PN Issue 117 / Winter 2020 Physiology News

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Physiology News Scientific Editor Keith Siew University College London We welcome feedback on our membership magazine, or letters and suggestions for articles for publication, including book reviews, from our Members. Managing Editor Please email Julia Turan at [email protected]. Julia Turan

Physiology News is one of the benefits of membership, along with reduced registration rates Editorial Board for our high-profile events, free online access to our leading journals, The Journal of Physiology, Ronan Berg University Hospital Rigshospitalet Experimental Physiology and Physiological Reports, and travel grants to attend scientific Angus Brown University of Nottingham meetings. Membership offers you access to the largest network of physiologists in Europe. Havovi Chichger Anglia Ruskin University Karen Doyle NUI Galway Join now to support your career in physiology: Visit www.physoc.org/membership or call 0207 269 5721. Lalarukh Haris Shaikh Palantir Technologies Richard Hulse Nottingham Trent University Philip Lewis University Hospital of Cologne Dervla O’Malley University College Cork Membership Fees for 2020 FEES Michael Preedy Queen Mary University of London Fellow £120 Christopher Torrens University of Southampton Member £90 [email protected] Retired Member – YOUTUBE LOGO SPECS

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2 Physiology News / Winter 2020 / Issue 117 Contents Help us improve diversity and inclusivity by updating your details on the member portal today! Welcome to the Winter 2020 edition of Physiology News

Introduction Features

5 Editorial: Space is in the air 22 Don’t lose sight under pressure: Cranial consequences of a life without gravity 6 President’s View: Looking back on a great year 26 Space brain: The adverse impact of deep space radiation 7 Letters to the Editor exposure on the brain

30 May the (Gz) force be with you: Gravity and human News and Views 36 The invisible space killers: The dangers of space radiation from both inside and outside the solar system 8 Reports of The Society’s recent committee meetings 40 Getting to the heart of it: The cardiovascular consequences 9 Physiology Feed of spaceflight 10 Physiologist among the stars: A conversation with Log into the portal to update your details now: Jim Pawelczyk physoc.org/details 12 Physiological discoveries abound within NASA samples Membership 14 Sex in space: Our final reproductive frontier 44 Why research space physiology? 15 Book Review: How to live in space by Colin Stuart 46 Obituary: William Stanley Peart TPS12405 - Diversity and inclusivity advert - text update V2REPRO.indd 1 13/08/2019 11:48:49 16 The NASA Twins studies 47 Obituary: Paul M Vanhoutte

Events

19 P artnerships, communities and inclusion to drive better research 21 Europhysiology 2020: Bringing together the physiology community

Cover image: “Knowledge Space” by Martin Sati. See more of his artwork at martinsati.com 3 NH 2

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From the current Space HO APPLYAPPLYAPPLYAPPLY FORFORFORFOR ECLSECLSECLSECLS 2020202020202020 APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYand pleasure that I introduce FORFORFORFORFORFORFOR the Space silence”.Indeed, ECLSECLSECLSECLSECLSECLSECLS life as we know it has evolved 2020202020202020202020202020 Physiology Special Issue of Physiology News, APPLYPhysiology Special Issue FOR of Physiology News, and adaptedECLS within Earth’s atmosphere and2020 I hope you gather that among the numerous - MORE INFORMATION - APPLYAPPLYAPPLYAPPLYAPPLYAPPLY FORFORFORFORFORFOR ECLSECLSECLSECLSECLSECLS 202020202020202020202020 APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYwhich I literally believe to be FORFORFORFORFOR FOR“outFORFOR of this gravitational ECLSECLSECLSECLSECLSECLSECLSECLS field, and thanks to decades of 20202020202020202020202020202020scientific fields that are required to accomplish APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYworld” due to the kind efforts FOR FORofFORFORFORFORFOR its many research using ECLSECLSECLSECLSECLSECLSECLS both Earth-based simulations 202020202020this,2020202020202020 the Second Space Age places physiology www.physoc.org/ecls2020 | +44 (0)20 7269 5712 | [email protected] APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYskilled contributors. FORFORFORFORFORFORFORand actual experiments ECLSECLSECLSECLSECLSECLSECLS in space, we now at 2020 20202020centre2020202020202020 stage. APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLY FORFORFORFORFORFORFORFORhave substantial ECLSknowledgeECLSECLSECLSECLSECLSECLSECLS about how the 20202020202020202020202020202020 APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYThe concept of a Second Space Age is FORFORFORFORFORFORFORphysiology of the human ECLSECLSECLSECLSECLSECLSECLS body is affected 2020202020202020202020202020 APPLYAPPLYAPPLYAPPLYAPPLYAPPLYAPPLYcontroversial, but is nonetheless often FORFORFORFORFORFORFORby their absence, both ECLSacutelyECLSECLSECLSECLSECLSECLS and over 2020202020202020202020202020 described as a “gold rush to the stars” that extended periods of time.

5 President’s View

Looking on back on a great year

Our Annual Conference, Physiology 2019, Shaping policy held in July in the welcoming city of Aberdeen was a fantastic showcase for the quality As the topic of Future Physiology illustrated, and breadth of physiology being undertaken the impact of physiological research reaches by the membership and colleagues. The well outside the laboratory. The policy work buzz was palpable throughout the meeting, of The Society leverages this broad impact of with plenary and keynote lectures covering physiology, as illustrated by two of our main diverse aspects of physiology, as well as projects this year. standing room only professional development sessions. You could say that the ceilidh at the The first of our policy projects, entitled Sport“ conference dinner served as an extended & Exercise Science Education: Impact on the networking session, with researchers of all UK Economy”, was a joint commission with career stages swinging each other around the GuildHE, the UK’s registered body for smaller dance floor. and specialist universities and colleges. The report found that Sport and Exercise Science Our focused conference of the year, Extreme (SES) courses provide enormous contributions Environmental Physiology, was held at the to the UK economy – to the tune of almost beginning of September in Portsmouth £4 billion every year, supporting almost and could not have come at a better time, 150,000 jobs. Research undertaken in SES with the world finally seeming to grasp the departments helps tackle global health urgency of fighting climate change. With challenges, such as obesity, diabetes, cancer sessions on cold, heat, hypo- and hyperbaric and depression. As The Physiological Society, physiology, micro-gravity and cross- we must do more to share these insights Bridget Lumb adaptation, as well as each session including within our universities and with the public President, The Physiological Society physiology, pathophysiology and comparative as a whole. As The Physiological Society’s physiology, this conference brought together membership continues to grow and expand, internationally renowned speakers, new Sport and Exercise scientists will play an researchers, comparative biologists and important role as we seek to reflect the physicians and highlighted the importance of impact of their physiological research. The beauty of the discipline of physiology is integrated physiology. the breadth it covers, uniting researchers in Our other key policy project focused on diverse subject areas to solve crucial issues To close the year, our conference geared the topic of healthy ageing, which was about the health of everyone inhabiting our towards early career physiologists, Future identified by The Society as an area of public planet. This diversity means it is relevant Physiology, was held for the second time, policy which would benefit from increased for all ages – cradle to grave, from school- this year at Liverpool John Moores University involvement from The Society and its children fascinated by what happens to our in December. This conference gave early Members’ research. The aim of this project bodies when we travel to space, through to career researchers the chance to organise was to identify ways in which physiology can grandparents benefiting from government a stimulating two-day scientific meeting support the UK Government’s Healthy Ageing policies that harness physiological research on featuring their peers, as well as more senior Grand Challenge target of an average of “five healthy ageing. This year at The Physiological scientists. This year’s chosen topic was healthier, more independent years by 2035”. Society, we have leveraged this diversity, “Translating Cellular Mechanisms into Lifelong The final reportGrowing Older, Better covers while also recognising the importance of Health Strategies”. Speakers gave insight into four main themes: the variety of physiological supporting the communities within the broad their current work and shared information research currently being undertaken into umbrella of physiology. on their career path to inspire the early ageing, the funding landscape for physiology, career physiologists present. By encouraging the importance of interdisciplinary working to Our events physiologists to collaborate with clinicians improve our understanding of healthy ageing and policymakers, the conference also helped and how to best integrate current physiological In March we held the Life Sciences 2019 to further the cause of healthy ageing. understanding into public health guidance. conference in collaboration with the British The report has been designed to be relevant Pharmacological Society and the Biochemical As part of our aim to share physiology more to a number of different audiences, with a Society, bringing scientists together widely, we hosted NASA astronaut and particular focus on funders and policymakers. around the subject of post-translational physiologist Jim Pawelczyk for our President’s modifications (PTMs). As PTMs have Lecture in July. This public engagement event Building our community implications throughout the body – such held at the prestigious Royal Institution as in neuronal signalling, cardiac function, also included a range of outreach activities In 2019 we sought to shine a spotlight on circadian rhythms, and diseases including that showcased space physiology and were the importance of the individual communities cancer and psychiatric disorders – this was delivered by our Members. Read more about within our broad discipline. We re-launched an opportunity for networking across the life Jim and his career on page 10. our Themes to provide a focal point for these sciences and learning from research areas communities and encourage support and adjacent to participant’s own. interactions. Our Themes are Cardiac and Vascular Physiology, Epithelia and Membrane

6 Physiology News / Winter 2020 / Issue 117 Transport, Human Environmental and Exercise Society and our Members to deliver on our issue would allow everyone to feel part of the Physiology, Endocrinology, Metabolic vision of Physiology Flourishing. Trustees conversation by either relating to some of Physiology, Neuroscience, and Education and presented these new Articles to Members for the experiences of the authors or by stepping Teaching. Each of these Themes is associated approval at a General Meeting in December, outside of comfort zones to confront our with a number of Specialities, and there is a and were officially approved in January. own actions and those of our colleagues matrix on our website physoc.org/themes and institutes. In the combined years of our that clearly explains how these two groupings New website launched Editorial Board, never has there been a topic work together to provide flexibility. We have that elicited so much audience engagement, a fantastic group of Theme Leads, who are We were excited to launch our newly designed so we have since been continuing to your point of contact, and also help us plan website in June. Not only does it deliver on commission content on this topic for our for the best scientific content, tailored to the visual appeal and act as our “window on the Members and wider audiences on our blog. Themes, at our upcoming events. Members world”, it also allows Members to easily find the who have signed up to Themes will have content they are looking for. We have a brand In the year ahead we look forward to received dedicated newsletters from their new careers section highlighting the exciting strengthening our community of Members. Theme Leads. and varied career options in physiology, as From Europhysiology 2020 in Berlin in well as directory of Society Representatives September, which will bring together the Governance structure with which members can search for the global physiology community, to our policy Representative at their relevant institution. plan to build on the Growing Older, Better In July of this year, we launched our new report, we are on track for yet another governance structure, designed to improve Diversity successful year. We hope you will join us as how The Society operates and, importantly, The Society seeks to deliver our vision of to establish structures that have the The Diversity Special Issue of Physiology “physiology flourishing”. potential to increase inclusivity and Member News, published in July, focused on the participation. We have created a clear, immutable characteristics of sex/gender, modern and legally compliant set of governing ethnicity/race, age, disability and LGBTQI+ documents that reflect best practice. Our within the STEM community. By featuring Check out the space physiology new Articles of Association improve our articles on a broad mix of science and the transparency and enable us to become more experiences of scientists/educators/students, career resources on our website: inclusive. We believe these Articles, and the as well as covering issues and policy around physoc.org/spacephysiology supporting Regulations, will best serve The diversity and inclusion in STEM, we hoped this

Letters to the Editor: Arthur John Buller References

Stanley Salmons counter most of the original arguments for 1. Buller AJ et al. (1960). Interactions between motoneurons Emeritus Professor of Applied Myology, rejecting the role of impulse activity. and muscles in respect of the characteristic speeds of their University of Liverpool, UK responses. The Journal of Physiology 150, 417 – 439. DOI: 10.1113/jphysiol.1960.sp006395 There remained one issue, stated in the original Buller, Eccles and Eccles paper: 2. Eccles JC et al. (1962). Further investigations on the Your Autumn issue (PN 116) carried a fine “It certainly would be surprising if the sharp influence of motoneurones on the speed of muscle obituary of Arthur J Buller. differentiation of muscles into fast and slow contraction. The Journal of Physiol 163, 324 – 339. DOI: 10.1113/jphysiol.1962.sp006978 types were affected by such a relatively Arthur’s seminal work with Jack and variable factor as the aggregate number 3. Salmons S (1967). An implantable muscle stimulator. Rosamond Eccles in Canberra established the of impulses fired by tonic and phasic motor The Journal of Physiology 188, 13 – 14P. plasticity of skeletal muscle. In the resulting neurons.” At a meeting in Konstanz in 1979 https://www.ncbi.nlm.nih.gov/pubmed/6030506 DOI: 10.1113/jphysiol.1967.sp008150 paper1, the role of impulse activity was I introduced the idea that the relationship carefully considered but rejected in favour of between activity and muscle type was 4. Salmons S, Vrbová G (1969). The influence of activity on a chemical trophic influence of motor neurons non-linear, a consequence of which was a some contractile characteristics of mammalian fast and innervating fast and slow muscles. This threshold for change from one type to the slow muscles. The Journal of Physiology 201, 535 – 549. hypothesis gained widespread acceptance other6. Arthur Buller was in the audience. DOI: 10.1113/jphysiol.1969.sp008771 and was the dominant paradigm throughout He greeted me afterwards and fully 5. Salmons S, Sréter FA (1976). Significance of impulse the 1960s. Unsurprisingly, a subsequent embraced this explanation, a response that activity in the transformation of skeletal muscle type. attempt in Canberra to demonstrate an illustrates well his open-mindedness and Nature 263, 30 – 34. DOI: 10.1038/263030a0 effect of impulse activity by applying external generosity. 6. Salmons S (1980). The response of skeletal muscle to stimulation for 10 minutes per day was met different patterns of use – some new developments with limited success2. It was the development Buller and his colleagues made valuable and concepts. In: Pette D, ed., Plasticity of Muscle. of an implantable stimulator3 that made it confirmatory observations of the original Walter de Gruyter: Berlin, pp. 387 – 399. possible to stimulate intact fast muscles effect7. However, it would take a greater DOI: 10.1515/9783110837483-031 continuously over a period of weeks, and this variety of experimental approaches (recently 7. al-Amood WS et al. (1973). Long-term stimulation of revealed unequivocally the profound influence reviewed8) to achieve full recognition of cat fast-twitch skeletal muscle. Nature 244, 225 – 227. 4,5 of impulse activity . By postulating that the role of impulse activity and to displace 8. Salmons S (2018). The adaptive response of skeletal muscle: the removal of such activity allows a muscle the strongly entrenched support for the what is the evidence? Muscle & Nerve 57, 531 – 541. to return to a default fast state one could chemotrophic hypothesis. DOI: 10.1038/244225a0

7 News and Views

Reports of The Society’s recent committee meetings

The purpose of these short updates is to The Honorary Treasurer (Frank Sengpiel) Feedback from the event demonstrated that keep you informed about the work of our provided a summary of the key financials 100% of those who completed the survey committees. The following summaries detail reported in the Trustee Annual Report (TAR). enjoyed the event, knew what physiology the meetings of the past few months. The Board approved the 2018 TAR for was compared to before they attended and signature and submission to Companies House would attend another event. and the Charity Commission. The Board recognised the contributions of Council The Chair of the Membership Category Jim Pawelczyk as not only had he given the and Journey Review Task and Finish Group President’s Lecture but he also attended 4 June 2019 (Rachel Tribe) gave an interim report on Extreme Physiology where he gave the Public The President (Bridget Lumb) reported back progress to date. The first meeting had Lecture, chaired a session, interacted with on the successful trip to the Federation of focused on reviewing data and looking into presenters at the poster sessions and judged Asian and Oceanic Physiological Societies the early stages of the membership journey prizes. During his time in the UK he had also (FAOPS) at which The Society exhibited. and explored how to encourage longevity assisted in creating a “careers in physiology” The President and Chief Executive (Dariel and loyalty. Surveys were in development to video for the website, and an interview for Burdass) had utilised the opportunity to understand the motivations of non-members Physiology News. meet with the President of The Physiological who attend Society meetings and to further Society of Japan, The President of the understand the areas for membership growth. The Board received the M7 Management Korean Physiological Society, the President It was noted that the final report would be Accounts and reforecasts and acknowledged of FAOPS and the President of IUPS and submitted to Council in December. the 2020 – 2022 financial planning process. fostered a positive relationship and noted the They reviewed the key risks presented to enthusiasm with which The Society’s presence The Board discussed the imminent website them as part of the biannual risk review was greeted, as the Journal of Physiology launch and acknowledged it as a multifaceted undertaken by the Senior Management Team brand was widely recognised. platform that would constantly evolve and and approved a new Conflicts of Interest consequently approved a soft launch of the Policy in line with governance best practice. The Head of Policy & Communications site. The President thanked the staff website (Andrew Mackenzie) reported that The team, the President-Elect, David Patterson The Board also approved the terms of Society had collaborated with Guild HE on the and Chairs of the Committees for all their reference for the Nominations Committee, report “Sport & Exercise Science Education: hard work on the website. History and Archives Task Force, In vivo Task Impact on the UK Economy”.The official Force and the Theme Leads. launch had been held at Westminster and hosted by the Shadow Minister for Higher 18 September 2019 Following the launch of the new website, Education, Further Education and Skills – The Board received attendee figures, the Head of Policy and Communications Gordon Marsden. The event had been a great feedback and communications analytics on presented figures comparing traffic on the opportunity for networking. The President our Annual Conference, Physiology 2019 new website with the old one. Compared to thanked staff and Mike Tipton for their (P19). The Chair of Conferences Committee the same period in 2018, the new website efforts in creating a quality piece of work. (Sue Deuchars) commented that not only had a 46% increase in users, 50% mobile had the quality of the science been highly traffic increase, 127% home page visit The Publisher (Sally Howells) reported on the regarded, but P19 had also reinstated the increase and a 45% increase in visits to the new, engaging video feature from The Journal strong sense of community that The Society “What is Physiology” page. of Physiology called “Physiology Shorts” is known for and the welcome received by which aimed to deliver short, informative local Members and the city of Aberdeen research snapshots directly from the authors had created an energy that had lifted the of research papers. The videos have been experience. She noted that the combination well received, both in terms of the number of of a strong leadership presence in the views and social media engagement. Trustees, the visibility of the Theme Leads as well as the presence of staff added to the Finance Committee A specialist legal governance advisor from “family feel”.This inclusive atmosphere was BDB Pitmans joined the meeting and spoke particularly important in creating a good first During a meeting on 11 September 2019, about the revised Articles of Association and experience for the Undergraduate Members Finance Committee (FC) received and Regulations setting out how The Society who The Society hopes to nurture throughout discussed the July 2019 management could create a clear, modern and legally their membership journey. accounts. They also reviewed The Society’s compliant set of governing documents that cash flow management which seeks to reflect best practice as well as enabling The Following an overview from the President maximise bank interest while maintaining Society to improve transparency, inclusion on the success of the President’s Lecture, sufficient working capital liquidity. FC discussed and agility. The Board approved the revised the Chair of Education, Policy and Public the latest risk management report and was Articles and Regulations drafted by BDB Engagement Committee (Sarah Hall) and satisfied with the mitigation plans in place Pitmans and also agreed that BDB Pitmans the Head of Professional Development and and the recommended course of action for should submit the regulated alterations to the Engagement (Chrissy Stokes) reported back submission to Council. To maintain the requisite Charity Commission. on the successful uptake of the schools’ level of active Trustees, Charlotte Haigh agreed competition and the interactive activities. to join FC. Dean Sewell becomes the new

8 Physiology News / Winter 2020 / Issue 117 Physiology Feed

Inclusion and Diversity Champion and Havi The current programme for Europhysiology Read the latest press releases from Chichger the new Membership Champion. 2020 was noted, and outstanding plenary our journals at physoc.org/news and keynote speakers were discussed. An update was given on Europhysiology 2022, A rationale for a plyometric to be held in Copenhagen. Other conferences exercise countermeasure in for 2020 were confirmed as Processing and Modulation of Sensory Signals: From planetary exploration missions the Periphery to the Cortex to take place The mechanical unloading experienced by Education, Public in London in June 2020, and a conference astronauts in the presence of low Engagement and Policy on the topic of Regeneration to take place gravitational fields (hypogravity) causes in Edinburgh in December. The current muscle atrophy and bone loss. This so-called Committee programmes for these conferences were musculoskeletal deconditioning is offset, but discussed and revisions decided on. A Future not prevented, by aerobic exercise (e.g. The first meeting of the new Education, Physiology conference will also be held in running on a treadmill). Therefore, additional Public Engagement and Policy (EPEP) July 2020. The Committee agreed that exercise programmes are likely needed to Committee took place on 25 September Brighton would be a good location for this preserve musculoskeletal homeostasis in 2019. The Chair welcomed all participants. meeting. space. Using a Verticalised Treadmill Facility The Committee received its Remit and to mimic various levels of hypogravity, Terms of Reference, along with those of Suggested actions to improve the researches have demonstrated in eight the History and Archives and In Vivo Task environmental of The Society’s participants that hopping produces muscle Forces, which now report to EPEP. Updates meetings were discussed. The Committee contractions forceful enough to avert were presented on a number of ongoing received the suggestions positively. musculoskeletal deconditioning. Interestingly, projects that fall under the remit of EPEP, they show that the greater the hopping including the healthy ageing policy work, Introduction of an Equality, Diversity and height, the more beneficial the exercise. careers research project and grants review. Inclusion (EDI) code of conduct, a regular slot Further work is needed to ascertain whether The Committee also discussed proposals for for an EDI-focused workshop and pronoun analogous hop heights and beneficial effects strategic projects in 2020 including follow-up stickers were three recommendations put are attainable in hypogravity. work informed by the healthy ageing policy to the Committee to improve the equality, project, further work on the ‘Reward and diversity and inclusion of our conferences. DOI: 10.1371/journal.pone.0211263 Recognition’ of Teaching in Higher Education, The Committee agreed to the recommendations and various scoping projects considering how but questioned if our current code of conduct Impact of prolonged spaceflight The Society might develop its professional could be modified to consider EDI rather than on orthostatic tolerance during development opportunities for early career creating a new document. ambulation and blood pressure physiologists in future. Committee members then offered their own ideas for projects that The structure for the 2021 conferences was profiles in astronauts might help The Society achieve its Strategy, discussed. The Committee decided that there Orthostatic intolerance (OI) is characterised which will be developed into proposals for will be pre-symposia attached to Physiology by low blood pressure (BP) and light discussion at the next meeting. This meeting 2021, a Future Physiology conference, a headedness when upright, symptoms that finished with an update from the Scientific conference about the biological basis of elite are relieved when reclining. While Editor of Physiology News, which included a performance, and a conference on a “hot astronauts initially demonstrate OI upon discussion on how content can be made more topic”, for which there will be an open call their return to Earth, the chronic effects of discoverable and accessible for use as a free to members. prolonged spaceflight on OI are largely resource in the future. unknown. In this study of 12 astronauts, The Committee reflected on the impact of researchers monitored BP prior to, during, researchers withholding information when and following 6 months in space. Systolic presenting unpublished data. The decision BP decreases in spaceflight and returns to was made that it would negatively impact the normal upon landing, while diastolic BP is value of our conferences and that presenters unaffected. After spaceflight and during should be completely transparent so that regular activities of daily living, OI does not Conferences Committee robust and novel science is always shared. occur, and the researchers attribute this to effective exercise programmes during and The recent meeting of the Conferences following spaceflight. Committee was held on 17 October and DOI: 10.1161/circulationaha.119.041050 was chaired by Sue Deuchars, University of Leeds, UK. The first action of the Conferences Committee was to decide the recipient of the NASA’s Mars 2020 will hunt for 2019/2020 GL Brown Prize Lecture. microscopic fossils Mars 2020 is NASA’s next Mars rover due The committee then considered the proposals for launch in the summer of 2020. After submitted for the two pre-symposia hosted arriving in 2021, it will explore the red by The Physiological Society at Europhysiology planet in an attempt to determine whether 2020. It was noted that we will host symposia life ever existed on Mars. It’s landing site on the Themes of Human Environmental and will be the 45-km-wide Jezero Crater. Exercise Physiology and Neuroscience. A proposal was selected for each Theme. Physiology Feed continues on page 13.

9 News and Views

Physiologist among the stars: A conversation with Jim Pawelczyk

Agency developed SpaceLab module flown by which at the time was widely believed to be Ronan Berg the space shuttle Columbia. The flight orbited caused by a reduction in sympathetic output Guest Editor, Physiology News Earth 256 times, and the crew conducted to the cardiovascular system triggered by 26 experiments mainly on the effects of prolonged microgravity: microgravity on the brain and nervous Julia Turan system, serving both as research subjects “Our hypothesis was that we were going and operators. Two decades on, Pawelczyk to have this reversible form of autonomic Managing Editor, Physiology News remains an optimist who firmly believes that dysfunction if you will. That is tremendously we will be able to overcome the physiological exciting, at least in theory, because autonomic challenges associated with a manned mission dysfunction is not reversible. Once you’ve to Mars, so that we can set foot there in the got it, you’ve got it, and all you can do is Jim Pawelczyk is one of the very few with 2030’s. Physiology News met Pawelczyk in manage it. So if indeed it was reversible, think the credentials of a physiologist who has also London when he was in the UK to give The what that might mean for those half a million served as an astronaut. In 1996, he took a Physiological Society’s President’s Lecture Americans that have problems associated with leave of absence from a position as Assistant “What Price a Martian – Human Limits to poor blood pressure regulation.” Professor of Physiology and Kinesiology Exploring the Red Planet”. at Penn State University, as he was given In the experiments, the Neurolab crew the chance to enter the NASA astronaut Looking back at the Neurolab mission, which obtained direct recordings of sympathetic programme. Having grown up in the 1960s was incepted in what President George HW vasoconstrictor nerves and noradrenaline in the United States, he had been glued to Bush declared the “Decade of the Brain”, kinetics on each other. But to their surprise, the television to watch any launch; like many Pawelczyk is still thrilled by the results of there were no signs of autonomic dysfunction: other children of that generation, it was not the experiments that focused on one of his compared to pre-flight measurements an opportunity he was going to pass up. own principal areas of research, the neural obtained in supine position on Earth, there regulation of the cardiovascular system. was actually a slight increase in sympathetic Two years later he spent 16 days in orbit as These experiments sought to elucidate activity. Or as Pawelczyk laconically puts it: part of the seven-person crew of Neurolab, the mechanisms of orthostatic intolerance the final mission of the European Space experienced by astronauts after spaceflight, “A beautiful hypothesis ruined by data!”

For Pawelczyk, the results of the Neurolab experiments focusing on the neural regulation of the cardiovascular system fundamentally changed the perception on the adaptive responses of the autonomic nervous system to prolonged microgravity, and were subsequently published in three back-to-back papers in the January issue of The Journal of Physiology in 2002.

To this day, Pawelczyk remains a dedicated advocate for the continued research on the impact of the of the human body, and has testified before the US Senate on several occasions, arguing in favour of funding and conducting such studies on astronauts at the International Space Station. Pawelczyk explains why he considers research in space so important:

“In my opinion, the main reason is so that we can keep crews healthy to explore further and faster. Having said that, things that we do and learn in space, do ultimately have an effect.”

With reference to the interviewee’s glasses, Pawelczyk elaborates:

Neurolab was the module of the Spacelab mission focusing on the effects of microgravity “That scratch resistant coating that you have on the nervous system, which Pawelczyk was part of. on your lenses was originally created to coat visors of astronauts in flight… NASA engineers

10 Physiology News / Winter 2020 / Issue 117 Astronaut and physiologist Jim Pawelczyk gave our 2019 President’s Lecture. Over 200 members of the public enjoyed his fascinating talk and this was followed by hands-on activities related to physiology and space.

said, we’ve got to make sure that we protect these visors because our people need to see “The most wonderful thing about physiology is that well [...] when they are outside the vehicle. we are confronted with it every day, every moment” Somebody else got the bright idea and said, well you know we could take eyeglass lenses on the ground and use the same material to make them scratch resistant.”

Indeed, the problems experienced by astronauts in space are manifold. And “The gluteus has muscle tone, so you sort while Pawelczyk has studied the effects of of create this big lordotic curve when Jim Pawelczyk was born in Elma, New York, prolonged microgravity on the human body you’re in space, so you’re arching your back. USA, in 1960. He graduated with a BA in as a physiologist, it is thus also a personal And guess what? You wake up in the middle biology and psychology from the University experience in his case. Perhaps somewhat of the night with a big back ache. So the of Rochester (1982), followed by a MSc in surprisingly, a main problem experienced answer to that is you bring your knees up physiology from Pennsylvania State University, by the astronauts, including the Neurolab and you put a strap around your body, keep and PhD in biology/physiology at the crew, was back pain. Many consider this your knees up in position. Maintain more of a University of North Texas (1989). Following to be related to the marked elongation of natural, normal curvature of your spine – and a postdoctoral fellowship in cardiovascular the unweighted spinal column – indeed then everything is fine.” neurophysiology at the University of Texas astronauts usually “grow” several inches taller Southwestern Medical Center (1989 – 1992), during missions. Pawelczyk’s experience was, As our conversation comes to an end, he became Assistant Professor of Medicine at however, quite different. One night, while Pawelczyk reflects on what advice he’d give the University of Texas Southwestern Medical sleeping in his sleeping bag which he had tied to young physiologists out there – who may Center and Director of the Autonomic and to a rail in SpaceLab, he woke up “with the or may not become astronauts: Exercise Physiology Laboratories at the worst back ache of his life”: Institute for Exercise and Environmental “[...] I think particularly for budding Medicine and Presbyterian Hospital of Dallas “It was terrible. [...] You are sleeping with physiologists, always be curious. The most (1992 – 1995). Since 1995, he has served gravitational forces not really acting on you, wonderful thing about physiology is that as Assistant, and now Associate, Professor of so that the body posture that you assume is we are confronted with it every day, every Physiology and Kinesiology at the Penn State not defined by gravity, but by muscle tone.” moment, because we’re physiological beings. University. In 1996, he started astronaut We are a discipline that asks ‘why’ and ‘how’ training at NASA, and from 17 April to 3 May, It turned out that the gluteal muscle group all the time, relentlessly, and we should 1998, he spent 15 days 21 hours and 50 was the culprit: never stop asking or trying to answer those minutes in space as part of the payload crew two questions.” on the space shuttle Columbia.

11 News and Views

Physiological discoveries abound within NASA samples Elizabeth Keller Basal Vivarium Ground Flight NASA Ames Research Center, CA, USA 100

Ryan Scott 75 NASA Ames Research Center, CA, USA FLT R+1 50

-- StoryboardStoryboard (%) Abundance Relative 25 0

AEM R+1 Taxa Animals Bacteroidetes; Bacteroidia; Bacteroidales; Muribaculaceae Bacteroidetes; Bacteroidia; Bacteroidales; Tannerellaceae Deferribacteres; Deferribacteres; Deferribacterales; Deferribacteraceae Firmicutes; Bacilli; Lactobacillales; Lactobacillaceae Firmicutes; Clostridia; Clostridiales; Clostridiales vadinBB60 group Firmicutes; Clostridia; Clostridiales; Family XIII Firmicutes; Clostridia; Clostridiales; Lachnospiraceae Firmicutes; Clostridia; Clostridiales; Peptococcaceae Firmicutes; Clostridia; Clostridiales; Peptostreptococcaceae Firmicutes; Clostridia; Clostridiales; Ruminococcaceae Firmicutes; Erysipelotrichia; Erysipelotrichales; Erysipelotrichaceae Tenericutes; Mollicutes, Mollicutes RF39; __ Tenericutes; Mollicutes, Mollicutes RF39; uncultured bacterium Before humans risked their lives launching VIV R+1 Other into space aboard the Vostok Program and Mercury Project, various organisms were flown to determine if it was possible for life to Figure 1. Previous examples from ISC-BSP Tissue and Data Sharing. Left: Images of survive spaceflight. For decades, NASA, along histological mouse retina sections stained (red-brown) for caspase-3 from STS-133 with international partners, have continued treatment groups Flight (FLT; R+1), Animal Enclosure Module (AEM; R+1), and Vivarium- sending biological experiments to space. housed (VIV; R+7). © Zanello et al. (2013). Right: A stacked bar plot showing relative Potential biological hazards from spaceflight abundance of microbial families uncovered in each sample (Basal, Vivarium, Ground, Flight), include decreased gravity, increased exposure sorted by groups (taxa). © Jiang et al. (2019) and is licenced under CC BY 4.0. to radiation, altered light-dark cycles, and loads experienced during launch and landing. It is imperative to understand the Through NASA’s Biospecimen Sharing microgravity from long-duration missions. basic science and health risks associated Program (BSP), the samples in this biological Of particular concern to NASA is the loss of with spaceflight, along with developing repository are available for request by all visual acuity, which a significant number of countermeasures, as humanity ventures back researchers, including those based outside the astronauts have unexpectedly experienced. to the Moon, and then to Mars and beyond. United States. NASA is keen on getting researchers to work on elucidating the underlying cause(s) NASA Ames Research Center houses an A number of newly identified biological of this issue. In an effort to further the Institutional Scientific Collection (ISC) of knowledge gaps and astronaut health risks research progress on this topic, the NASA BSP spaceflight biological specimens and tissues. have emerged from extended exposure to coordinated the sharing of mouse eyes from the STS-133 Shuttle mission. The study led by Susana Zanello1 conducted histological examinations of the mouse eyes from “Through NASA’s Biospecimen Sharing Program, post-flight days 1, 5 and 7. Gene expression analysis suggested that reversible molecular the samples in this biological repository are damage occurs in the retina of mice exposed to the spaceflight environment, and that available for request by all researchers, including protective cellular pathways are induced in the retina and optic nerve in response to those based outside the United States” these changes. While correlation of research findings in the mouse tissues to human astronauts presents a set of challenges,

12 Physiology News / Winter 2020 / Issue 117 Physiology Feed

Recently shown to contain carbonate “Observations from her analyses shed light on deposits within its inner margin, Jezero may the specific environmental factors that have encompassed a lake that was perhaps hospitable to life. Carbonates are calcium- contributed to a robust effect on the gut rich rocks that, when stuck together with bacteria, form stromatolites. If stromatolites microbiome during spaceflight, with important are detected by Mars 2020, they may provide insight into how the Martian environment implications for mammalian metabolism” has changed over time, and could offer fossil evidence of life on the red planet. go..gov/2EEnG80

Is oral health affected in long- the mouse model is an excellent way to Space Station flight investigations, but period space missions only by characterise underlying changes at the cellular also included in the collection are ground- microgravity? and molecular levels that are simply not based specimens from spaceflight-model Various aspects of spaceflight, including available with the human crew. experiments. Tissues are predominantly microgravity, radiation, stress, and isolation, from mice and rats, though samples are may adversely affect the oral physiology of The costly effort of sending organisms also available from bacteria and quail. The astronauts. In this systematic review, 12 into space makes space-flown biological specimens include tissues from many systems studies were surveyed for evidence of the specimens a rare and valuable resource. including musculoskeletal, neurosensory, effects of microgravity during short- and Quite often, when life science samples are reproductive, respiratory, circulatory, and long-term spaceflight on oral health. retrieved from completed missions, there digestive. The samples are stored at -80°C, During short spaceflights, the stress are surplus tissues which remain unused by -20°C, or +4°C, depending on the fixative hormone cortisol is elevated, as is the the Principal Investigators and collaborators. used. Detailed metadata are available for all antibody IgA in saliva. Long-term missions In this scenario the tissues are harvested, samples. Historically, these tissues have been are associated with changes in the oral preserved, and archived in the NASA ISC used for a wide range of analyses, including microbiome, with greater anaerobic at the Ames Research Center to ensure histology, genomics, and transcriptomics. bacteria (e.g., Streptococcus mutans) the maximum scientific return from space The NASA Ames Life Sciences Data Archive present in astronauts’ dental plaque and missions in the belief that new discoveries (ALSDA) has been shipping samples to saliva. The authors warn that such changes can be made from the samples. investigators since 1995. may promote oral pathologies that could compromise long-term space missions, and An important recent finding was made How to request tissues from the NASA ISC recommend that appropriate preventative possible by the study of what would have Tissue requests are initiated by submitting an measures are utilised to mitigate this. previously been considered waste: rodent online Biospecimen or Data Request. If the fecal pellets. Through NASA’s BSP, Martha requested tissues are available, the requestor DOI: 10.1016/j.actaastro.2019.11.015 Vitaterna, from Northwestern University will be sent instructions for submission of a obtained mouse fecal pellets from a 37- short proposal. Visit the NASA ISC website for Space farming day mission aboard the International Space more information: nasa.gov/ames/research/ For sustainable human space colonisation Station and examined them for the effects space-biosciences/isc-bsp Contact the we must develop the means to produce of spaceflight on gastrointestinal microbiota2. ALSDA team: [email protected] food that meets all our nutritional Findings from previous studies have requirements. To date, several vegetables demonstrated a change in the gut microbial such as peas, wheat, bok choy (Chinese diversity and community structure during cabbage), mustard and several lettuces spaceflight, but it was unclear what the have been successfully grown in space. functional relevance of those microbiome References This list continues to grow with NASA changes were. Using 16S rRNA gene amplicon announcing it will soon test its first fruiting sequencing, Vitaterna and her team profiled 1. Zanello SB et al. (2013). Spaceflight effects and plant, namely the Española chilli pepper, in the microbiome of the fecal samples. They molecular responses in the mouse eye: observations an effort to alleviate food boredom and then compared the microbiome changes to after shuttle mission STS-133. Gravitational and Space provide a boost to their other relevant datasets and integrated the Research 1(1), 29 – 46. astronauts. SpaceX will send hemp and gut microbiome data with publicly available 2. Jiang P et al. (2019). Reproducible changes in the coffee plant tissue cultures to the ISS in transcriptomic data in the liver of the gut microbiome suggest a shift in microbial and host March 2020 to explore how their metabolic same animals for a systems-level analysis. metabolism during spaceflight.Microbiome 7(1), 113. pathways and growth are affected by Observations from her analyses shed light DOI: 10.1186/s40168-019-0724-4 microgravity. Researchers have also shown on the specific environmental factors that that it is possible to grow crops such as contributed to a robust effect on the gut tomato, quinoa and radish in simulated microbiome during spaceflight, with important lunar and martian soils, but perhaps the implications for mammalian metabolism. strangest of all farming endeavours was the successful proof-of-concept Russian– Available tissues for physiology research Israeli collaboration to grow and 3D print The NASA ISC at Ames Research Center beef “meat”. currently stores over 32,000 specimens. Most come from Shuttle and International DOI: 10.1515/opag-2019-0051

13 News and Views

Sex in space: Our final reproductive frontier

whether mouse embryos which had been space sperm were just as able to develop into Adam Watkins generated on Earth would develop in space. healthy adult mice as the control sperm. University of Nottingham, UK However, in both cases, the experiments did not yield positive results. Separate studies The next step for some is to test the effects conducted on the Russian space station Mir of microgravity and space travel on human also showed that microgravity seemed to gametes and embryos. While some may view Over recent decades, our ability to regulate have negative effects on the eggs and such experiments as unethical, many believe and manipulate our own reproduction has embryos of a range of species including that in order to understand the impact of expanded significantly. We have developed salamanders, sea urchins and quails. space travel of , the use the ability to collect and manipulate gametes, of human sperm, oocytes and embryos is a fertilise the oocyte outside of the body, culture Together, these studies seem to suggest necessity. In a study presented to the the embryo in a dish and transfer it back to reproduction in space might not be as European Society for Human Reproduction the uterus to continue its development. To straightforward as it is here on Earth. and Embryology (ESHRE) in 2019, date, over eight million babies have been born However, more recent experiments have researchers explored the effects of from assisted reproductive technologies approached the question of sex in space from microgravity on human sperm6. Using a (ART) such as in vitro (IVF)1. a different position. The current thinking is specially modified plane, normally used for Using ART, we are able to delay having to send freeze-dried sperm, oocytes or training astronauts, the researchers exposed children until a time that suits us best, putting embryos across space, like an interplanetary 10 human sperm samples to reduced gravity. our fertility on ice, literally. reproductive delivery service. The simple Using the same array of tests normally reason for this is that frozen gametes and undertaken within a fertility clinic, the While ART such as IVF have enabled millions embryos take up far less space and resources research saw there was no detrimental effect of people to have a family of their own, our on a spaceship than living humans do, and can of the microgravity on sperm quality. ability to collect and store sperm, oocytes and potentially be stored for decades. Once at embryos may have one unexpected benefit, their destination, they can be revived and While such studies show that aspects of potentially helping the human race to colonise implanted. The downside to this is that in human reproduction are possible in space, other planets. This is because sex in space is space, the levels of cosmic radiation are there is still a long way to go before we see surprisingly difficult. Firstly, just staying in close significantly higher than here on Earth. the whole reproductive process undertaken contact with each other under zero gravity is Thankfully for us, our atmosphere shields out outside the confines of our home planet. hard. Secondly, as astronauts experience lower significant amounts of solar radiation, but in blood pressure while in space, maintaining space, astronauts, and their gametes, are and arousal are more problematic exposed to doses hundreds of times higher than here on Earth. If that’s not enough, then than on Earth. This high-energy radiation the sheer lack of privacy on shuttles and space can damage DNA, causing mutations and References craft mean there are no rooms into which two impairing the development of an embryo3. 1. Crawford GE, Ledger WL (2019). In vitro fertilisation/ astronauts can retreat for some time together. Therefore, researchers and space agencies intracytoplasmic sperm injection beyond 2020. BJOG : Therefore, it’s probably not surprising that to want to know whether sending gametes and an International Journal of Obstetrics and date there have been no confirmed accounts of embryos on long journeys into space is safe. 126, 237 – 243. DOI: 10.1111/1471-0528.15526 astronauts having had sex in space. In 2017, researchers sent packages of freeze-dried mouse sperm to the 2. M ishra B, Luderer U (2019). Reproductive hazards However, astronauts have been International Space Station (ISS) for nearly of space travel in women and men. Nature Review experimenting with reproduction for many 10 months4. When it returned to earth, they Endocrinology 15, 713 – 730. DOI: 10.1038/s41574- 019-0267-6 years2. A range of animals have been blasted compared it to control fresh samples taken into space to see how microgravity might from the same mice. The first observation 3. Rienzi L et al. (2019). Sperm DNA fragmentation affect their reproduction. Initially, rats and was that the sperm which had been on the to predict embryo development, implantation, and mice were sent to see if they would mate and ISS had more fragmented DNA than the miscarriage: still an open question. Fertility and Sterility if their would develop normally. control sperm. As high levels of sperm DNA 112, 466. DOI: 10.1016/j.fertnstert.2019.05.016 Unsurprising to anyone who uses rodents to fragmentation are associated with male . study reproduction, the significant disruption infertility and increased miscarriage risk, these 4.Wakayama S et al. (2017). Healthy offspring from freeze-dried mouse spermatozoa held on the of travelling into space and back meant none observations were a worry5. However, when International Space Station for 9 months. Proceedings of the females actually developed to term used in IVF, the space sperm were able to of the National Academy of Sciences of the United with their pregnancies. Similarly, astronauts generate the same number of embryos as the States of America 114, 5988 – 5993. DOI: 10.1073/ explored whether IVF could be done using sperm which stayed on Earth. Furthermore, pnas.1701425114 isolated mouse sperm and oocytes, or following transfer, embryos derived from the 5. Jayasena CN et al. (2019). Reduced testicular steroidogenesis and increased oxidative stress in male partners as novel markers of recurrent miscarriage. Clinical Chemistry 65, 161 – 169. “The research saw there was no detrimental DOI: 10.1373/clinchem.2018.289348

effect of the microgravity on sperm quality” 6. h ttps://www.eshre.eu/ESHRE2019/Media/2019- Press-releases/Boada

14 Physiology News / Winter 2020 / Issue 117 Book Review

How to live in space by Colin Stuart

Colin Stuart is an astrophysicist, successful There is interesting information on how tricky Karen Doyle author and scientific communicator. He it is for humans to live in space. There are NUI Galway, Ireland is passionate about communicating the details describing how oxygen is generated science of space with the public, and he is and carbon dioxide removed from the air passionate about the need for interdisciplinary and details of water recycling on the ISS. It collaboration to advance space research. is possible to recycle shower run off, sweat This book is a self-described space manual, and urine from everyone on board, be they describing what astronauts experience during human or animal. The Russians draw the line training, the impact on an astronaut’s body at recycling urine, but the Americans happily of living in space and the implications to any drink it! future space exploration and tourism. The effects of months in space on the human There are interesting factoids throughout, body is particularly fascinating. Astronauts many of them general knowledge, but some are likely to develop chicken legs, puffy face specifically physiological. For example, did and kidney stones. A six-month stay in orbit you know – space starts 100 km above reduces bone density by the equivalent of the Earth, at the Kårmån line, the point at 10 years on earth, reduces physical work which aeronautics becomes astronautics. capacity by 40% and exposes astronauts It takes 9 minutes from lift-off to reach to heightened cosmic radiation, increasing an orbit 220 km above the earth. Earth’s cancer risk. Astronauts have to readjust escape velocity is 11.2 km per second, and to Earth’s gravity in many ways upon their a typical lift-off subjects an astronaut to 3G return – even the muscles for articulation are – substantial enough forces, but this pales affected by space. The astronauts exercise to insignificance when faced with the typical for 2.5 hours daily on the ISS, with a mix of 8G force of re-entry. In preparation for weights and aerobic exercises to minimise space, astronauts train underwater where the musculoskeletal loss, but much more research Colin Stuart of is simulated. is needed to understand how to minimise the Smithsonian Books (2018) Training in centrifuges allows astronauts to impact on long space missions. ISBN: 9781588346384 prepare for high G-force environments. Much of this training focuses on muscle flexing The physical changes observed in astronauts and breathing techniques. Exhaling is no on the ISS suggest that should humans leave problem in such an environment, but inhaling Earth in search of a new home far, far away, is extremely difficult, so astronauts need to the human body would change to adapt to learn to restrict breathing to short, sharp low gravity – we would likely become taller, inhales and exhales. thinner, may struggle to give birth naturally and would be crippled by the high gravity “A six-month stay in orbit Another key physiological concern is the conditions when returning home for a visit. nausea associated with weightlessness. reduces bone density by Astronauts train in the “vomit comet”, where This book is a very interesting read for the equivalent of 10 they are subjected to parabolic arc flight anyone interested in science – touching sequences of sharp ascents and precipitous on physiology, chemistry and of course years on earth, reduces descents while flying high above the Nevada astrophysics, as well as interesting general desert. Space sickness, also known as knowledge that will be invaluable for future physical work capacity space adaptation syndrome, affects 75% of space tourists and pub quiz enthusiasts! astronauts. The degree of space sickness is by 40% and exposes very individual and is measured using the Garn scale – a scale based on the worst case ever astronauts to heightened recorded – a poor unfortunate who needed to be Velcro-ed to a wall on the International cosmic radiation, Space Station (ISS) for the duration of the trip to minimise his sickness. The cause of space increasing cancer risk” sickness is the effect of weightlessness on the fluid in the vestibular organs, activating the hair cells in a manner that conflicts with visual signals, disorientating the brain and usually lasting for 2 – 4 days.

15 News and Views

Image: Johnson Space Center of the United States National Aeronautics and Space Administration

The NASA Twins studies The “NASA Twins” Mark (left) and Scott (right) Kelly (b. 1964). Mark served as an astronaut at NASA from 1996 to 2011 and logged a total of 54 days in orbit. Scott served as an astronaut at NASA from 1996 to 2016, and over the course of four missions, he spent a total of 520 days in orbit. The NASA studies were a unique opportunity to study the effects of long-term spaceflight on the human body, by comparing Scott who was on board the ISS for a year, to Mark who remained on Earth during that time.

The microbiome in space, from the Apollo missions to present

celebrated Neil Armstrong’s 39th birthday. Nearly 50 years after the Apollo 11 mission, Martha Hotz Vitaterna This was a precautionary measure against the the scientific investigation of another Northwestern University, IL, USA possibility of contagious potential pathogens landmark human space expedition, (“moon germs”), a risk considered as unlikely astronaut Scott Kelly’s 342 days on board but uncertain at the time. Following Apollo 14, the International Space Station (ISS), this quarantine is not required, nor is testing culminated in a publication earlier this year in Peng Jiang astronauts’ blood by injecting it into mice. the journal Science1. This year-long mission Northwestern University, IL, USA Over the past 50 years, research approaches marked the longest of towards astronaut health, the physiological a US astronaut, and was even more unique effects of space, and microorganisms have because Scott Kelly’s identical twin brother, dramatically shifted, reflective of the explosive retired astronaut Mark Kelly, agreed to Fifty years ago, when the Apollo 11 advancements in biomedical research during participate in the study. This provided an astronauts Neil Armstrong, Buzz Aldrin, and this time. These are clearly illustrated by the unprecedented opportunity to study the Michael Collins returned to Earth, they were NASA Twins Study, and studies of the gut effects of long-term spaceflight on the quarantined for 21 days, including some days microbiome in space, in which we have had human body. NASA assembled a consortium in a converted Airstream trailer where they the privilege to be involved. of 10 investigator teams to study the twins

16 Physiology News / Winter 2020 / Issue 117 in preparation for future long-term missions such as those around the Moon, asteroids “The Twins Study exemplifies how scientific and ultimately Mars. approaches have evolved over the years” The Twins Study exemplifies how scientific approaches have evolved over the years. Rather than ten discrete investigations, the study was designed to develop a cross- disciplinary picture of how various systems, Inclusion of the gut microbiome as a topic these spaceflight-specific effects with other, from cognition to physiological and molecular for this kind of integrated evaluation of the related systems can lead to an understanding processes, may respond, in concert with adaptation to spaceflight also would not of the role of the microbiome in adaptation one another, to the challenge of spaceflight. have been imagined 50 years ago, when to spaceflight. Such “small steps” of scientific The result is a rich and intriguing data set. bacteria were primarily viewed with suspicion progress, continuing into the next few The study was further strengthened by of pathogenicity. Now, modern high- decades, can advance health in space as well the ability to obtain comparable data from throughput sequencing approaches reveal a as on Earth, so that we are ready for future the “ground twin” so that an assessment of dynamic, diverse and complex “ecosystem” of giant leaps for mankind. expected variability over time in a genetically microorganisms inhabiting the gastrointestinal matched individual with a busy, varied life on tract and interacting with mammalian Earth could be made. In this manner, variance physiology, that change in response to outside that range seen in the “space twin” spaceflight and might in fact have the potential could be more confidently attributed to to help astronauts to adapt to spaceflight. References space flight. 1. Garrett-Bakelman FE et al. (2019). The NASA Twins From a high-level view, some alterations Study: A multidimensional analysis of a year-long Spaceflight-induced microbiome changes in the gut microbiome in response to human spaceflight.Science 364(6436), eaau8650. seen in the Twins Study were modest, and spaceflight are consistent across studies: DOI: 10.1126/science.aau8650 quickly diminished after the astronaut an increase in the microbial diversity and a returned to Earth. Nonetheless, these shifted microbial community structure have 2. Voorhies AA et al. (2019). Study of the impact of long- changes were beyond the day-to-day been identified in the NASA Twins Study1 as duration space missions at the International Space fluctuations in the gut microbiome well as another, subsequent astronaut study 2, Station on the astronaut microbiome. Scientific Reports 9(1), 9911. DOI: 10.1038/s41598-019-46303-8 composition in the ground twin during the and even in mice that have flown on the ISS3. same period of time. Many of our colleagues’ Development of a new analytic strategy, 3. Jiang P et al. (2019). Reproducible changes in the other measures exhibited parallel spaceflight a tool called STARMAPs, revealed that the gut microbiome suggest a shift in microbial and host response profiles; future studies can test consistencies of the effects of spaceflight metabolism during spaceflight.Microbiome 7(1), 113. hypothesised links among these mirrored on the gut microbiome go far deeper: the DOI: 10.1186/s40168-019-0724-4 Image: Johnson Space Center of the United States National Aeronautics and Space Administration responses. Neither the integrated, multi- overall patterns of the microbial composition system approach nor the computational and changes are reproducible when comparing molecular analyses were methods available mice flown on the space shuttle to those 50 years ago. flown on the ISS3. Now, studies to integrate

Telomeres and genomic instability during long-duration spaceflight

government agencies (e.g. China, India, The NASA Twins Study is clearly limited in Nicholas A Vernice Israel), and will involve months to years of the sample size (n=1 per group), and thus Cornell University, NY, USA exposure to spaceflight conditions. Yet, the experiments were designed to create even as we commemorate 50 years since benchmarks that can be used in later the first landing on the Moon, very little missions to optimise crew health, improve in- biomedical data exist on the health effects flight collections, and to compare measures Susan M Bailey of long-duration spaceflight, since very few of acute or long-term flight risks. Data were Colorado State University, CO, USA missions (n=8) have lasted for greater than generated across a myriad of modalities 300 days. Indeed, only four individuals have of human and microbial biology, including ever participated in spaceflight missions stool, saliva, skin, urine, and blood samples. lasting longer than one year. Thus, while the The Study used a wide battery of measures, Christopher E Mason effects of short-duration spaceflight on the which included various whole-genome, RNA, Cornell University, NY, USA human body have been well documented, and metagenome sequencing techniques, as there is a paucity of data on the effects of well as proteomics and metabolomics, and long-duration spaceflight, and almost no numerous other techniques. data using modern methods in molecular The first astronauts for the American biology. These fundamental limitations in Blood analyses elucidated several physiological (1960) and Russian (1959) space programs our knowledge, concomitant with the changes that long-term spaceflight has demonstrated that spaceflight was emergence of several new, active spaceflight on the genome, including the impact physiologically possible for the human body, agencies, helped to inspire the NASA Twins on telomeres. Telomeres are repetitive while also inaugurating a new era of human Study: a multi-dimensional characterisation nucleotide sequences found at the physical exploration of space. This led to current- of the effects of a year-long spaceflight on ends of eukaryotic chromosomes, which day plans for missions to the Moon and the body1. are critical for maintaining genome stability. Mars, which include new commercial and During each cycle of cell division, telomeres

17 shorten due to the end-replication problem, Indeed, and as expected with any significant by microgravity. A cognitive assessment which results in the inability to replicate to physiological stress, thousands of genes revealed no dramatic changes in the space the very end of newly synthesised lagging changed their expression levels during twin’s higher cortical functions during his strands. As such, telomeres serve as “buffer spaceflight, including pathways related to time in space with respect to the ground zones”, preserving the genes that lie medial telomere maintenance, immune (T-cell) twin; upon landing, however, the space to them. However, because telomeres activation, and DNA repair. Moreover, of the twin exhibited a pronounced decrease shorten with ageing, as well as with a genes that changed expression in spaceflight, in speed and accuracy while performing variety of lifestyle factors and stresses, they ~91% returned to normal ranges within 6 cognitive tasks which persisted for six eventually become so short that cells enter months post-flight. While the overwhelming months upon re-acclimation. Additional a state of senescence and stop dividing. majority of transcriptional changes returned analyses demonstrated that the space twin’s This process is also associated with ageing- to pre-flight levels, a distinct subset of 811 spaceflight resulted in a 7% decrease in body related pathologies such as cardiovascular genes involved in either immunity or DNA mass, a dynamic osteocyte turnover rate disease and cancer. Interestingly, and damage remained altered post-flight, which which first increased and then stabilised contrary to expectation, the NASA Twins has provided insight into candidate genes during the latter six months of flight, Study found that long-duration spaceflight that are more susceptible to extended increased inflight and urinary lactic resulted in a significant increase (~15%) spaceflight and which may be driving the acid levels, increased inflight mitochondrial in telomere length in the “space twin” as continued re-adaptation to gravity. DNA and ATP-dependent respiration, and compared with his pre-flight and post-flight increased carotid artery intima-media telomere lengths, as well as those of the DNA repair pathways and re-acclimation thickening that persisted into the post-flight “ground twin”. Given that the space twin’s mechanisms are likely confounded as part of period, among other findings. Additionally, telomeres dramatically shortened within the normal response of returning to gravity, the NASA Twins Study determined that 48 hours of returning to Earth, it is but evidence of DNA damage was observed. cephalad fluid shifts observed in the space postulated that spaceflight-specific telomere In the analysis of genomic instability, twin corresponded to retinal oedema, as well elongation may have occurred in response the space twin demonstrated increased as elevations in urinary aquaporin-2 (AQP2): to galactic cosmic radiation exposure; frequencies of chromosome aberrations, a protein involved in regulation of water results are consistent with one other ISS particularly inversions (i.e. rearrangements resorption that might be implicated in the study in C. elegans2. It is also worth noting, within chromosomes), during spaceflight: pathogenesis of ophthalmologic disorders however, that while the space twin’s a finding consistent with exposure to observed during and after spaceflight. average telomere length stabilised to ionising radiation, particularly high linear approximately his pre-flight levels, cell- energy transfer (LET) cosmic radiation3,4. In summary, the Twins Study demonstrated by-cell FISH analysis revealed an increased Moreover, the space twin’s chromosomal that the human body is extraordinarily number of short telomeres post-flight, inversion frequencies remained elevated adaptive to the changes incurred during potentially suggestive of ongoing damage, post-flight, suggesting continued instability a one-year mission, and that it should be instability, accelerated ageing and/or future and possibly radiation-induced DNA damage possible to survive the transit to Mars and adverse health effects. to multipotent haematopoietic stem cells of then return back to Earth. However, the long-term health effects of long-duration spaceflight are exceedingly difficult to assess, and more work must be done to examine whether physiological effects, such “It should be possible to survive the transit as post-flight telomere shortening, stem cell alterations, and/or genomic instability to Mars and then return back to Earth” have detectable long-term adverse health effects on individuals exposed to the space environment for prolonged periods of time.

DNA methylation has also become a widely the bone marrow, which could have a long- used proxy for assessing the ageing process, term impact on the genetic health of both References with methylation “clocks” being used myeloid and lymphoid fractions. Thus, even successfully to predict age and mortality longer spaceflight missions should involve 1. Garrett-Bakelman FE et al. (2019). The NASA Twins in several different species. The addition of an expanded focus on the haematopoietic Study: A multidimensional analysis of a year-long a methyl group to a DNA strand typically systems. human spaceflight.Science 364(6436), eaau8650. results in local cessation of transcription. DOI: 10.1126/science.aau8650 Thus, methylation in a gene’s promoter While a full discussion of the results 2. Z hao Y et al. (2006). A mutational analysis of region is related to reduced expression presented in the Twins Study is beyond Caenorhabditis elegans in space. Mutation Research of that gene, and is a common epigenetic the scope of this article, it is worth noting 601, 19 – 29. DOI: 10.1016/ j.mrfmmm.2006.05.001 marker of gene expression regulation. While that the Study evaluated the effects of genome-wide methylation changes in the long-duration spaceflight on several other 3. Ray FA et al. (2014). Directional genomic hybridization: space twin were within the range of variation physiological areas as well. For example, Inversions as a potential biodosimeter for retrospective of those of the ground twin, gene ontology in its assessment of the immunome, the radiation exposure. Radiation and Environmental enrichment analysis revealed enrichment Twins Study revealed that inoculation Biophysics 53, 255 – 263. DOI: 10.1007/s00411- 014-0513-1 of epigenetic discordance in several genes with an annual flu vaccine in space, as well indicative of immune stress. Thus, as with as subsequent inoculation on Earth the 4. Cornforth MN, Durante M (2018). Radiation quality previous studies demonstrating changes in following year, were both successful in and intra- chromosomal aberrations: Size matters. the immune system of astronauts, this is an initiating an appropriate T cell-mediated Mutation Research 836(part A), 28 – 35. area for continued surveillance and focus on response in the space twin, thereby DOI: 10.1016/j.mrgentox.2018.05.002 future long-duration missions. suggesting that the immune system’s defenses are not functionally impaired

18 Physiology News / Winter 2020 / Issue 117 Events Meeting Notes

Partnerships, communities development. We also know that some within for ethnic groupings with genetics. Ethnic the science and health research sector are groupings are often problematic due to their and inclusion to drive systematically excluded from attending, poor alignment with genetics and, as they better research contributing to or participating fully in these get used as proxies for genetic difference, events. We experimented with new ideas to personal and cultural contexts of diseases and 9 September 2019, increase access and participation, and we’ve phenotypes are lost. shared the different ways we did this in our Francis Crick Institute, delegate booklet that’s available online1. Emma Baple also presented work in genetics London, UK on developing deep, mutually beneficial and At the EDIS symposium, Katherine Cowan, culturally sensitive research partnerships Senior Advisor to the James Lind Alliance, with isolated communities. These can spoke about the need to work with help to develop novel insights into known researchers, clinicians, patient groups and inherited diseases. These relationships take Lilian Hunt communities together on an equal level to time and respect but a community, clinical, determine research priorities. Working in this biomedical and social science interdisciplinary Programme Manager at EDIS way can fundamentally change the topics collaborative framework can address (Equality, Diversity and Inclusion in of research that are prioritised for different research and healthcare inequalities and Science and Health) diseases and build understanding and mutual unmet needs. Baple’s team have developed respect between “researchers” and “those a course detailing their community approach whom research is being done to”. Examples to genomic medicine and research where include the autism community’s ask for key concepts could be explored in other funding to be shifted from neuroscience fields5. Findings from population-specific The EDIS Symposium 2019 was held on to social care2, and the schizophrenia genetic testing can also be translated globally, 9 September at the Francis Crick Institute community’s need for more research to be reaching others whose diagnosis has so far on the theme of inclusive research and focused on tackling weight gain3,4. evaded discovery through typical clinical experimental design. We wanted to explore phenotyping6. the concepts of equality, diversity and The merging of basic biomedical science with inclusion (EDI) in relation to how we fund, social science to better understand disease, Understanding that, as scientists, no work design and conduct research for the benefit of patient and societal context is imperative. is done in isolation but as part of a complex human health. Creating these links between This is particularly true within the field of research system that is accountable to EDI and research helps show how inclusivity in population genetics as it focuses more on public health should be fundamental to how all its forms can improve research and health personalised genomic medicine. However, we work. Holding this understanding at the outcomes, and importantly how ignoring the literature of genomics is littered with the core of decision-making, research design these ideas can actively harm them. language of social constructs such as race, and how we conduct research helps bring and this can be a barrier to understanding. a people-centred approach to biomedical, In addition, the symposium had the aim of Ewan Birney presented alternative language medical and health research. If we include creating an inclusive culture at the event and to use within the field, moving from underrepresented groups, areas of unmet removing barriers to participation. We know societal ethnic classifiers (such as “Western need and co-production in our research that attending and presenting at research European”) to pluralised ancestry descriptors we are far more likely to produce results conferences is vital to career progression, (e.g. “European Ancestries”) as a possible that benefit communities long-term and as well as personal and professional method to move away from current terms tackle health inequalities. The importance of inclusive research and experimental design cannot be emphasised enough; however, we must integrate biomedical, medical and social sciences to build trust and meaningful relationships to do so.

References

1. edisgroup.org/edis-symposium-2019/977-2/

2. autistica.org.uk/downloads/files/Autistica-Scoping- Report.pdf

3. jla.nihr.ac.uk/priority-setting-partnerships/ schizophrenia/top-10-priorities/

4. assets.publishing.service.gov.uk/government/uploads/ system/uploads/attachment_data/file/591875/ obesity_in_mental_health_secure_units.pdf

5. futurelearn.com/courses/community-genetics

6. ncbi.nlm.nih.gov/pubmed/30996339 DOI: 10.1038/s41433-019-0436-9

19 Europhysiology 2020 Join us in Berlin

Abstract submission open from 5 March–25 May

Engage with cutting edge physiology

Present your work to over 1200 scientists

Expand your network and forge new collaborations

Find out more at: physoc.org/europhysiology2020

Europhysiology 2020 11–13 September 2020 Estrel Congress Center, Berlin, Germany

TPS12652 - Europhysiology 2020 poster V3 REPRO.indd 1 05/12/2019 09:43:47 fostering of collaborative ventures similar to channel, through to “inhibitory mechanisms in Meeting Preview those that have already proved fruitful from cortical information flow”. There are also four Europhysiology 2018. focused pre-symposia on cardiac physiology, Europhysiology 2020 skeletal muscle, renal physiology and vascular Europhysiology 2020: The four plenary lectures, one chosen by physiology with programmes being finalised each participating society, provide thought- as we speak, so do check our website! Two Bringing together the provoking overviews of physiology, delivered other satellite symposia, sponsored by The physiology community by some of the top leaders in their fields. The Physiological Society have more complete Join us in Berlin Physiological Society is delighted to host it’s programmes. The first on “Ionotropic 11 – 13 September 2020, Annual Review Prize lecture in Berlin, given glutamate receptors: structure, function by David Attwell, University College London and dysfunction” will consider proteins that Estril Congress Center, whose extensive work on neurovascular regulate properties of this family of ligand- Berlin, Germany interactions and elucidating the roles of gated ion channels and de novo mutations pericytes, which he describes as “power in ionotropic glutamate receptor subunits Abstract switches in the brain” is truly inspirational. underlying neurological disorders. The We look forward to hearing about his most second, entitled “Can exercise prevent the submission open from recent work looking at pericytes in human age-related decline in adaptive homeostasis? Susan Deuchars brain tissue. The Michael de Burgh Daly Prize Evidence across organisms and tissues” will 5 March–25 May Lecture will be delivered by Fiona Gribble from bring together leaders in the fields of exercise Chair of Conferences Committe, the University of Cambridge. Her research physiology and ageing research to discuss The Physiological Society determines the actions of gut hormones the current understanding and research gaps & University of Leeds, UK on target tissues. In understanding how gut in this research. Importantly for our early hormones are released, they aim to target career physiologists, there will be a dedicated ways of modulating this release, which may symposium for them, with a programme lead to the development of new drugs or developed across the societies and relevant diets that treat diabetes and obesity. The third to all. We have ensured that there is no clash We are delighted to be looking forward to of our prize lectures announced so far is the between subject-specific symposia and this Europhysiology 2020, which will take place in Bayliss-Starling Prize Lecture given by Maria early career symposium so that you can Berlin, home to world-renowned universities Fitzgerald, University College London, who is choose to attend both, if you wish. These and a fascinating city for culture and history. internationally recognised for pioneering work pre-symposia will take place at the same Europhysiology 2020 is a continuation of a in the basic developmental neurobiology of venue. Registration for all of these is free but series that started with Europhysiology 2018 in pain, central processes underlying hyperalgesia you do have to be registered for the main London with the third conference taking place and allodynia, and the understanding of conference to attend and there will be limited in Copenhagen in 2022. The overwhelming pain in infants and children. We also have spaces, so be sure to register early. success of our first Europhysiology conference plenary lectures by Heidi McBride (McGill in London, was due in part to superb plenary and University, Montreal) on post-translational The conference will take place at the Estrel keynote lectures, thought-provoking symposia modification of mitochondrial function Congress Centre in Berlin from 11 to 13 and a plethora of oral communications that and Volker Vallon (University of California, September 2020, with pre-symposia on highlighted the importance of interactions San Diego) on the role of the kidney in the 10 September. We look forward to seeing between the physiological societies in Europe. regulation of blood pressure, renal clearance you all in Berlin; we are anticipating a great Our packed programme in Berlin promises of exogenous and endogenous compounds, conference celebrating physiology at its best! to keep this momentum going and we look and the underlying pathophysiology of the forward to maintaining that fantastic buzz early diabetic kidney. Amongst the keynote and enthusiasm in discussing new advances lectures, Holger Gerhardt from the Leuven Engage with cutting in physiology research. Center for Cancer Biology, Belgium, has a Key dates focus on tumour angiogenesis with an aim to 15 January 2020: edge physiology Based on Europhysiology 2018, we expect consider the refinement of anti-angiogenesis more than 1400 participants involved in all and vessel normalisation therapy. These Online registration opens aspects of physiology. This is your chance lectures often provide us with potential new 5 March 2020: Present your work to to broaden your network of physiology directions or techniques to consider in our Abstract submission opens colleagues and hear the latest research across own research, regardless of the differences over 1200 scientists the full breadth of research topics. There are in the organ or system studied. For a full 25 May 2020: over 100 oral communication slots and three list of all plenary and keynote lectures, visit Abstract submission closes poster sessions that allow physiologists of europhysiology2020.org 15 June 2020: Expand your network and all career stages to showcase their research. Early registration closes These, together with the workshops and the During the main conference, we have forge new collaborations informal events being planned, both across symposia on topics ranging from “The 15 July 2020: our Themes and across the societies, will athlete’s heart”, microbiota, oxygen sensing Late-breaking abstract submission encourage mingling, lively discussions and in health and disease, and the cardiac sodium closes (poster only) 1 September 2020: Find out more at: physoc.org/europhysiology2020 Late registration closes “We look forward to seeing you all in Berlin; 10 September 2020: we are anticipating a great conference celebrating Pre-Meeting Symposia 11 – 13 September 2020: Europhysiology 2020 physiology at its best!” Meeting dates 11–13 September 2020 Estrel Congress Center, Berlin, Germany 21

TPS12652 - Europhysiology 2020 poster V3 REPRO.indd 1 05/12/2019 09:43:47 Features

Don’t lose sight under pressure Cranial consequences of a life without gravity

Although humans evolved under the constant weight of Earth’s gravity, they appear to be particularly susceptible to changes in gravitational gradients. An example of this is the so-called spaceflight-associated neuro-ocular syndrome, which was first reported in astronauts that experienced impairments in their vision during and after long-duration missions onboard the International Space Station. The symptoms were initially thought to result from intracranial hypertension due to a microgravity-dependent redistribution of fluid volume to the upper parts of the body. While the existence of this syndrome indicates that Earth’s gravity field has an important influence on the structure and function of the optic apparatus, it was not until recently that intracranial pressure was experimentally measured during microgravity. Justin S Lawley

University Innsbruck, Austria Manned exploration of the galaxy is a all three major circulations: arterial, venous dangerous business, not only because and cerebrospinal fluid. For example, arterial of the technical and logistical issues blood pressure at the level of the brain is surrounding space travel (to date, all ~80 mmHg, at heart level ~100 mmHg and deaths in human space flight have been at the level of the feet ~200 mmHg. In stark due to catastrophic loss of the crew contrast, in the supine posture, the effect of vehicle), but due to prolonged exposure gravity is limited to the short chest-to-spine

to isolation and confinement, hostile and fluid column (Gx) with arterial blood pressure closed environmental conditions, radiation being ~100 mmHg at the level of the brain, (see Limoli p. 26 and Whittaker p. 36) and heart and foot. importantly the lack of gravity (see Mekjavic p. 30). Life on Mars will no doubt be tenuous, These large changes in fluid pressures and as astronauts will be living in only three- subsequent redistribution of fluid volume to eighths of Earth’s gravitational force for many the lower extremities makes standing up a months to years. Thus, a broad scientific challenge to the cardiovascular system most understanding of how the human body humans do not consider on a daily basis, as copes with prolonged periods of reduced complex involuntary reflex adjustments make gravitational loads will be imperative for it possible. Yet, after long-duration space mission success. missions or prolonged periods of bedrest, standing up in Earth’s gravity is difficult and How does gravity affect the fainting is common. Thus, physiologists have Benjamin D Levine cardiovascular system? taken a keen interest in how the human body adapts to both microgravity and bedrest and Texas Health Presbyterian Dallas, In the upright posture, gravity acts on the its implications for blood pressure regulation

USA long head-to-foot fluid column (Gz) within on Earth (see Norsk p. 40).

22 Physiology News / Winter 2020 / Issue 117 14 13 12 A

(mmHg) 11 10 Ventricular pressure Ventricular

E 10 8 “Careful examination of 6 astronauts experiencing 4

(mmHg) B 2 D neuro-ocular syndrome 0

Central venous pressure venous Central noted flattening of the eyeball, folds in 120 the choroid, widening 110 90 of the optic nerve, (mmHg) 70 cotton wool spots on Arterial pressure Arterial 50 the retina and, in a few cases, swelling of the C optic disc”

Figure 1. Schematic of experimental set-up. Intracranial pressure (A) and central venous pressure (B) were measured directly via fluid coupled pressure transducers connected to the Ommaya reservoir with a butterfly needle and catheter placed in the right atrium, respectively. Additionally, non-invasive measurements of beat-by-beat arterial blood pressure were taken by finger photoplethysmography(C), brachial arterial sphygmomanometry (D) and jugular venous cross-sectional area was assessed by cardiac- gated B mode ultrasonography (E). Note that intracranial, central venous and arterial pressure recordings were referenced to the external auditory meatus and right atrium, respectively (dashed lines). (Taken from Lawley et al., 2017).

Spaceflight associated neuro-ocular role of raised intracranial pressure be and accurate recordings. For our study syndrome substantiated. we recruited five men and three women with Ommaya reservoirs, and combined Careful examination of astronauts Attacking the problem of accurately measurements of intracranial pressure with experiencing neuro-ocular syndrome noted measuring regional pressures central venous and arterial blood pressures, flattening of the eyeball, folds in the choroid, measured at the level of the right atrium of widening of the optic nerve, cotton wool Precise measurement of pressure within the heart via catheterisation of the brachial spots on the retina and, in a few cases, the human body requires the insertion of a vein and determined by non-invasive finger swelling of the optic disc (Mader et al., catheter or needle into the fluid compartment artery photoplethysmography and brachial 2011). These observations, reminiscent of interest. So, measuring pressure inside the artery electronic sphygmomanometry, of patients with intracranial hypertension brain of healthy volunteers in microgravity respectively (Fig. 1). (i.e. pathologically high pressure in the is a real challenge! Fortuitously, Benjamin brain), alongside the known headward fluid Levine recalled a group of patients from his Quantifying the effect of various shifts in microgravity, rang alarm bells with days as a medical resident whom had an changes in gravitational gradients concerns of raised intracranial pressure as Ommaya reservoir (catheter placed from the underlying mechanism of what was the lateral ventricle to a reservoir under the We set out to answer several fundamental initially termed Visual Impairment Intracranial scalp) inserted for the delivery of prophylactic research questions. The first question Pressure (VIIP) syndrome. However, like central nervous system chemotherapy as we asked was simply what happens to the great British detective Sherlock Holmes part of their treatment for haematologic intracranial, arterial and venous pressures advocates, “There is nothing more deceptive malignancy. In many of these patients, the with normal changes in posture on Earth? The than an obvious fact”. Thus, the space flight reservoir is left in place permanently, even second question we asked was how these community agreed that only through precise after complete recovery. Intracranial pressure regional pressures would be affected by long measurements of regional pressures in the can therefore be measured by placing a small periods of cephalad fluid shifts with simulated human body during both real and simulated butterfly needle into the reservoir while microgravity. The third question was how microgravity can the pathophysiological sutured securely to allow free movement intracranial, arterial and venous pressures

23 Figure 2. Typical set-up for a participant in a -6° head-down tilt bedrest study. (Image Credit: DLR).

change during freefall-generated acute (Fig. 3) and repeated the set-up protocol low and 8 hours in the supine posture during “microgravity” over the course of a series of and measurement procedures in a mock sleep where pressure is “relatively” high. With earthbound parabolic flights. Furthermore, environment for a week prior to each 24 hours on -6° head-down tilt bedrest, we wished to assess how these test campaign. Staffing each flight typically intracranial pressure changed minimally and conditions may be affected by the addition involved one participant, a study director, there was no hint of a progressive rise over of atmospheric carbon dioxide (0.7%, v/v) an ultrasonographer, a research nurse, a time. However, contrary to expectations, and resistance exercise, both of which may neurosurgeon and a research engineer with when lying down onboard parabolic flight, increase intracranial pressure on Earth and a typical participant schedule as follows: intracranial pressure actually fell as soon as during microgravity. the flight entered the microgravity phase Day 1: ~12:00 pm, pick up participant from of each parabola. Yet, although intracranial While we assessed the first question by Houston airport and obtain Ellington airfield pressure fell, it did not fall to values observed asking participants to change posture from badge identification; ~2:00 pm, individualised in the upright posture on Earth. Therefore, sitting upright to lying down while obtaining equipment set-up and subject familiarisation, when unaffected by Earth’s gravity, the relevant measurements, the two other ~5:00 pm, participant briefing on flight intracranial pressure is constantly in between questions required some thoughtful logistics procedures. the states of upright and supine postures and rehearsal. For example, the second found on Earth. Moreover, independent of question addressing the effects of protracted Day 2: 6:00 am, instrumentation of invasive gravitational load, exposure to a mild increase cephalad fluid shifts was assessed by placing pressure monitors; 7:00 am, equipment in atmospheric carbon dioxide added very participants on -6° head-down tilt bedrest check and calibration; 8:00 am, subject little to intracranial pressure, while resistance for 24 hours to simulate microgravity (Fig. 2). instrumentation with non-invasive devices; exercise only transiently elevated intracranial Whereas the third question was much more 8:30 am, pre-flight and medical briefing; pressure, not dissimilar to that observed on elaborate, as the participants needed to 9:00 am, board plane, take off and data Earth. Ultimately, if we consider a typical be secured to avoid free floating during acquisition; 12:00 pm, post-flight debrief; 24-hour day on Earth, intracranial pressure parabolic flight, but no pressure could be ~1:00 pm, participant tour of Johnson Space is likely relatively elevated in space, but applied to the abdomen, as this is known to Center, thereafter take participant to Houston pathologically high intracranial pressures, such increase both central venous and intracranial airport for departure. as those observed in patients with intracranial pressures. Moreover, performing resistance hypertension, are unlikely (Lawley et al., 2017). exercise without the counter force of gravity Is pressure in the brain elevated in is challenging. A typical flight campaign is space? It’s all relative Our findings uncovered the possibility that as flown over 4 – 5 consecutive days with one human evolution occurred under the constant flight per day. Prior to flight, all research The findings from the first series of studies pull of gravity, and humans habitually spend equipment needs to be stowed securely and showed that on Earth, intracranial pressure their waking hours upright with the brain once at a cruising altitude deployed, set- is high when lying down compared to sitting and eyes at the top of a long fluid column, up and calibrated in under a few minutes. upright. Thus, pressure in the brain on Earth the optical structures and their function may With the team at Wyle Laboratories, Inc, we during a typical day is split into roughly 16 require fluctuations in pressure and volume to built and set-up the necessary equipment hours in the upright posture where pressure is operate normally / optimally. However, this

24 Physiology News / Winter 2020 / Issue 117 (1) Design (2) Construction (3) Integration

(4) Implementation “Carrying the great weight of the world often symbolises disadvantageous consequences, but ... components of human physiology may actually require the interaction between Earth’s gravitational force and Figure 3. Pathway to performing integrative physiological experiments with zero gravity, carbon dioxide inhalation and resistance exercise onboard parabolic flight. habitual changes in posture to function raises a fourth perplexing question: why do Preserving astronauts’ visual acuity is an area participants who take part in long periods of of considerable concern for long-term space optimally” bedrest (up to 60 days) not report changes flight (i.e. manned mission to Mars) and a in their vision, as pressure in the brain would high-priority area of research for many space be relatively high and constant for the entire agencies. Therefore, experimental models of duration? We addressed this question by a SANS will be important for testing potential keen observation that during previous bedrest countermeasures, as well as investigating studies participants were typically allowed the pathophysiology and novel therapies a pillow to aid comfort (Fig 2), which means for Earthbound hypertensive and diabetic that while the heart is still -6° below the patients who develop optic disc oedema. feet, the head is elevated and experiences relative gravitational effects. We found that wadding even a very small pillow substantially reduces pressure in the brain in the -6° Justin S Lawley won The Journal of Physiology head-down tilt position, therefore providing Early Investigator Prize in 2017. See a list of a simple explanation for the lack of signs all winners here: bit.ly/380eWWm and symptoms of space-flight-associated neuro-ocular syndrome in previous bedrest studies. Indeed our observations were later verified by Laurieet al. (2019) who showed development of optic disc oedema and increased retinal thickness in subjects after References

30 days of strict -6° head-down tilt bedrest Laurie SS et al. (2019). Optic disc edema after 30 days without the use of a pillow or repositioning of strict head-down tilt bed rest. Ophthalmology 126(3), to eat during meals. 467 – 468. DOI: 10.1016/j.ophtha.2018.09.042

Lawley JS et al. (2017). Effect of gravity and microgravity Conclusion on intracranial pressure. The Journal of Physiology 595(6), 2115 – 2127. DOI: 10.1113/JP273557

Carrying the great weight of the world often Mader TH et al. (2011). Optic disc edema, globe symbolises disadvantageous consequences, flattening, choroidal folds, and hyperopic shifts but our publication in The Journal of observed in astronauts after long-duration space flight. Physiology (Lawley et al., 2017) highlights Ophthalmology 118(10), 2058 – 2069. that components of human physiology may DOI: 10.1016/j.ophtha.2011.06.021 actually require the interaction between Earth’s gravitational force and habitual changes in posture to function optimally.

25 Features

Space brain The adverse impact of deep space radiation exposure on the brain

Until recently, the effects on the brain of solar and galactic cosmic rays (GCR) at total doses (≤50 cGy) and dose rates (~1 mGy/day) that define the space radiation environment were unknown. Of the wide range of physiological stressors that astronauts would be exposed to during a deep space mission, this is perhaps the most concerning, as these radiation fields possess energies sufficient to penetrate the hull of the spacecraft and tissues of the body, leaving a wake of subcellular damage along the particle trajectories that can compromise the functionality of cells, tissues and organs. Space- relevant radiation exposure to the brain elicits a wide range of behavioral decrements in rodents, and has been shown to occur following a variety of exposure paradigms (radiation types, doses, dose rates) which poses certain concerns to NASA since with our current technology, there is no way to completely protect or shield Charles Limoli astronauts from space radiation.

University of California, USA To begin with, significant effort has been research. At that time, technical capabilities devoted to simulating space radiation on provided for exposures to single ion types Earth, which as one might imagine is not at various doses, but capabilities have a trivial undertaking. Most of our current advanced to allow delivery of combinations knowledge about the biological effects of of different ions on the same or different space radiation exposure have come from days. Another important advancement was studies conducted at the NASA Space the development of a larger, uniform field Radiation Laboratory (NSRL). The NSRL uses size that allowed investigators to irradiate beams of heavy ions extracted from the greater numbers of experimental models booster accelerator at Brookhaven National (e.g. cells, tissues, animals) at the same Laboratory (BNL) to simulate exposures to time. Moreover, an enhanced capability to various combinations of cosmic rays (see “switch” beam types and energies to provide Whittaker p.36). It is interesting to note how more realistic simulations of the space this state-of-the-art facility has evolved radiation environment was also developed. over the last 20 years during which time More recently, physicists at BNL have made NASA has funded researchers to unravel the the necessary advancements to provide a various biological consequences of exposure remarkably complex and realistic simulation to space radiation. NASA opening the NSRL of GCR; namely, sequential exposure of (circa 2003) that featured a dedicated multiple samples to a complex mixture of beam line for radiobiological studies 33 beams comprised of multiple ion types represented a massive step forward for and energies. The capability to deliver this

26 Physiology News / Winter 2020 / Issue 117 Figure 1. The beam line at NASA’s Space Radiation Research Laboratory (NSRL). Charged particles travel horizontally within the vacuum tube as they are propelled toward the target area by a series of magnets (left). The target area at the NSRL beam line can be configured to hold a variety of samples including shielding material, tissue culture flasks or animals within holders (shown at right). Upstream magnets and dosimeters provide for beam shaping, beam uniformity and dose quantification.

complex radiation field in a single day or even Behavioural and neurocognitive types used than that commonplace in clinical over weeks provides investigators with an changes triggered by cosmic radiation practice. Findings from multiple research labs unprecedented tool to determine the effects documenting widespread neurocognitive of the most realistic terrestrial-based GCR As the use of these highly sophisticated deficits spanning multiple regions of the simulation available on physiology. Some radiation facilities continues, what brain (e.g. hippocampal, medial prefrontal examples of the NSRL facility and a typical have scientists learned regarding the cortex, perirhinal cortex, among others) experimental set-up are shown in Fig. 1. consequences of space radiation exposure to suggest that whole-body exposures will elicit the brain? The answer is not good, at least widespread, network-level disruptions in As with most experimental set-ups involving for behavioral performance. Several studies neurotransmission. accelerator-based research, operational conducted using rodent models over the last logistics pose practical limitations that decade at BNL and more recently at the CSU Implementation of a variety of behavioral preclude operation of the NSRL around the neutron facility – implementing single ion, tasks designed over the years to interrogate clock. This necessitated a slightly different combined ions, or various versions of the the functionality of specific regions of the approach to more accurately simulate the most current GCR simulation – uncovered rodent brain have routinely uncovered cosmic- constant low dose rate environment of space. significant radiation-induced deficits in radiation-induced deficits when compared To this end, a neutron irradiation facility at learning, memory and distress behaviors to similarly treated, yet unexposed, cohorts. Colorado State University (CSU) has been (Parihar et al., 2015, 2016). If the results As cognitive data sets have accumulated, built that implements the radioactive isotope hold true for humans, which neurocognitive some surprises have emerged. For one, 252Californium (252Cf) to allow long-term, data from the NASA Twins Study indeed neurocognitive outcomes measured after a chronic exposures at realistic dose rates. suggest may be the case (Garrett-Bakelman variety of exposure paradigms do not show In this instance, the experimental setup is et al., 2019; see p. 16), it may influence an a strong dependence upon radiation quality, rather distinct from that at the NSRL, where astronaut’s ability to adapt and respond to a term that reflects the energy deposition the radioactive 252Cf source is raised and unexpected or stressful situations during and ionisation pattern that a given type of lowered within a lead-shielded compartment the near complete autonomy of deep space radiation causes within a cell. Moreover, to bathe a room with neutron and photon travel. Clearly, this is an undesired outcome there are ill-defined dose-responses in the irradiation. Experimental models can be and could jeopardise astronaut safety and low dose range (≤50 cGy) that would be arranged in an annulus around the source at a mission success. representative of the accumulated absorbed defined distance that prescribes the desired dose on a mission, for instance, to Mars. dose rate. The source is raised while the Radiation-induced cognitive dysfunction Given these low doses, most of the CNS samples accumulate the desired dose but can has been a bane for clinicians engaged effects are unlikely to result from overt cell be lowered for animal husbandry purposes. in the radiotherapeutic management of death. Cosmic-radiation-induced cognitive With this system, researchers now have CNS malignancies for decades. While dysfunction is also persistent, and shows at their disposal a new-found capability to cranial radiotherapy has proven useful little signs of improvement, at least over the expose specimens over the course of several for forestalling brain tumor growth, the timeframe of most published studies (3 to 12 months to low radiation dose rates that progressive and debilitating cognitive deficits months). The lack of dependence on radiation simulate many of the dosimetric qualities of resulting from such brain tumor treatments quality and total radiation dose, as well as the the space radiation environment. An example have remained an unmet medical need for persistence of such cognitive deficits found of the neutron irradiation facility at CSU and decades. This reality has foreshadowed in rodent studies, have brought to question typical cage arrangement surrounding the many of the findings uncovered by NASA precisely what the critical radiation-sensitive 252Cf source is shown in Fig. 2. investigators despite much lower total target in the brain is. radiation doses and much different radiation

27 “[While] galactic cosmic ray exposure [is thought] to be a significant obstacle to deep space travel, it should not be viewed as a deal breaker for the long- term presence of humans in space” Figure 2. The neutron irradiation facility at CSU. Shown are the annular arrangement of rodent cages around the lead-shielded 252Cf source that can be lowered and raised for maintenance and animal husbandry procedures. The arrangement of the cages can be modified to accommodate a variety of samples and configurations, and depending on the actual distance from the source, dose rates can be adjusted accordingly.

A B

C D

Figure 3. Fluorescent images of hippocampal neurons. Dendritic branching in unirradiated controls (A) is more extensive and complex compared to the dendritic structure of neurons subjected to 30 cGy of silicon ions and analysed 1 month following exposure (B). Similarly, higher-magnification images of the dendritic tree reveal that the density of dendritic spines (visualised as protuberances from the dendritic shaft) is much higher in the unirradiated (C) versus irradiated brain (D). Data such as these have revealed that space radiation exposure compromises the structure of neurons at many levels.

28 Physiology News / Winter 2020 / Issue 117 Cosmic radiation-induced structural communication within the irradiated brain for deep space radiation exposure to alterations in the brain and promoting the onset of cognitive compromise neurocognitive functionality dysfunction. presents a concern it also represents a While the foregoing highlights some of the challenge that can be overcome. With complexities and paradoxes surrounding Neuroprotection in space? proper knowledge, motivation and resource the functional responses of the space- allocation, deep space exploration can be irradiated brain, or “Space Brain”, some hints What recourse does NASA and humanity undertaken with acceptable risk. Despite at the underlying mechanisms have been have in protecting the brain and overall the known and the unknown risks of “Space uncovered. Past work from us and others health of astronauts exposed to space Brain”, humankind will persevere and continue has found that mature neuronal populations radiation? At present, two approaches are the exploration of the cosmos. in the brain are subject to radiation-induced the most promising for limiting the adverse structural alterations. Dendrites of many health effects of cosmic radiation exposure. different subclasses of neurons are thin The first and perhaps most obvious involves projections that interconnect to other improvements in radiation shielding. While neurons and mediate neurotransmission. cost and technology limit the payloads we Cosmic radiation exposure has been shown to can launch into space, a problem that may compromise the integrity of these structures in part be resolved by manufacturing and References leading to marked and persistent reductions assembling shielding materials in space at Dickstein DL et al. (2018). Alterations in synaptic in the length, branching and overall orbiting gateways, the fundamental problem plasticity and myelination in response to exposure complexity of the dendritic tree (Parihar remains, namely increasing the number of to high-energy charged particles. The Journal of et al., 2015, 2016). Dendritic spines that nuclei in between the cosmos and the body Comparative Neurology 526(17), 2845 – 2855. decorate the length of dendrites represent of an astronaut. In the end, this equates to DOI: 10.1002/cne.24530 the structural correlates of learning and increasing hull thickness and/or redistributing Garrett-Bakelman FE et al. (2019). The NASA Twins memory and contain the synaptic machinery the payload cargo (e.g. instrumentation, Study: A multidimensional analysis of a year-long that mediates neurotransmission. Cosmic food and water) within the ship to provide human spaceflight.Science 364(6436), eaau8650. radiation exposure causes dramatic more optimised regions of minimal radiation DOI: 10.1126/science.aau8650 reductions in dendritic spine density, exposure. More advanced engineering along with drops in synapse density and options are certainly under development Limoli CL (2017). Deep-space deal breaker. axonal myelination – all factors that can of which specialised space helmets may be Scientific American 316(2), 54 – 59. DOI: 10.1038/scientificamerican0217-54 compromise neurotransmission and cognition particularly important for neuroprotection. (Parihar et al., 2015, 2016; Dickstein et al., Parihar VK et al. (2015). What happens to your 2018). Examples of some radiation-induced The second approach involves identifying brain on the way to Mars. Science Advances 1(4), structural changes to neurons are shown in pharmacologic/dietary countermeasures e1400256. DOI: 10.1126/sciadv.1400256 Fig. 3. for protecting the brain and the rest of the Parihar VK et al. (2016). Cosmic radiation exposure body against radiation-induced normal tissue and persistent cognitive dysfunction. Scientific Coincident with the structural alterations toxicities. This is a multifaceted approach Reports 6, 34774. DOI: 10.1038/srep34774 are increases in neuroinflammation, where that is limited in part, as with other aspects Parihar VK et al. (2018). Persistent nature of cosmic-radiation-induced elevations in of the space program, by practicality and alterations in cognition and neuronal circuit microglia serve to perpetuate the footprint resources. At this juncture, NASA is not excitability after exposure to simulated cosmic of radiation injury in the CNS (Parihar et al., in the business of drug development and radiation in mice. Experimental Neurology 305, 2016). Activated microglia can actively re- is better suited to an approach aimed at 44 – 55. DOI: 10.1016/j.expneurol.2018.03.009 shape and prune the dendritic landscape and identifying and/or repurposing an agent trigger inflammatory cascades that disrupt already known to be safe and efficacious the delicate balance between excitatory for an alternative indication. Current and inhibitory signaling in the irradiated brain. research is actively exploring compounds The fact that inflammation remains elevated possessing antioxidant, anti-inflammatory over extended post-irradiation times and metabolic enhancement properties that (≤12 months) suggest this to be contributory have shown some promise in rodent models if not causal to many of the cognitive at reducing radiation-induced complications decrements observed in rodents exposed to in the brain and peripheral tissues. cosmic radiation. Adjusting diets to include foods containing many of the aforementioned properties At the electrophysiological level, circuits represents a complementary approach. connecting the neurons into networks While further studies are clearly needed, a have been found to operate less efficiently. combination of pharmacologic and/or dietary Intrinsic cell properties were altered, countermeasures along with enhanced communication between individual cells shielding should provide some meaningful was disrupted and memory facilitation mitigation to the radiation problems inherent along defined networks was impaired, to deep space travel. with a collective and adverse impact on neurotransmission at multiple levels While the work from our laboratory and that (Parihar et al., 2018). Resultant perturbations of our colleagues implicate GCR exposure to to oscillatory circuits, broken connections in be a significant obstacle to deep space travel, combination with altered neurotransmitter it should not be viewed as a deal breaker for availability, radiation-induced oxidative the long-term presence of humans in space stress and changes in lipid oxidation are (Limoli, 2017). Research identifies risks and all additional factors identified by various uncertainties and provides for contingencies, investigators that could conceivably play thereby minimising the adverse impact of significant roles in disrupting electrical unexpected events. While the potential

29 Features

May the (Gz) force be with you Gravity and human space exploration

Whether discovering how cells sense oxygen and adapt to its availability (a discovery awarded the 2019 Nobel prize in Physiology or Medicine), or exploring new continents, exploration and discovery are probably among the most exciting human endeavours. How else would Shackleton have assembled a ship’s complement for the Endurance to explore the Antarctic based on the following advertisement (Time, 2003):

“Men wanted for hazardous journey. Small wages, bitter cold, long months of complete darkness, constant danger, safe return doubtful. Honour and recognition in case of success.”

Since Gagarin’s 108-minute orbital that a diet of citrus fruits prevented and flight in 1961, the investment in space cured scurvy, a disease that afflicted sailors research and technology has allowed us exploring the newly discovered continents. to visit the Moon on several occasions, His discovery drastically reduced the number and in this century to maintain a constant of scurvy-associated deaths, not just Igor Mekjavic aboard one of among the explorers, but also among the the most complex structures assembled general population. Similarly, our current Jozef Stefan Institute, by an international community of scientists preparations for the exploration of the Moon Ljubljana, Slovenia and engineers. This century will witness and Mars can only continue unimpaired with the establishment of human settlements an understanding of the effects of space on the Moon and Mars. The research travel on physiological systems, and with programme coordinated by the Human the development of suitable measures and and Robotic Exploration section of the strategies to counter the pathophysiological European Space Agency explores the many consequences of prolonged space travel that facets of travelling in deep space on human may ultimately lead to the colonisation of the physiological systems. Research in aid of Moon and Mars. deep space travel and colonisation of Mars should not be viewed from the perspective Withdrawal of the head-to-foot gravitational

of the handful of astronauts, who will vector (Gz) induces adaptations in all undertake these missions, but from the physiological systems (i.e. loss of skeletal potential of harnessing the knowledge to muscle mass, bone demineralisation, help specific Earth-bound populations. An haemodynamic changes, etc.) (see Norsk analogy of the translational nature of life p. 40; Rittweger, Frings-Meuthen, 2013; sciences aiding explorers venturing into McDonnell et al., 2019). Safe return to extreme environments can be found in the Earth’s gravitational field relies on the work of Scottish physician James Lind (1753), prevention of these potentially harmful who worked as chief physician of the Royal adaptations. The initial focus of space Naval Hospital at Gosport. He demonstrated physiology research has been understanding

30 Physiology News / Winter 2020 / Issue 117 390 km/h 8,500 m

650 km/h 7,500 m 47˚ 47˚ 650 km/h

810 km/h 810 km/h

6,500 m Steady Horizontal Steady Horizontal Flight Hypergravity Microgravity Hypergravity Flight 1 g 1.5 – 1.8 g 0 g 1.5 – 1.8 g 1 g 20 Seconds 20 Seconds 20 Seconds

Figure 1. Studies during parabolic flight manoeuvres. The upper panel shows the flight pattern of the Airbus during one parabola (photo: ESA). The zenith of the parabola offers 20 seconds of microgravity. The lower panel depicts human motor-control experiments in zero-gravity environment investigating how the brain encodes gravity and how we can prepare astronauts for the challenging environment during and after space flight (photo courtesy ESA). Principal investigator: Jan Babič, Jozef Stefan Institute, Slovenia.

the process of microgravity-induced maintaining their health and well-being, of microgravity (although this varies adaptations, and this has been followed by and ensuring a safe return to Earth as depending on the flight pattern). The “vomit research investigating mitigating strategies suggested by Herman Noordung 90 years comet”, as it used to be called prior to the (i.e. exercise, nutrition, etc.). Establishment ago (Noordung, 1929). Regarding this, introduction of pre-flight anti-motion- of a permanent presence on the Moon and the ESA has established a 5-year research sickness medication, conducts parabolas Mars will, for logistical reasons, require that programme to investigate the manner in whereby the Airbus “laboratory” ascends the internal environment of habitats be which artificial gravity (using short-arm from 6,000 m to 8,500 m and back again, hypobaric and hypoxic (as discussed later in human centrifuges) can be employed in conducting this several times in succession. the text). As a consequence, one focus of mitigating maladaptation to microgravity. During the zenith of the parabolas Space Life Sciences research has been on passengers experience brief periods of the effect of hypoxia on the microgravity- Earth analogues microgravity during which they can conduct induced adaptations observed in normobaric their experiments. During the nadirs of normoxia. Parabolic flights the parabolas, there is an increase in the Despite the limited opportunities to conduct gravitational force. By altering the angle of Despite the many countermeasures experiments in space, Space Life Sciences attack of the flight pattern (i.e. parabolas) developed to prevent adaptation to micro- have been able to progress due to the many the flight can also simulate Mars (38% Earth’s (during space travel and sojourns on the ground (Earth)-based research facilities gravity) and Moon (17% Earth’s gravity) International Space Station) and reduced- that offer valid simulations of the effects gravity. This may be sufficient to examine (during sojourns on the Moon and Mars) of microgravity on human physiological some acute effects of microgravity and gravity, it is now apparent that intermittent systems. The most well known of these reduced gravity, but certainly not sufficient exposure of astronauts to artificial gravity facilities are the parabolic flights (Fig. 1), to gain insight into the effects of prolonged might be the most efficient solution for which offer up to approximately 20 seconds exposure to microgravity.

31 Figure 2. The Nordic Centre Planica in the Tamar valley (Rateče, Slovenia). The Jozef Stefan Institute Planetary Habitat (PlanHab) Laboratory (ESA ground-based research facility) is located at the Olympic Sport Centre visible in the lower left-hand corner (photo courtesy of the Nordic Centre Planica).

Bed rest experimental model Concordia Antarctic Research Station decompression procedures required when As astronauts continued to extend their A major issue in spaceflight is the extended exiting a normobaric habitat. To prevent sojourns in space, the adaptations to confinement in small quarters which need to decompression sickness during current weightlessness became more apparent. As be shared by the entire crew. Such conditions extravehicular activities (EVAs), as a result in other extreme environments, such as heat place a large strain on the psychological of the transfer from the 1 ATA environment and altitude, all physiological systems were status of the crew members. This strain is of the International Space Station to the observed to adapt to the 0 G environment, not so evident in the bed rest models, as pressure within the space suit (about but the kinetics of the adaptation varied. The there is constant interaction with the medical 1/3 of an atmosphere), the astronauts adaptations to weightlessness were very similar staff and researchers. As a consequence, ESA prebreathe oxygen during a slow and gradual to the adaptations observed in healthy adults has partnered with the Italian (Programma decompression, a procedure that requires rendered inactive and confined to bed for the Nazionale di Ricerche in Antartide) and several hours and the assistance of the same duration (Sandler and Vernikos, 1986). French (Institut polaire français Paul-Émile remaining crew. This protocol is logistically Thus was born the bed rest experimental Victor) research facility Concordia Antarctic not practical, and by maintaining a hypobaric model, which could be used on Earth to study Research Station. Scientists now have access environment, the astronauts will be able to the process of adaptation of physiological to the volunteers within the over-winter transfer from within the habitats to the suit systems to microgravity. In these studies, crews to study their health and well-being without the need for lengthy and complex subjects are rendered inactive and their during their one-year assignments at the decompression procedures. However, weight-bearing limbs unloaded by confining station. hypoxia induced by such a hypobaric them to horizontal bed rest for extended environment will be too severe, and the periods (up to several months). To increase the Planetary habitats fraction of oxygen may be elevated to fidelity of the Earth-based analogue, and make prevent the deleterious effects of hypoxia life more interesting for the subjects, some bed The Concordia Antarctic Research Station at such a simulated altitude. It is envisaged rests are performed with the head in the -6° is situated at an altitude of 3,200 m, that the partial pressure of oxygen within head-down tilt, as this causes a headward shift which introduces the element of hypoxia the habitats will be equivalent to altitudes of body fluids, giving rise to the appearance in all observations. This has proven to be between 3,000 m and 4,000 m. As a result of a “puffy face”, as seen in astronauts. In a favourable coincidence, as hypobaric of this development, recent research at the Europe, bed rest facilities supported by ESA and hypoxic environments are now Planica facility in Slovenia (Olympic Sport are the Institut Médecine Physiologie Spatiale being considered within future planetary Centre Planica) has focused on the issue – MEDES (Toulouse, France), Deutsches habitats (and possibly vehicles). The main of the manner in which hypoxia affects Zentrum für Luft- und Raumfahrt – DLR (Koln, reason for this new strategy in the design the process of adaptation of physiological Germany), and Olympic Sport Centre Planica – of habitats is the concern regarding the systems to bed rest (Fig. 2). To date, all PlanHab (Rateče, Planica). potential deleterious effect of frequent other bed rest studies have been conducted

32 Physiology News / Winter 2020 / Issue 117 Figure 3. Short-arm human centrifuge to be installed in the Planetary Habitat (PlanHab) Laboratory at the Olympic Sport Centre Planica. Photo courtesy of European Space Agency.

in normoxic environments, whereas the (Olympic Sport Centre Planica, Slovenia) Life science on Earth for life in space ongoing bed rest studies in Planica have will host 60-day bed rests investigating the (and on the Moon and Mars) examined these processes in hypoxia. As efficacy of artificial gravity in combination with would be anticipated, there are benefits of exercise, nutritional strategies and hypoxia The principal aim of ESA is to support science adaptation to a hypoxic environment in some in mitigating inactivity/unloading-induced in space in support of humans on Earth responses, and not so in others. changes to the physiological systems (Fig. 3). (Life in Space for life on Earth). However, our research endeavours on Earth are not Countermeasures Of the many factors that influence the health only crucial for our continued exploration of and well-being of astronauts during space space, but will also be of relevance to specific A major cornerstone of Space Life Sciences travel, and will impact on them during their populations on Earth. research is the development and assessment life on the Moon and Mars, two critical areas of measures that would counteract remain unresolved. The first is the effect The current lifestyle of a significant portion the cardiorespiratory, musculoskeletal, of solar and galactic cosmic radiation (see of the population in Western societies neurohumoral, etc., adaptation to microgravity. Limoli p. 26; Whittaker p. 36). This will most favours inactivity, which is often coupled As a consequence of these efforts resulting likely need to be resolved with appropriate with unloading of the lower limbs. The from ground-based (bed rest) studies, shielding (underground habitats perhaps). similarity between this and the bed rest astronauts have a comprehensive schedule The second is the unexplained loss of vision exposure is obvious, and the consequences of resistance training and aerobic exercise, in astronauts exposed to microgravity for are similar. The difference is that the subjects coupled with a regulated diet. Despite the prolonged periods, which has been termed in bed rest may revert to a more active relative success of these countermeasures, Spaceflight-associated neuro-ocular lifestyle once the experiment is complete. ESA is considering implementing short-arm syndrome (SANS) (see Lawley and Levine These studies have catalogued the rate of human centrifuges on board vehicles on deep p. 22). It is most likely attributed to the change in the structure and function of space missions to provide astronauts with increase in intracranial pressure, which physiological systems, and extrapolation intermittent and short-term artificial gravity. impacts the intraocular pressure, causing of the results to a younger population with A programme of research opportunities will morphological and functional changes in the inactive lifestyles yields alarming predictions. be announced by ESA shortly, to focus on eye. Ongoing experiments in our laboratory Based on her experience in coordinating Life the efficacy of artificial gravity, or rather the suggest that the resistance exercise coupled Sciences studies at NASA, Joan Vernikos optimal exposure to a gravitational load in with the hypercapnic environment (due to (2011) coined the phrase Gravity deprivation order to prevent the microgravity-induced inefficient capacity of the CO2 scrubbers, the syndrome, to encompass all of the adaptations. The previously mentioned ESA fraction of CO2 may be 15 to 20 times that detrimental effects of an inactive lifestyle, ground-based facilities in Toulouse (MEDES, on Earth) of the ISS may contribute to the resulting in a reduction/elimination of the France), Koln (DLR; Germany) and Planica aetiology of SANS (Fig. 4). head-to-foot gravitational force (Gz).

33 Mae he os o your eership

Figure 4. Assessment of the separate and combined effects of bed rest, hypoxia and hypercapnia on the retinal layers using optical coherence tomography, OCT (left panel) and intraocular pressure in the prone -6° head-down tilt position (right panel). PI: Polona Jaki Mekjavic, University of Ljubljana Medical Faculty & University Medical Centre Eye Clinic, Slovenia.

Recent bed rest studies confining healthy with statistical procedures. “Outliers” and individuals to inactivity and hypoxia provide “non-responders” are normally the bane of insight into illnesses which render the patient many theses and reports. Understanding such References similarly inactive and hypoxic, such as individual variability in physiological responses Atkinson G, Batterham AM (2015). True and false chronic obstructive pulmonary disease. The has now sparked researchers to gain a interindividual differences in the physiological importance of such studies was elegantly better understanding of the magnitude of response to an intervention. Experimental Physiology summarised by Harriet Tuckey in her anticipated variability and the source of such 100(6), 577 – 588. DOI: 10.1113/EP085070 biography of her father (Tuckey, 2013), one variability (Atkinson and Batterham, 2015). Lind J (1753). A Treatise of the Scurvy in Three Parts. of the most prominent Extreme Environment ESA has tasked a consortium of physiologists Containing an Inquiry into the Nature, Causes, and physiologists, Griffith Pugh: to investigate individual variability of the Cure, of that Disease; Together with a Critical and physiological responses to bed rest to better Chronological View of what has been published on the “Lowland people suffering from chronic understand why some individuals are more Subject. 1st ed. Edinburgh: A. Kincaid and A. Donaldson. egisraio opens for 3 steps pply for a esearch Grant of up illnesses such as heart disease, bronchitis, and resilient to the effect of inactivity/unloading DOI: 10.1017/CBO9781107256644 to career success: a webinar series to 10,000 by 2 February emphysema lived with long-term deprivation than others1. This knowledge will be of benefit McDonnell AC et al. (2019). The LunHab project: for early career researchers on of oxygen. Lacking a comprehensive in determining crew members for prolonged Muscle and bone alterations in male participants understanding of what happens to the space flights, since it would allow choosing following a 10 day lunar habitat simulation. Exp January ropose a echniues orkshop healthy body when deprived of oxygen over candidates who would exhibit a lesser degree Physiol 104, 1250 – 1261. DOI: 10.1113/EP087482 a long period, it was hard for physicians of musculoskeletal atrophy and cardiovascular for 2020 by 31 arch Noordung H (1929). Das Problem der Befahrung des to distinguish which of their symptoms deconditioning. This knowledge is the basis of Weltraums. Berlin: Richard Carl Schmidt & Co. pply for funding to carry out were caused by their bodies adapting – the new field of personalised medicine. ‘acclimatising’ – to the shortage of oxygen Rittweger J, Frings-Meuthen P (2013). Bone loss a summer research proect by ig up to host a summer placement and which were the direct result of their As with the pioneering work of Lind, Space in microgravity. Physiology News 92, 38 – 41. DOI: 10.36866/pn.92.38 2 February for a 1yearold by 1 pril illnesses. Anaesthetists handling patients Life Sciences research may be initiated to in intensive care also required a better support human exploration, but the results Sandler H, Vernikos J (1986). Inactivity: Physiological understanding of the impact of oxygen lack on of the discoveries will aid many Earth-bound effects. Orlando, FL (USA): Academic Press Inc. the healthy body, as did engineers designing populations (particularly those suffering from DOI: 10.1016/b978-0-12-618510-2.x5001-5 pressurisation and oxygen equipment for high- sarcopenia, osteoporosis, inactivity, hypoxia, Time (2003). The Great Survivor: Ernest Shackleton. flying aircraft and space capsules.” etc.). This century will introduce a new era [Online] Time. Available at: http://content.time.com/ of human space exploration, the success time/specials/packages/ isit .physoc.org to learn more about your membership The physiological aspects of of which will, to a large degree, depend on Tuckey H (2013). Everest. The First Ascent. The crew selection upcoming generations of physiologists. Untold Story of Griffith Pugh, the Man who made it Possible. London, UK: Random House Group Ltd. We tend to report the physiological responses Vernikos J (2011). Sitting Kills, Moving Heals. How of subjects exposed to an experimental Simple Everyday Movement will Prevent Pain, Illness, intervention, such as bed rest, as averages and Early Death – and Exercise Alone Won’t. Fresno, psoc with standard deviations from the mean. 1ESA Contract No. 4000124642/18/NL/PG/gm: CA (USA): Quill Driver Books. eershipphysoc.org A requirement necessitated by the ability Individual variation in human responses to prolonged bed eoc to compare the effect of these responses rest in Slovene bed rest programme. 020 2 50 .physoc.org soc

34 Physiology News / Winter 2020 / Issue 117

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egisraio opens for 3 steps pply for a esearch Grant of up to career success: a webinar series to 10,000 by 2 February for early career researchers on January ropose a echniues orkshop for 2020 by 31 arch pply for funding to carry out a summer research proect by ig up to host a summer placement 2 February for a 1yearold by 1 pril

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The invisible space killers The dangers of space radiation from both inside and outside the solar system

When we talk about dangerous radiation on Earth the public generally think of short-wavelength electromagnetic radiation such as X-rays and gamma rays. While there are many environmental challenges to the physiology of space travellers, the biggest danger comes from ionising high-energy particles which literally “punch” through spacecraft shielding and cause numerous problems for the human body. But where does this radiation come from and how much danger is there?

Even before the advent of the space race, Of course, even without radiation there are there was interest in exploring far-off multiple challenges to the human body during worlds. This included an application form spaceflight and time off planet, including for an interplanetary tour reservation in muscle loss and a decrease in bone density, the magazine “Popular Science Monthly” in as well as less obvious stressors such as the August 1952. The names and addresses were change in the day/night cycle and the effect to be kept on file at Hayden Planetarium this can have on circadian rhythms. The ready for the first space trip. The form human body is conditioned to live on Earth Ian Whittaker even had checkboxes for which planets the well, but in any other environment, pressure applicant wanted to visit! Since then there and thermal control will be needed to survive. Nottingham Trent University, UK have been visits to the moon in the 1960s Meaning humans will always have to be and 1970s, and plans to return to the moon enclosed in some way, whether a capsule, in every decade since. base, or spacesuit.

The idea of a human presence on Mars An important first step then is to understand was first suggested by Wernher von Braun the health risks involved in space travel due in 1948 and has been the goal of space to radiation; this will aid in the development agencies ever since (Zubrin and Baker, 1991; of appropriate shielding and allow maximum Williamson, 2017). This destination is travel times for future space missions. significantly more difficult to reach than the Moon due to the travel time and increased The sun as a source of danger fuel required. The time factor means that potential Martian visitors spend longer in a The sun produces a wide range of very dangerous environment. electromagnetic radiation with a peak in the visible region (specifically yellow). The short, The main risk to human health during wavelength emission changes through the spaceflight is ionising radiation exposure, solar cycle though; a process in which the which has been well established as a cause sun goes from having a magnetic field like a of enhancing degenerative tissue defects bar magnet, to having a looped and twisted when leaving the protection of the Earth’s magnetic field at solar maximum, at roughly atmosphere and magnetic field. five and a half years later. The sun then

36 Physiology News / Winter 2020 / Issue 117 “A specific proton event in 1972 was calculated to result in absorbed dose rates of 1.4 Gy/h. An astronaut exposed to this event would develop radiation sickness within half an hour of exposure and, probably, neurovascular death within 14 hours of exposure.”

Figure 1. An EIT 304 Angstrom and LASCO C2 composite image showing a widely spreading coronal mass ejection as it blasts more than a billion tons of matter out into space at millions of kilometres per hour. [Image Credit: NASA/GSFC/SOHO/ESA].

returns to the bar magnet configuration over roughly $2 trillion USD. While these events counter and was designed to measure cosmic another five and a half years. are rare, they pose a serious risk to humans in radiation; discovering the radiation belts was a space as the Earth’s magnetic field is not there complete accident! At solar maximum, areas of the sun called to protect them. active regions are observed that build up solar These radiation belts exist because charged material before ejecting them out into the A CME can also be accompanied by the particles get trapped within two distinct solar system. Typically, we see this as a solar emission of highly energetic protons, termed regions of the Earth’s magnetic field at high flare which includes a large burst of X-rays. a Solar Proton Event or Solar Particle Event altitudes, these generally sit at between 700 These flares can produce X-rays up to 10% (Fig. 1 and 2). These protons are accelerated and 10,000 km above the equator (inner of the sun’s total brightness. While these can up to several GeV (a speed very close to the belt) and between 13,000 and 60,000 vary, an expected radiation dose is roughly speed of light), and these events can last km above the equator (outer belt) The 0.05 Gray due to the very short time of from a few hours to several days. A specific altitudes are given above the equator as the burst of emission (Thirupathaiah et al., proton event in 1972 was calculated to they come closer to the surface at increasing 2019), not enough to be imminently lethal on result in absorbed dose rates of 1.4 Gy/h latitude. The outer belt is also significantly its own. (Parsons and Townsend, 2000). An astronaut more dangerous than the inner belt. As exposed to this event would develop radiation the particles bounce back and forth along Far more dangerous are the particles which sickness within half an hour of exposure and, the field lines they increase in speed and follow such an event called a coronal mass probably, neurovascular death within 14 hours become dangerous. Solar activity and CME ejection (CME) (Fig. 1). These are very dense of exposure. impact can rapidly increase the danger of clouds of solar material (primarily hydrogen the radiation belts to astronauts. Especially and helium, but many heavier elements are This is immensely scary as there is very little as high solar activity can move the radiation present too) emitted at the same time as that astronauts can do to protect themselves. belts radially inwards and outwards from the the flare. However, while it takes only a few These are directed beams though and – Earth, depending on the strength of the solar minutes for the X-rays to reach Earth, the because of the distance from the sun to the magnetic field. Normally, these radiation CME takes from two to four days to arrive. Earth – an astronaut would have to be very belts produce only the equivalent dose of The impact of CMEs on Earth have been unlucky to be hit continuously by this form a medical X-ray for a spacecraft travelling responsible for massive infrastructure damage of radiation. through them in as short a path as possible due to ground-induced currents. Our ability to (on average ~70 mGy a day). The danger predict these types of events are still limited. The Earth surely only protects us? comes from either staying too long in one of For instance, an immensely strong CME in these belts or travelling during a solar storm. 2012 which narrowly missed the Earth was Another source of ionising radiation is actually For unmanned high-altitude satellites which only detected because it hit a near-Earth generated on the Earth. The Van Allen orbit through the radiation belts this radiation solar observing satellite (Ngwira et al., 2013). radiation belts were first discovered in 1958 is mitigated by switching all equipment The predicted infrastructure damage if this when the Satellite Explorer 1 was launched off and lowering thick shielding to reduce had been a direct event is estimated to be (Fig. 3). This satellite had an on-board Geiger instrument damage.

37 Figure 2. Earth’s magnetic field (pale blue lines) provides shielding from both the sun and distant cosmic events such as supernova explosions which constantly shower the earth with charged particles, so-called solar energetic particles (grey lines and yellow arrows) and galactic cosmic rays (purple lines and red arrows), respectively. [Image Credit: NASA/JPL-Caltech/SwRI].

Figure 3. The Van Allen Belts are giant swaths of radiation, shown here in yellow, with green representing the spaces between the belts. In 2012, observations from the Van Allen Probes showed that a transient third belt can sometimes appear between the inner and outer belts depending on solar activity. [Image Credit: NASA/Van Allen Probes/Goddard Space Flight Center].

38 Physiology News / Winter 2020 / Issue 117 The dangers of the radiation belts were bases as the moon has no atmosphere to An alternative to shielding is active magnetic known before the Apollo missions were protect it either. field protection. This may seem like a sci-fi launched and the mitigation method was to concept but research has been ongoing since just get through them as fast as possible. The risk for astronauts from GCR is a heavily the 1960’s in this field. The idea of a magnetic There have been near misses. For instance, studied topic, and current guidelines suggest shield works well against solar proton events one of the strongest solar events observed that astronauts should not receive more but models suggest it is largely useless occurred in August 1972 between the than a 3% lifetime excess risk of cancer against GCR. A design from the late 1970s launches of Apollo 16 and Apollo 17. If mortality. A study by Cucinotta and Durante intended to use a magnetic field to protect the launch of either had been moved by a (2006) gave the percentage of this fatal against GCR and calculated that the shield few months it could have resulted in a fatal risk allowance being achieved in different would weigh more than 1 million tons, and accident. The Apollo 11 capsule returned scenarios. In the case of a 180-day lunar was 100 m square in size (Paluszek, 1978)! on 24 July 1969 and the radiation belts had mission, the lifetime excess risk from GCR Something largely impractical for a spacecraft been quiet during the trip; but a geomagnetic is relatively low at an average 0.7%. In but potentially possible for a colonisation storm which occurred only two days later comparison, a Mars exploration mission of attempt. could have given a very different end to the 1,000 days (allowing roughly one year on astronauts if they had been delayed at any the surface) gave an average risk of 4.6%, For short-term missions, the risks to point in the mission. suggesting one in every 20 missions could be astronauts are relatively low. When we want fatal without protection! to explore further afield, the health risk Cosmic rays from radiation will increase tremendously. Mitigating the danger While new solutions are being researched, Galactic Cosmic Rays (GCR) is the final no specific mitigation method is currently source of ionising radiation in our solar The best approach to avoiding space radiation available; the protection of our space system, and the only one to originate outside is simply to not be there. Travelling to other explorers should be our primary concern as (Fig. 1). GCR are very energetic particles bodies in the solar system is not a simple we move into the era of planetary visits and which are thought to be ejected from concept as straight-line travel is close to commercial space flights. supernovae and collapsing stars, and consist impossible. To reach the moon or another mostly of protons and alpha particles (which planet the most fuel-efficient path involves are ionisied helium atoms); the rarer heavier performing many orbits of varying shape, until ions are referred to as HZE (literally high the target is reached (known as Hohmann [H] atomic [Z] energy [E]) particles, which transfers). Any spacecraft starts by orbiting are heavier high-energy charged elements, the Earth, requiring no fuel once the orbit is moving at relativistic speeds which have been reached, firing rockets at any point turns your References completely ionised. orbit more or less elliptical depending on the direction of thrust. The orbit transfer process Cucinotta FA, Durante M (2006). Cancer risk from The rate at which GCR arrive in the solar makes this ellipse large enough to encompass exposure to galactic cosmic rays: implications for space system also depends on our solar activity. both the Earth and the target then reduce exploration by human beings. Lancet Oncology 7, Towards solar maximum, the magnetic fields the size of the orbit to only include the 431 – 435. DOI: 10.1016/S1470-2045(06)70695-7. of the sun flow outwards faster, which acts target object. This process takes a lot of Ngwira CM et al. (2013). Simulation of the 23 July to deflect GCR away from us and makes the time; thus, increasing the risk of exposure for 2012 extreme event: What if this solar system safer. As previously mentioned anybody onboard. extremely rare CME was Earth directed? Space Weather though, solar maximum is when the most 11, 671 – 679. DOI: 10.1002/2013SW000990. solar energetic particle events occur so there Shielding is employed in most space missions, Paluszek MA (1978). Magnetic radiation shielding is a risk with whatever part of the solar cycle but only limited amounts can be installed for permanent space habitats. The industrialisation of you choose to travel in. due to the weight. To reach orbit from a space: Proceedings of the twenty-third annual meeting. planetary surface using current technology, American Astronautical Society. 36, 545 – 574. We are largely protected from the worst a rocket has to be mostly fuel with only a effects of GCR by our dense atmosphere on very limited weight allowance for the payload Parsons JL, Townsend LW (2000). Interplanetary crew dose rates for the August 1972 solar particle event. Earth. The discovery of cosmic rays was made (in this case humans and their capsule). This Radiation Research 153, 729 – 733. DOI: 10.1667/ in 1912 during a high-altitude balloon flight weight budgeting results in most shielding 0033-7587(2000)153[0729:icdrft]2.0.co;2. and ever since then high-altitude balloons being a thin layer (10s of mm) of aluminium have been used to measure the level of GCR. as it is one of the lightest shielding materials Thirupathaiah P et al. (2019). Characteristics of Although, what the balloons are measuring available. The thickness of the shielding is solar X-ray flares and their effects on the is not in fact the rays themselves but the the biggest factor in human protection, the ionosphere and human exploration to Mars: MGS radio science observations. Icarus 330, 60 – 74. secondary particles produced when rays ISS shielding blocks a large proportion of the DOI: 10.1016/j.icarus.2019.04.015. interact with the atmosphere. These particles, low-energy radiation, although this is because as they are travelling so fast, actually show it sits at a very low altitude (~500 km). Still, Williamson M (2017). Missions to Mars. evidence of time dilation, where time is the personal dosimeters range from 12 to 29 Engineering and Technology 12(5), 54 – 57. moving slower for the particle than the mRads a day. DOI: 10.1049/et.2017.0507. observer (which for physicists such as myself Zubrin R, Baker D (1991). Humans to Mars in 1999. is fascinating). Thicker shielding can also be problematic Space transportation propulsion technology symposium though; while it would stop a much higher 3, 881 – 891. Available at: https://ntrs.nasa.gov/ While we are protected on Earth, there is no proportion of low-energy radiation, the archive/nasa/casi.ntrs.nasa.gov/19910018923.pdf such protection in space. The relative vacuum high-energy ionising radiation would also [Accessed 25 Oct 2019]. of space compared to the Earth’s atmosphere start to be absorbed by it. This high-energy means that any cosmic rays not deflected by radiation is usually travelling fast enough that the sun’s magnetic field at the edge of the the probability of interaction is low, when solar system will be largely unimpeded from they do hit shielding (or humans), they create striking a spacecraft. This radiation is also a dangerous secondary particles. major concern for lunar landings or permanent

39 Features

Getting to the heart of it The cardiovascular consequences of spaceflight

Human spaceflight started 58 years ago with the launch of the Russian cosmonaut, Yuri Gagarin, who completed one orbit around Earth on 12 April 1961. Eight years later, 50 years ago, NASA landed the first humans, Neil Armstrong and Edwin (Buzz) Aldrin, on the lunar surface with Apollo 11. Since then, the longest human mission in space is 438 days on board the Russian Space Station, Mir, by Valery Polyakov in 1995. As of today, 574 humans have visited space. The return journey to Mars from Earth will take 1,000 days, and there are several physiological challenges to overcome in bringing humans safely back to Earth.

One is managing the shift of blood and fluid grant to support scientists, who participated into the heart and head that occurs during in the human spaceflight programs of weightlessness and ensuring that no harm the European Space Agency (ESA). We will occur to central nervous function and the specialised in how the cardiovascular system cardiovascular system. Another is maintaining and the associated regulation of fluid and adequate muscle and bone strength electrolyte balance adapts to weightlessness Peter Norsk by efficient exercise prescriptions with in space. specialised equipment, designed to fit into Baylor College of Medicine, small vehicles and habitats. Another concern A prominent problem was – and still is – the TX, USA is maintaining an efficient immune system magnitude of the headward blood and fluid and supplying the crews with sufficiently shift that occurs because of weightlessness nutritious and palatable food. Finally, it is (0 G), where no gravitationally induced a challenge to protect astronauts against hydrostatic pressure gradients exist. In 1993, the long-term effects of space radiation, we aimed to estimate the change in central particularly the effect on brain function and venous pressure (CVP) in one astronaut the cardiovascular system. before, during and a couple of hours after launch into space in the Space Shuttle to Pumping blood in a weightless estimate the increase in cardiac preload environment caused by the fluid shift. In two previous Space Shuttle missions, a US team had My space research career started in August observed – much to their and our surprise of 1978. Before that, I had been fascinated – that CVP in three astronauts decreased by the Apollo program and as a high school in space compared to in the supine body student during the Moon landings, I knew position on the ground (Buckey et al., 1996). all the details of the missions. This fostered We observed the same decrease (Foldager an interest in combining my medical studies et al., 1996). This was surprising, because with spaceflight health issues, and in 1978 the expectation had been that the fluid shift I became a student fellow in a Danish space in weightlessness would induce an increase physiological research group using a national in CVP to somewhat above that of being 1

40 Physiology News / Winter 2020 / Issue 117 G supine. In both cases, CVP was measured through invasive catheters fed into the superior vena cava through a cubital vein either with a fluid-filled system connected to a transducer outside the body (Buckey et al., 1996) or with a transducer at the catheter tip (Foldager et al., 1996).

Shortly thereafter, we (Videbaek and Norsk, 1997) repeated the measurements in eight subjects during 20 seconds of 0 G during parabolic flights (Fig. 1). Buckeyet al. (1996) had also observed in their three astronauts that even though CVP decreased in space, left ventricular end diastolic volume as estimated by echocardiography increased; a paradoxical result. However, our parabolic Figure 1. Parabolic flight in a Caravel in France in 1991, during which we measured central flight data revealed the same, but we also venous pressure invasively in eight subjects during short periods (20 s) of weightlessness measured oesophageal pressure through a (Videbaek and Norsk, 1997). The aircraft followed a Keplerian trajectory, whereby a free- balloon-tipped air-filled tube positioned via fall condition (0 G) was created symmetrically around the top. The 0 G phase was preceded the nasal cavity, down the oesophagus to by 20 seconds of pulling up to 2 G and then again followed by an up to 2 G descending lodge behind the heart. Simultaneously with phase of similar duration. the decrease in CVP, we observed an even greater decrease in oesophageal pressure indicating that 0 G expands the thoracic (Norsk et al., 2015) between three and six Thus, systemic vascular resistance decreases cage compared to being 1 G supine. This months of flight. Thus, stroke volume and (calculated as mean arterial pressure divided mechanical expansion dilates the heart and cardiac output increase more during long- by cardiac output) (Shykoff et al., 1996; increases transmural CVP. Cardiac preload duration flights than short. The same foreign Norsk et al., 2015). The mechanism for the therefore increases in weightlessness as a gas rebreathing technique for both space decrease in systemic vascular resistance, combination of an expansion of the thorax missions for estimating cardiac output was which is indicative of peripheral arterial and the head-ward fluid shift (Videbaek and used (Clemensen et al., 1994; Gabrielsen et al., vasodilation, is currently unknown, because Norsk, 1997). 2002). The reason for the more pronounced sympathetic nervous activity is maintained increase in stroke volume and cardiac output in space at the same level as being seated According to Starling’s law of the heart during longer missions versus shorter is not upright on the ground (Norsk et al., 2015; (Patterson and Starling, 1914) an increase clear at present but could be because of the Fig. 2). A suppression of the efferent in cardiac preload induces an increase in efficient cardiovascular effects of the physical sympathetic nervous activity is therefore not stroke volume and thus cardiac output, a exercise on the International Space Station the mechanism for the decrease in systemic phenomenon that also occurs in space. We (Hughson et al., 2012). vascular resistance. observed in an investigation on the Space Shuttle in 2003 an increase in stroke volume At the same time as cardiac output is To identify the mechanisms of the and cardiac output of 22% (Norsk et al., increased by 0 G in space, systolic, diastolic blood pressure reduction and peripheral 2006) a week into the flight. Later on the and mean arterial pressures decrease by vasodilatation in space is one of the International Space Station, we found even some 10 mm Hg (Shykoff et al., 1996; challenges for the future. more pronounced increases of 35 – 41% Baevsky et al., 2007; Norsk et al., 2015).

41 24 h mean arterial pressure

120

730±130 720±90 730±100

mmHg 100 “Physiologists are most concerned about

the combined effects 80 of weightlessness PRE FLIGHT POST and space radiation on Figure 2. The numbers at the top indicate plasma concentration of noradrenaline (ng/L, the central nervous, mean ± SEM) in cubital venous blood sampled in seated (n = 8) astronauts before (Pre), three to six months during (Flight) and two months after (Post) spaceflight on the ocular, cardiovascular, International Space Station. The columns represent ambulatory mean arterial pressures as averages (± SEM) over 24-h periods around the same time as noradrenaline was sampled sensorimotor and (Norsk et al., 2015). As can be seen, venous plasma noradrenaline was unchanged in space in comparison to the seated posture in 1 G, whereas blood pressure decreased significantly immune systems” (*, p = 0.006). Thus, the efferent sympathetic nervous system does not seem to be a mediator of the decrease in blood pressure in space.

Spaceflight-associated neuro-ocular In addition to SANS, concerns also exist syndrome (SANS) regarding possible impacts of spaceflight on not only the ocular but also the central More than 10 years ago, astronauts started nervous system. Structural changes by to report occurrences of vision changes magnetic resonance imaging of the brain in space. They were mostly of refractory in the days following landing from the character and corrected for by adjustable International Space Station have been glasses (Stenger et al., 2017). NASA detected (Roberts et al., 2018). Whether flight surgeons started to monitor other they have any clinical health or functional ocular variables such as retinal changes by impacts are unknown at present. fundoscopy, which in some cases indicated disc oedema. By using optical coherence Cardiovascular remodelling in tomography (OCT) and ultrasound imaging, spaceflight more details have later been obtained, and choroidal folds, cotton wool spots, increases Results of ground-based rodent studies in optic nerve sheath diameter and globe have indicated that changing the pressure flattening have also been detected (Maderet distribution by shifting blood and fluid to or al., 2011; Stenger et al., 2017). Collectively, away from the head by body tilts induces one or more of these manifestations changes in the structure of the arterial walls constitute what is called SANS. Recent data (Zhang, 2013). Thickening of arterial walls have revealed that disc oedema is preceded is also evident in hypertension, for example by gradual increases in retinal thickness. (Mulvany, 2012). Data from two studies Laurie et al. (2019) were able to induce some on the International Space Station indicate of these changes during strict, 30 days of six that the carotid artery increases in stiffness degrees head-down tilted bed rest, which during and immediately following spaceflight indicates that the shift of blood and fluid to (Hughson et al., 2016; Arbeille et al., 2017). the head is a pivotal mechanism. It appears In one astronaut with almost one year in that some astronauts are more sensitive space on the International Space Station to SANS than others, indicating that there (340 days), carotid wall thickness increased maybe a genetic disposition to this syndrome as well as biomarkers indicating increased (Smith and Zwart, 2018). inflammation and oxidative stress in the cardiovascular system (Garrett-Bakelman FE SANS is one of the highest prioritised health et al., 2019). Thus, there are some indications risks of long-duration spaceflight, and much that the carotid arterial wall structure may research is initiated by the space agencies change during long-duration spaceflight. The to understand the details of the mechanisms of clinical implications of these observations the syndrome and how to counteract it during, are, however, currently unknown. for example, a three-year mission to Mars.

42 Physiology News / Winter 2020 / Issue 117 Other physiological effects We know how weightlessness affects the landing astronauts from the Gateway habitat sensorimotor system, and that all astronauts to the surface of the Moon, with the first In 2011, I joined NASA as a contractor to experience balance problems immediately mission to land a female astronaut in 2024. lead the physiological research in the Human after landing (Mulavara et al., 2018). This is Research Program. At that time, I had been of concern after landing on Mars, where the It is of high priority to understand the mostly involved in cardiovascular and fluid key question is, how long after landing will it combined effects of weightlessness and volume regulation research concerning take the astronauts to recover and be able deep space radiation on oxidative stress spaceflight. Thus, I had to understand to perform the required mission tasks? The and cellular damage, and how this impacts the status of other physiological areas immune system is attenuated by spaceflight, health and performance. Currently, only 24 concerning effects of long-duration flights. leading in some cases to viral reactivations astronauts, as part of the Apollo program and rashes, and major efforts are directed (1968 – 1972), have been in deep space Apart from the cardiovascular system, towards a host of protective interventions, and only for a maximum of 12 days. the main areas of concern are the ocular, mainly to decrease operational stress and Therefore, very little is known regarding central nervous, sensorimotor, immune and supply foods with antioxidants (Crucian et the physiological effects of long-duration musculoskeletal systems and to determine the al., 2018). Finally, defining the optimal food exposures to the deep space environment. most efficient nutritional composition of the composition as well as identifying which food food systems to maintain astronaut health and items are most applicable for physiological Conclusion performance during long-duration missions. health protection is a challenge (Smith and Regarding the musculoskeletal system, Zwart, 2018). Surprises and paradoxes concerning how the maintaining muscle strength for performance cardiovascular system adapts to spaceflight of the required mission tasks is important, Future plans for deep space missions defy explanation, for example mean arterial as is maintaining sufficient bone strength to pressure and systemic vascular resistance avoid an increased risk of fracture due to bone NASA is currently planning for future human decrease during months of spaceflight demineralisation. The key countermeasure deep space missions beyond the van Allen despite an unchanged efferent sympathetic against these effects is regular resistance Belts with the so-called Gateway project. nervous tone. For future deep space exercise. The future challenge is to develop an The plans concern regular human missions to missions, to the Moon in the 2020s and to exercise device that can be accommodated a small habitat orbiting the Moon. The idea Mars in the 2030s, physiologists are most in a small space vehicle or a habitat and still is to have a crew of four visit the habitat for concerned about the combined effects be able to fulfill the musculoskeletal and some 45 – 60 days on an annual basis with of weightlessness and space radiation on aerobic requirements (Ploutz-Snyder et gradual increases in durations as a human the central nervous, ocular, cardiovascular, al., 2014). SANS is of particular concern, as test bed for understanding the impacts sensorimotor and immune systems, and well as whether brain function is affected of the deep space environment on human these will be the focus of intense research in (Mader et al., 2011; Stenger et al., 2017). physiology. The plans now also include the coming years.

Hughson RL et al. (2012). Cardiovascular regulation Patterson SW, Starling EH (1914). On the mechanical References during long-duration spaceflights to the International factors which determine the output of the ventricles. Space Station. Journal of Applied Physiology 112, 719 – 727. The Journal of Physiology 48, 357 – 379. Arbeille P et al. (2017). Carotid and femoral arterial DOI: 10.1152/japplphysiol.01196.2011 DOI: 10.1113/jphysiol.1914.sp001669 wall distensibility during long-duration spaceflight. Aerospace Medicine and Human Performance 88, Hughson RL et al. (2016). Increased postflight carotid Ploutz-Snyder LL et al. (2014). Integrated resistance 924 – 929. DOI: 10.3357/AMHP.4884.2017 artery stiffness and inflight insulin resistance resulting and aerobic exercise protects fitness during bed rest. Baevsky RM et al. (2007). Autonomic cardiovascular from 6-mo spaceflight in male and female astronauts. Medicine and Science in Sports and Exercise 46, 358 – and respiratory control during prolonged spaceflights American Journal of Physiology 310, H628 – H638. 368. DOI: 10.1249/MSS.0b013e3182a62f85 DOI: 10.1152/ajpheart.00802.2015 aboard the International Space Station. Journal of Roberts DR et al. (2018). Effects of spaceflight on Applied Physiology 103, 156 – 161. DOI: 10.1152/ Laurie SS et al. (2019). Optic disc edema after 30 days of astronaut brain structure. The New England Journal of japplphysiol.00137.2007 strict head-down tilt bed rest. Ophthalmology 126, 467 Medicine 378, 582 – 583. DOI: 10.1056/NEJMoa1705129 Buckey JC Jr et al. (1996). Central venous pressure in – 468. DOI: 10.1016/j.ophtha.2018.09.042 Shykoff BE et al. (1996). Cardiovascular response space. Journal of Applied Physiology 81, 19 – 25. to submaximal exercise in sustained microgravity. DOI: 10.1152/jappl.1996.81.1.19 Mader TH et al. (2011). Optic disc edema, globe flattening, Journal of Applied Physiology 81, 26 – 32. choroidal folds, and hyperopic shifts observed in astronauts Clemensen P et al. (1994). A modified photo- and DOI: 10.1152/jappl.1996.81.1.26 after long-duration space flight.Ophthalmology 118, magnetoacoustic multigas analyzer applied in gas 2058 – 2069. DOI: 10.1016/j.ophtha.2011.06.021 exchange measurements. Journal of Applied Physiology Smith SM, Zwart SR (2018). Spaceflight-related ocular changes: the potential role of genetics, and the potential 76, 2832 – 2839. DOI: 10.1152/jappl.1994.76.6.2832 Mulavara AP et al. (2018). Physiological and functional of B vitamins as a countermeasure. Current Opinion in alterations after spaceflight and bed rest.Medicine and Crucian BE et al. (2018). Immune system dysregulation Clinical Nutrition and Metabolic Care 21, 481 – 488. Science in Sports and Exercise 50, 1961 – 1980. during spaceflight: potential countermeasures for deep DOI: 10.1097/MCO.0000000000000510 space exploration missions. Frontiers in Immunology DOI: 10.1249/MSS.0000000000001615 9, 1437. DOI: 10.3389/fimmu.2018.01437 Stenger MB et al. (2017). Evidence Report: Risk of Mulvany MJ (2012). Small artery remodelling in hypertension. Spaceflight Associated Neuro-ocular Syndrome (SANS). Foldager N et al. (1996). Central venous pressure in Basic and Clinical Pharmacology and Toxicology 110, 49 – 55. [Online] NASA https://humanresearchroadmap.nasa. humans during microgravity. Journal of Applied Physiology DOI: 10.1111/j.1742-7843.2011.00758.x gov/evidence/reports/SANS.pdf 81, 408 – 412. DOI: 10.1152/jappl.1996.81.1.408 Norsk P et al. (2006). Vasorelaxation in space. Hypertension Gabrielsen A et al. (2002). Non-invasive measurement Videbaek R, Norsk P (1997). Atrial distension in humans , 69 – 73. DOI: 10.1113/jphysiol.2014.284869 of cardiac output in heart failure patients using a new 47 during microgravity induced by parabolic flights. foreign gas rebreathing technique. Clinical Science Journal of Applied Physiology 83, 1862 – 1866. Norsk P et al. (2015). Fluid shifts, vasodilatation and (London), 102, 247 – 252. DOI: 10.1042/cs1020247 DOI: 10.1152/jappl.1997.83.6.1862 ambulatory blood pressure reduction during long duration Garrett-Bakelman FE et al. (2019) The NASA twins spaceflight.The Journal of Physiology 593, 573 – 584. Zhang LF (2013). Region-specific vascular remodeling study: A multidimensional analysis of a year-long human DOI: 10.1113/jphysiol.2014.284869 and its prevention by artificial gravity in weightless spaceflight.Science 364 (144), 1 – 20. DOI: 10.1126/ environment. European Journal of Applied Physiology science.aau8650 113, 2873 – 2895. DOI: 10.1007/s00421-013-2597-8

43 Membership

Why research space physiology?

We asked space physiologists around the world to tell us about their research, and what inspired them to pursue research into the worlds beyond our own.

Julia Attias Manchester Metropolitan University, UK Carsten Lundby To understand what happens to our body in extreme environments, Lillehammer University College, Storhove, Norway we first have to understand more fully how it functions in a normal environment. As gravity is the fundamental contributor to why I have for a long time been interested in how physical exercise humans have evolved as they have, we can glean extensive and inactivity affect human physiology, and specifically studying physiological knowledge by studying exposure to environments the latter in space. Our long-term goal is to quantify blood that lack it. volume in space. In my opinion, this is a much overlooked factor that may prove important to monitor during prolonged missions to for example Mars. We have developed an automated blood volume analyser – the Detalo Performance – and thus far have tested our equipment during parabolic flights that deemed our device as effective for our mission.

Jörn Rittweger German Aerospace Center (DLR), Cologne, Germany Derek O’Keefe Space physiology fascinates me for several reasons: its foundation NUI Galway, Galway, Ireland on science and engineering, the opportunity to study organismic responses to extreme challenges, and not least the opportunity for A Martian day (referred to as a sol) lasts 24.65 h rather than the discoveries that matter to medicine on Earth. For example, we 24 h day on Earth. As part of a team, I carried out an experiment found in bed rest studies (a ground-based model of microgravity) on sleep disruption and sleep deprivation in a Martian analogue that resistive vibration exercise can prevent muscle wasting and base in the high arctic, where there is continuous sunlight. Our bone loss. This is not as trivial as one might think, as the effort summary thoughts were that while subjective data demonstrate required for preservation is much greater in bed and in space than in improved sleep and alertness during the sol, objective data a normal 1 G environment. Strangely, the countermeasure is not demonstrate no significant alteration of sleep patterns. based on suppressing exaggerated bone resorption, but rather by Importantly there was no apparent cognitive decline over the fostering bone formation to match the resorptive boost. course of the mission.

44 Physiology News / Winter 2020 / Issue 117 Damian Bailey University of South Wales, Pontypridd, UK Lonnie Petersen Astronauts returning from long-term spaceflight encounter a University of California San Diego, San Diego, USA variety of health problems that are similar to those found in the elderly (accelerated ageing). Spaceflight-associated neuro-ocular I am fascinated by space as a scientific platform which allows us to syndrome (SANS), related to a build-up of pressure inside the generate knowledge about human physiology we could not learn brain, is considered the top health risk for long-duration in other ways. Through our efforts to develop and test counter- spaceflight. Our research is the first to demonstrate that measures to reduce pressure and volume overload in the brain of gravitational transitions result in a minor opening of the blood- astronauts during long-term spaceflight, we have also uncovered brain barrier due to the combined effects of increased blood flow the significant clinical potential of the same intervention for especially to the back of the brain and the formation of free patients on Earth with disrupted brain pressure regulation, such as radicals, invisible molecules floating around the blood stream. following head trauma or stroke. The aim of my work is to maintain human health during exploration class missions, but I am equally excited about the spin-down applications which really increases my target patient population from a select few space-travelers to include millions of patients here on Earth.

Thu Jennifer Ngo-Anh European Space Agency (ESA), Netherlands Adam McDonnell I have both a medical and a neuroscience background; Institute Jozef Stefan, Ljubljana, Slovenia understanding how the body, and specifically brain, works has always interested me. Space is the most extreme environment I’ve always been interested in extreme human performance. When one can think of; studying the changes that the body and mind I was younger I read essentially any book I could about the first go through when exposed to the space environment is therefore polar explorers which seemed remote and I suppose at the time extremely fascinating. What I find most striking is to see how almost as isolating as spacefarers. Quite fascinatingly, more the human body is able to adapt very quickly and efficiently to people have been to space now than have circumnavigated the all the changes caused by the space environment. There has not globe solo by sail. When I was a teenager and then in college I was been a single crewmember who has not adapted to microgravity drawn to Olympic athletes and to the feats they could perform. and space conditions! Understanding what happens and But it was in my final year I started to realise that the human race identifying countermeasures to mitigate those risks and changes survived by a collective ability to perform and explore rather than is something that is not only relevant for enabling future safe and by advances of any one very talented individual. This is where my sustainable missions into deep space, but also has very practical love for understanding how humans as a species perform in applications for life on Earth. In addition, we have and will learn a adverse environments came from. The space aspect slowly grew lot about ourselves! I am convinced we will continue to do so on me from there and I’ve spent the last 13 years investigating with the human spaceflight activities that are in the works. space life science and its translational role to earth. Image credit: NASA

45 Membership

Obituary: William Stanley Peart 1922 – 2019

the vasoconstrictor effects of the effluent to the enormous national and international from the spleen. After a series of painstaking cardiology meetings, a small International experiments, he realised the nature of splenic Hypertension Group of no more than 50 sympathin could not be adrenaline but was participants held its first meeting in northern noradrenaline. This result published in The Italy. This embryonic hypertension club has Journal of Physiology in 1949. now evolved into an International Society with over 4,000 members. By 1952, Pickering was convinced that the future of hypertension research involved the During the 70s and 80s, Peart chaired the identification of components of the renin- Medical Research Society, a society which was angiotensin aldosterone system (RAAS). probably responsible for the development of The technology to investigate the RAAS was academic medicine in Britain. He was appointed not available in the laboratories at Mary’s to the board of the MRC. He also became a and Peart moved his work to the MRC Wellcome Trust trustee. By today’s standards, laboratories at Mill Hill. The challenge was to the Trust was then extremely small with a purify and identify the nature of the blood- limited budget of around £1.5 million per year. pressure-raising substance, angiotensin. His early work involved the development After being elected a Fellow of the Royal of reverse-phase chromatography and the Society in 1969 and knighted in 1985 for ultimate identification by electrophoresis his contribution to medicine, Peart retired in Stanley Peart and spectrophotometry of the amino acid 1987. This allowed more time for a passion sequence of the decapeptide angiotensin 1. for opera. He loved the blood and thunder In collaboration with Don Elliott, the resulting operas – those with manifestly aggressive Amongst the great British clinician scientists classic paper was published in Nature in 1956. actors and singers – Don Giovanni and Tosca of the twentieth century, Stanley Peart was a giant. His international fame was based on his remarkable scientific research on the autonomic nervous system and the renin- “His early work involved the development of angiotensin system – two systems that play a vital role in the regulation of the circulation reverse-phase chromatography and the ultimate and the kidney. identification by electrophoresis and Born in South Shields, County Durham, Peart was a Tynesider. The family moved several spectrophotometry of the amino acid sequence times during his childhood and eventually to of the decapeptide angiotensin 1” London. At King’s College School Wimbledon, he excelled in the sciences and entered St Mary’s Hospital Medical School with a scholarship in 1938. A year later, with the outbreak of World War Two he was persuaded to continue his medical studies. By 1943, as a Peart left Mill Hill in 1954 to return to the were his favourites. With Italy in mind, a house physician he was advised by his mentor, Medical Unit at St Mary’s, where he was Festschrift (a collection of writings in honour George Pickering, to spend a short time in invited to apply for Pickering’s Chair. The of a scholar) was arranged for him in his the laboratory of Alexander Fleming. This was youngest applicant by far, he was appointed favourite place on the banks of Lake Como. It Peart’s first exposure to research. to the post. The St Mary’s Unit had evolved was a memorable occasion attended by over under Pickering’s influence into the field of 100 of his former friends and colleagues. At the end of his house jobs, Peart applied for a hypertension with a focus on how the renin- Medical Research Council (MRC) studentship angiotensin aldosterone system actually As a family man, Peart owed an enormous to work with John Gaddum in Edinburgh in worked. The Swiss pharma company Ciba had amount to his wife, Peggy. He died on 14 1946. Gaddum was a shy, gangling figure, synthesised angiotensin and this was used March 2019. He was one of the last real awkward in conversation, but a superb mentor. for exploratory studies in the laboratory to professors of medicine – a scientist, a teacher Peart was challenged to work on sympathin, establish its actions. The interests of the team and always a clinician. Those who followed a substance putatively released from widened, influenced by Roy Calne, a future and were fortunate to have worked with him sympathetic nerves. There was uncertainty as internationally renowned transplant surgeon. remember the brilliant mind, the charisma, to whether this was adrenaline or some other The team had the experience and ability to the sense of humour and, perhaps, the bow mediator. The question was “what actually start renal transplantation. This was no doubt tie and the red socks. is released from the nerve endings and how stimulated by the recent availability of the could you measure it?” Peart realised that, immunosuppressive agent, azathioprine. rather than the ewe’s liver, then used, a much better experimental model was the perfused Hypertension in the early 60s was considered Written by Peter Sever (Imperial College spleen, with a rabbit ear as the bioassay for the poor relation of cardiology and, in contrast London).

46 Physiology News / Winter 2020 / Issue 117 Obituary: Paul M Vanhoutte 1940 – 2019

“Publishing extensively in both The Journal of Physiology and the American Journal of Physiology, his scientific output was prodigious: he co-authored or edited 36 books, published 669 original research papers, and 574 editorials and reviews”

editorial boards of numerous physiology and Paul inspired a genuine warm loyalty from pharmacology journals, he was particularly all who ever spent time with him. At every exercised to ensure the highest quality of major scientific conference, there would be an scientific publication, and became Editor- impromptu Paul Vanhoutte dinner attended by Paul M Vanhoutte in-Chief of the Journal of Cardiovascular all the ex-trainees attending the conference. Pharmacology and an Associate Editor of the If there was a conflict with any other event, it American Journal of Physiology (Heart and was the other event that would be missed. In Paul M Vanhoutte died in Paris, France, Circulatory Physiology). particular a surprise 60th birthday gathering on 23 August 2019 after a fall. He will was held for him in Paris where over 100 be remembered as a leading figure in Paul was a polymath but certainly regarded former mentees from around the world paid cardiovascular physiology and pharmacology physiology as one of his prime disciplines. their way to celebrate the day. and as a great friend and mentor by those Physiology underlay his interests in who were lucky enough to work with him. pharmacology and medicine. At each Paul was generous and astute with advice, International Congress of IUPS for many great fun to work with and also to relax with Born and trained as an MD in Belgium, Paul decades Paul was involved with the after work. He enjoyed good company, good received his postdoctoral training in the organisation of a series of satellite meetings food, good wine and good jokes (and the Department of Physiology at the Mayo called “Mechanisms of Vasodilatation”. It was occasional cigar). He had many memorable Clinic in Rochester with JT Shepherd, who at one such meeting that, at Paul’s invitation, sayings such as “I feel a paper coming on” surely infected him with the physiology Robert Furchgott gave one of his first talks on and “There are three kinds of people, those bug. Paul’s subsequent career spanned his new ideas about an endothelium-derived who make things happen, those who watch academia, industry and three continents. He relaxant factor, the seminal work that led to what happens and those who wondered held professorial positions at the University a huge explosion of work on the physiological what happened”. He was in the first category of Antwerp, The Mayo Clinic, and Baylor roles of the endothelium, and ultimately to and made good things happen for the young College of Medicine. In 1992 he moved Furchgott’s Nobel Prize in 1998. It is hard scientists he trained during his career and for into industry as Vice President of R&D at to underestimate Paul’s contribution to this his co-workers. the Institut de Recherches Internationales field. Named lectures have been established Servier, in France. However, in 2003, and until in his honour and he received honorary Paul Vanhoutte leaves a wife Jacqueline, his death (he never retired), he returned to doctorates from nine universities. A member four children and seven grandchildren. All academia, becoming Distinguished Visiting of many learned societies, he was also one who knew him will remember his scientific Professor and the Director and Founder of the of the few who have been awarded honorary insight and influence, his “art-de-vivre”, the Biopharmaceutical Development Centre at membership of both The Physiological Society seemingly impossible travel schedules, his the University of Hong Kong. (in 2009) and The British Pharmacological quick wit and his infectious laugh. Society. His early research evolved from a study of the control of the veins to understand why Those of us who had the privilege to work acetylcholine is a vasodilator. This led him to with him will always remember his charismatic Written by Michael Collis (Retired) and research the control of sympathetic neuro- scientific leadership and guidance. He had Ian McGrath (University of Glasgow and effector junctions and of the interaction of unbounded energy and enthusiasm for University of Sydney). vasodilator and vasoconstrictor substances science, for people and for life. He travelled with the vascular endothelium. His major prodigiously, meeting all the leading scientific contribution was the analysis of cardiovascular researchers. We will not Further reading the importance of endothelial cells for the forget the metal briefcase (or was it two?) control of vascular smooth muscle in health containing slides that he carried around on Boulanger et al. (2019).Tribute to Paul M. Vanhoutte, and disease. Publishing extensively in both the off-chance that he would be expected MD, PhD (1940 – 2019). Arteriosclerosis, Thrombosis, The Journal of Physiology and the American to concoct a talk. On a visit to Scotland he and Vascular Biology 39, 2445 – 2447. DOI: 10.1161/ Journal of Physiology, his scientific output actually gave two entirely different talks ATVBAHA.119.313461 was prodigious: he co-authored or edited 36 for different audiences, all made up in about See also the “Paul M. Vanhoutte – Commemorative Issue” books, published 669 original research papers, half an hour, once he knew who the published by The Journal of Physiology in November 2019. and 574 editorials and reviews. On the audiences were. DOI: 10.1113/JP279124

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