; are there radiation-induced effects innovative biological model systems; on immune and cardiovascular systems, muscle • For these studies, particle microbeam facilities and bone; what are the molecular bases for these and access to ground-based accelerator facilities effects; and what is the contribution of spaceflight are needed. For verification of data obtained environment? under terrestrial conditions access to spaceflight platforms will be necessary. Proposed investigations and recommendations

Trans-disciplinary aspects • A thorough review of heart complications in patients treated with X-rays or heavy ions would This issue has strong relations with neurophysiology. be the first approach for performing meta-analysis of the corresponding human data;

10 Radiation Effects on Humans • Innovative biological models for cardiovascular diseases in radiation experiments have to be tested first with X-rays and thereafter with high-LET radiation; • For these investigations, access to ground-based accelerator facilities and to spaceflight platforms are needed.

Trans-disciplinary aspects

This issue is linked to cardiovascular system alterations in space.

1.2.6. Key Issue 6: Is there a risk of hereditary effects from low doses of GCR?

Relevance for space exploration missions

It is generally accepted that there is a genetic component in many diseases. Radiation-induced hereditary effects not only concern the space travellers themselves, but also their offspring. Accordingly, the appearance and transmittance of hereditary effects to future generations is a health risk for space travel.

Earth benefits and applications

Understanding the mechanisms of hereditary effects and its dependence of radiation quality would be of help for the definition of radiation protection criteria.

Brief review of latest developments

The results on germ-line mutations and trans-generational instability in mice challenge the recommendations of the International Commission on Radiological Protection (ICRP) on hereditary effects, but are not confirmed by epidemiology. Animal experiments show increased cancer risk in the offspring of male mice irradiated with neutrons, but no heavy ion data are available.

Figure 2: Astronaut David Wolf performing an Knowledge gaps and research needs (EVA) outside the ISS (Credit: NASA). Very little is known on the hereditary effects induced by heavy ions. Critical questions include: are there biomarkers suitable for determination of radiation induced teratogenic and trans-generational effects; what is the effectiveness of heavy ions in inducing hereditary effects; are there interactions of radiation and multiple stressors in spaceflight environment on fertility and hereditary effects?

Radiation Effects on Humans 11 Proposed investigations and recommendations factors depending on particle charge and energy.

• Hereditary effects have to be investigated in Knowledge gaps and research needs accelerator-based experiments followed by space Mathematical modelling approaches are currently based experiments using animal models; being used for determination of space radiation risk • Germline mutation rate and trans-generational in the field of physics. Biological modelling is needed instability following exposure to heavy ions and to solve urgent questions such as: how can systems X-rays should be compared; radiation biology approaches unravel the risk of late • Effects on spermatogenesis and oogenesis should effects; is it possible to model signalling pathways also be determined; following radiation exposure; how can the quality • For that, access to ground-based accelerator factor approach be replaced to model radiation facilities and, in the future, to spaceflight platforms quality dependent risk; how can the effects of mixed including on-board radiation facilities is needed. radiation fields be modelled?

Trans-disciplinary aspects Proposed investigations and recommendations

This issue is relevant to the design and management • Modelling approaches which are based on of the life support system. microdosimetry and/or particle track structures have to be developed and investigated for space 1.2.7. Key Issue 7: How will multi-scale mechanistic- radiation risk assessment; based modelling of space radiation improve risk • Studies are needed to transfer small scale estimates? molecular and cellular models into larger multi- scale models representing the overall response of Relevance for space exploration missions a tissue; • Modelling should include immune response and Radiation protection is essential for humans to live inflammation; and work safely in space. Modelling approaches • Such large macroscopic models will most likely for simulating the radiation field in space, for dose require rule-based modelling such as agent- approximation and for determination of depth dose based models. distributions are currently being used to determine the space radiation risk. Biology-based modelling will Trans-disciplinary aspects also add knowledge to mechanistic understanding of space radiation risk and should be integrated in the Radiation dosimetry aspects are heavily involved in design of experiments. this modelling effort.

Earth benefits and applications 1.2.8. Key Issue 8: How can radiation effects be effectively mitigated? Significant modelling will contribute to the development of evidence-based radiation protection, Relevance for space exploration missions important for ion therapy, and comparison to normal tissue response. Mechanism-based models will also Mitigation of radiation effects by shielding or other lead to better regulation of low dose effects of ionising countermeasure strategies have to be improved to radiation. protect astronauts from space radiation. Although it is known that radiation can be shielded using different Brief review of latest developments absorbers, optimal shielding conditions for space radiation have not been defined. As physical shielding NASA is now proposing a different model for radiation is not always effective, biological countermeasures risk estimates based on risk of radiation-induced death may be necessary to protect against the harmful (REID) probability distributions and revised quality effects of space radiation.

12 Radiation Effects on Humans Earth benefits and applications for radiation protection be targeted by molecular medicine approaches? Findings and developed countermeasures could potentially have a high impact on mitigating the side Proposed investigations and recommendations effects from particle therapies, radiological accidents, and terrorism. • Accelerator-based experiments on biological Brief review of latest developments systems exposed behind different shielding materials; Improvements in the Monte Carlo transport codes • Biologically motivated optimisation of the are useful in shielding design. The failure of the Alpha shielding; Magnetic Spectrometer (AMS) superconducting • Development of low-toxicity radioprotectors; magnet, which was dismissed because of an • Development of specific biomedical anomalous heating and replaced with a conventional countermeasures for cancer and non-cancer permanent magnet, shows that the technology of effects; cryogenic magnets is still not mature enough for • Development of innovative biomolecular spaceflight and active shielding. Using non-cryogenic approaches; superconducting magnets remains only a possible • For these investigations, access to ground-based future perspective. accelerator facilities and to spaceflight platforms including on-board radiation facilities are needed, Knowledge gaps and research needs as well as access to clinical cohort databases.

The following information is needed: how is the Trans-disciplinary aspects radiation field and biological response modified by shielding; do influences on biorhythms and physical Shielding and physical countermeasure development activity modify radiation response, which dietary obviously requires interactions with radiation or pharmacological supplements are effective dosimetry experts. Also, developments of countermeasures for radiation protection; which radioprotective drugs and dietary supplements are of radioprotectors are effective against solar particle interest for this issue. events; and how can biological pathways relevant

1.3. Conclusion A thorough risk assessment of space radiation requires Radiation Laboratory (NSRL) at Brookhaven National a large research effort in multiple fields. To study the Laboratory (Upton, NY, USA), and has produced biological effects, ground-based experimentation is experimental data in the past few years of great crucial to understand the risks associated with space relevance for reducing uncertainty of the risk. However, radiation exposure, since the dose rate of space the complexity of the issues at hand require large, radiation is too low to get sufficient data in reasonable international efforts. To foster European research in the time. Although space experiments are difficult field, the European Space Agency (ESA) has recently and expensive, further experiments with selected initiated a ground-based radiobiology programme, endpoints are necessary to investigate the effects which will be located at the high-energy synchrotron of microgravity on radiation damage expression. of the Gesellschaft für Schwerionenforschung (GSI) in Investigating the interplay between microgravity and Darmstadt (Germany). radiation is only possible through space studies, using an artificial on-board radiation source. A clear terrestrial application of this research is in heavy-ion cancer therapy (hadron therapy), where The NASA-funded Space Radiation Health Programme beams of high-energy carbon ions are used to is built upon the capabilities of the NASA Space sterilise solid cancers. One major consequence of this

Radiation Effects on Humans 13 treatment is the risk of secondary cancer, especially for pediatric patients. Information on heavy-ion cancer risk, sought by researchers in space radiation, is also essential for estimating the incidence of secondary malignancies in these patients. Therefore the two research fields share many common issues and concerns.

While translation from basic research to cancer risk assessment is far from straightforward, for moon-based activities, cancer risk does not appear to be a showstopper, while the uncertainty is still too high for a go/no-go decision on a mission to Mars. Cosmic radiation exposure certainly presents a major hurdle for extended space exploration, but much can still be done to better understand and mitigate it. A fruitful NASA-ESA collaboration in accelerator-based research should be fostered in the future years in order to reach a consensus on radiation cancer risk for a Mars mission within the next ten years. Intensified research on countermeasures is also urgently needed in order for such Figure 3: Profile of a heavy-ion beam (yellow a mission to become reality. spot) shown on one of four fluorescent ‘flags’ (Credit: BNL).

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18 Radiation Effects on Humans 2 Radiation Dosimetry

2.1 Introduction

The major objective of space radiation research is to port codes, which model the atomic and nuclear assure that during any mission the crew will be sub- interactions of the incident particles, are usually ap- ject to as low of a radiation exposure as reasonably plied to describe how the external radiation field is al- achievable (ALARA), enabling human exploration of tered on its passage through the spacecraft structure. the solar system within an acceptable radiation risk. However, the high degree of complexity of both the This requires quantification and reduction of space shielding distribution and the generation of second- radiation health hazards, with the goal of maximising ary charged and uncharged radiations make it virtu- the number of days that may be spent in space. The ally impossible to simulate in detail the change of the research to be carried out will support all phases of resulting particle fluence and energy distributions of human exploration including mission planning, com- the radiation field constituents within a spacecraft. ponent design, operation and post-flight studies. In Unlike terrestrial exposures, the high cost of launch- mission planning, over-estimating the risk of radiation ing mass into space puts limitations on spacecraft would result in a reduction of mission duration, while size and shielding thicknesses, precluding the purely on the other hand under-estimating might cause mis- engineering solution of providing as much additional sion aborts. Accurate assessment of radiation expo- shielding material as needed to reduce radiation ex- sure is therefore needed to avoid curtailment of mis- posure to a desired level. Also, shielding materials sion objectives and minimising danger to the crew. need to be properly selected to limit the production of secondary particles, like target and projectile frag- Radiation constitutes one of the most significant haz- ments, which can cause secondary radiation fields ards for crew members participating in long-duration with even higher biological consequences than the space missions, especially outside of the geomagnet- incident field. ic field. Astronauts face exposures to radiation levels that exceed those routinely received by terrestrial ra- In order to effectively minimise radiation exposure diation workers. Radiation fields encountered in space and assess space radiation risk, the radiation protec- include GCR, solar energetic particles (SEPs), mostly tion programme must also include the development protons from sporadic solar particle events, protons of radiation detectors and data processing tools to and electrons during traversals of the radiation belts, evaluate changes in the exposure characteristics, ide- as well as exposure to possible radioactive sources ally in real time. This evaluation must include sufficient used on board for power generation or medical test- physical characterisation and mapping of the radia- ing. In low-Earth orbit (LEO) the exposure to GCR and tion fields to determine the radiation doses received SEPs is reduced thanks to protection by the Earth’s by astronauts and to estimate the reduction in these magnetic field, which deflects galactic and solar ions doses that could be achieved by moving to areas of with low rigidities, preventing them from reaching the spacecraft that provide better shielding. the spacecraft orbit. The degree of protection is there- fore a function of spacecraft . In ad- Therefore, an essential first step in radiation research dition, significant shielding is provided by the Earth is to produce a detailed understanding of the radia- itself. Hence, particle fluence rates from GCR and SEP tion environment the astronauts will live in: in LEO, sources are much lower in LEO compared to what will during interplanetary cruise phases, on the Moon and be encountered in future lunar and interplanetary the Mars, in space habitats (temporary and permanent missions. planetary bases) and during extravehicular activities.

Currently, radiation exposure inside a spacecraft can Radiation biology findings strongly suggest that one only be reduced through shielding provided by the of the main issues to address is the role and effects of spacecraft structure and its interior. Radiation trans- different kinds of radiation. Recent results lead us to

Radiation Dosimetry 19 assume that the risk from irradiation with low versus radiobiological effectiveness. It is probable that the high linear energy transfer (LET) can be very different. concept of dose itself (and dose rate) is in need of new Therefore, the results obtained for the former should specific approaches. not be extrapolated to the latter just on the basis of rescaling factors, but rather are specific strategies The described evidence requires increasingly detailed needed for high-LET radiation. To understand specific knowledge of the radiation field characteristics in features of high-LET radiation damage and its mecha- terms of elemental abundance (input energy, nuclei, nisms, the starting point must be based on track struc- fluence rate and angular distribution). To this end, ture studies. Moreover, the quantity ‘dose’ (absorbed more detailed measurements and advanced radiation dose) for low-dose, high-LET exposures is of limited detectors are needed. Currently, Europe is a leader in meaning. Very low doses of high-LET radiation must this field and should maintain its position as the state- be considered (and studied), with small numbers of of-the-art. cells irradiated with significant doses. The particular spatial distribution of excitation and ionisation and The following sections present the conclusions of the their clustering properties may cause phenomena ‘Radiation Dosimetry‘ Expert Group. This group met that are peculiar to high-LET radiation. Moreover, the during two expert workshops in 2010. The workshops very short timescale (of the order of picoseconds) were organised sessions focused on considering the relative to energy deposition of a high-LET particle key questions to address, the latest developments, traversal can have a crucial effect in modifying the the gaps to fill and the Earth-based applications.

2.2. Key Issues

2.2.1. Key Issue 1: Experimental determination of tion risks, which will be necessary for deep space ex- radiation field parameters ploration (see Key Issue 7). For exploration missions, radiation risk assessment will predominately rely on Relevance for space exploration missions models. The reliability of these models needs to be optimised through a series of tests against a wide set Currently, there is a substantial lack of radiation in- of measurements at sites/conditions where instru- struments and measurements that sufficiently char- ments are available or can be made available. More acterise the radiation field in free space, as well as in- and more radiation details are needed to correctly as- side and outside a spacecraft. This calls for novel and sess radiation risks, and this requires detailed model improved radiation detector assemblies as well as ex- outputs to be tested against proper measurements. tended calibrations, detector inter-comparisons and analysis algorithms. New measurements are a prereq- Earth benefits and applications uisite for reliable risk assessment, a crucial input for radiation source modelling, and are also needed for The development of new and higher performing real-time calibration of the detectors. This would al- space radiation detectors will require pushing for- low for detailed understanding of the radiation envi- ward the limits of the knowledge about radiation ronment the astronauts are going to live in: in LEO, detection, thus providing benefits to the production during interplanetary cruise phases, on the Moon and of tools (hardware, software) needed for monitoring the Mars, in space habitats (temporary or permanent and controlling instances where ionising radiation is planetary bases) and during extravehicular activities. an issue on Earth as well as in space (particle accel- erator facilities, nuclear plants). Improved description Furthermore, determination of radiation field param- of the radiation environment in free space, as well as eters on the ISS is a mandatory issue from the stand- the larger degree of confidence obtained by models point of medical operations. Eventually, this informa- and simulations through optimised testing against tion can be provided directly to the crew, allowing measurements will have significant value also on sev- decision autonomy of the crew with regard to radia- eral terrestrial activities such as: (i) monitoring and

20 Radiation Dosimetry improving the reliability of spacecraft electronics, for ex- ample terrestrial and satellite telecommunication and nav- igation systems (GPS, mobile communication, Galileo etc.); (ii) monitoring aircrew exposure; (iii) understanding failure rates in aircraft electronics; (iv) improving ion therapy and nuclear medicine; (v) developing climate models.

Brief review of latest developments

On the ISS, several radiation measurements have been/are performed, either under the frame of science experiments or as operational monitoring for crew safety. The Dosimet- ric Mapping (DOSMAP) experiment was the first effort to map dose and dose equivalent as a function of location in the US Laboratory and in Node 1 of the ISS. The experi- ment was flown as part of NASA’s Human Research Facility (HRF) between March and August 2001, together with the Japanese Bonner Ball experiment, a US tissue-equivalent proportional counter (TEPC), and a human phantom torso. Figure 4: Figure 4: ESA astronaut Paolo Nespoli Italian scientists have used various silicon strip detectors installing ALTEA hardware for the ALTEAshield- over the last years, as part of the Alteino/ALTCRISS and the survey experiment, aimed at performing a 3D ALTEA experiments, which aim for a precise determination survey of the radiation environment in the US of the abundance of heavy ions in the space radiation en- Laboratory of the ISS. (Credit: NASA). vironment. ALTEA is also designed to study the ‘light flash phenomena’ mostly caused by space radiation in the eyes of astronauts. In two different experiments, ALTEA is cur- rently surveying the 3D heavy-ion radiation flux in the US Laboratory, able to measure the trajectory of each particle, determine the nuclear species of the radiation and calcu- late the input energy.

The operational systems are based on the concepts of microdosimetry (TEPC), silicon detector technology (CPDS and DB-8) or on ionisation-chamber principles (R-16). A semi-active device is the Hungarian Pille system, which is an automatic on-board reader for passive thermolumines- cence detectors (TLDs), also used for dose determination during an astronaut’s EVA. The main advantage of the ac- tive system lays in the constant monitoring capabilities as well as in the built in ‘Radiation Alert Functions’, as in the NASA TEPC, providing ‘real-time’ information about the ra- diation load and the possible fast change of it due, for ex- ample, a . In free space, well-established contributions have come from GOES (measuring X-ray, electron and proton fluxes at geostationary orbit) and of ACE (measuring solar , interplanetary magnetic field and higher energy particles accelerated by the , as well as particles accelerated in the and the galactic regions beyond). More recently, Pamela has provided free

Radiation Dosimetry 21 space radiation monitoring at variable altitude (350 2.2.2. Key Issue 2: Modelling of radiation environ- to 610 km) of electrons, positrons and ions up to oxy- ments gen. Relevance for space exploration missions Knowledge gaps and research needs An accurate modelling of the radiation environment Determination of radiation field parameters such as is a mandatory step in the radiation risk assessment elemental abundance, energy and fluence rate is still process. This task features a high integration with sev- incomplete: thorough spatial and temporal mapping eral other tasks: the understanding of the sources of inside and outside a space vessel is still lacking. There space radiation and of the processes behind the radia- is also a strong demand for further development of tion flux transformation during transport in materials improved radiation detectors. Measured values for (Key Issues 4, 5 and, with respect to the body, 6). The the radiation fluence rate, energy and charge distri- goal is to allow construction of valuable simulations/ butions as well as ion composition and direction in- models describing the dynamics of the whole radia- side and outside LEO are missing. The neutron role in tion spectra, from the sources to almost anywhere in the total radiation environment has also yet to be fully space and time. These models, once benchmarked quantified. Obviously, a large amount of available ra- and validated against proper measurements, will diation data has not been fully exploited. permit, as an example, the prediction of the radia- tion field inside a spacecraft during a Mars voyage or Proposed investigations and recommendations determination of the radiation impinging on human inner organs. • Available experimental data should be reviewed, and fully evaluated. This Key Issue addresses the required improvement • Detailed characterisation of the radiation en- of simulations/models of GCR, SEPs and the trapped vironment (input energy, charge, fluence rate, radiation in the quest for an efficient and possibly direction) needs to be carried out through con- fully integrated model of the radiation environment tinuous measurements over successive solar cy- impinging on space habitats. It addresses model im- cles in preparation for long-duration exploration provements, advances in the understanding of fun- missions. damental physics and processes involved in radiation • New radiation detector assemblies should be generation including new benchmarking. calibrated (and inter-compared) to a well-defined subset of the space radiation environment using Earth benefits and applications ground-based accelerator facilities. These facili- ties, when possible, should implement mixed ra- The development of detailed and fully tested radia- diation fields to mimic the space radiation field as tion environment models to support space explora- close as possible. tion will also provide significant value for several ter- • Space-borne inter-comparison of detector re- restrial activities. The design of spacecraft electronics, sponses is also seen as an important prerequisite including terrestrial and satellite telecommunication for operational implementation. and navigation systems (GPS, mobile communication, • Development should address area detectors pro- Galileo etc.), as well as aircraft electronics, will benefit viding real-time information about the radiation from a more accurately determined radiation environ- field parameters and having alert capabilities. ment. This will allow proper countermeasures to be • Real-time calibrations while the instruments are taken to minimise radiation-driven electronic failure in operation should be explored. rates. Deeper insights into aircrew exposure, which can be provided based on these advances, will per- Trans-disciplinary aspects mit further optimisation of the crew utilisation. Also, accuracy of climate modelling may benefit from the The Expert Group identified clear links between this outcome of these studies. issue and radiation effects on humans, habitat man- agement and medication in space.

22 Radiation Dosimetry Brief review of latest developments against experimental data. • Process and calibrate existing data, make them Various models have been developed for each of the available to the scientific community and feed radiation components, many of which are available them into improved source models. online through SPENVIS (http://www.spenvis.oma. • Data availability must be improved. For the future, be/) and CREME96 (https://creme96.nrl.navy.mil/ or, investigations should always include resources to recently, https://creme.isde.vanderbilt.edu/). NASA properly process and make available data prod- uses the Badhwar-O’Neil model for galactic cosmic ucts to the scientific community. rays. Improved AE-9/AP-9 models are under develop- ment as part of the Proton Spectrometer Belt Research Trans-disciplinary aspects (PSBR) Programme by a consortium of institutions, such as the National Reconnaissance Office, Aero- The Expert Group identified clear links between this space Cooperation, the Air Force Research Laboratory issue and radiation effects on humans, habitat man- (AFRL), the Los Alamos National Laboratory and the agement and medication in space. Naval Research Laboratory. 2.2.3. Key Issue 3: Space weather forecast Knowledge gaps and research needs Relevance for space exploration missions While the mentioned models are easily available, they still suffer several shortcomings. The space environment is highly variable on differ- ent time scales as a result of the variability of the Sun, GCR models which in general affects all aspects of the space envi- There is an inadequate characterisation of solar-cycle ronment. SPEs are an obvious manifestation of explo- dependency and of the scaling with heliocentric dis- sive processes on the Sun, are the most dramatic ra- tance. diation events and may constitute in several mission scenarios a potentially serious hazard. All the radiation SEP models components (including GCR and trapped particles) are The understanding of the acceleration mechanism of also modulated by SEPs. A clear example is the rapid the transport through the heliosphere is still inade- decrease in the observed GCR following a SPE due to quate, and the prediction capability is mostly missing the magnetic field of the plasma , known as (this aspect is also addressed in the next Key Issue). Forbush decrease. While SPEs are probably the most dramatic radiation events, they are mostly composed Radiation belt models of low-energy protons, for which a successful shield- The current state of the Earth’s is no ing strategy can be set up. This, however, requires an longer reflected in the radiation belt models, and there accurate prediction of the SPEs. A usable solar system is still a substantial lack in ability to properly describe forecast for the SPEs is therefore a mandatory element the dynamic behaviour of the trapped particles. for an efficient shielding approach during an explora- tion mission. Proposed investigations and recommendations Earth benefits and applications • Improve the understanding of the fundamental physics processes on the Sun and of transport The understanding and proper forecasting of solar and acceleration of the solar wind through the events is an important part of the more general issue heliosphere.• Develop a strong research effort to- of radiation source modelling. Possible spill-over ef- wards a deeper knowledge of the fundamental fects on Earth applications are therefore very similar processes in the magnetosphere (wave-particle to those mentioned for the previous Key Issue. As interactions, source and loss processes and accel- stated, these will focus on minimising radiation driv- eration mechanisms). en electronic failures (for example, for terrestrial and • Perform reliable benchmarking and validation satellite telecommunication and navigation systems

Radiation Dosimetry 23 as well as for aircraft electronics, or to avoid potential dam- age to power grids, pipelines, aircraft electronics and navi- gation), but also on radiation protection for occupational exposure (commercial and military flights, first respond- ers). Additionally, it will help optimising the utilisation of aircrew personnel and preparing, for example, best-choice ‘escape flight routes’ during SPEs. Climate modelling may also benefit from the outcome of these studies.

Brief review of latest developments

There are some observation platforms available, such as GOES, SOHO, ACE and STEREO, on which – together with neutron monitor information – space weather will be de- scribed and forecasted. Through observation of several hundreds of coronal mass ejections (CMEs) by the STEREO mission, it has been found that the general structure of a CME is consistent with large-scale magnetic flux ropes. This was the first time that direct, continuous tracking of CMEs over the entire distance from Sun to Earth became possible. At higher solar activity, several bipolar magnetic regions on the Sun can be destabilised in turn, leading to Figure 5: The Earth is superimposed on this im- the release of multiple CMEs in a few hours. These CMEs age of a solar eruptive prominence as seen in ex- can merge in interplanetary space. A fast CME is a neces- treme UV light (Credit: NASA). sary ingredient for a strong SPE. For the forecast of parti- cle fluxes and energy spectra of SPEs, magnetic coupling to the source regions of solar eruptions, especially to CME onset regions, plays a fundamental role. This will be inves- tigated in detail in the newly selected EU project eHEROES (Environment for Human Exploration and Robotic Experi- mentation in Space).

A more reliable space weather forecasting system is only possible with the provision of additional instrumentation in the different fields of space weather. There is an on-go- ing ESA design study, in which based on customer require- ments a list of needed instruments are defined together with their location in space, their characteristics, and the degree, to which user requirements can be fulfilled. The se- lected instruments will proceed to Phase 2 of the project for concrete mission/platform definition/specification/im- plementation.

The ESA Space Weather Working Team (SWWT), a forum of experts in scientific and application oriented fields relating to space weather, seeks to identify and discuss potential collaborations and/or synergies with other structures or organisations such as EC Framework & COST programmes, INTAS and SpaceGRID. The SWWT advises ESA about the

24 Radiation Dosimetry response to the pilot project activities observed with- the spacecraft/base walls, the radiation field is trans- in the scientific and user communities. It also assists formed by fragmentation, scattering, Coulomb inter- ESA in evaluating the lessons learned from the opera- action, neutron production etc. before entering the tion of pilot projects and how these changes can be body of an astronaut. Once inside the body, the ra- implemented within a strategy for any future space diation field undergoes further transformation. Trans- weather programme. port codes are needed to describe the interactions during the traversal of radiation through matter, both Knowledge gaps and research needs shielding matter (such as the spacecraft hull, but also the material, such as racks and experiments, inside Knowledge and understanding of the processes oc- the spacecraft) and living matter (skin, tissue etc.). The curring on the solar surface and in the , development of reliable transport codes is therefore including formation, coronal mass ejections, mandatory to produce accurate risk assessments for flares and transmission through space, is still inad- personnel and equipment on long-term space mis- equate and should be improved. Propagation mod- sions. elling must be improved as well. This will provide information to improve forecasting through real time Earth benefits and applications observation, which is needed to set up the proper countermeasure strategies. Optimised transport codes would be of significant value in the improvement of ion therapy strategies as Proposed investigations and recommendations well as in the optimisation of radiation protection for occupational exposure (in hospitals, accelerators, nu- • Develop SPE forecasting and prediction capabili- clear plants, commercial and military flights and first ties able to describe interplanetary shocks and responders), and for aircrew exposure. Protection of coronal mass ejections. electronics in environments where radiation is an is- • Develop and/or improve predictions for fluence sue would also provide benefits to other applications, distribution and time evolution at different posi- including terrestrial and satellite telecommunication tions in space and on different planets. This would and navigation systems (GPS, mobile communication, allow identifying precursors and signatures, which Galileo etc.), aircraft electronics as well as electronic would improve the detection of fast CMEs. circuit and accelerator design and nuclear plant de- • Forecast and identify quiet periods of solar activ- sign. ity to support mission planning. • Intense observations using present and new Brief review of latest developments spacecraft are necessary to improve our under- standing of basic space plasma physics phenom- Codes may be one- or three-dimensional, determin- ena in the solar-terrestrial environment and to istic or based on Monte Carlo (MC) methods. Deter- improve our understanding of short-term and ministic computer codes are based on approxima- long-term solar variability. tions of the Boltzmann transport equation and rely on models for the relevant quantities in the transport Trans-disciplinary aspects calculation. Many existing codes are tailored to a spe- cific application, often leading to significant simpli- The Expert Group identified clear links between this fications. Some well-known deterministic computer issue, radiation effects on humans and medication in codes include the High-Charge-and-Energy Transport space. (HZETRN) code and the Heavy-Ion Bragg Curve Cal- culator (HIBRAC). HZETRN and HIBRAC are based on 2.2.4. Key Issue 4: Transport codes the one-dimensional formulation of the Boltzmann transport equation with a straight-ahead approxima- Relevance for space exploration missions tion. Deterministic codes do not take into account all action products and their correlations, but rather Passing through a during an EVA or through focus on only one reaction product at a time. All in-

Radiation Dosimetry 25 formation about correlations on event-by-event basis ethylene, Kevlar®, Nextel® and other different pol- is therefore lost. The main advantage of deterministic ymers, aluminium, iron, copper etc. The energies codes, however, is seen in the low demand for com- should range from below 100 MeV/u to at least putational resources and the comparatively small cal- 10 GeV/u. It is important to measure differential culation times. The interaction of a heavy ion with a (angular distributions) and double differential material is a complex process that includes a variety (energy and angular distributions) cross-sections of diverse activities including ionisation, excitation, as well as multiplicities for the light fragments. nuclear fragmentation, production of positron-emit- Measurements are needed for both projectile and ting nuclei and de-excitation through rays. especially target fragmentation. These processes are not fully accommodated with deterministic models, and their complexity requires Trans-disciplinary aspects the use of a numerical method for solving the prob- abilities of different events, e.g., a MC method. Several This issue is mostly related to the study of radiation MC codes are used nowadays throughout the world effects on humans. (MCNP, FLUKA, GEANT4, SHIELD-HIT, HETC-HEDS, MARS, PHITS). However, in several instances deter- 2.2.5. Key issue 5: Shielding ministic codes give results that agree with those from the more complex MC codes. Relevance for space exploration missions

Knowledge gaps and research needs This issue includes the work needed to characterise and develop shielding materials, as well as the stud- A detailed understanding of the physics governing ies and developments needed to make active shield- the traversal of an ion, electron or neutron through ing a feasible alternative. Continuous optimisation of matter is a key point in defining transport codes. Un- shielding measures and strategies is of primary impor- derstanding the hadronic physics at the basis of the tance in order to keep the radiation exposure of space particle transport and cross sectional data tables must travellers as low as reasonably achievable (ALARA). therefore be improved to further develop the codes. Exposure to ionising radiation can be reduced by (i) There is especially a lack of experimental cross-section increasing the distance from the source, (ii) reducing data for light fragments and neutrons. In this pano- the exposure time (for example, exploiting nuclear- rama, it is also of paramount importance to define based propulsion for exploration missions), and (iii) in detail the strengths and weaknesses of the codes using active or passive shielding. Currently, the only via properly designed validation and benchmarking proven and practical physical countermeasure to re- procedures against experimental data, including data duce the exposure to cosmic radiation during space obtained with advanced anthropomorphic phantoms travel is passive shielding and reducing exposure exposed at accelerators. time. Passive shielding, however, does not always re- duce the radiation risks. Unlike for low-LET gamma Proposed investigations and recommendations or X rays, the shielding of energetic charged parti- cles may even cause an increased risk. Secondary ra- • Codes need to be improved to treat all primary diation, composed of projectile and target fragments and secondary cascades including photons, pro- (including neutrons) from the interaction with the tons, light ions, heavy ions, mesons and electro- shields, may deliver a higher dose than what would magnetic cascades. have been absorbed from the primary radiation. For • The nuclear interaction database needs to be up- physical reasons, a shielding material with a low mean dated, especially for neutrons and light ions. atomic mass is needed to provide an efficient reduc- • The codes should be carefully benchmarked tion of the radiation risk. Understanding the effects against ground-based experiments, using both of shielding materials and the optimisation of the thin and thick targets as well as anthropomorphic shielding strategy is therefore a mandatory issue for phantoms. The projectiles should range from pro- . tons up to iron, with suitable targets, e.g., poly-

26 Radiation Dosimetry Earth benefits and applications er, the mass and power budget required by the avail- able technology on superconducting systems at the The knowledge of cosmic ray shielding will have sig- time of the studies is prohibitive. nificant value for terrestrial activities wherever expo- sure to a significant amount of ionising radiation is an Knowledge gaps and research needs issue. This includes, but is not limited to, ion therapy centres, radiation protection for occupational expo- Shielding optimisation is required. This relies on the sure (hospitals, accelerators, nuclear plants, commer- maximum permissible radiation doses for exploration cial and military flights), and aircrew exposures. Sig- missions beyond LEO (considering also the risk of ear- nificant contribution could also be given to nuclear ly deterministic and late stochastic effects) and must plant design and operational support. Finally, pro- take into account all new knowledge about simple tection of electronics from radiation-driven failures and multilayer materials. An important point will be to would benefit from these studies. This includes the determine the shielding distribution function of the failure induction/propagation in electronic circuits habitats in order to benchmark the simulated charac- and accelerators. teristics. Research to characterise and develop shield- ing materials is also needed. While passively shielded Brief review of latest developments temporary shelters for solar events are probably feasi- ble in the near future, it is much harder to foresee an It has been shown that in order to provide an efficient effective system based on passive shielding for galac- reduction of the radiation risk, a shielding material tic cosmic rays during an interplanetary voyage. This with a low mean atomic mass (high content of hydro- consideration, and the important technological ad- gen) is needed. This would minimise fragmentation vances in the last decade on superconducting mag- and the consequent production of secondaries. A nets, materials and cryostats, prompt the need for a large number of materials (several with low content of revision of the above mentioned pioneering studies hydrogen) have been properly tested on ground and in view of a new combined (active and passive) shield- some of them in space. Passive shielding produces ing strategy enabling a long permanence of humans limited risk reduction, in the order of a few tens of per in deep space. In this scenario, active shielding needs cent. further studies to provide feasible implementations.

Active shielding has been studied in Europe during Proposed investigations and recommendations 2002 to 2004 by two research programmes supported by the European Space Agency: one through a dedi- • The ISS and free-flying are further con- cated Topical Team group (on the thematic ‘Shielding sidered a basic test bed for estimating the per- from cosmic radiation for interplanetary missions: ac- formance of shielding structures. tive and passive methods’) in the framework of life and • New materials and combinations of materials physical sciences, and the other an industrial study (e.g., multilayers) shall be studied by simulations (through an Invitation To Tender) concerning the ‘ra- using transport codes and ground-based testing diation exposure and mission strategies for interplan- in accelerators. etary manned missions to Moon and Mars’. Both pro- • Knowledge of shielding properties of in-situ re- grammes were primarily aimed at finding a solution sources on celestial bodies such as regolith or for the shielding against energetic solar events and regolith-derived compounds shall be improved. concluded that, outside the protection of the magnet- • Studies on active shielding in the search for break- osphere and in the presence of the most intense and throughs that could make this approach techno- energetic solar events, mission protection from radia- logically feasible as a complement to the passive tion cannot rely solely on the mechanical structures strategy shall be resumed. of the spacecraft, but rather a temporary shelter must be provided. Because of the limited mass budget, the Trans-disciplinary aspects studies suggested the use of superconducting mag- netic systems. For protection against galactic cosmic This issue is mostly related to the study of radiation rays during long-duration missions, it was concluded effects on humans. that the use of active shielding is mandatory. Howev-

Radiation Dosimetry 27 2.2.6. Key Issue 6: Individual radiation exposures

Relevance for space exploration missions

This effort partly represents a bridge between the Expert Group on Radiation Dosimetry and the Expert Group on Ra- diation Effects on Humans. The aim is to work collaboratively to provide all experimental radiation information and rela- tive codes needed to achieve an efficient risk assessment, while also minimising uncertainties in the final risk estima- tions. One of the most important final goals for radiation dosimetry is the detailed estimation of radiation exposure of inner organs, tissues and/or cells. Today, this is achieved by folding the energy deposition with relative biological effectiveness (RBE) for specific endpoints or appropriate weighting factors (in general, risk coefficients). This can be based on (i) the simulation of the radiation fields (particle type, energy and fluence rate) folded with a human model (particular person if required), (ii) results from surface-po- sition personal dosimeters and algorithms relating these results to organ energy deposition, and (iii) a combination of (i) and (ii) with the calculations and the results of personal dosimeters being used to correct for occupancy in defined radiation fields. An improvement on the use of the risk coef- ficients mentioned above is the determination and use of a detailed transfer function between advanced personal/area radiation detector readings (and, if needed, simulated radia- tion quantities) and risk-related quantities. To this end, it is necessary to develop and use adequate active personal ra- diation detectors with real-time capabilities and to carry out Figure 6: ESA astronaut sets up an improved characterisation (input energy, nuclear abun- the MATROSHKA phantom on the ISS (Credit: dance, fluence rate, direction) of the radiation field both in NASA). the environment as well as on the body of the astronaut. A detailed shielding distribution function of the body and proper transport codes will permit the input radiation field to be related to the radiation incident on the organs, tissues and/or cells. In this frame, it is important to provide all the information needed to establish the uncertainties of the or- gan final risk estimates. An alternative method is to measure the doses at critical organ sites with the help of anthropo- morphic phantoms inside and outside the ISS during a full . Skin measurements and depth dose distribution in the phantom would be used to determine organ doses using a voxel model and the ratio between skin and organ doses. From a measurement with a personal dosimeter on the astronaut’s body, the effective organ doses could be cal- culated.

28 Radiation Dosimetry Earth benefits and applications

In addition to supporting space exploration, the knowl- edge acquired will have significant value for terrestrial activities including radiation protection for occupational exposure (hospitals, accelerators, nuclear plants, commer- cial and military flights) and aircraft crew exposure control. It will also provide contributions to the strategy to set up optimised therapy plans in ion therapy.

Brief review of latest developments

The MATROSHKA experiments provided the first time depth dose distributions in a human phantom in an axtra- and intravehicular activity situation on board the ISS. The detailed analysis of these experiments is the main task of the FP7 project HAMLET (http://www.fp7-hamlet.eu).

Knowledge gaps and research needs

Radiation biology results continually suggest that many interactions with organs/tissues/cells depend on detailed parameters, such as charge and input energy. This de- pendency propagates into the risk parameters and there- fore, there is a need for a much more detailed picture of the radiation environment and the mere folding of energy deposition where RBE appears more and more insufficient to lead to a reliable set of radiation risks. The pattern of en- ergy deposition (timing, local density) should be taken into account.

Active personal radiation detectors with alert capabilities and the ability to measure radiation field parameters are still not available. Access to an active real-time personal dosimeter will allow the user to monitor his/her radiation exposure and seek out preferable regions to reduce their radiation risk.

Finally, there is still a lack of an efficient translation between life science issues and experimental data into astronaut ra- diation protection activities. Figure 7: ESA astronaut Thomas Reiter wearing a European Crew Personal Dosimeter on the ISS Proposed investigations and recommendations (Credit: NASA).

• Further use of human phantoms is mandatory to pro- vide measurements of doses at organ sites in order to benchmark models with these results. • New small active detector systems need to be devel- oped delivering optimised information of the radia- tion field parameters.

Radiation Dosimetry 29 • Simulation and radiobiology results must be used ground, a mandatory step to be fulfilled to allow deep to determine the transfer function between radia- space exploration. tion detector readings and risk related quantities. • Optimisation of cross-links with human space- Earth benefits and applications flight operations with strong collaboration be- tween physicists and physicians is needed. The organisation derived from this work will provide significant value to terrestrial activities involving com- Trans-disciplinary aspects plex operational issues. Nuclear plants design could benefit as well as the design of their operational sup- This issue is mostly related to the study of radiation port strategies. A limited number of extreme Earth effects on humans but has also links with medication activities also could take advantage of the results of aspects. these studies.

2.2.7. Key Issue 7: Support to mission planning and Brief review of latest developments operation The space industry is well aware of the issue of radia- Relevance for space exploration missions tion protection and performing independent studies on materials, trying to combine structural require- Improvements in modelling radiation sources, accura- ments and radiation shielding efficiencies of the ma- cy of radiation transport codes, and radiation monitor- terials. A new ESA Invitation to Tender on radiation ing will contribute to improved risk assessments and shielding by in-situ resource utilisation (ISRU) and/or provide increased confidence that the mission can be innovative materials study has just been released. The carried out as planned. Deviations from the planned ultimate objective of this study is to gather relevant mission scenario may require curtailment of planned information on radiation shielding for manned space- activities or provide opportunities to enhance or aug- craft, habitats, or EVA suits. Radiation risk cannot be ment planned activities. Astronauts will be especially considered alone in exploarative missions, therefore vulnerable during EVAs, when they are monitored in there are already activities set up for an integrated risk real-time by a biomedical suite of sensors to assess approach taking into account all risks. physiological parameters such as core body tempera- ture, oxygen uptake, skin conductivity and environ- Knowledge gaps and research needs mental parameters such as the radiation environment. In addition, space weather predictions and remote Until now, spacecraft design has only partly taken satellite and areas instrumentation will augment the into account radiation risk mitigation by special con- personal astronaut radiation instrumentation. These structive measures. This must and will change in ex- real-time measurements will be transmitted to the ploration missions. Due to the complexity of such a EVA control node in real time to assess the status of mission, radiation risk cannot be treated alone and the activity and provide guidance to the astronaut. In integrated risk models need to be developed. This addition, radiation exposure assessments made avail- will be achieved by developing strategies to assess able directly to the astronaut in real-time, with alarms, improvements in the relevant mission parameters. In- will enhance the astronaut’s confidence in the activity tegrated tools based on real-time radiation readings, and increase productivity. It is therefore mandatory to risk determinations and space weather forecasts, will use this integrated knowledge for a real-time support allow the simulation and support of mission scenarios of the mission scenarios from the standpoint of radia- as well as assessments of the overall mission impacts tion risk mitigation. It should also be underlined that of uncertainties, provide adequate estimates of astro- most of this support can be made available directly naut exposure in real-time, and suggest changes in to the astronaut. This would provide a tool that could mission scheduling to maintain the total risk below eventually move the decision-making processes relat- predefined limits. ed to radiation towards ‘autonomy’ of the crew from

30 Radiation Dosimetry Proposed investigations and recommendations real-time and suggest changes in mission sched- uling to maintain the total risk below predefined • Use this integrated knowledge for a real-time sup- limits. port of the mission scenarios from the standpoint • Provide the supporting tools needed by the crew of radiation risk mitigation. This will be achieved to exploit its autonomy in all radiation related by developing strategies to assess improvements decision-making processes. in the relevant mission parameters. • Develop integrated tools based on real-time ra- Trans-disciplinary aspects diation readings, risk determinations and space weather forecasts that will permit the simulation This issue is mostly related to the study of radiation ef- and support of mission scenarios as well as assess fects on humans but has also links with habitat design the overall mission impacts of uncertainties, pro- and management. vide adequate estimate of astronaut exposure in

2.3. Conclusion

Understanding the sources of space radiation (Key Is- of improved processes, are therefore required to pro- sues 2 and 3) and the processes behind radiation flux vide the necessary information for accurate radiation transformation during transport in materials (Key Is- risk assessment in order to reduce these risks to an ac- sues 4, 5 and, with respect to the human body, 6) al- ceptable level. lows the construction of valuable simulations/models to describe the dynamics of the whole radiation spec- tra from the sources to almost anywhere in space and time. These models, once benchmarked and validated against proper measurements (performed in space for source models and mostly at ground-based ac- celerators for transport models), will therefore permit, as an example, the prediction of the radiation envi- ronment inside a spacecraft during a Mars voyage or determination of the radiation impinging on human inner organs.

Measurement results and models are already avail- able. However, these are still too few and too incom- plete (most of them regarding only a few of the im- portant radiation parameters), while the most recent models still rely on incomplete understanding of the physics of the generation/transport processes and are validated against a very limited set of measurements. New instrumentation, permitting measurements of a larger number of the radiation field parameters with greater sensitivity is mandatory. Further measure- ments, including, for example, body phantom meas- urements, and new models, based on the knowledge

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Radiation Dosimetry 37 3 Annex: Composition of Expert Groups

Space Radiation Cluster Coordinator:

Günther Reitz German Aerospace Centre, Germany

Radiation Effects on Humans Expert Groups Members:

Marco Durante (Chair) GSI Helmholtzzentrum für Schwerionenforschung, Germany Christa Baumstark-Khan (Rapporteur) German Aerospace Centre, Germany Roberto Amendola Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Italy Sarah Baatout Belgian Nuclear Research Centre, Belgium Nicolas Forey Institut national de la santé et de la recherche médicale, France Yoshia Furusawa National Institute of Radiological Sciences, Japan Tom Hei Columbia University, USA Gerda Horneck German Aerospace Centre, Germany George Iliakis University of Duisburg-Essen, Germany Andrea Ottolenghi Università degli Studi di Pavia, Italy Peter O’Neill University of Oxford, United Kingdom Laure Sabatier Commissariat à l’énergie atomique et aux énergies alternatives, France

Radiation Dosimetry Expert Groups Members:

Livio Narici (Chair) Università degli Studi di Roma Tor Vergata, Italy Michael Hajek (Rapporteur) Vienna University of Technology, Austria David Bartlett Health Protection Agency, United Kingdom Thomas Berger German Aerospace Centre, Germany Pawel Bilski Polish Academy of Sciences, Poland Tsvetan Dachev Bulgarian Academy of Sciences, Bulgaria Daniel Heynderickx DH Consultancy, Belgium Richard Horne British Antarctic Survey, United Kingdom Dennis O’Sullivan Dublin Institute for Advanced Studies, Ireland Vince Pisacane US Naval Academy, USA Günther Reitz German Aerospace Centre, Germany Blai Sanahuja Universitat de Barcelona Yukio Uchihori National Institute of Radiological Sciences, Japan

38 Annex: Composition of Expert Groups Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-03-1 printed in E.U. march 2012

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Cluster 4: Habitat Management - Report

CLUSTER4 March2012 1

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Towards Human Exploration of Space: a EUropean Strategy

Cluster 4: Habitat Management - Report

Microbiological Quality Control of the Indoor Environment in Space

Life Support: Management and Regeneration of Air, Water and Food THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low Earth orbit have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus:

Cluster 1: Integrated Systems Physiology Cluster 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space medicine Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

4 Table of Contents

1. Introduction to Habitat Management in Space...... 5

2. Microbiological Quality Control of the Indoor Environment in Space...... 6 2.1. Introduction...... 7 2.2. Microbiological Quality Control of the Indoor Environment in Space – Key Issues...... 8 2.2.1. Key Issue 1: Define correct upper and lower thresholds for indoor environmental quality control of air, water, food and surfaces in space habitats...... 8 2.2.2. Key Issue 2: Develop efficient materials and methods to prevent environmental microbial contamination in space...... 10 2.2.3. Key Issue 3: Develop adequate environmental contamination monitoring (prediction, detection, identification) systems for use in space...... 12 2.2.4. Key Issue 4: Develop materials and methods to mitigate environmental microbial contamination and its harmful effects in space...... 13 2.2.5. Key Issue 5: Acquire better knowledge on microbial community (microbial ecosystem) dynamics and microbial cell evolution over time in confined manned habitats in space...... 15 2.3. References...... 17

3. Life Support: Management and Regeneration of Air, Water and Food...... 19 3.1. Introduction...... 20 3.2. Life Support: Management and Regeneration of Air, Water and Food – Key Issues...... 22 3.2.1. Key Issue 1: Develop and adopt common metrics for evaluation of different Life Support System (LSS) architectures, technologies, and their evolution...... 22 3.2.2. Key Issue 2: Develop model-based regenerative Life Support via a system level approach...... 23 3.2.3. Key Issue 3: Further develop Life Support subsystems and components for long-duration space flight and planetary surface mission phases...... 25 3.2.4. Key Issue 4: Improve autonomy of LSS via monitoring and control...... 27 3.2.5. Key Issue 5: Improve LSS robustness, reliability, availability, maintainability, safety, acceptability in long-term integrated operations...... 28 3.2.6. Key Issue 6: Screen and develop high performance materials for LSS...... 31 3.2.7. Key Issue 7: Develop and demonstrate capabilities to exploit resources available on other planets (In-Situ Resource Utilisation - ISRU) for life support...... 31 3.2.8. Key Issue 8: Improve LSS architecture to increase habitability...... 32 3.3. References...... 34

4. Annex: Expert Group Composition...... 37

5 1 Introduction to Habitat Management in Space

Despite the many benefits of using robots to explore The priorities of research necessary to support the universe, the ultimate goal and attraction remains foreseen space travel and planetary exploration in human beings discovering and experiencing space. represent a unique set of problems whose solutions The habitat (spaceship or space station) that will demand an in-depth understanding of the whole house future space travellers plays a crucial role in human body and cross-disciplinary work between making any space endeavour a success (Nicogossian life scientists, engineers and technologists. All the et al. 1992). necessary expertise was been acquired by European scientists during the past decades. In the context of the Humans in space need a habitat that provides: THESEUS project, the objective of the expert cluster on ‘Habitat Management in Space’ was to gather this • protection from environmental hazards (e.g. European expertise and create synergies that allow objects, pressure, temperature, radiation), for an integrated approach on which priorities of • supplies and consumables to survive (air, water, research emerge. Because of the necessary holistic food), approach, those research programmes obviously • removal and stabilisation of waste in order to required the involvement of scientists whose expertise ensure maximum mass recycling. is disseminated across Europe.

The habitat should contain systems to assure:

• control of the indoor environment (quality of air, water, food, surfaces, waste), • production or regeneration of air, water and food, • removal and treatment of waste for recycling and stabilisation of irrecoverable fraction.

In all systems, microbes play an important role and should be controlled if harmful or used for the benefit of the mission to the maximum extent possible.

In this context, two themes related to habitat management in space were identified and taken into account within the scope of the THESEUS project:

• Microbiological quality control of the indoor environment in Space • Life support: management and regeneration of air, water and food

6 Introduction to Habitat Management in Space 2 Microbiological Quality Control of the Indoor Environment in Space

2.1. Introduction

The subsequent sections present the recommenda- In addition to microbiological contamination, it was tions from the Expert Group focused on ‘microbio- recognised that chemical compounds (e.g. logical quality control of the indoor environment in gasses in the air including volatile organics such as space’ as well as the rationales behind them. In this ethylene, formaldehyde, iodine or silver in water) also context, the group focused on indoor environmental contribute to the indoor environmental quality. The quality control and thus environmental microbiology importance of particles (e.g. dust) on environmental in space in order to reduce potential hazards for the quality is also highlighted, as particles are considered crew and the infrastructure, including: to be major carriers of microbial contamination. Even when not posing a direct risk for crew, some chemicals • health hazards of microbial origin, including and dust may interfere with hardware or scientific human exposure to e.g. pathogens, antigens, investigations inside the habitat, and thus should be allergens, toxins, volatile organics, controlled. However, no specific recommendations • infrastructure hazards of microbial origin, on these topics are formulated in this report. including e.g. biofilm development on surfaces, biocorrosion of metal surfaces, and Furthermore, monitoring the external environment biodegradation of polymers surfaces. (e.g. lunar dust) and its impact on the indoor quality control in lunar, Martian or asteroid surface habitats The subject of monitoring and understanding the should also be taken into account, but is not discussed behaviour of ‘the human microbiology’ (e.g. dental, in this report. skin, intestinal, vaginal microflora) in space was not considered as a priority topic here, as it was already The following sections present the key issues emphasised by the THESEUS Immunology and identified by the ‘microbiological quality control of Nutrition/Metabolism Expert Groups. the indoor environment in space‘ Expert Group. This group met during two expert workshops in 2010. Nevertheless, it has to be emphasised that the These workshops were organised sessions, aimed human microbiome plays a key role in the health (e.g. at considering the key questions to address the digestion) of the astronauts in space and is in fact latest developments, gaps to fill and Earth-based the major source of environmental microbial load in applications. space habitats.

2.2. Microbiological Quality Control of the Indoor Environment in Space – Key Issues

2.2.1. Key Issue 1: Define correct upper and lower human risk, the importance is lower for a LEO (ISS) thresholds for indoor environmental quality control mission as crew fast return is possible, compared to a of air, water, food and surfaces in space habitats long duration mission to Mars where fast return is no longer possible. However in respect to economics, the Relevance for space exploration importance is not negligible in LEO missions as up and down load of replacement hardware and water supplies Setting correct thresholds for microbial control in that were lost due to contamination is expensive. space vehicles becomes increasingly important for longer duration missions. This importance is linked Terrestrial interest and application to the intrinsic semi-closed loop characteristics of air and water supply in space vehicles that may amplify Defining upper and lower thresholds for indoor and enhance microbial contaminations. In respect to environmental quality control that correctly reflect

Microbiological quality control of the indoor environment in space 7 beneficial or harmful impacts of environmental contaminants and pollutants is of importance on Earth for assuring healthy housing and working areas (e.g. allergies, sick building syndrome, etc.), preventing nosocomial infections (e.g. in hospitals) and for the ecotoxicology field (e.g. exposures to low pollutant concentrations in water or air). However, experience and expertise has been build up over the years for controlled inhabited environments on Earth, and adequate thresholds have been defined. Therefore, additional information from space would mainly be useful to further optimise or adapt thresholds that are already in place for certain Earth environments.

On Earth, limits are set for many chemical and biological agents present in indoor environments (e.g. WHO, 2000) and workplaces. Most occupational limits are given for short term exposure (15 min to 8 hours per day) and are usually based on irritation or other short-term harmful properties of the agents.

Background and European Strengths

In space vehicles, exposures are continuous (24 hours per day, Figure 1: NASA astronaut Dan Burbank cleans for months or even years). In addition, the immune status of cabin air bacteria filters in the Tranquillity node astronauts in space is compromised due to stressors (radiation, of the ISS (Credit: NASA) microgravity, isolation) (Sonnerfeld, 2005; Williams et al., 2009) and microbes may change behaviour (e.g. become more pathogenic) (Wilson et al., 2007), thus special thresholds may be required for space habitats.

Currently, standards and thresholds are internationally agreed upon for the working and living modules of the International Space Station (MORD, 2009). However, no/different thresholds are set for the cargo modules travelling to the station (e.g. the MORD document is not applicable for ATV). They are defined as maximum allowed concentrations (MAC) of fungi and bacteria, in air, potable and hygienic water, and surfaces (MORD, 2009), and are defined in viable and agar cultivable cell numbers. Other microbial environmental contaminants (such as fungal allergens, viruses, protozoa, amoebae, mites, etc.), which could be equally important sources of infection, allergies, or material destruction, are not listed. The current thresholds for the ISS are very conservative and generally lower than applicable on Earth (i.e. only low levels of microbes are allowed). Most of the time, the thresholds are defined on concentrations which are technically achievable for prevention or detection, but lack often a medical or infrastructural hazard basis.

8 Microbiological quality control of the indoor environment in space Nevertheless, microbial induced structural damages on the ISS have been observed and reported (fungal biofilms on air exposed metal and polymeric surfaces, bacterial water contamination, etc.) (Novikova et al. 2006). This infrastructural damage will become even more of a risk for longer missions when routine replacement of parts is no longer feasible and more intense regeneration of air, water and waste into food is required. It is true, however, that with the current thresholds implemented on the ISS, very few medical incidents are reported (not published). Then again, questions can be posed on if severe reduction of microbial levels (in food for instance) does not pose a risk in itself, as the human body needs microbes (Jermy, 2010).

Many European institutes have microbiological research groups that have performed valuable work to evaluate the health hazards of agents present in indoor environments. Guideline or threshold limits have been set for harmful chemi- cals and some microbes for given environments (e.g. hospi- tals), and are correctly based on combination of toxicological and epidemiological studies.

Proposed investigations and recommendations

• Define the list of microbes and their thresholds (maximum allowed levels) to be controlled before flight in the crew habitat. • Define thresholds primarily based on scientific data and mathematical models as basis for correct assessment of risk for crew and infrastructure, and then secondary evaluated these thresholds versus the technological achievable detection limits • Define thresholds taking into account potential ‘essential/ beneficial’ effects of microbial compounds (e.g. trigger and keep active the immune system, enhance natural protective microbial barrier) • Define thresholds at an integrated level, taking into account the combined (synergistic or antagonist) effects and risk assessment of exposure of crew and infrastructure to: • multiple contaminants of microbial origin, including e.g. viruses, bacteria, yeasts, fungi, amoebae, ciliates and other protozoa, dust mites, exo- and endo-toxins, mycotoxins. • multiple sources including e.g. air, water, food, surfaces, waste, other crew members. • multiple stress factors including, e.g. microbial contamination and others such as chemical and dust contamination, radiation and gravity.

Microbiological quality control of the indoor environment in space 9 • Use in priority ISS as a validation platform (e.g. are thresholds achievable under daily operations in space stations) for thresholds in space habitat settings, and secondary use relevant Earth analogues such as remote and confined locations that require long-term habitation without access to outdoors (e.g. Mars500, Concordia, submarines/submersibles, Antarctic/Arctic stations, hospitals, clean rooms)

2.2.2. Key Issue 2: Develop efficient materials and methods to prevent environmental microbial contamination in space

Relevance for space exploration

In respect to human risk, the importance of prevention procedures is lower if fast crew return is possible, but becomes more important in long-duration missions.

In respect to economics, the importance of prevention procedures is high, as significant are possible due to up and down load of replacement hardware and water supplies that are lost for consumption due to contamination.

Terrestrial interest and application Figure 2: The Herschel spacecraft in a clean room at ESA ESTEC (Credit: ESA) On Earth, efficient mitigation procedures are mostly in place. Additional terrestrial interest may lie in the health sector (e.g. improving indoor air quality in public buildings such as hospitals, schools, and public transport), or in the artistic and cultural sector for the preservation of art or historic buildings. There is also a strong interest for industry using clean room production facilities such as in pharmacies, and electronics or food preparation and packaging. For food and pharmaceutical industry, such methods and materials are of interest to prevent spoilage and increase shelf life of products. Novel multifunctional materials including, for example, antimicrobial coatings (silver nanoparticles, biosurfactants, etc.) or novel (non-volatile) biocides are also of industrial interest for a wide variety of industrial applications.

Background and European strengths

A large scientific and industrial community exists that deals with prevention of microbial contamination (e.g. work in clean rooms) and air, water, food and surface preservation. However, this knowledge and technology is not always directly transferable or applicable for the specific materials and environmental conditions in space.

10 Microbiological quality control of the indoor environment in space that are continuous, autonomous, compact in In most spacecraft assembly rooms, there is a size and weight, long-lasting, compatible with control of the total particle burden (e.g. through space materials, not using toxic or flammable air filtration and protective clothing of personnel) chemicals and with low requirements for energy, in an effort to indirectly control the particle-linked consumables and maintenance. bioburden (Victoria et al., 2006; Warmflash et al., • Develop efficient materials that prevent microbial 2007). Additionally, surface sterilisation methods adherence, proliferation and biofilm formation are sometimes used such as UV light irradiation or on surfaces, and metal biocorrosion and polymer disinfection with chemicals. biodegradation (e.g. antimicrobial nanostructures or coatings, silver nanoparticles, biosurfactants) However, history shows that these strict quarantine • Develop novel biocides (non-toxic for the crew, procedures were not effective in preventing e.g. bacteriocines) and/or alternative measures contamination of some spacecraft (Schuerger, 1998). to control microflora (e.g. physical) to apply in air Microbial contamination studies in spacecraft over the and surfaces or water and food. last 30 years indicate that a high diversity of bacteria, • Develop systems and procedures to prevent fungi, and Actinomycetes are commonly carried on- water and food spoilage during in-situ production board, most likely via clothing, equipment, air currents or storage. Quality control of water and food, in during spacecraft handling and loading, food, and the specific, will become more important when water astronauts themselves (Novikova et al., 2006). It has and food will be in-situ produced, prepared, and been demonstrated that microbial contamination stored (‘fresh’) during long term missions. in confined manned habitats is primarily originating • Develop Prophylactic measures to fend off a from human and human activities (Van Houdt et al., disease or another unwanted consequence 2009). such as crew dysmicrobiosis or infection, for example by suppression of harmful agents via A large industry exists in Europe dealing with air, water, competition with beneficial agents on skin or food and surface quality assurance, for occupational mucous tissues, by use of pre- and probiotics or health, food and pharmaceutical industry, antifouling fermented food products to prevent impact of in the marine field, and biosafety laboratories. Space consumption of sterilised food over prolonged research could benefit from the current and on-going periods on intestinal microflora and digestion, developments on Earth in these sectors without by strengthening e.g. the colonial resistance and having to develop independent R&D strategies. prevention of vaginal bacteriosis. However, the existing technologies are not always • Evaluate the efficiency of prevention design and directly transferable or applicable for the specific maintenance procedures in space (e.g.in ISS, materials and environmental conditions in space, and under standard upload or crew operations) or thus adaptations will be required. relevant analogues on Earth. • Develop models describing the contamination Proposed investigations and recommendations kinetics in a closed system, including multiple microbial species in competition and possible • Apply better facility design that allows preventing sinks of contamination, in order to predict and contamination (e.g. smooth edges, no corners, control contamination. use of HACCP analysis). • Define the list of microbes (e.g. latent viruses, 2.2.3. Key Issue 3: Develop adequate environmental opportunistic pathogens) that should be contamination monitoring (prediction, detection, confirmed as absent in the crew before flight, identification) systems for use in space as crew will be the major source of the microbes dispersed in the environment. Relevance for space exploration • Develop efficient maintenance systems for prevention of microbial dispersion through In respect to human risk, the importance of monitoring air (e.g. air filtration, adsorption processes) is lower when fast crew return in possible, but very

Microbiological quality control of the indoor environment in space 11 important for long-duration missions. throughput cellular and molecular analysis systems In respect to economics, the importance is high as (e.g. microfluidics devices) coupled with bioinformatics significant losses are linked to up and down load of that allow ‘de novo’ detection (without prior sequence for replacement hardware and water supplies that knowledge) of DNA sequences, proteins or lipids were lost for consumption due to contamination. etc. This could help the development of fast, on-line detection systems (Sakamoto et al., 2007; Stîngu et al., Terrestrial interest and application 2008; Fricke et al. 2009). Unfortunately, these systems are currently large in size, require many consumables The development of early detection and warning and operator interventions, and will need to be systems for environmental contamination and redesigned for any future space application. pollution is of common interest for space and on Earth. Such autonomous systems could be used to Europe is rich in scientific and industrial communities assure healthy environments in housing and working dealing with environmental hygiene in hospital and buildings, in hospitals for fast screening of incoming industry. Also valuable expertise in risk assessment patients (carrier state), emergency situations, for the exists in many European countries. prevention of nosocomial infections in public areas and public transport, and in pandemic control in case Proposed investigations and recommendations of natural catastrophes. Potential medical applications are ample, including on-site infection detection and • Develop a due point monitoring system (sensors identification, and diagnosis. In addition, such systems to most critical niches) will be of interest for continuous quality monitoring • Develop adequate sample collection procedures of air, water, surfaces and products in production and mobile sampling systems, exploiting facilities for the food and pharmaceutical industries. novel collection techniques and materials (e.g. filtration, adhesion, absorbents, electrostatic Background and European strengths attraction, etc.), that allow to correctly assess the microbial contamination on multiple locations in Despite effective contamination prevention measures, the habitat data shows the successful colonisation of space station • Develop sample analysis systems that environments by microbes (Novikova et al, 2006). It • are rapid (real-time), on board, compact, has been demonstrated that microbial contamination automated, sensitive (detect low in confined, manned habitats is primarily originating concentrations), allow quantification and from humans and human activities (Van Houdt et al., identification, not using toxic or flammable 2009). Harmful microorganisms emerge naturally, even chemicals and with low requirements for in the absence of indigenous hosts, and are able to energy, consumables and maintenance. adapt to and become dominant in closed spaceships • deliver in priority a rapid total contamination or stations (Warmflash et al. 2007; Bernasconi et al., assessment (total microbial burden), and in 2010). a second (potentially slower) step a more detailed identification and quantification Thus, such fluctuations in microbial concentrations of the specific components of the and trends in contamination events suggest the need contamination. for continued diligence in monitoring and evaluation, • detect also the ‘in advance unknown’ (new as well as further improvements in engineering arising) microorganisms or events systems (Castro et al. 2006). The knowledge obtained • detect, in addition to the presence and from microbial control during past missions is critical quantity, also the ‘activity’, of the microbial in driving the design of future spacecraft monitoring population systems. • Develop sampling and analysis systems that allow simultaneous monitoring of multiple microbial Over the last decade, rapid developments have been contaminants, including viruses, bacteria, yeasts, made in molecular biology and genetics using high fungi, amoebae, ciliates and other protozoa, dust

12 Microbiological quality control of the indoor environment in space mites, exo- and endo-toxins, mycotoxins, volatile significant microorganisms low during a space organic compounds, etc. mission. Nevertheless, microbial proliferation in the • Develop sampling and analysis systems that are environment causing infection of crewmembers and preferentially applicable to multiple sources, harmful effects on the cabin may still occur. Adverse including air (in priority), air cleaning systems (e.g. effects of microbes on technological equipment and filters, heating/drying coils), water, surfaces, food, cabin have been reported (Novikova et al., 2006) waste, and/or crew (e.g. dental, skin or intestinal and some effects were potentially life threatening microflora, breath chemical composition, as for the crew (Novikova, 1999). Because of such markers for crew health). Microbial quality control cases, adequate systems and procedures to deal of water and food, in specific, will become more with the problem (including emergency response important when water and food will be in-situ and corrective actions) have to be in place. Thus, produced, prepared, and stored during long term it is necessary to determine the efficacy of current missions. mitigation strategies and countermeasures for long • Develop an ad hoc statistical model based term space missions and if needed, to formulate approach for predicting colonisation hotspots additional recommendations for operational remedies and optimising sampling procedure to cure harmful microbial contamination events.

2.2.4. Key Issue 4: Develop materials and methods A large scientific and industrial community exists to mitigate environmental microbial contamination in Europe which is dealing with air, water, food and and its harmful effects in space surface decontamination (e.g. sterilisation procedures in food industry, in hospitals, in pharmaceutical Relevance for space exploration industry). However, existing technologies are not always directly transferable or applicable for the In respect to human risk, this research priority specific materials and environmental conditions in might be lower for LEO missions as fast crew return space. in possible, but will become more important for long term missions where fast return is no longer Proposed investigations and recommendations possible. In respect to economic development and implementation of decontamination procedures, • Apply better facility designs that allow easy this topic is important for both short and long term decontamination (e.g. smooth edges, no corners, missions, as even in short term missions significant use of HACCP analysis, etc.) losses are encountered due to up and down load of • Develop contamination mitigation products or replacement hardware and water supplies that were systems that are highly efficient, rapid, compact, lost for consumption due to contamination. compatible with space materials, not using toxic or flammable chemicals and with low requirements Terrestrial interest and application for energy, consumables and maintenance. • Develop contamination alleviation procedures Development of microbial decontamination that are preferentially applicable to samples from procedures for space will be of interest for water multiple sources, including air (primarily), water, quality control on Earth, hospital management, the surfaces, food, waste, and/or crew. food production and processing industry (cleaning • Develop contamination alleviation procedures for technology and hygiene control), and the material food and water decontamination. Quality control industry (self-cleaning surfaces or easily cleanable of water and food, in specific, will become more surfaces). important when water and food will be in-situ (‘fresh’) produced, prepared, and stored during Background and European strengths long term missions. • Develop contamination mitigation procedures Precautionary measures can keep the presence and that allow removal of microbial biofilms from abundance of many medically and/or technologically surfaces (e.g. non-volatile biocides, electrical

Microbiological quality control of the indoor environment in space 13 currents, radiation including UV, etc.), stop metal biocorrosion, and polymer biodegradation.

• Develop contamination mitigation procedures that allow treatment and curing of human dysmicrobism (an imbalance of the normal flora) and infections, e.g. via modulation the human microflora by use of pre- and probiotics or fermented food products.

2.2.5. Key Issue 5: Acquire better knowledge on microbial community (microbial ecosystem) dynamics and microbial cell evolution over time in confined manned habitats in space

Relevance for space exploration

In respect to human risk, the importance of inflight decontamination is lower when fast crew return in possible, but very important for long-duration missions.

In respect to economics, the importance is high as significant losses are linked to up and down load of replacement hardware and water supplies that were lost for consumption due to contamination.

Terrestrial interest and application

In space vehicles, only a ‘simplified’ microbial community is able to develop (only source is the humans, without interaction with plants, soil, animals). Space research Figure 3: An example of microbial could give a better understanding of microbial community contamination that developed on an interior dynamics under environmental conditions, which could panel aboard the ISS. Attempts to clean the be of interest for more complex Earth communities. A panel with supplies aboard the ISS failed and better knowledge and database of indicator organisms the panel and to be replaced. (Credit: NASA, for expected/dominant microbial populations in confined image ISS010E11563) habitats is also relevant for indoor environmental air quality in housing and living buildings on Earth in general, or for specific applications such as treatment of immune- depressed patients in hospital. A better insight into the processes of acquisition and selection of resistances to antibiotics and biocides is also highly valuable for the medical sector. Intestinal microbiota are likely involved in many disease states, and understanding not only how these bacteria are influenced by environmental parameter, but also how to modify the microbiota to effectively reduce these diseases are highly needed.

14 Microbiological quality control of the indoor environment in space Background and European strengths and cells over time in air (in priority), water, surfaces, food, waste, and human microflora Because microbial contamination of spacecraft communities (e.g. identify favourable conditions cannot be avoided, research must be initiated to and niches). better understand how microorganisms and microbial • Identify and describe the processes involved communities evolve and interact with humans, in changes in microbial abundance, diversity, animals, plants and materials in space environments interaction (including gene transfer), and microbial (Gu et al. 2007, Castro et al., 2006). For example, the ecosystem equilibrium; genetic evolution over influence of reduced microgravity, reduced gas or multiple generations (mutation rates by natural liquid convection and settling of particles, higher replication errors or mobile genetic elements, doses of radiation, and lower pressure and oxygen and induction and selection processes), evolution concentration in space on microbial distribution and of chromosome length and gene expression development in space habitats is not known. The fast (e.g. activation of pathogenicity), evolution of developments in molecular biology and genetics cell proliferation rates, surface attachment and using high throughput cellular and molecular analysis colonisation etc. systems (e.g. –omics tools for genome, proteome, • Identify key microbial players and representative metabolome, profiling, microfluidics analysis early indicators (e.g. certain bacterial species, or devices) coupled to bioinformatics allow ‘de novo’ even bacterial phages) and markers for microbial detection (without prior sequence knowledge) of presences and activity that can be used in DNA sequences, proteins or lipids etc., for microbial monitoring systems for air (primarily), water, community and activity analysis could help to surfaces, food, waste, and human microflora significantly improve our knowledge (Sakamoto et al., communities (human microbiome) (e.g. dental, 2007; Fricke et al. 2009). skin, intestinal, vaginal microflora). • Investigate the evolution of model microbial The community of environmental microbiologists communities under space conditions (e.g. long- in Europe is very active, with many teams of world term space flight experiments). The ISS would importance. Specialties include human microbial be an excellent platform for long-term evolution ecology (intestine, skin, etc.), animal microbial experiments using in-situidentified microbes. ecology (rumen cow, etc.), plant microbial ecology • Develop mathematical models based on a (root, leaves, etc.), soil bacterial ecology, water comprehensive understanding of the underlying microbiology, microbial genetics (Mobile Genetic phenomena for explaining and use them for better Element), biotechnology industry etc. global management (prediction, control and modulation) of microbial community evolution. Proposed investigations and recommendations

• Collect new data on microbial community dynamics and microbial cell evolution in confined habitats in space (e.g. ISS) or analogues on Earth under space relevant conditions, by sampling and analysis, and by building a shared database (i.e. of sequences and physiological, biochemical, ecological data, etc.) and a shared space microbial culture collection. • Identify and describe the role of environmental parameters (temperature, humidity, confinement, increased radiation, reduced gravity, reduced pressure, modified chemical composition of the atmosphere, growth substrates) for induction or selection of changes in microbial communities

Microbiological quality control of the indoor environment in space 15 2.3. References

Bernasconi C., Rodolfi M., Picco A.M., Grisoli P., Dacarro C., Rembges D. Pyrogenic activity of air to characterize bioaerosol exposure in public buildings : a pilot study. Letters in Aplied Microbiology. 2010. 1-7

Castro V. A, Rebekah.C. Mark Ott and D. L. Pierson The Influence of Microbiology on Spacecraft Design and Controls: A Historical Perspective of the Shuttle and International Space Station Programs. 2006-01-2156 (review).

European Commission, Recommendations from Scientific Committee on Occupational Exposure Limits, 2009, http://ec.europa.eu/social/keyDocuments.jsp?type=0&policyArea=82&subCategory=153&country=0&year=0 &advSearchKey=recommendation&mode=advancedSubmit&langId=en

Fricke W.F., David A. Rasko, Jacques Ravel The Role of Genomics in the Identification, Prediction, and Prevention of Biological Threats PLoS Biology 2009 Volume 7 Issue 10 | e1000217

Gu J-D., Microbial colonization of polymeric materials for space applications and mechanisms of biodeterioration : A Review. International biodeterioration and biodegradation. 2007 59:170-179. (Review)

International Space Station Medical Operations Requirements Document (ISS MORD). International Space Station Program. Revision C. January 2009.

Jermy A. Bacteria ensure injury is only skin deep. Research highlights Nature Reviews Microbiology. 2010. VoLume 8/ p1.

Natalia Novikova, Patrick De Boever, Svetlana Poddubko, Elena Deshevaya Nikolai Polikarpov, Natalia Rakova, Ilse Coninx Max Mergeay Survey of environmental biocontamination on board the International Space Station Research in Microbiology 157 (2006) 5–12

Natalia Novikova. Review of the knowledge of microbial contamination of the Russian manned spacecraft in Microbial Ecology 47 (2) (2004) 127-132.

Nicogossian AE, Gaiser KK. The space life sciences strategy for the 21st century. Acta Astronaut. 1992 Jun;26(6):459-65. (Review)

Sakamoto C., Yamaguchi N., Yamada M., Nagase H., Seki M. Nasu M. Rapid quantification of bacterial cells in potable water by using a simplified microfluidic device. Journal of Microbiological methods, 2007. 68:643-647.

Schuerger AC. Microbial contamination of advanced life support (ALS) systems poses a moderate threat to the long-term stability of space-based bioregenerative systems, Life Support Biosph Sci. 1998;5(3):325-37. (Review)

Sonnenfeld, G. (2005) The immune system in space, including Earth-based benefits of space based research. Curr Pharm Biotechnol 6: 343-349.

Stîngu C.S., Rodloff A.C., Jentsch H., Schaumann R., Eschrich K..Rapid identification of oral anaerobic bacteria cultivated from subgingival biofilm by MALDI-TOF-MS. Oral Microbiology Immunology 2008: 23: 372–376

Van Houdt R. Patrick De Boever, Ilse Coninx, Claire Le Calvez, Roberto Dicasillati, Jacques Mahillon, Max Mergeay, Natalie Leys. Evaluation of the Airborne Bacterial Population in the Periodically Confined Antarctic Base Concordia. Microb Ecol. DOI 10.1007/s00248-008-9462-z

Victoria A. Castro and Rebekah.C. Mark Ott and D. L. Pierson The Influence of Microbiology on Spacecraft Design and Controls: A Historical Perspective of the Shuttle and International Space Station Programs. 2006-01-2156 (review)

16 Microbiological quality control of the indoor environment in space Warmflash D, Larios-Sanz M, Jones J, Fox GE, McKay DS. Biohazard potential of putative Martian organisms during missions to Mars. Aviat Space Environ Med. 2007 Apr;78(4 Suppl):A79-88. (Review)

WHO air quality guidelines for Europe, 2nd edition, 2000, http://www.euro.who.int/document/aiq/3summary.pdf

Williams, D., Kuipers, A., Mukai, C. and Thirsk, R. (2009) Acclimation during space flight:effects on human physiology. Cmaj 180: 1317-1323.

Wilson, J. W., Ott, C. M., Honer zu Bentrup, K., Ramamurthy, R., Quick, L., Porwollik, S., et al. (2007) Space flight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq. Proc Natl Acad Sci U S A 104: 16299-16304.

Microbiological quality control of the indoor environment in space 17 3 Life Support: Management and Regeneration of Air, Water and Food

3.1. Introduction The subsequent sections present the recommenda- trolled manner: (i) it provides the input resources re- tions issued from the Expert Group focused on ‘Life quired for humans and other biological species in the Support: Management and Regeneration of Air, Water habitat, and (ii) it processes human and other outputs and Food’ as well as the rationales behind them. and waste.

The group’s interest covers life support for self-sus- The requirements of life support systems change tainability via regenerative processes using physical, drastically when humans are subjected to exploration chemical and biological technologies. This includes: type missions facing interplanetary and planetary en- • air revitalisation (CO2 removal & O2 production), vironments. Different issues have to be considered for • water supply and recycling, the transfer phases from Earth to the Moon or Mars, • food supply (plants, microbial), and back, and for the stay on the surface of the ce- • waste management (removal & recycling). lestial body. Thus far, available life support techniques are based almost entirely on physical-chemical proc- Whenever human beings live and work in a confined esses. Long-term and repeated exploration missions habitat over extended periods of time, it is the task however demand for alternative methods, including of the life support system to achieve and maintain a (i) biological processes for food production mimicking physiologically acceptable environment within the natural processes of the Earth’s biosphere, and (ii) the habitat. An efficient environmental control and life use of natural resources available on extra-terrestrial support system (ECLSS) essentially takes charge of bodies. The basic reasoning behind this is that hu- two complementary functions in a balanced and con- man beings cannot survive in the absence of organic

Figure 4: The current baseline for the ISS ECLSS system (Credit: NASA)

18 Life support: management and regeneration of air, water and food life, making food production a primary issue. This must be linked to other life support functions as well, such as water and waste recycling. In turn, this calls for an integrated vi- sion and approach to studies of life support technologies using intertwined biological, physical and chemical proc- esses.

A key driver in the design (and ultimately selection) of life support processes for human space exploration is the need to minimise the use of consumables. This is impor- tant because of the tremendous costs associated with transporting mass to space. In general, the issues are re- lated to safety, reliability, microgravity operation, attention to consumables and waste products, complexity of closed systems, simplicity in operation, maintenance, repair and control, materials selection, human factors and interfaces, level of maturity and uncertainty, minimisation of con- sumables, scale of design and operation, mass system, and integration with other operations.

This involves a broad variety of subjects and levels, from material science to system level evaluation, each needing attention and research. The Expert Group has chosen to classify the different topics following a hierarchical logic, from global aspects (metrics development; system level

Figure 5: Steps necessary for life support studies) to specific issues (subsystems improvement and system development development) and transverse issues (material science, modelling issues) (Figure 1).

It was also recognised that life support system design and implementation should be part of an overall sustainable and ergonomic habitat design, i.e. implementing resource and energy efficient buildings, sustainable construction practices, healthy and productive indoor environment, as well as energy-efficient housing and working. Thus, -ar chitectural and psychological aspects will also have to be taken into account when considering life support systems. It is well established and acknowledged that this point is a policy implementation issue, not a research priority.

The following sections report the conclusions the ‘life sup- port: management and regeneration of air, water and food‘ Expert Group. This group met during two expert work- shops in 2010. Those workshops were organised sessions aimed at considering the key questions to address, the latest developments, the gaps to fill and the earth-based applications.

Life support: management and regeneration of air, water and food 19 3.2. Life Support: Management and Regeneration of Air, Water and Food – Key Issues

3.2.1. Key Issue 1: Develop and adopt common met- Proposed investigations and recommendations rics for evaluation of different Life Support System (LSS) architectures, technologies, and their evolu- • due to the fact that LSS is an integration of sys- tion tems or subsystems, consider dynamic and flex- ible approaches that can integrate new emerging Background and European strengths criteria. • develop a LSS system model and a support tool- The life support system is a major, multipurpose mat- box evaluator firstly working with some a priori ter for human exploration. Currently, different metrics significant criteria. are used by different space agencies. While the NASA • deploy an overall simulator and use ALISSE - Ad- equivalent system-mass (ESM) approach is still the vanced Life Support System Evaluator - for actual baseline (BVAD), it is now considered to be too nar- case studies (Brunet, 2009). row. There is a need for an independent selection pro- • deploy standards for collecting, validating and cedure to evaluate LSS solutions in order to provide making available the data for system evaluation inputs to the CDF (Concurrent Design Facility) data- and multi-criteria optimisation. base. The approach of this evaluation and selection • evaluations of operational results from LSS with is a difficult trade-off between technical, safety, cost ALISSE and strategic considerations. For any LSS project, it would be necessary to take a multi-criteria approach, Terrestrial interest and application including emerging criteria, due to the fact that LSS is an integration of systems or subsystems. Today, the major studies on environment issues and sustainability, e.g. in the field of industrial ecology, The integrated methods and tools must: mainly focus on one requirement at a time (energy consumption, water consumption or any other). How- • evaluate global LSS behaviour in closed loop, ever, there is a need to approach systems with a much • assess and score safety & reliability, more integrated view, taking multiple requirements • take into account all its enabling logistics. into account. Although the key criteria are may be not the same for space and Earth applications, the meth- There are important trends and European strengths odology and metrics used for space certainly could (University of Lausanne) for managing the transition be valuable for Earth-based systems as well. As LSS from today’s unsustainable arrangements to more complexity (required variety) is currently not known sustainable projects (Erkman, 2003). This is the subject precisely, assessment methods and tooling will surely of eco-restructuring and industrial transformation. evolve. Assessment needs and methods have to have These topics are strictly linked to new bodies of eco- a simultaneous and continuous approach with LSS nomic and political theory and practice and are highly development and increasing level of complexity. This dependent on system evaluation methods. This is the completely matches with the methods of integrating core of research and developments regarding com- environmental concerns in industrial developments mon metrics for evaluation of different Life Support by finding innovative solutions to complicated envi- System architectures, and technologies. Industrial ronmental problems, as in the emerging domain of ecology is central to these fields with an emerging industrial ecology (Erkman, 2003). body on theory, tools and practices.

The International Society for Industrial Ecology seeks to build a community of interest, support cumulative learning, produce quality research, and promote so- cial change.

20 Life support: management and regeneration of air, water and food 3.2. Life Support: Management and Regeneration of Air, Water and Food – Key Issues 3.2.2. Key Issue 2: Develop model-based regenerative Life Support via a system level approach

Background and European strengths

Life Support Systems must be conceived as an integrated sum of unit operations. This requires on one hand, a sys- temic approach of complex, highly branched systems with important feedback loops and, on the other hand, the study of a set of unit operations in charge of the elementa- ry functions constitutive of the entire Life Support System. The technologies must be developed in a generic way, considering that the final technical solutions will depend on the constraints and on the objectives of the mission’s scenarios. The modelling approach by knowledge models constitutes a mandatory guideline for evaluating and de- signing the processes. This also leads to base control and management strategies. This is the brain-level of the man- made ecosystem; it is materialised by the mathematical de- terministic modelling supporting the understanding of the system and subsystems at various interacting scales; this also allows for simulation of the different interacting parts of the system. This brain-level description also contains the fundamental laws of physics and chemistry, starting from Figure 5: NASA astronaut Jeffrey Williams -in conservation laws (conservation of elements – carbon; hy- stalls the Urine Processor Assembly/Distillation drogen; oxygen; nitrogen; phosphate; sulphur - that is of Assembly in the Water Recovery System rack primarily importance for closed systems – energy conser- on the ISS (Credit: NASA) vation laws…etc.) with special attention for cycles and fate of micro-contaminants in the system.

The current ESA strategy puts priority firstly on air and wa- ter supply, and secondly on waste and food management. First independent units should be developed, which grad- ually can be coupled to fully closed systems (Klein, 2009). Current life support systems are indeed functional and very efficient using multiple independent processes units. Al- though open-loop systems have been used successfully in the past for short-duration missions, the economics of cur- rent and future long-duration missions in space will make nearly complete recycling of air and water imperative. A variety of operations will be necessary to achieve the goal of nearly complete recycling. These include separation and reduction of carbon dioxide, removal of trace gas-phase contaminants, recovery and purification of humidity con- densate, purification and polishing of wastewater streams, and others. However, it should be demonstrated that these modular systems could be integrated into fully closed loop systems that are equally efficient or even better than the systems currently applied in space.

Life support: management and regeneration of air, water and food 21 Also model-based development of technologies is • Develop models describing the fate of micro- mandatory to utilise and exploit extra-terrestrial plan- contaminants on the molecular level and develop et resources for human life-support system replen- countermeasures for adverse effects. ishment (ISRU). The development of those processes • Provide conclusive demonstration for the closure, must be conceived in a generic way in order to be including integrated testing. adaptable to a broad variety of applications and en- vironmental conditions (non- terrestrial gravity, low Terrestrial interest and application external pressure, radiation exposure, etc.) Modelling and understanding issues are the basis of While other space agencies (e.g. American, Russian) current improvements of different processes. Any thor- have reduced or other agencies only recently begin ough understanding of chemical and/or biochemical (e.g. China, Japan) their activities in this area, Europe processes has potential applications in industrial en- has continued to invest in this topic over the past 3 gineering, whatever the domain, from environmental decades. A large know-how has been gathered and processes to pharmaceutical processes. expertise been build, making Europe a leader on this topic, with a large potential to further grow. Follow- Closed loop recycling and production systems are ing the opinion of Gitelson and Mc. Elroy in 1999 “… useful platforms for eco-toxicological research. Minia- elements of a complete recycling system (MELiSSA) turised artificial ecosystems are of interest for investi- were developed fundamentally, which is traditional gating in more detail the ecological impact and fate in European culture, putting together separate links of micro-pollutants in ecosystems (e.g. fate and ac- elaborated in several European countries which is a cumulation of xenobiotics, biocides, antibiotics, hor- good example of international co-operation”. mone derivatives, and pharmaceutical compounds). Improved effluent polishing systems could for exam- Proposed investigations and recommendations ple also be useful for removal of bioactive pharmaceu- ticals in hospitals, municipal wastewater streams, etc. • Improve understanding and functioning of closed loops via multiple parameter analysis and model- For terrestrial applications, closed loop waste water ling with dedicated multi-physics and multidisci- recycling systems could be of interest for applications plinary algorithms and software tools, including on boats and cruise ships, in remote hotels (eco-tour- models for thermo-fluid-dynamics, biological ism), remote stations for exploration and/or exploita- processes, human metabolism and respiration, tion of remote area’s (e.g. Antarctica, dessert…etc.). urine and faecal production, etc. • Develop adequate mathematical models and 3.2.3. Key Issue 3: Further develop Life Support sub- algorithms to allow correct simulation and pre- systems and components for long-duration space diction of system performance in a multiple im- flight and planetary surface mission phases plemented conditions or constraints. This can be a valuable alternative for empirical, costly tests Background and European strengths non-fully representative of all conditions. If one can predict the outcome, it may allow reducing Any LSS is composed of an assembly of different sys- considerably the risk, preparing spare parts, ad- tems and subsystems supporting different functions dressing non-nominal modes, etc. and unit operations (e.g. separation, evaporation, • Identify needed robust control strategy and buff- reaction, and bioconversion). Depending on the mis- er capacity, and start-up and emergency storage sion’s scenario and on the targeted degree of closure scenarios. of the LSS, physical systems could be involved alone • Develop supporting databases containing actual whether in association with chemical reactors some data on tested equipment, biological processes, chemical transformations and other functions can be plants, human, etc. envisaged. Association with biological compartments

22 Life support: management and regeneration of air, water and food allows food production to be at least partly supported. If no chemical transformation is included, physical systems are sufficient (adsorption of CO2, water purification…. etc.). In that case all consumables are refurnished (O2, food, part of water). If O2 is regenerated (by Sabatier process by ex- ample) chemical transformations are mandatory. If carbon and nitrogen recycling is envisaged, LSS must include food production calling for biological processes. Whatever the inherent large diversity of the possible life support subsys- tems and their hybridising in the global system (that calls once more for a generic engineering approach in terms of metrics and of modelling) there are different degrees of maturity for use of such subsystems for human space mis- sions.

Adsorption processes, for instance, have historically played a key role in life support on U.S. and Russian piloted space- craft. These processes are good candidates to perform separations and purifications in space due to their- grav ity independence, high reliability, relative high energy ef- ficiency, design flexibility, technological maturity, and re- generative nature (DallBauman and Finn, 1999).

Another example comes from the use of bioreactors and higher plants chambers (HPC). Presently, bioreactors and

Figure 6: Cosmonaut Mikhail Tyurin performs HPC for terrestrial applications have relatively low spe- an inspection of the Plants-2 experiment on cific volumetric bioconversion rates. Consequently their the ISS (Credit: NASA) energetic efficiency may be questionable and they re- quire among others installations with large masses and volumes, energy supply and maintenance time. For space missions, and especially for long-term missions, knowing that masses and volumes and resources will be highly con- strained (Salisbury, 1999), bioreactors and HPC must have to be strongly intensified and miniaturised. In addition op- erational and biological processes will need to be adapted to the space environmental conditions (Haque et al. 1993; Monje et al., 2003).

New technologies and materials are developed every day and there is still room for improvements that should be investigated for future long-durations space missions. In addition, a detailed characterisation and understanding of novel proposed processes under space flight conditions (reduced gravity, radiation exposure, etc.) is a prerequisite (Haque et al. 1993; Monje et al., 2003).

A large community of scientists is involved in environmen- tal biotechnology and active in food and pharmaceutical industry in Europe.

Life support: management and regeneration of air, water and food 23 Proposed investigations and recommendations ical or electrical failures of pump, detector, valve, etc.) can occur and have to be taken into account. Continu- • Develop and test prototypes for regenerative ous process monitoring and control is needed. LSS in relevant environmental conditions (e.g. ground, modified-g, radiation, pressure, tem- Presently, the quality of, for example, the water perature, light, ISS, lunar lander) including more stored or produced in the life support system of the efficient microbial bioreactors and plant growth spacecraft such as ISS, is off-line and often relying chambers and dealing with: on ground analysis equipment. This introduces large • Air regeneration response times, and makes any life support system • Water regeneration (e.g. filtration) dependent on ground equipment. For future space • Waste management (e.g. incineration) exploration missions, more advanced, autonomous • Genetic stability of biological systems in-situin-situ on-line process monitoring and control • Improve efficiency and yield of biological conver- equipment is required. This is especially true if man- sion made ecosystems are used as regenerative life sup- • Characterise performances of the biological ele- port systems, as they differ from their prototype bio- ments in relevant environmental conditions (e.g. sphere by the principle of control (Farges et al. 2008). modified-g, radiation, pressure, temperature, The Earth Biosphere is sustainable by stochastic con- light) trol and very large time constants. By contrast, in a • Investigate genetic stability of the essential bio- closed ecosystem, a deterministic control may often logical specimens in reactor systems and space be a prerequisite of sustainable existence. In addition, environment future regenerative life support systems will be an as- • Capture and take into account gaps that currently sembly of subsystem in a complex architecture, and emerge (and many more will in the future) from their optimisation will only possible if the design as LSS operations both in space and on Earth (e.g. well as the control is based on a strong and advanced ISS, submarines), even in very classical systems, to control strategy. make a lessons learned catalogue available to a wider community This, in terms, calls for a as complete as possible fine • Improve understanding of multi-phase mass / understanding of the different levels of the system, heat transfer processes under modified-gravity handled by mathematical modelling. Mathematical and incorporate solutions into equipment design modelling accounts for the deterministic aspect of the control. This is particularly true for a complex as- Terrestrial interest and application sembly of several subsystems, interacting with com- pletely different time constants and mass and energy This issue is relevant to domestic waste treatment and flows. Therefore process monitoring and control re- water recycling, zero-emission technology, subma- quires a multilayer (hierarchical) approach. The reli- rines, isolated extreme environments. ability is included in a thorough understanding of the processes (including living organism’s behaviour) and Synergies with biotechnological research and devel- using the basic principles of mass, energy, exergy (en- opments in agriculture, food production and process- tropy), momentum conservation laws. ing, pharmacy, waste treatment for high valuable product recovery can also be highlighted. Proposed investigations and recommendations

3.2.4. Key Issue 4: Improve autonomy of LSS via • Take advantage of existing state-of-art systems monitoring and control currently applied in other research such as envi- ronmental sciences (e.g. real time water quality) Background and European strengths and biotechnology (e.g. bioprocesses control in pharmacy) and adopt for spaceflight As in any system that is in continuous operation, crew • Thorough characterisation and understanding operational mishaps or technical failures (e.g. mechan- of the different subsystems and processes what-

24 Life support: management and regeneration of air, water and food ever the level: genetic and metabolic behaviour life support systems are by definition required to be for microorganisms and higher plants, analysis of highly safe, reliable, available, and low maintenance. coupling between physical phenomena (transfer For future manned mission beyond LEO, where fast kinetics and physiological behaviour for living rescue to Earth will be no longer possible, this require- organisms), mass and energy conservation for ment will only become more stringent. For long-du- integrated processes, kinetics responses and time rations missions, life support systems will have to be evolution for subsystems, etc. error-free over a longer time frame. • Support developments of miniaturised sensors, network management, control modelling, algo- Bioreactors and biotechnological processes are used rithms and software for use in the spaceflight en- worldwide in our daily life on Earth. The actual sci- vironment entific and technological know-how is very high. For • Perform extensive integrated system testing example, large volumes of industrial and domestic including software, as many unresolved issues waste water is treated in biological basins, single-use might arise from the system interactions, not the bioreactors up to 2,000 m3 are successfully used eve- individual subsystems alone. Sub-systems may of- ry day in the pharmaceutical or food industry for pro- ten satisfy their individual requirement, yet the in- duction of e.g. , fermented beverages. How- tegrated system fails due to overlooked interface ever, currently, still no bioreactor has been accepted requirements or interactions (Graf et al., 2002). for application in space, but showed promising results during the 90-day study at NASA JSC (LMLSTP Phase Terrestrial interest and application III, 1997). Unlike natural ecosystem on Earth, miniatur- ised artificial closed loop ecosystems used as BLSS in Management of complex systems is known to be a space, lack buffer capacity and therefore are believed major challenge of 21st century (Edgar Morin). Proc- to be much more challenging to control. But concep- ess engineering (based on chemical engineering prin- tual studies have shown that closed loop controlled ciples) and systems engineering (based on a hierar- ecological life support system is not only feasible, but chical approach of control of interacting subsystems) also eminently practical (Schwartzkopf SH., 1997). are the clues for modern developments of industrial Nevertheless, the perception and ‘general acceptance’ processes, whatever the size and the functionality. of the recycled product, produced directly from waste When developing and installing a rationale for a spe- in only a limited number of steps, remains still and is- cific purpose such as life support systems for space sue, which should perhaps be addressed at a “collec- applications (especially systems including living or- tive” social, psychological and education level. ganisms), the methodology and the approach will be completely transferable to other applications. Con- It is essential to test hardware for longer-duration trollability, modularity and reliability requirements for functionality and in the correct representative envi- LSS are excellent examples of future developments in ronment for the planned mission (e.g. Moon or Mars modern industrial technology. Applications to any en- conditions), and using representative air, water, food vironmental process are straight forwards. and waste streams for recycling processes. Testing individual subsystems to interface performance re- 3.2.5. Key Issue 5: Improve LSS robustness, reliabil- quirements in clean rooms on Earth or in ISS environ- ity, availability, maintainability, safety, acceptability ment are typically insufficient to address the complex in long-term integrated operations system interactions, and integrated system tests in re- alistic operational environments are difficult (Allen et Background and European strengths al., 2003), often not planned nor budgeted, resulting in on-orbit surprises. Any failure in a life support system can have severe consequences for human life (suffocation due to lack Russia has built the longest and strongest expertise of O2 or excess CO2 water and food shortage, disease, over the last 50 years in long duration testing in in- etc.), but potentially also for infrastructure (fire, ex- tegrated and confined habitats (e.g. BIOS facilities in plosion) and economically (e.g. abort mission). Thus, Krasnoyarsk, IMBP facility in Moscow). Large scale in-

Life support: management and regeneration of air, water and food 25 tegrated test facilities were also built in Japan (e.g. CEEF) (Nitta, 2005) and US (e.g. Biosphere 2) (Allen et al. 2003), with variable success. Europe, however, has mainly relied on the Russian expertise through collaborative projects (e.g. MARS100, MARS500), and only recently initiated con- struction of own facilities and independent investigations (e.g. utilisation of Concordia station on Antarctica - Van Houdt et al., 2009), MELiSSA pilot plant in Spain (Godia et al., 2004), FIPES (Hammersley, 2006) and CAPSULES habitat feasibility studies, etc. Thus, Europe still a large potential to grow in this area develop more expertise and facilities.

Large community of scientists and industry involved in environmental biotechnology, bioreactor and greenhouse technology, agriculture and biological waste treatment present in Europe.

Proposed investigations and recommendations

• Development of a thorough understanding of the processes using a systemic (holistic) viewpoint with a particular attention to how the knowledge of the sys- tem depends upon the position and scale of experi- mental observation. • Improvement of predictability of the system by under- standing and modelling in order to found the control strategy and to enlarge the field of conditions of ap- Figure 7: A view inside the MELiSSA pilot plication, including back-up scenario. plant at the University Autònoma of Barcelona • Implement failure tolerant functions (Credit: ESA/UAB) • Design and construct facilities on Earth for long-dura- tion and integrated testing, including several modules of LSS (e.g. reactors, bioreactors, higher plants cham- bers, separators, purification processes), in combina- tion with other habitat and crew activities (e.g. EVA activities, medical-psychological-behavioural-accept- ability aspects). Long duration integrated test facilities must be modular, flexible to accommodate alternative elements, robust and easy to reactivate and expand. • Application of current HACCP and GMP methods to these processes in order to guarantee the same level of safety (and encourage acceptability) that is now ex- isting for food and pharmaceuticals • Exploit ISS and other space flight opportunities (e.g. Bion) as a test bed for life support system technology including physicochemical treatment for air regenera- tion, higher plants chambers, analysis of the effects of microgravity on living microorganisms. • Test miniaturised components and life support sys- tems on Lunar Lander to assess environmental factors on system performance.

26 Life support: management and regeneration of air, water and food Terrestrial interest and application In Europe several companies are running with antimi- crobial coatings (mainly Silver). New approaches to In terms of applications, simple and reliable systems use bio-inspired coatings are running (for example: are required for numerous applications, including BIOCOAT at University of Liège (B). In the frame of a domestic applications (e.g. water treatment) and government funded project OHB (D) is also testing confined systems (e.g. atmosphere decontamination bio-inspired coatings based on proteins for Space and treatment for industrial application e.g. nuclear Habitat application) – Life Science people are more plants, pharmacy, industry of electronics). In terms of and more involved. waste treatment (agricultural waste, industrial waste, domestic waste) including the treatment the valorisa- Proposed investigations and recommendations tion and eventually the confinement, there are also many potential applications. The development of ro- • Develop materials and solutions to reduce mass bustness of such systems is mandatory for many pur- and volume of life support systems poses, knowing that future environmental technolo- • Develop and test materials to be compatible with gies will be much more distributed than today. This changed fluid and gas behaviour in space envi- calls for an improved autonomy and smaller units. The ronment gains in performance and reliability will be in logical • Improve biocompatibility of materials for safe extension of the generic approach that is developed contact with crew or for use in biological life sup- for LSS. port systems, and for long-term use in sealed en- vironments Confined manned habitats on Earth or in Space • Incorporate new functionalities (e.g. flexible, could also be prototypes allowing profound testing transparent, surface tension control, ‘bio-func- and evaluation of sustainable, i.e. environmentally- tional’, biodegradable, resistant to sterilisation, conscious (green), housing and working designs and resistant to biofouling, etc.) in materials, also technologies. Such habitats are unique test platforms considering “bio-inspired” materials, used for life for recycling processes, and for sociological and eco- support systems, working in commonality with toxicological research. industry.

The perception and general acceptance of recycled Terrestrial interest and application products (e.g. food products), produced directly from waste in only a limited number of steps, remain still an Synergies can be identified with materials science and issue, which should perhaps be addressed at a collec- engineering and biotechnology, with potential appli- tive social, psychological and education level. Similar cations for the medical field, agriculture, food produc- approaches could be valid for a larger number of top- tion and processing, pharmacy, waste treatment for ics, including GMO’s. high valuable product recovery.

3.2.6. Key Issue 6: Screen and develop high perform- 3.2.7. Key Issue 7: Develop and demonstrate capa- ance materials for LSS bilities to exploit resources available on other plan- ets (In-Situ Resource Utilisation - ISRU) for life sup- Background and European strengths port

The design, materials, and systems that are common- Background and European strengths ly used for bioreactors for terrestrial processes, are not all suitable and applicable in space. New ‘space com- In-Situ Resource Utilisation (ISRU) implies not only patible’ materials and systems need to be developed. recovery of water but should be investigated much This can involve improvements of artificial light sys- broader. It could for example also include investiga- tems, anticorrosion materials and shielding materials. tions in the potential of rocks (regolith) as sources of oxygen (e.g. 40% of the moon rock is containing bound-oxygen as e.g. silicates.) (Lunar Source Book,

Life support: management and regeneration of air, water and food 27 1991; Churchill, 1997; Spudis, 1996; Heiken, 1995; Sil- 3.2.8. Key Issue 8: Improve LSS architecture to in- berberg, 1985; Nealy, 1988; Hayashida, 1991; Ander- crease habitability son, 1994; , 1995; Lindsey, 2003) or as shield- ing material (Townsend, 2005). Background and European strengths

Proposed investigations and recommendations LSS architecture requirements are: • maximising usability with high efficiency (sim- • Evaluate how ISRU affects LSS at the system level ple and practical) and high safety levels (austere) • Establish links with other disciplines for ISRU (Jones and Harry, 2003; Jones and Harry, 2010) technology exchange, such as propulsion, radia- • minimising space and mass tion protection. • minimising maintenance • Develop links with groups traditionally not rep- • minimising production costs resented in aerospace necessary for these ISRU In principal for safety reasons all systems such as LSS, tasks (mining, civil engineering, large mass mov- should be modular – so to speak plug-and-play parts ing equipment) in case a part fails to work in one place the astronaut • Develop technologies to identify and extract rel- can put it into another place (Imhof, 2005). evant resources, e.g.: • Test efficacy of Lunar/Mars regolith simu- Habitability issues lants now, and return samples later, as sub- strates for growth of candidate crop species. The LSS and their relationship with aspects of hab- Because of the likely fine particulate size itability become very prominent during long-term (and small pore space), simulants will need stays (from 6-months onwards). Therefore it is crucial to be retested for plant-growth efficacy in to incorporate specific aspects of habitability as listed microgravity (ISS), and then real regolith below, even if this implies an LSS efficiency decrease. tested at 0.17xg on the Lunar surface and then at 0.38xg on the Mars surface. • Maintenance: Astronaut system time is approxi- • CO2 extracted from the Mars atmosphere mately 30% and mostly incorporates maintain- should be tested for ability to support crop ing the systems. This is an important aspect of photosynthesis. habitability because maintenance limits free time • Perform demo testing in analogues for ISRU sys- which is very low already, and thus reduces the tems operations (large scale) quality of habitability. Additionally, issues of mal- • Perform demo testing on the moon for specific functioning can further degrade habitability. ISRU technologies for LSS (small scale) • Noise: The noise level of the LSS is still much too • Improve knowledge of Martian soil from robotic high in the ISS. Every astronaut wears ear plugs missions, from an ISRU for LSS standpoint (for wa- because of the approx. up to 60dB of ventilation/ ter and oxygen production) fan noise. Reduction of noise levels means a sig- • Prepare a scenario for ISRU demonstration on nificant increase of habitability. In the quite new- Mars ly private cabins of Node 2 (2009) the noise levels of the high-speed fans are reduced through thick Terrestrial interest and application noise bumper material constructions. However, the noise still has different levels in different Potential synergies with research to improve CO2 se- modules. For example, the European module is questration on Earth can be put forward. less noisy than the American laboratory module. • Ventilation: Sometimes crew members suffer from if areas are not sufficiently ventilated (Adams and Constance, 1998). re- ported on her first mission to ISS 1999 , and Chris Cassady had to interrupt a spacewalk

28 Life support: management and regeneration of air, water and food because of a malfunctioning air scrubber and ris- related comfortable environments and the LSS ing CO2 levels . Too much ventilation can cause (lessons learned from ISS, previous space sta- drafts, which is also perceived uncomfortable by tions, and analogue simulations). some crew members. Other factors in this area • Identify trade-offs between habitability and LSS are the composition of air in relation to the pres- requirements: Where does habitability become sure. On ISS the pressure levels are different from detrimental for LSS requirements and vice ver- Earth. they are lower than 1 bar. Thus the mixture sa? Consequently, establish optimal conditions of oxygen and nitrogen also is adapted accord- where both taken together lead to maximized ingly to fit approximatively the relationship of productivity. these factors on Earth. • Ergonomics of the LSS-Human-Machine Inter- • Odor: Malfunctioning toilets cause a serious deg- face: How must the machinery be built so that radation of habitability not only through reduced there is easy maintenance and easy access to ad- comfort, but also through odor issues. In 2009, just comfort levels of fans, air ventilation, water astronauts Frank de Winne and Mike Barratt (USA recycling and food production). Today, 2009) had to do major repair work on the • Safety of the LSS-Human-Machine Interface: ISS’s toilets. But also in simulation-habitats like How must the systems be designed in order to the Mars Societies’ MDRS in Utah problems with optimise safety, taking into account efficient op- the toilet have occurred . eration. • Plants: These can also provide non-nutritive ben- efits and resemble effective countermeasures Terrestrial interest and application against deprivation (Imhof, 2003) in isolated/ extreme environments (Bates, 2009). In Mars500 Derived from the MELiSSA ECLSS there have been al- people were encouraged to work in the green- ready applications regarding grey water treatment for house if they wanted, which increased crew co- hotel complexes. The Dutch company IP-STAR is cur- hesiveness and relaxation (Imhof and Schartner, rently implementing these applications. Furthermore, 2001). grey water treatment can become important to every major urban development, especially new ones and Apart from large European industries such as TAS-I or can lay the path for a more sustainable way of living EADS Astrium, there are also SMEs with a very high on Earth. This applies to all Life Support Systems tech- capability of advanced and design nologies. Especially in deprived urban areas where expertise including a history in working with the big good water quality is lacking, there could be afford- industry and the space organisations NASA and ESA. able spin-off applications of Advanced Life Support (e.g. LIQUIFER Systems Group, Architecture and Vi- Systems for a more habitable environment (Adams, sion) 2004; Imhof, 2007).

Proposed investigations and recommendations LSS and habitability are important issues on ISS, just like they are on Earth, in offices or spaces with full -ar There has been some research in the area of the re- tificial air-conditioning. The room temperature and lationship between LSS and habitability (ESA, 2004; air circulation (including other factors of HVAC - heat- Broyan, 2010; Imhof, 2005), but for long-duration ex- ing, ventilating, air-conditioning) are always issues ploration missions this relationship needs to be stud- of discussion amongst the office people/astronauts ied in much more detail. because they depend on personal perception. Never- • Identify technical habitability factors of LSS: theless, well-working LSS or HVAC which are easy to Which requirements/factors of the Life Support adjust are simply vital for a comfortable and produc- Systems are vital for habitability, easy mainte- tive working environment. Parallel studies on Earth nance, comfortable and productive environ- and in space might reveal similarities and allow draw- ment. ing conclusions from earlier Earth research. • Identify trade-offs between individual human-

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Life support: management and regeneration of air, water and food 31 4 Annex: Expert Group Composition

Habitat management cluster coordinators

Natalie Leys SCK•CEN, Belgium Felice Mastroleo SCK•CEN, Belgium

Microbiological quality control of the indoor environment in space – Expert Group Members:

Jean Pierre Flandrois (Chair) Université Lyon-Sud, France Pertti Pasanen (Rapporteur) University of Kuopio, Finland Petra Rettberg DLR Institute of Aerospace Medicine, Germany Rob Van Houdt SCK•CEN, Belgium, Siegfried Praun V&F medical development, Germany Vacheslav Ilyin IBMP, Russia Masao Nasu Osaka University, Japan

Life support: management and regeneration of air, water and food – Expert Group Members:

Francesc Godia (Chair) UAB, Spain Cesare Lobascio (Rapporteur) Thales Alenia Space, Italy Claude-Gilles Dussap Université Blaise Pascal Polytech’ Clermont-Ferrand, France Klaus Slenzka OHB, Germany Francesco Canganella University Tuscia, Italy Alexander Hoehn Technische Universität München, Germany Heleen De Wever Vito, Belgium Angelo Vermeulen Biomodd, Belgium Barbara Imhof Liquifer systems group, Austria Mark Kliss NASA, USA

32 Annex: Expert Group Composition Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-04-8 printed in E.U. march 2012

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Cluster 5: Health Care - Report

CLUSTER5 March2012 1

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein. Towards Human Exploration of Space: a EUropean Strategy

Cluster 5: Health Care - Report

Space Medicine

Medication in space THESEUS: Towards Human Exploration of Space – a European Strategy

Past space missions in low Earth orbit have demonstrated that human beings can survive and work in space for long durations. However, there are pending technological, medical and psychological issues that must be solved before adventuring into longer-duration space missions (e.g. protection against ionizing radiation, psychological issues, behaviour and performance, prevention of bone loss, etc.). Furthermore, technological breakthroughs, e.g. in life support systems and recycling technologies, are required to reduce the cost of future expeditions to acceptable levels. Solving these issues will require scientific and technological breakthroughs in clinical and industrial applications, many of which will have relevance to health issues on Earth as well.

Despite existing ESA and NASA studies or roadmaps, Europe still lacks a roadmap for human exploration of space approved by the European scientific and industrial communities. The objective of THESEUS is to develop an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.

THESEUS Expert Groups The basis of this activity is the coordination of 14 disciplinary Expert Groups (EGs) composed of key European and international experts in their field. Particular attention has been given to ensure that complementary ex- pertise is gathered in the EGs.

EGs are clustered according to their focus:

Cluster 1: Integrated Systems Physiology Cluster 3: Space Radiation Bone and muscle Radiation effects on humans Heart, lungs and kidneys Radiation dosimetry Immunology Neurophysiology Cluster 4: Habitat Management Nutrition and metabolism Microbiological quality control of the indoor environment in space Cluster 2: Psychology and Human-machine Life support: management and regeneration of air, Systems water and food Group/team processes Human/machine interface Cluster 5: Health Care Skill maintenance Space medicine Medication in space

Identification of Research Priorities and Development of the THESEUS Roadmap Each Expert Group based their work on brainstorming sessions dedicated to identifying key issues in their specific field of knowledge. Key issues can be defined as disciplinary topics representing challenges for human space exploration, requiring further attention in the future. These key issues were addressed to the scientific community through an online consultation; comments and inputs received were used to refine them, to consi- der knowledge gaps and research needs associated to them, as well as to suggest potential investigations.

The outcomes and main findings of the ‘Integrated Systems Physiology’ EGs have been synthesised into this report and further integrated to create the THESEUS roadmap.

4 Table of Contents

1. Space Medicine...... 6 1.1. Introduction...... 7 1.2. Health Maintenance – Key Issues...... 7 1.2.1. Key Issue 1: Insufficient control of infectious diseases, potentially exacerbated by on-board micro-organism mutations, drug inefficiencies and drug resistance - Provide an on-board available means to deal with the risk of infectious disease...... 7 1.2.2. Key Issue 2: the acute risk to health from radiation exposure, in particular solar flares - Provide on-board physical and/or pharmacological countermeasures and/or protection...... 8 1.2.3. Key Issue 3: dietary and nutrition-related space flight disorders and complaints - Provide on- board countermeasures...... 9 1.2.4. Key Issue 4: sub-optimal physical countermeasure hardware for health maintenance - Identify and provide improved solutions to current bone and muscle loss countermeasures...... 9 1.3. Diagnostic Procedures – Key Issues...... 10 1.3.1. Key issue 5: Insufficient on-board medical imaging hardware - Provide on-board means to maintain medical risks at an acceptable level...... 10 1.3.2. Key issue 6: Insufficient on-board smart sensors / smart devices for health monitoring & medical diagnostics. - Provide on-board means to maintain medical risks at an acceptable level...... 11 1.3.3. Key issue 7: Insufficient on-board expert systems / decision support systems for medical diagnostics. - Provide on-board means to maintain medical risk at an acceptable level...... 12 1.3.4. Key issue 8: Insufficient on-board drugs for medical/surgical procedures. - Provide the capability to offer sufficient drugs and appropriate procedures to maintain on-board medical risks at an acceptable level...... 12 1.3.5. Key issue 9: Insufficient on-board equipment to make sufficient medical procedures available for appropriate health care delivery. - Provide on-board capability to maintain medical risks at an acceptable level...... 13 1.3.6. Key issue 10: Insufficient on-board surgical techniques and devices (e.g. endoscopic procedures, restraint systems etc.) - Provide sufficient on-board surgical techniques and devices to maintain medical risks at an acceptable level...... 13 1.4. Medical Education and Skill Maintenance – Key Issues...... 14 1.4.1. Key issue 11: Insufficient provision of virtual reality training systems/human patient simulators. - Provide on-board capability to maintain medical risks at an acceptable level during human exploration missions...... 14 1.4.2. Key issue 12: Lack of provision of appropriate medical curricula for physician astronauts. - Provide capability to achieve and maintain physician skill sets and knowledge to maintain medical risks at an “acceptable” level during human exploration missions...... 14 1.5. On-Board Medical Resource Management – Key Issue...... 15 1.5.1. Key issue 13: Lack of provision of methods to define the minimum on-board medical infrastructure needed to maintain medical risks at an “acceptable” level during human exploration missions...... 15 1.6. Ethical, Legal and Moral Considerations in Space Medicine –Key Issues...... 15 1.6.1. Key issue 14: What triage decisions and medical capability limitations shall be acceptable during human exploration missions?...... 15

5 1.6.2. Key issue 15: What criteria shall be accepted for the medical selection of astronaut crews for human exploration missions?...... 16 1.6.3. Key issue 16: What psychological criteria shall be used for the medical selection of astronaut crews for human exploration missions?...... 16

2. Medication in Space...... 16 2.1. Introduction...... 16 2.2. Importance of Effective Drug Treatment in Human Spaceflight– Key Issues...... 17 2.2.1. Key Issue 1: Is there evidence supporting changes in drug efficacy in-flight?...... 17 2.2.2. Key Issue 2: Which systems/pathways are operationally important for human spaceflight and why?...... 17 2.3. Unwanted Side Effects and Toxicity of Medication in Space – Key Issues...... 18 2.3.1. Key issue 3: What classes of drugs should be studied as a priority to sustain the health and performance of astronauts during spaceflight?...... 18 2.3.2. Key issue 4: Which drugs may have what important unwanted effects? What classes of drugs should be studied to prevent toxicity and risk issues during human spaceflight? What are the important drug interactions that should be avoided?...... 19 2.3.3. Key issue 5: What pre-flight or in-flight tests should be conducted to avoid or assess possible side effects such as allergic reactions, problems from pharmaco-genetics or influences on performance?...... 19 2.3.4. Key issue 6: What tests should be conducted to assess the possible influences of medication on pre-flight and in-flight performance and sleep quality?...... 19 2.4. Effects of Spaceflight on Pharmacokinetics– Key Issue...... 19 2.4.1. Key issue 7: It is important to know whether the pharmacokinetics of various drugs in space is altered. What pharmacokinetic changes in what classes of drugs have the most important clinical impact in space?...... 19 2.5. Effects of Spaceflight on Pharmaco-Dynamics – Key Issues...... 20 2.5.1. Key issue 8: What evidence exists of pharmaco-dynamics changes resulting from posture and physical (in)activity seen in clinical studies (bed ridden patients, sedentary people)?...... 20 2.5.2. Key issue 9: What models should be used to study pharmaco-dynamics?...... 20

3. Annex: Expert Group Composition...... 21

6 Table of content 1 Space Medicine

1.1. Introduction

The ‘Space Medicine’ Expert Group based its work scientists during the past decades. In the context on the evaluation of 35 issues that were identified of the THESEUS project, the objective of this Expert as relevant for this area of expertise. Of the 35 issues, Group was to gather this European expertise and the group considered received from the community create synergies, allowing an integrated approach and came up with a list of 16 Key Issues of the highest on emerged priorities of research. Because of priority, grouped into six overarching themes: the necessary holistic approach, those research • Health maintenance programmes obviously required the involvement • Diagnostic procedures of scientists whose expertise is disseminated across • Health care delivery Europe. • Medical education and skill maintenance • On-board medical resource management The following sections present the conclusions the • Ethical, legal and moral considerations in space ‘Space Medicine‘ Expert Group. This group met during medicine two expert workshops in 2010. Those workshops were aimed at considering the key questions to address, The priorities of research necessary to support the latest developments, the gaps to fill and the Earth- foreseen space travel and planetary exploration based applications. represent a unique set of problems whose solution demands an in-depth understanding of the whole The Expert Group recommends that key issues human body and cross disciplinary work between presented in this report are considered at their true life scientists, engineers and technologists. All the value and addressed in future research programmes. necessary expertise has been acquired by European

1.2. Health Maintenance – Key Issues

1.2.1. Key Issue 1: Insufficient control of infectious The following recommendations are made: diseases, potentially exacerbated by on-board micro- organism mutations, drug inefficiencies and drug • Conduct a state of the art investigation (including resistance - Provide an on-board available means to the terrestrial healthcare domain, closed deal with the risk of infectious disease environments and space) with the collection of past data (i.e. conduct a data mining exercise). The possibility of micro-organism mutation occurring • Provide the capability to prevent, monitor and as a result of the high radiation environment is not treat infectious disease in-flight. negligible. This presents a threat to the crew due to • Support R&D activities in real time in-situ bio- the possibility of increased incidence of infectious monitoring for all potential infectious organisms. disease as a result of such mutations if adequate • Support R&D activities in the elimination and/or therapies are not available during an exploration control of all potentially infectious organisms. mission, where the possibility of Earth return does not • Support R&D activities in the treatment of harmful exist. Since the 1980s, the field of terrestrial healthcare effects caused by infectious organisms. has been engaged in a “permanent fight” against hospital-borne, resistant infections (nosocomial). The Interdisciplinary aspects threat is still high and requires significant attention. Any progress in this field in the space medicine For the mutations aspects, links with radio-biology domain is very likely to have immediate applications and infection medication efficiency in space are to terrestrial heath care. comprehensive.

Space Medicine 7 1.2.2. Key Issue 2: the acute risk to health from radiation exposure, in particular solar flares - Provide on-board physical and/or pharmacological countermeasures and/or protection

The possibility of acute exposure to radiation from solar flares will be a permanent threat to crew during exploration missions. Little progress has been made in the last decade in the field of acute exposure to ionising radiation therapy. Any progress in this domain will be directly applicable to terrestrial radio-therapy domains, in particular for the treatment of cancer.

The following recommendations are made:

• Conduct a state of the art investigation (data mining) in the field. • Provide the capability to monitor, predict, prevent and treat exposure to the effects of solar flares. • Support R&D activities for real time in-situ bio- dosimetry. • Support R&D activities that may predict acute cosmic radiation events. • Support R&D activities that may prevent or reduce the effects of acute and chronic radiation. • Support R&D activities in the treatment and management of acute and chronic radiation effects. • More accurately define radiation effects and radiation limits as well as ethical constraints.

Interdisciplinary aspects Figure 1: Surface, Water and Air Bio- characterisation (SWAB Experiment) on-board Clear links exist with the radiation-biology and radiation- the ISS (Credit: NASA) protection domains, in particular with respect to hazardous environment operations such as working with nuclear reactors or on-board nuclear vehicles (e.g. submarines).

1.2.3. Key Issue 3: dietary and nutrition-related space flight disorders and complaints - Provide on-board countermeasures

The dietary regime should not contribute to health disorders induced by micro-gravity. The unavailability of fresh food, and thus monotony of preserved foods, will be a dominant crew experience during Earth – planet transfer periods. Consequently, particular care must be applied to crew nutrition and dietary considerations. Presently, several

8 Space Medicine dietary studies are being conducted on the ISS and Interdisciplinary aspects during space mission simulations. These are focussed on improving knowledge of the effects of salt load on There are clear links with the domain of physiology, the body and bone related factors, such as Vitamin D. in particular in relation to bone, muscle and exercise capacity. For the condition of osteoporosis, improved The following recommendation is made: knowledge of the mechanical factors concerning bone remodelling will augment the prevention • Support R&D activities to improve the availability and treatment for terrestrial sufferers. Human and palatability of “fresh” and preserved food for spaceflight research has already contributed to a long periods to prevent nutritional disorders. better understanding, but additionally will contribute (Assumption: food is delivered in appropriate to identification and development of better nutrient mix). countermeasures to prevent osteoporosis, bone loss and muscle atrophy. Interdisciplinary aspects

There are clear links with the domains of physiology, psychology and behaviour. Research progress in support of the above mentioned space issues will improve knowledge on the interaction of diet and health in terrestrial circumstances as well, in particular with regards to the effects of high sodium load on human health and improved means to maintain bone.

1.2.4. Key Issue 4: sub-optimal physical countermeasure hardware for health maintenance - Identify and provide improved solutions to current bone and muscle loss countermeasures

Micro-gravity induced bone and muscle loss seen Figure 2: Concept of centrifuge on-board ISS (Credit: in the lower body is an unresolved aspect of human NASA) spaceflight. Crew undertaking long term exploration missions will face this problem, which if not countered successfully, will have operational consequences. Mastering these problems remains one of the highest priorities for human exploration missions. At the present time, a number of studies concerning bone and muscle loss are being (or are planned to be) conducted on the ISS and during bed rest studies.

The following recommendations are made:

• Advocate the use of artificial gravity and support R&D activities investigating its use. • Support R&D activities investigating integrated countermeasure systems which positively affect multiple physiological systems, and which may include the combination of mechanical and pharmaceutical systems.

Space Medicine 9 1.3. Diagnostic Procedures – Key Issues

1.3.1. Key issue 5: Insufficient on-board medical imaging hardware - Provide on-board means to maintain medical risks at an acceptable level

The need for user-friendly medical imaging devices in- flight is mandatory, however, it is difficult to anticipate (other than for ultrasound) what will be available for use within the next decade or two. This need has been con- sidered to be at the highest priority level because of its criticality. Compact and portable digital X-Ray equipment is already in existence, capable of auto-diagnostic and 3D imaging, and the provision of an expert system for the di- agnosis of bone mineral density disorders.

The following recommendations are made (they assume that efficient on-board imaging techniques will be abso- lutely necessary):

• Support R&D activities to develop user friendly imag- ing techniques for trained operators. • Support R&D activities to develop layman useable im- aging techniques with the following characteristics (note: these techniques will also be useful for research) : • Auto-diagnosis Figure 3: Ultra-sound eye imaging on-board • Real-time use ISS (Credit: NASA) • True-life fidelity • 3D imaging

Interdisciplinary aspects

Links with other disciplines exist (medical e.g. bone loss, national security e.g. counter-terrorist, disaster relief e.g. survivor triage), however, to date it is mainly a space medi- cine concern.

1.3.2. Key issue 6: Insufficient on-board smart sensors / smart devices for health monitoring & medical diagnostics. - Provide on-board means to maintain medical risks at an acceptable level.

Continuous medical monitoring is necessary due to the inevitable high risk activities that will be conducted during human exploration missions. This monitoring should not disturb the crew in any form, and thus the use of smart body sensors within clothing and environmental sensors within (and external to) the habitable volume will be required. In the last decade, the European Commission has supported research concerning smart sensors.

10 Space Medicine 1.3. Diagnostic Procedures – Key Issues The following recommendation is made:

• Support R&D activities in the development of smart and advanced sensors and devices for the measure- ment and intelligent analysis of multiple physiological and environmental parameters: • Human standpoint: invasive and non-invasive, • Habitat standpoint: internal and external.

Interdisciplinary aspects

There are not many obvious links with other disciplines as this is primarily a space-related issue, however, progress in this field will lead to a smart monitoring capability for high risk professions and persons in hostile environments.

1.3.3. Key issue 7: Insufficient on-board expert systems / decision support systems for medical diagnostics. - Provide on-board means to maintain medical risk at an acceptable level.

For exploration missions, the crew will need to be as au- tonomous as possible for medical issues. On-board expert systems will be required to support this capability. ESA has been supporting developments in the domain of aug- mented reality since 2009.

The following recommendations are made: • Conduct a state of the art investigation into existing and expected medical expert systems. • Support R&D activities to develop next generation medical expert systems that: • Aid the prevention (including detection) of harmful medical conditions • Aid the diagnosis of medical conditions • Support the treatment of medical conditions • Support and optimise the management of available medical resources • Enable physician’s skill maintenance

Interdisciplinary aspects

There are clear links with many other health care disci- plines because medical expert systems such as these will be useful for everyday medical practices on Earth.

Figure 4: Possible 0-g surgical glove box (Credit: NASA)

Space Medicine 11 1.3.4. Key issue 8: Insufficient on-board drugs for Interdisciplinary aspects medical/surgical procedures. - Provide the capability to offer sufficient drugs and appropriate procedures Links with other disciplines and Earth applications are to maintain on-board medical risks at an acceptable for example: emergency preparedness for terrestrial level. expeditions, military operations and small group, iso- lation and confinement activities. This is a key issue of the highest priority for space medicine operations during manned space explora- 1.3.6. Key issue 10: Insufficient on-board surgical tech- tion missions. For details of relevance, latest develop- niques and devices (e.g. endoscopic procedures, re- ments, Earth benefits and applications, see the report straint systems etc.) - Provide sufficient on-board sur- from THESEUS “Medication in Space” expert group. gical techniques and devices to maintain medical risks at an acceptable level. 1.3.5. Key issue 9: Insufficient on-board equipment to make sufficient medical procedures available for This is an open issue for space medicine operations appropriate health care delivery. - Provide on-board required for human space exploration missions. The capability to maintain medical risks at an acceptable health care technology field is a domain that continu- level. ally progresses and evolves. Considering the long time before implementing the This is a key issue of the highest priority for space development of human space exploration missions, medicine operations during human space explora- tion. The health care technology field is a domain that the following recommendations are made: continually progresses and evolves. • Support the development and update of risk as- Considering the long time before the actual develop- sessment protocols to be used to enable the iden- ment of a human space exploration mission, tification of the surgical techniques and devices required for exploration. the following recommendations are made: • Support R&D activities in to microgravity compat- ible surgical techniques and devices. • Support the development and update of risk as- sessment protocols that can be used to enable Interdisciplinary aspects the identification of medical equipment and pro- cedures required for exploration. Links exist with other disciplines, however, there is • Support R&D activities in microgravity compat- little cross over with terrestrial healthcare except for ible medical equipment and procedures. situations where small groups are required to exist in long duration confinement circumstances.

Figure 5: ISS Crew Restraint System (Credit: NASA)

12 Space Medicine 1.4. Medical Education and Skill Maintenance – Key Issues

1.4.1. Key issue 11: Insufficient provision of virtual reality training systems/human patient simulators. - Provide on- board capability to maintain medical risks at an acceptable level during human exploration missions.

The maintenance of on-board medical skills is an issue of the highest priority for space medicine operations for human space exploration missions. The field of electron- ic training is presently in a state of exponential growth, promising to produce highly useful and effective tools in the near future.

The following recommendation is made: Figure 6: Surgery Trainer (Credit: Ohio Super- computer Center) • Support the development of virtual techniques, sys- tems and simulators for the maintenance of medical skills, treatment and crew education.

Interdisciplinary aspects

Links exist with other disciplines where skill maintenance in an isolated environment is required. With the exception of small group isolation/confinement activities, there are few terrestrial operational applications, however, advances in e-skills training may be applied in many industries to re- duce the need for direct expert lead training.

1.4.2. Key issue 12: Lack of provision of appropriate medi- cal curricula for physician astronauts. - Provide capability to achieve and maintain physician skill sets and knowledge to maintain medical risks at an “acceptable” level during hu- man exploration missions.

The provision of space medicine-specific academic -cur ricula is an issue of high priority for space medicine opera- tions in preparation for human space exploration missions, to ensure on-board medical knowledge is appropriate. The domain of medical training is constantly evolving and will continue to do so.

The following recommendation is made:

• Support the identification and development of space- health specific curricula which include physical,- psy chological and social elements in relation to mission scenarios/constraints.

Space Medicine 13 Interdisciplinary aspects

Links exists between this domain and other terrestrial human medical specialities where space specific aca- demic content is relevant e.g. baro-medicine, disuse atrophy.

1.5. On-Board Medical Resource Management – Key Issue

1.5.1. Key issue 13: Lack of provision of methods to Interdisciplinary aspects define the minimum on-board medical infrastructure needed to maintain medical risks at an “acceptable” Many links are possible with other human activities level during human exploration missions. where risk and its mitigation is of concern. The risk as- sessment models will be applicable to various aspects This is a key issue of high priority for future space med- of space missions but also to terrestrial endeavours icine operations. The methods defined shall be coher- such as military operations, expeditions and extreme ent with exploration mission safety objectives where environment resource acquisition (e.g. oil rig opera- medical issues will be but one aspect of risk among tions). others. The current approach is the probabilistic risk Due to the limitations of health care delivery and assessment method; an evolution of this method or diagnostics capabilities which are below terrestrial new forms of risk assessment will be required. standards, an adaptation of ethical, legal and moral norms is required for human space exploration. The following recommendation is made:

• Support the development of updated risk assess- ment methods and associated mitigation strate- gies to be used prior to the finalisation of explora- tory mission design and associated infrastructure.

1.6. Ethical, Legal and Moral Considerations in Space Medicine –Key Issues

1.6.1. Key issue 14: What triage decisions and medical Interdisciplinary aspects capability limitations shall be acceptable during hu- man exploration missions? Many links are possible with other disciplines, and al- though applications to terrestrial domains e.g. sociol- This is a key issue of high priority for space medicine ogy, philosophy and military will be in-direct, benefits operations. These considerations shall be coherent are still likely to result. with international ethical practice and mission safety objectives. Ethical practice is under continual debate. 1.6.2. Key issue 15: What criteria shall be accepted for the medical selection of astronaut crews for human ex- The following recommendations are made: ploration missions?

• Encourage the international discussion, debate This is a current and on-going issue for space and knowledge exchange on human exploration medicine. Future medical selection will be coherent mission related ethical decisions with state of the art knowledge, capabilities and ac- • Support the development of ethical and medical cepted ethical practices. Astronaut medical selection flight guidelines and rules is under continuous evolution, but remains in-line • Support the development of adequate training with the progress of medicine. for the conduct of medical flight guidelines, rules and ethical decision making.

14 Space Medicine The following recommendations are made:

• Maintain the best practice for minimal individual risk exposure. • If genetic screening or other screening methods are proven to reduce risk, these methods should be con- sidered for use.

Interdisciplinary aspects

Many links are possible with other disciplines and although applications to terrestrial domains e.g. sociology, philoso- phy and military will be in-direct, benefits are still likely to result.

1.6.3. Key issue 16: What psychological criteria shall be used for the medical selection of astronaut crews for human ex- ploration missions?

This is a current and on-going issue for space medicine in that society and personal behaviour norms evolve over time. All aspects of psychological selection will be coher- ent with state of the art knowledge, experiences and ac- cepted ethical practices. Astronaut psychological selection is continually under evaluation in line with terrestrial psy- chology and psychiatry progress.

The following recommendation is made:

• If psychological screening methods are proven to re- duce mission risks and optimise team dynamics whilst also increasing the likelihood of selecting appropriate crew for exploration missions, then these methods should be evaluated and considered for use.

Interdisciplinary aspects

There are clear links with other social and psychological / psychiatric disciplines in relation to space and terrestrial healthcare for similar circumstances involving small group dynamics and stressful activities.

Space Medicine 15 2 Medication in Space

2.1. Introduction Whenever drug treatment is needed, medica- • Effects of spaceflight on pharmaco-dynamics tion must be effective. Drugs may be used- dur The priorities of research necessary to support fore- ing spaceflight for several purposes, including: seen space travel and planetary exploration represent a unique set of problems whose solutions demands • Emergency situations an in-depth understanding of the whole human body • Acute intervention (emergency drugs, possibly and cross-disciplinary work between life scientists, en- including stored blood products) gineers and technologists. All the necessary expertise • General medical issues (e.g. pain, infection, sleep has been acquired by European scientists during the problems, gastrointestinal problems) past decades. In the context of the THESEUS project, • Pharmacological countermeasures during tran- the objective of this Expert Group was to gather this sition phases to support the cardiovascular and/ European expertise and create synergies, allowing or vestibular systems during launch and landing, an integrated approach on emerged priorities of re- or to ameliorate the effects of long-term stays in search. Because of the necessary holistic approach, space (bone, muscle, radiation, cardiovascular those research programmes obviously required the system, sleep, immune system, kidney, vitamin involvement of scientists whose expertise is dissemi- supplementation etc.) nated across Europe.

The ‘Medication in Space’ Expert Group based its work The following sections present the conclusions the on the evaluation of issues it identified as relevant for ‘Medication in Space‘ Expert Group. This group met its area of expertise. Of these issues and considering during two expert workshops in 2010. The workshops the inputs received from the community, the Group were organised sessions aimed at considering the key came up with a list of 9 Key Issues of the highest prior- questions to address, the latest developments, the ity grouped in four overarching themes: gaps to fill and the Earth-based applications.

• Importance of effective drug treatment in human The Expert Group recommends that key issues spaceflight presented in this report are considered at their • Unwanted side effects and toxicity of medication true value and addressed in future research pro- in space grammes. • Effects of spaceflight on pharmacokinetics

2.2. Importance of Effective Drug Treatment in Human Spaceflight– Key Issues

2.2.1. Key Issue 1: Is there evidence supporting conducted for adequate insight in to the matter. The changes in drug efficacy in-flight? expert group recommends implementation of a struc- tured programme to increase knowledge of drug effi- The fact that a gap in knowledge currently exists on ciency in space, and thus, ensure proper treatment of this topic caused the expert group to consider this astronauts in-flight. of highest priority given the unacceptable risks that would result during an exploration mission should Interdisciplinary aspects space-induced drug changes be evidenced in-flight. There is some evidence of changes in pharmaco-dy- There is a clear link with radiation and immunology namics and kinetics and reports of altered molecular issues. Progress in the field of space pharmacology is mechanisms due to space flight. Unfortunately, too of concern to the terrestrial pharmacology domain few in-flight or ground simulation studies have been as increased knowledge concerning space induced

16 Medication in Space pharmaco-dynamic and kinetic changes in relation be relevant to human exploration missions and will to microgravity will have a bearing on pharmaceuti- aid the understanding of and improve the ability to cal use in the 1-G supine, seated and upright positions master mission related risks. At the present time, few and will thus be of clinical interest. studies have been conducted in relation to this issue. Future studies should focus on the systems of high 2.2.2. Key Issue 2: Which systems/pathways are opera- importance for drug efficiency in space that are most tionally important for human spaceflight and why? likely influenced by microgravity.

Studies with micro-arrays have demonstrated that Interdisciplinary aspects many systems (e.g. adrenergic system, immune reac- tivity pathways and metabolism) change with altered Clear links exist between Earth and space medicine gravity. issues and a better knowledge of drug receptor sys- tems and pathways, in particular linked with the en- There is a knowledge gap concerning human drug re- vironment, will be of benefit to both terrestrial and ceptor systems and pathways under spaceflight con- space medicine. ditions. Any improvement in related knowledge will

2.3. Unwanted Side Effects and Toxicity of Medication in Space – Key Issues

2.3.1. Key issue 3: What classes of drugs should be Several classes of drugs should be prioritised for study studied as a priority to sustain the health and perform- in order to properly sustain the health and perform- ance of astronauts during spaceflight? ance of astronauts during spaceflight. Future work and suggested solutions should take into account the The following classes were highlighted: possible frequency of use of various drugs by astro- • Alpha-mimetics (orthostatic intolerance) nauts in space, which drugs are commonly used, dur- • Analgesics (back pain) ing what situations (extant and expected), preventa- • Antiemetics (Space Adaptation Syndrome) tive use and possible impacts on performance in ad- • Catecholamines (emergency medicine) dition to possible unwanted side-effects. Drug tests • Sleeping pills should also involve terrestrial analogues such as bed • Antibiotics (bacterial Infection) rest, animal models, cellular and molecular studies as • Anti-mycotics (fungal infections) well as in-flight studies with astronauts as subjects. • Medication against bone changes (bisphospho- nates etc.) Interdisciplinary aspects • Medication for Radiation Protection (e.g. solar particle events) Clear links exist with many medical and physiological • Nutraceuticals (specific nutrition based medica- issues. Improvements in the knowledge of the side ef- tion) fects and toxicity of medication in the space context is of concern to the terrestrial pharmacology domain The fact that a gap in knowledge currently exists con- in so far as it increases the knowledge of drug use in cerning the side effects and toxicity of medications relation to human physiology and the effects of the (some already used in space) has caused the experts environment on this relationship. to view this issues as a highest priority given the unac- ceptable risks that would result during an exploration mission should this issue not be resolved. Unfortu- nately, too few in-flight and ground simulation stud- ies have been conducted to date for adequate knowl- edge on the matter.

Medication in Space 17 Figure 7: ISS Medication Kits (Credit: NASA)

2.3.2. Key issue 4: Which drugs may have what for the selection of crew for human exploration mis- important unwanted effects? What classes of drugs sions. The expert group is aware of only one study should be studied to prevent toxicity and risk issues conducted during microgravity ground simulations during human spaceflight? What are the important (head down tilt bed-rest). Genetic screening for possi- drug interactions that should be avoided? ble hereditary alterations in drug effectiveness should be implemented during the basic medical assessment Each drug from the list above may have important of astronauts, as it may save them from future nega- unwanted effects, however, very little is known con- tive side–effects of drug use. cerning additional, space-specific side effects and/or interactions. This gap in knowledge is relevant to hu- Interdisciplinary aspects man space exploration, but unfortunately, no studies have been conducted in-flight or during microgravity This is essentially a terrestrial medical matter. How- ground simulations. The development and use of a ever, a clear link with space medicine exists in relation database on drug side effects and interactions is rec- to the selection of astronauts. In this regard terrestrial ommended as a precursor to operational use of drugs progress can be applied for space medicine benefit. during space exploration missions. Consequently, it will be necessary to establish a pharmacovigilance 2.3.4. Key issue 6: What tests should be conducted to system on the adverse effects of drugs and of drug assess the possible influences of medication on pre- interactions used in space. flight and in-flight performance and sleep quality?

Interdisciplinary aspects Some examples of standard tests that should be con- ducted include; neuro-physiological measurements Clear links exist with medical and physiological is- (including EEG, EMG and EOG) and psychomotor tests sues. Improvements in the knowledge of the side ef- including cognitive batteries. To avoid additional risk, fects and toxicity of medication in use in space will the expert recommendation is that the influences of be of benefit to terrestrial pharmacology through an medication on astronaut in-flight performance should increased understanding of the generic pharmaco- be conducted before human space missions begin. At dynamics and kinetics of drug use. the present time only anti-emetic medication is test- ed before flight due to their systematic use pre- and 2.3.3. Key issue 5: What pre-flight or in-flight tests in-flight. As there are currently no standard tests for should be conducted to avoid or assess possible other medication use in the spaceflight, aviation or side effects such as allergic reactions, problems from driving domains, appropriate assessments should be pharmaco-genetics or influences on performance? developed as a high priority. These tests should first be applied on earth and subsequently in flight when To avoid additional risks, the expert group recom- they are established. mends that genetic screening for possible hereditary alterations in drug effectiveness should be conducted

18 Medication in Space Interdisciplinary aspects fields where a high level of vigilance is required. Con- sequently clear links exist with the aero-space, military Effective sleep and high performance are crucial for and driving domains. Terrestrial progress in this regard the safety of astronauts and other humans working in will be of benefit when applied to space medicine.

2.4. Effects of Spaceflight on Pharmacokinetics– Key Issue

2.4.1. Key issue 7: It is important to know whether the quired on the spaceflight-induced pharmacokinetic pharmacokinetics of various drugs in space is altered. changes of different classes of drugs and on the iden- What pharmacokinetic changes in what classes of tification of those likely to have the most important drugs have the most important clinical impact in clinical impact during manned space. space? This needs to be addressed especially for drugs that The spaceflight environment induces physiological are expected to be used in-flight. Drugs with a nar- changes which may influence drug pharmacokinet- row therapeutic window will require more attention. ics at different levels. These physiological effects may Investigations should be achieved in relation to the modify the pharmacokinetics of the drugs adminis- environment, under micro- and hyper gravity condi- tered in-flight producing a modified disposition lead- tions as well as with respect to sedentary lifestyle and ing to reduced pharmacological activity or the ap- subject position (upright, seated, supine/bed rest, pearance of adverse side-effects. Data from bed rest head-down tilt). studies have demonstrated changes in pharmacoki- netics of certain drugs used as probes, e.g., lidocaïne Tests should also be done in flight with sub-clinical (hepatic blood flow), oral acetaminophen or promet- doses to assess changes in the kinetics of the respec- hazine (digestive absorption). tive drug. They should also include different routes of administration to find out the best method of use in It is important to know whether the pharmacokinet- space. ics of various drugs in space is altered. Research is re-

2.5. Effects of Spaceflight on Pharmaco-Dynamics – Key Issues

Evidence from molecular research has demonstrated Animal studies are also prioritised. Wild type and trans- that expression and function of some receptors and genic mouse models may be used to answer specific signal transduction mechanisms in several cell types, questions arising from observations in astronauts or may be changed in microgravity (e.g. adrenergic re- molecular changes observed in cellular studies. These ceptor sensitivity, lymphocyte second messenger sys- animal studies may be most appropriately performed tems). Therefore the effectiveness, i.e., the pharmaco- using Biosatellites. Cellular/molecular studies shall also dynamic characteristics, of several classes of drugs are be considered a top priority. likely to be altered in space, however, no detailed stud- ies have addressed this topic yet. Cellular/molecular studies are easy to be implemented Human studies shall have top priority. A data base and can deliver high quality information on changes in should be established to document the clinical effec- drug effects and signal transduction cascades as well tiveness and side effects of drugs used in space and to as in pathogen physiology. Clinostats and centrifuga- compare these with terrestrial equivalents. To closely tion experiments will help to better characterise the monitor drug effects, specific and standardised tests effects of gravity on cells and to identify the most rel- and questionnaires should be developed and used evant questions that can be addressed by in-flight ex- during human space flight operations. The tests and periments. In the next few years the excellent Russian questionnaires must be short and simple to use to and ISS facilities should be extensively used in minimise in-flight crew time use. this respect.

Medication in Space 19 2.5.1. Key issue 8: What evidence exists of pharmaco-dy- namics changes resulting from posture and physical (in) activity seen in clinical studies (bed ridden patients, seden- tary people)?

There is a knowledge gap concerning pharmaco-dynamics and subject posture and activity levels. Any improvement in knowledge will be relevant to human exploration mis- sions and will aid the understanding of and improve the ability to master mission related risks. At the present time few studies have been conducted in relation to this issue

2.5.2. Key issue 9: What models should be used to study pharmaco-dynamics?

Appropriate models for the study of space induced chang- es in pharmaco-dynamics are; human studies i.e. bed rest (supine vs. upright, head down tilt), space flight and dry immersion; animal studies (tail suspension, hyper-gravity, space flight, wild type, transgenic/knock out), tissue/cel- lular/molecular studies such as Klinostat/random position- ing, centrifugation, and in-flight experiments (e.g. bios- atellites, ISS), as well as computer simulation models (in silico).

20 Medication in Space 3 Annex: Expert Group Composition

Health Care - Cluster Coordinator:

Bernard Comet MEDES, France

Space Medicine Expert Groups Members:

Volker Damann (Chair) ESA-EAC, Germany Bernard Comet (Rapporteur) MEDES, France Simon Evetts Wyle Europe – EAC, Germany Kevin Fong Centre for Altitude Space and Extreme Environment Medicine, UK Götz Kluge DLR - Institute of Aerospace Medicine, Germany Philippe Poignet CNRS – Lirmm, France Ulrich Straube ESA-EAC, Germany Martin Trammer DLR - Institute of Aerospace Medicine, Germany Regitze Videbaek Copenhagen Hospital, Denmark

Medication in Space Expert Groups Members:

Rupert Gerzer (Chair) DLR - Institute of Aerospace Medicine, Germany Audrey Berthier (Rapporteur) MEDES, France Anne Pavy-Le Traon (Rapporteur) Brest and Toulouse University Hospitals, France Reiner Frey Bayer, Germany Martin Mengel Bonn University, Germany Cristoph Coch University of Bonn, Germany Brigitte Godard MEDES, France Philippe Zitoun Notocord, France

Annex: Expert Group Composition 21 Edition : INDIGO 1 rue de Schaffhouse • 67000 Strasbourg tél. : 06 20 09 91 07 • [email protected]

ISBN : 979-10-91477-05-5 printed in E.U. march 2012

The THESEUS Coordination and Support Action has received funding from the European Community’s 7th Framework Programme (FP7/2007-2013) under grant agreement n°242482. This document only reflects the views of the THESEUS Consortium. The European Commission is not liable for any use that may be made of the information contained therein.