OPEN ACCESS GOVERNMENT NORTH AMERICA ANALYSIS
THE ROLE OF RESEARCH IN THE FUTURE OF AGEING DR YVES JOANETTE, SCIENTIFIC DIRECTOR AT THE CIHR INSTITUTE OF AGING EXPLORES HOW CANADA’S RESEARCHERS ARE MEETING THE NEEDS OF AN AGEING POPULATION
IN THIS ISSUE
Dr Juan C. Meza, Division of Mathematical Jaime Adams and Anne Mims Adrian, PhD Leora Fox, Jennifer Simpson and George Sciences at the National Science Foundation share their views on advancing open access and Yohrling from the Huntington’s Disease Society reveals why mathematics is such a powerful tool open data in higher education of America explore the sources of funding in the for understanding the world around us development of therapies for the disease
Featured eBook Supported by Gene expression and Huntington’s disease
Naoko Tanese from New York University explores how monitoring gene expression can be used to treat Gene expression and Huntington’s disease neurodegenerative diseases such as Huntington’s.
Click here to view our ebook
Naoko Tanese, PhD Associate Dean for Biomedical Sciences Director, Sackler Institute of Graduate Biomedical Sciences Jonathan Miles Editor Production Coordinator INTRODUCTION Nick Wilde
Designers Welcome to the packed July 2018 edition Also, in this summer edition, we are Andrew Bosworth Ben Green of North America Analysis. One of the pleased to feature an article on advancing many insights in this edition comes open access and open data in higher from Leora Fox, Jennifer Simpson and education. This comes from Jaime The editor does not necessarily agree George Yohrling from the Huntington’s Adams at the U.S. Department of with or endorse any of the views or contents of the articles and features Disease Society of America. In their Agriculture and Anne Mims Adrian, within this document. All articles and article, they explore the sources of PhD at Auburn University. editorials remain the copyright of the authors, organisations and other funding in the development of therapies relevant authorities by whose kind for Huntington’s disease (HD) in the Finally, one guest article worth mention- permission they are reproduced. All U.S. today. ing here is from Marta Pierkarska, information has been checked and is correct at the time of going to press. Director of Developer Ecosystem at The publisher will not be liable for any We also include a fascinating piece Hyperledger who reveals her thoughts loss suffered directly or indirectly as a result of the use of or reliance on from Dr Yves Joanette, Scientific Director on the current status of blockchain the information contained herein. at the CIHR Institute of Aging. In his technologies in the world today. © Adjacent Digital Politics Ltd 2018 insightful comment piece, he explores how Canada’s researchers are meeting I trust that you find this publication Adjacent Digital Politics Ltd and its suppliers collect and process personal the needs of an ageing population, now useful and insightful. Please do reach information for the purposes of and in the future. out if you have any ideas for compelling customer analysis and market research. Our group/affiliate companies may content for the future, or perhaps also wish to contact you about our A further health insight comes from you’d like to provide comments on this products or services, or the products of carefully selected third parties that David Bearman, M.D., Executive VP of edition. ■ we think you may be interested in. the American Academy of Cannabinoid Medicine. In his analysis, he details the research priorities for cannabis, one of the most thoroughly studied plants of all time.
Heading up the research & innovation focus, we are thrilled to feature a compelling article by Dr Juan C. Meza, Division Director for the Division of Adjacent Digital Politics Ltd Datum House Mathematical Sciences (DMS) at the Electra Way Crewe Business Park National Science Crewe Cheshire CW1 6ZF Foundation (NSF). This article reveals Jonathan Miles Registered in England & Wales. Company Reg No. 8667479. exactly why mathematics is such a Editor VAT Registration No. 169 9152 64. powerful tool for understanding the world around us, we find out. @Jonathan_AdjDig CONTENTS NORTH AMERICA ANALYSIS | JULY 2018
USA
RESEARCH & INNOVATION Mathematics: A powerful tool for understanding the world 36Dr Juan C. Meza, Division Director for the Division of Mathematical Sciences at the National Science Foundation (NSF) reveals why mathematics is such a powerful tool for understanding the world around us
Microbes and the rigour of space flight 44William B. Miller, Jr., M.D. argues that without the planning to do so, we have launched microbial life from this planet
How developmental biology changes our lives 48Shyh-Jye Lee (Jeff), Ph. D, President of the Taiwanese Society of Developmental Biology (TSDB) explains the way in which developmental biology impacts upon our lives Nanomedicines: Depicting human health risks 06hindering clinical translation Cecilia Van Cauwenberghe from Frost & Sullivan shares her expertise on the Muscular dystrophy: Present world of nanomedicines, with a special concerns and foreseen focus on depicting human health risks 22opportunities hindering clinical translation Cecilia Van Cauwenberghe from the TechVision Group at Frost & Sullivan provides a detailed analysis of the present concerns and foreseen opportunities HEALTH & SOCIAL CARE around muscular dystrophy (MD) Sources of funding in the Cannabis: One of the most development of therapies for thoroughly studied plants ever Huntington’s14 disease 30David Bearman, M.D., Executive VP of the ENVIRONMENT Leora Fox, Jennifer Simpson and George American Academy of Cannabinoid Promoting polar science in the Yohrling from the Huntington’s Disease Medicine details the research priorities for United States Society of America explore the sources of cannabis, one of the most thoroughly 52Open Access Government examine the funding in the development of therapies studied plants of all time work of the Office of Polar Programs (OPP), for Huntington’s disease (HD) part of the National Science Foundation Acute respiratory distress The diagnosis and treatment of syndrome – diagnostics and Ocean sciences: Advancing cancer in the United States 32therapeutics the frontiers of knowledge 18The vital work of the National Cancer Cecilia Van Cauwenberghe, from TechVision The56 activities of the Division of Ocean Institute, part of the National Institutes of Group, Frost & Sullivan provides a detailed Sciences (OCE), a section of the National Health, is placed under the spotlight here analysis of acute respiratory distress Science Foundation (NSF), in advancing by Open Access Government, including the syndrome, focussing on the evolving the frontiers of knowledge around ocean dissemination of new findings on the diagnostics and therapeutics in the sciences, are reviewed here by Open diagnosis and treatment of cancer precision era of medicine Access Government EDUCATION & YOUNG PEOPLE What next for children and young people with speech, 78language and communication needs? Mary Hartshorne, I CAN’s Head of Evidence shares her thoughts on the report Bercow: Ten Years On and the next steps for children and young people with speech, language and communication needs
The research priorities for the cereals and oilseeds 68sector. Tim Isaac, Head of Arable at the Agriculture and Horticulture Development Board shares his thoughts on research into the cereals & oilseeds sector
BLOCKCHAIN INNOVATION ENERGY AGRICULTURE The current status of Fusion energy: Making history Advancing open access and blockchain technologies Laban Coblentz, Head of Communi - open data in higher education 82Marta Pierkarska, Director of Developer 62cation at ITER explains his thoughts on how 74Jaime Adams and Anne Mims Adrian, PhD Ecosystem at Hyperledger reveals her history is being made when it comes to the shares their views on advancing open thoughts on the current status of exciting world of fusion energy access and open data in higher education blockchain technologies
CANADA
Educational philosophy and The role of research in theory: Priorities and new Canada for the future of directions84 for research 90 Dr Yves Joanette, Scientific Bruce Maxwell, Lauren Bialystok, Kevin ageing. Director at the CIHR Institute of Aging McDonough and David Waddington, explores how Canada’s researchers are outline their views on promising new meeting the needs of an ageing directions for research in educational population, now and in the future philosophy and theory
Why Canada urgently needs a national strategy to tackle the diabetes94 epidemic Kimberley Hanson, Director of Federal Affairs at Diabetes Canada argues that the country urgently needs a national strategy to tackle the diabetes epidemic HEALTH & SOCIAL CARE
Nanomedicines: Depicting human health risks hindering clinical translation
Cecilia Van Cauwenberghe from Frost & Sullivan shares her expertise on the world of nanomedicines, with a special focus on depicting human health risks hindering clinical translation
y way of background, although nanomedicines and combined behaviour of atoms and molecules to hold the promise of contributing to provide build complex functional medicines, ranging from drug therapeutically efficient and early-stage delivery vehicles, diagnostic and imaging technologies, Bdiagnostics accuracy, the clinical translation of nano - analytical tools and theranostic platforms, among medicines face numerous challenges. Reproducible many other products, for their application in medicine manufacturing, efficient scaling-up, appropriate (Vance et al., 2015; Sharma et al., 2017). formulation, accurate characterisation, in vivo instability and bioavailability, disease heterogeneity, epigenomic Regarding basic design, a nanomedicines library impact, potential toxicity, immune response, regulatory comprises of a combinatorial approach based on: 1) barriers, safety issues and ethical concerns, represent size, ranging from 1 to 100 nanometers (nm); 2) shape, some of the multiple hurdles hindering the clinical usually sheet, tube, fibre, sphere, cube; 3) surface, translation of nanomedicines. varying charge, crystalline structure, coatings, defects, impurities; and 4) functionality, related to optical, elec- Furthermore, despite the vast number of opportunities trical, mechanical, or chemical behaviour. Regarding in treating complex and rare diseases, including targeting design, nanomedicines can be structurally, cancer, derived from the advent of nanomedicines chemically and thermodynamically built to carry small development, the dichotomy between nanotechnology molecules, genes, antibodies, peptides, or radioactive and nanotoxicology remains unresolved. Novel materials, either inside or at their functionalised sur- methods attempting to address this concern are face. Among the most commonly used nanomedicines, emerging driven by the advent of new paradigm-shift liposomes, polymers, metals and metal oxides and approaches. composites, can be cited. Ideally, nanomedicines respond to certain parameters, such as pH, temperature, Nanomedicines overview: or light, to trigger a controlled release of their payload. The nanoscale effect This controlled action also helps to protect both the Singular features and industry impact host from unintended exposure to an active drug or Engineered at an unparalleled small scale, nanomate- compound and the drug or agent from being detected rials display distinct chemical, physical and biological by the host’s surveillance system or being disinte- properties in comparison to those observed in the grated by an adverse microenvironment. Therefore, same compounds at a larger scale. Consequently, it is a great specificity and fine-tuning control must be these features that make nanomaterials extremely guaranteed (Etheridge et al., 2013). versatile and potentially applicable to all industries impacting upon modern lifestyle, including biomedi- Clinical validation: cine. Nevertheless, the same properties could make The nanotoxicity potential nanomaterials increasingly unpredictable once Understanding complex biology interacting with other agents, especially where cells Overall, biological effects induced by nanomedicines and tissues are concerned. are associated with their fluctuating, random and sometimes unstable physicochemical behaviour within Nanomedicine constitutes a field of molecular medicine tissue microenvironments. Naturally, through the that exploits the ability to control individual properties complete past decade, notable efforts have been
6 HEALTH & SOCIAL CARE
devoted to developing suitable in vivo, in vitro and in human health risk assessment is yet to be instituted. silico toxicity testing assays, intending to assess Meanwhile, in vitro human cell culture models and nanotoxicity. One of the first impediments found is in silico approaches combining molecular biology, related to nanomaterials insolubility and tendency to artificial intelligence and adaptive omics data analytics, aggregate, which derives from all types of test sensitivity more oriented to mimic complex biology, are gaining failures and significant interference with optical attention. measurements, hence remarkably challenging test validation methods. Concerning epigenetic regulation An aspect that cannot be ignored when analysing the Furthermore, the extremely high degree of variables human health risks of nanomedicines pertains to their because of a potentially unlimited set of nanomedi- interaction with the genetic material and potential cines constructions, along with the multiple biological induction of genotoxicity and mutagenicity. By mediating functions and pathways impacted by each nanomedi- inflammatory responses and oxidative stress process, cine, make conventional test validation obsolete (Hare nanomedicines may trigger epigenetic modifications et al., 2017). related to the onset of cancer. DNA methylation, histone modifications and interacting regulative non-coding Accordingly, while the development and expectations RNAs, constitute the epigenetic mechanisms strictly of nanomedicines generally increase, a standard regulating gene expression in both the normal and methodology for safety testing of nanomedicines and disease microenvironment (Van Cauwenberghe, 2018a).
7 HEALTH & SOCIAL CARE
Consequently, nanomedicines validation requires a complexity to carry out sensitive toxicity testing solid demonstration of null nanomaterial-induced approaches and drug safety evaluation strategies genotoxicity, that is, nanomedicines must not impair (Agrahari and Agrahari, 2018). Artificial intelligence (AI), the expression of genes involved in DNA methylation including machine learning and deep learning reactions, methylation or acetylation of histones approaches, among many other developments, is and/or expression of micro RNA (Smolkova et al., prone to improve the complete nanomedicines devel- 2017). opment process by exploiting large sets, multisource data, to transform them into usable and actionable Meeting artificial intelligence (AI) knowledge and decision-making tools, while leaving Cellular functions are controlled by sophisticated behind years of trial-and-error drug development. By communication routes and signalling pathways allowing the assessment of dozens of trillion data between cells, driven by knotty networks of genes, points in a single tissue sample, the building of multi- peptides, proteins and metabolites that interact with physics modelling and simulation and the correlation each other operating as messengers, sensors, regulators, of thousands of sources, AI platforms can be optimally promoters and/or inhibitors of internal and external suited to identify new drug targets and to design novel signals (Halappanava et al., 2017). nanomedicines, while minimising screening time and enhancing patterns identification, among many other Due to their size and ability to interact at tissue applications. The necessary step is a strong combina- microenvironment levels, nanomedicines studies tion of AI-based technology with biological sciences, demand an in-depth knowledge of systems biology especially metabolomics.
8 HEALTH & SOCIAL CARE
This branch of science allows carrying out the quantita- Acknowledgements tive and qualitative scrutiny of all metabolites present I would like to thank all contributors from industry in the human body because of both normal and involved with the development and delivery of this article disease processes in diverse organs and tissues. Hence, from the TechVision Group at Frost & Sullivan. technologies based on metabolomics approaches, enable the translation of biological outputs to thera- Further reading peutic candidates. Moreover, the assessment of drug 1 Agrahari, V. and Agrahari, V., 2018. Facilitating the translation of efficacy and safety can be carried out by detecting nanomedicines to a clinical product: challenges and opportunities. changes in metabolite profiles, which can be measured Drug discovery today. significantly faster and simpler than genetic or protein 2 Etheridge, M.L., Campbell, S.A., Erdman, A.G., Haynes, C.L., Wolf, S.M. responses (Van Cauwenberghe, 2018b). and McCullough, J., 2013. The big picture on nanomedicine: the state of investigational and approved nanomedicine products. Nanomedi- In addition, the smart synergy between omics science cine: nanotechnology, biology and medicine, 9(1), pp.1-14. and AI technologies may outstandingly help to 3 Halappanavar, S., Vogel, U., Wallin, H. and Yauk, C.L., 2018. Promise maximise the benefits of the unique combination of and peril in nanomedicine: the challenges and needs for integrated adaptive, omics-based biological data and advanced AI systems biology approaches to define health risk. Wiley Interdiscipli- machine learning algorithms to build accurate predictive nary Reviews: Nanomedicine and Nanobiotechnology, 10(1). models for nanomedicines clinical validation. 4 Hare, J.I., Lammers, T., Ashford, M.B., Puri, S., Storm, G. and Barry, S.T., 2017. Challenges and strategies in anti-cancer nanomedicine devel- Final remarks opment: An industry perspective. Advanced drug delivery reviews, The clinical translation of nanomedicines presents several 108, pp.25-38. hurdles. Indeed, at the very early stages of discovery 5 Sharma, R., Mody, N., Agrawal, U. and Vyas, S.P., 2017. Theranostic and development, nanotoxicity, including nanomaterial- nanomedicine; a next generation platform for cancer diagnosis and induced genotoxicity, constitutes one of the principal therapy. Mini reviews in medicinal chemistry, 17(18), pp.1746-1757. challenges to overcome in the future. 6 Smolkova, B., Dusinska, M. and Gabelova, A., 2017. Nanomedicine and epigenome. Possible health risks. Food and Chemical Toxicology, 109, Systems-level approaches appear highly promising, pp.780-796. especially due to their capability to evaluate individual 7 Van Cauwenberghe, C., 2018a. Innovations in RNA Interference and parts of the system, such as the tissue microenvironment, MicroRNA Therapies. Frost & Sullivan, Drug Discovery Technology, very precisely, accurately, promptly, systematically and TechVision Opportunity Engines, D951/1C. exhaustively. Leveraging terabytes of data generated 8 Van Cauwenberghe, C., 2018b. Innovations in Cell Targeting and by a single experiment by high-content omics Reprogramming. Frost & Sullivan, Genetic Technology News, TechVision technologies, the industry is focusing its attention on Opportunity Engines, D758/78. artificial intelligence (AI) learning approaches allowing 9 Vance, M.E., Kuiken, T., Vejerano, E.P., McGinnis, S.P., Hochella Jr, M.F., assessing, interpreting, organising and controlling the Rejeski, D. and Hull, M.S., 2015. Nanotechnology in the real world: quality and reproducibility of big data generated by Redeveloping the nanomaterial consumer products inventory. each of these systems. Hence, the impact of nanomed- Beilstein journal of nanotechnology, 6, p.1769. icines on the genome, proteome, lipidome and metabolome can be smartly assessed thanks to the development of AI-based intelligent frames for data mining, model curation, statistics visualisation and pattern correlation. Cecilia Van Cauwenberghe, PhD, MSc, BA Although still in progress, this technology convergence Associate Fellow and Senior Industry Analyst is expected to significantly impact upon the healthcare TechVision Group, Frost & Sullivan sector soon, enabling the emergence of programmable [email protected] nanomaterials, highly appropriate to precision medi- ww2.frost.com cine approaches. www.twitter.com/Frost_Sullivan
9 PROFILE
CD33-directed therapy: Current and future perspectives on targeted therapy in acute myeloid leukaemia (AML) Mohammed Gbadamosi and Jatinder K Lamba from Department of Pharmacotherapy and Translational Research at the University of Florida explain CD33-directed therapy for acute myeloid leukaemia (AML), focussing on current and future perspectives
cute myeloid leukaemia (AML) well as other CD33-directed therapies starting with accelerated approval in is a complex heterogeneous using newer technology like bispecific 2000 based on promising results from disease characterised by a T cell engaging antibodies (BiTE) and phase II studies, voluntarily with- Avariety of cytogenetic abnormalities chimeric antigen receptor T-cell drawn in 2010 due to increased induc- and recurrent molecular mutations (CART) therapy. The efficacy of these tion death and no observed survival and aberrant expression patterns. As CD33-directed therapies is rooted in benefit in the post approval phase III the most common and second most the ubiquitous nature of CD33 as an study. Despite these setbacks, much common leukaemia in adults and antigen marker present on AML blasts has been and still remains to be children respectively, many strides and in 90% patients making it a potent dis- learned from the story of GO and efforts using new technologies and tinguisher of AML blasts.3 While its results from multiple subsequent personalised treatment approaches specific biological function is yet to be phase III clinical trials have allowed are being undertaken to address and elucidated, CD33 is a known regulator recent breakthrough re-approval of improve therapy surrounding the of various cell processes related to GO as a low fractionated dose for disease. calcium mobilisation, cytokine release treatment of AML.6-8 and transcriptional activation.4 Addi- However, despite these efforts, out- tionally, CD33 is internalised when Following GO, several other ADCs comes surrounding the disease remain engaged with antibodies thus making directed to CD33 were designed and abysmal. In particular, for younger it an ideal vehicle for antibody-based are currently undergoing develop- patients, complete remission (CR) rates therapies. ment. Vadastuximab talirine (SGN33A) of greater than 80% are achievable, is generated through conjugation the however, the 5-year overall survival Emergent CD33-directed CD33-directed antibody lintuzumab 9 (OS) still remains relatively low at therapies and a pyrolobenzodiazepine dimer. ~40% in comparison to other cancers The recognition of this internalisation Early clinical trials in relapsed AML due to high relapse rates. The out- mechanism is the inspiration behind have shown encouraging results, but come is even worse for older patients many of the ADCs targeting CD33 unfortunately, due to a higher rate of with five-year overall survival at less such as gemtuzumab ozogamicin deaths in phase III clinical trials, all than 25%.2 To address these poor out- (GO; Mylotarg™) which recently SGN33A studies have been placed on comes, several targeted therapeutics received reapproval by the FDA in hold. At this time, the cause of these have become popular additions to the September 2017. GO is structurally early deaths is not clear, further work mainstay 7+3 induction therapy. composed of hP67.6, a CD33-directed will be required before the potential monoclonal antibody, covalently of SGN33A can be re-evaluated for Among these promising options are linked to the cytotoxic agent N-acetyl treatment of AML. IMGN779 is CD33-directed immunotherapeutics gamma calicheamicin.5 The story of another ADC directed to CD33 using a including antibody drug conjugates, as GO in AML has been remarkable, humanised anti-CD33 antibody
10 PROFILE
Rs12459419 C>T
lg-V domain lg-C domain 1 2 3 4 56 7B How can we improve CD33-directed therapy? Rs12459419 = C Rs12459419 = T tccccacag/GG GCC CTG GCT tccccacag/GG GTC CTG GCT With a growing catalogue of CD33- SFRSF2 binding SRSF2 binding compromised directed therapeutics, interest sur- rounding treatment paradigms CD33-WT=Full length CD33-D2 (loss of exon 2) utilising CD33 have been piqued 112 334 556 7B 4 6 7B GO (Figure 1). Specifically, factors influ-
CART33 encing crucial steps related to inter- lgV As of now, there are no CD33-directed agents for the nalisation processes, release and shortened isoform lgC IMGN779 activation of a therapeutic warhead, the intracellular levels and DNA bind- ing capabilities of cytotoxic agents, as ITIM SGN33A well as the efficiency of downstream DNA damage repair pathways and apoptotic pathways can play a critical 225Ac-lintuzumab CD33/CD3 BiTE role in defining the therapeutic effi- cacy of CD33-directed agents.
Abbreviations: GO (gemtuzumab Expression levels of CD33 have been T-Cell ozogamicin), CART33 (CART-Cell directed against CD33 expressing cells) evaluated from multiple phase II and phase III clinical trials of GO. Previ- ously, in vitro data have shown CD33 expression to be associated with Z4681A and contains DGN462, a novel and the activation pathway of T-cells greater GO efficacy; however, results DNA-interacting IGN molecule. 10 With through CD3 binding.13 In essence, from initial clinical trials in adult AML encouraging results from in vitro stud- AMG330 works by recognising CD33+ patients have shown conflicting ies, phase I trials are for IMGN779 cur- AML blasts and forming a link to results with CD33 expression with rently underway. Newer approaches neighbouring T-cells. The connected clinical response. Overall, the relation- using alpha particle therapy and other T-cell then releases proteins, which ship between CD33 blast expression radioimmunology-based strategies induce apoptosis of the AML blast. levels is inconclusive with follow-up have also shown encouraging results. Ex vivo and in vivo studies using patient studies needed, however, this infor- 225Ac-lintuzumab, the premiere the samples and immunodeficient xeno- mation can be used to determine therapeutic of this drug class for AML graph mice models respectively have patients should receive CD33-directed uses 225Ac to generate α-emitting iso- demonstrated effective recruitment agents based on the potential benefit to pes, which induces a cytotoxic dose of T-cells by AMG330 and significant to be gained. of alpha radiation killing AML blasts.11 inhibition of tumour growth. Chimeric Promising preliminary results from a antigen receptor T-cell (CART) therapy, In our group, we have described first-in-man safety and pharmacology using CD33 as a target, is being inves- genetic polymorphisms in CD33 that study, as well as preliminary data on the tigated as well. CART cells targeted to may be related to the response of feasibility of combinatorial treatment CD33 (CART33) are developed by GO.15 Through our studies, we have regimen are currently available.12 using a disarmed virus to engineer the identified rs12459419 (C Continued on page 13 11 YOUR OPINION MATTERS Whether you agree, disagree, or have another viewpoint with any news and features on our website, we want to hear from you. Leaving a comment on any item on our website is easy, so please engage and join the debate today. OPEN ACCESS www.openaccessgovernment.org GOVERNMENT PROFILE 8. Petersdorf, S. H. et al. A phase 3 study of gemtuzumab ozogam- icin during induction and pos tconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121, 4854–4860 (2013). 9. Sutherland, M. S. K. et al. SGN-CD33A: a novel CD33-targeting antibody–drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood (2013). doi:10.1182/blood-2013-03-491506 10. Kovtun, Y. et al. IMGN779, a Novel CD33-Targeting Antibody- Drug Conjugate with DNA Alky lating Activity, Exhibits Potent An- titumor Activity in Models of AML. Mol. Cancer Ther. (2018). doi:10.1158/1535-7163.MCT-17-1077 11. Jurcic, J. G. et al. Phase I Trial of the Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33; HuM195) in Acute Myeloid Leukemia (AML). Blood 118, 768 (2011). Mohammed Gbadamosi Jatinder Lamba 12. Jurcic, J. G. et al. Phase I Trial of Targeted Alpha-Particle Therapy with Actinium-225-Lintuzumab and Low-Dose Cytarabine Continued from page 11 (LDAC) in Patients Age 60 or Older with Untreated Acute of the V-set antibody binding domain tions that may arise, however, the Myeloid Leukemia (AML). Blood 128, 4050 (2016). has two significant implications: it future for the role of immunotherapy 13. Aigner, M. et al. T lymphocytes can be effectively recruited for appears that most (perhaps all) in AML treatment remains bright and ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3-bis- available diagnostic antibodies are propitious. pecific BiTE antibody construct. Leukemia 27, 1107–1115 directed at the V-set domain, thus (2013). carriers of the T allele for rs12459419, 14. Kenderian, S. S. et al. CD33-specific chimeric antigen receptor would appear to be CD33 negative References T cells exhibit potent preclinical activity against human acute due to the lack of inclusion of the 1. Dombret, H. & Gardin, C. An update of current treatments for myeloid leukemia. Leukemia 29, 1637–1647 (2015). V-set domain. More importantly, loss adult acute myeloid leukemia. Blood 127, 53–62 (2016). 15. Lamba, J. K. et al. CD33 splicing polymorphism determines of the V-set domain would directly 2. Thein, M. S., Ershler, W. B., Jemal, A., Yates, J. W. & Baer, M. R. gemtuzumab ozogamicin response in de novo acute myeloid affect the binding, internalisation and Outcome of older patients with acute myeloid leukemia: An Anal- leukemia: Report from randomized phase III children’s oncology clinical efficacy of CD33-directed ysis of SEER Data over 3 Decades. Cancer 119, 2720–2727 group trial AAML0531. J. Clin. Oncol. 35, 674–2682 (2017). therapeutics. Altogether, these results (2013). suggest that loss of IgV domain due 3. Paul, S. P., Taylor, L. S., Stansbury, E. K. & McVicar, D. W. Myeloid Funding from National Cancer Institute (R01-CA132946 and R21- to presence of the splicing SNP com- specific human CD33 is an inhibitory receptor with differential CA155524) supported AML pharmacogenomics in Lamba Lab. promises GO efficacy and, similar to ITIM function in recruiting the phosphatases SHP-1 and SHP-2. expression levels, CD33 genotype can Blood 96, 483–90 (2000). be used as a means of stratification to 4. Ravetch, J. V & Lanier, L. L. Immune inhibitory receptors. Science decide patients who will benefit from 290, 84–89 (2000). regimens including CD33-directed 5. Hamann, P. R. et al. Gemtuzumab ozogamicin, a potent and se- therapeutics. lective anti-CD33 antibody - Calicheamicin conjugate for treat- ment of acute myeloid leukemia. Bioconjug. Chem. 13, 47–58 Mohammed Gbadamosi While targeted immunotherapy is still (2002). Jatinder Lamba relatively young in the realm of AML 6. Bross, P. F. et al. Approval summary: Gemtuzumab ozogamicin in Department of Pharmacotherapy and treatment, their potential in changing relapsed acute myeloid leukemia. Clin. Cancer Res. 7, 1490– Translational Research the field forever is palptiable. Ultimately, 1496 (2001). University of Florida much more additional research is 7. Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival http://ptr.pharmacy.ufl.edu/ needed to understand the capacity of of adult patients with de-novo acute myeloid leukaemia (ALFA- these therapeutics, the factors affect- 0701): A randomised, open-label, phase 3 study. Lancet 379, ing efficacy and the potential limita- 1508–1516 (2012). 13 HEALTH & SOCIAL CARE Sources of funding in the development of therapies for Huntington’s disease Leora Fox, Jennifer Simpson and George Yohrling from the Huntington’s Disease Society of America explore the sources of funding in the development of therapies for Huntington’s disease (HD) untington’s Disease (HD) is an inherited brain standing of rare and complex diseases, paving the way disorder affecting approximately 1 in 10,000 for novel therapies in humans. people in the United States.1,2 HD patients Hsuffer from a triad of debilitating cognitive, emotional Limited funding in the HD field leaves little space for and movement symptoms that usually strike during a high-risk, high-reward projects and creates intense person’s prime working years but can sometimes competition that can discourage a young scientist’s appear as young as early childhood. Huntington ’s commitment to a rare disease like HD. As a result, disease is defined as a rare disorder because of its research funding through private entities like non-profit prevalence of fewer than 200,000 affected individuals foundations must be present to foster medical in the United States.3 An estimated 30,000 people in progress. The HD field is extremely fortunate to have the US are symptomatic, with an additional 200,000 at dedicated sources of non-government funding; the risk.4,5 In comparison, 5.7 million Americans are affected largest, CHDI Foundation, a privately-funded, not-for- by Alzheimer’s disease and 14 million are projected to profit biomedical research foundation, is focused be diagnosed by 2050.6 Given this disparity in medical solely on the development of therapeutics for Hunting- and social impact, the development of treatments for ton’s disease. CHDI has an estimated annual budget of rare and debilitating disorders like HD requires the $100 million,9 nearly three times the reported NIH con- collective efforts of public and private entities. tribution to HD research in 2016. To avoid duplicate efforts and maintain collaborative relationships, other The management of Huntington’s disease relies on HD organisations carve out complementary niches in conventional, non-specific medications to address indi- their research focus or grant funding programmes. The vidual psychiatric symptoms like anxiety and psychosis Huntington’s Disease Society of America, for example, and to calm the characteristic involuntary movements funds HD research initiatives that focus on human- known as chorea. These approaches can temporarily centric projects, engaging promising young scientists, mask the signs of a deteriorating brain, but they are promoting opportunities for community engagement not reparative or restorative. Designing therapies in trials and providing support to researchers aimed at the genetic and biological causes of HD with strong mentorship who are committed to requires an in-depth understanding of its underlying becoming independent and devoting their professional biology and pathology. Traditionally, such research has lives to HD. been the realm of government entities like the National Science Foundation (NSF) and the National Institutes Ultimately the goal of government and non-profit of Health (NIH). As the largest public funder of biomed- investments in HD research is to bring effective ical research worldwide,7 the NIH dedicated more than treatments to market. This is greatly expedited by $2 billion to neurodegenerative disease research in public-private partnerships and requires investment 2016, with $37 million devoted to HD-specific projects, from industry, especially as novel potential therapies comprising just under 2% of the spending on neuro- enter the clinical phases of the research pipeline. In the logical diseases.8 Funding of studies that look at the HD field, the efforts of researchers supported by the biology and pathology of rare neurodegenerative government, the not-for-profit sector and industry diseases like HD are essential to furthering our under- funding, combined with the tenacity and dedication of 14 HEALTH & SOCIAL CARE affected families, culminated recently in a clinical trial 4 Huntington’s Disease: A Family Guide [Pamphlet]. New York, NY. to test the safety of a novel gene therapy designed with Huntington’s Disease Society of America (2016). the underlying biology of HD in mind. Its success, 5 Huntington’s Disease Society of America. What Is Huntington’s announced in December 2017 and detailed at the 2018 Disease? Ret rieved from http://hdsa.org/what-is-hd/ CHDI HD Therapeutics Conference, has led to a signifi- 6 Alzheimer’s Association. (2018, March 19). Latest Alzheimer’s Facts cant investment from Roche Pharmaceuticals to plan and Figures. Retrieved from https://www.alz.org/facts/ and execute a critical Phase 3 trial.10 Beyond support- 7 National Institutes of Health. Impact of NIH Research. (2018, May 08). ing and contributing to the medical research itself, Retrieved from https://www.nih.gov/about-nih/what-we-do/impact- public-private partnerships help to speed the regulatory nih-research processes behind drug development and approval. In 8 US Department of Health and Human Services. (3 July 2017). March 2018, the Critical Path Institute (C-Path) and Estimates of Funding for Various Research, Condition, and Disease CHDI announced the official launch of the Huntington’s Categories https://report.nih.gov/categorical_spending.aspx Disease Regulatory Science Consortium (HD-RSC), 9 The precious participation of the Huntington’s disease community in which will include representatives from various sectors the quest for treatments: A report on the 2015 HD Therapeutics Con- and will focus on cost reduction and efficiency in HD ference. (2015, March 25). Retrieved from http://www.newshd.net/or- drug development.11 ganization/7007/the-precious-participation-of-the-huntingtons-disease -community-in-the-quest-for-treatments-a-report-on-the-2015-hd- With the field poised on the brink of several promising therapeutics-conference/ trials, diverse funding sources and collaborative 10 Ionis Pharmaceuticals. (2017, December 11). Ionis Pharmaceuticals initiatives between government, the not-for-profit Licenses IONIS-HTT Rx to Partner Following Successful Phase 1/2a sector and industry remain critical to expand our Study in Patients with Huntington’s Disease. Retrieved from knowledge of HD biology and hasten the progress of http://ir.ionispharma.com/news-releases/news-release-details/ionis- medicine. The rarity of Huntington’s disease does not pharmaceuticals-licenses-ionis-htt-rx-partner-following lessen the needs of affected families, and additional 11 C-Path and CHDI launch consortium to accelerate development of resources serve to solidify a collaborative research Huntington’s disease therapies. (2018, March 28). Retrieved from community and power faster medical innovations both https://c-path.org/c-path-and-chdi-launch-consortium-to-acceler- inside and outside of the HD field. Therefore, we need ate-development-of-huntingtons-disease-therapies/ to be vigilant in ensuring increased access to funding for rare disease projects. This includes working to increase the visibility of rare disease research in such a way that both public and private entities recognise the potential of their investments to inform broader medical applications, pave the way for novel method- Leora Fox, PhD ologies, and shape policy for the Huntington’s disease Manager of Research and Mission Programs community and beyond. ■ Jennifer Simpson, LCSW References Senior Manager of Advocacy and Youth Programs 1 Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington’s disease: a systematic review George Yohrling, PhD and meta-analysis. Mov Disord. 2012;27(9):1083-91. Senior Director of Mission and Scientific Affairs 2 Rawlins MD, Wexler NS, Wexler AR, et al. The Prevalence of Hunting- ton’s Disease. Neuro epidemiology. 2016;46(2):144-53. Huntington’s Disease Society of America 3 National Organization of Rare Diseases. Rare Disease Resources & [email protected] FAQs. Retrieved from https://rarediseases.org/for-patients-and- http://hdsa.org/ families/information-resources/resources-faqs/ www.twitter.com/HDSA 15 PROFILE What’s in an aggregate? Therapeutic intervention in Huntington’s Naoko Tanese from New York University School of Medicine outlines their work around Huntington’s disease (HD) and effective new targets for therapeutic intervention untington’s disease (HD) is a rare hereditary neurodegen- erative disease that strikes patientsH in mid-life. American physician George Huntington first described the disease in 1872 after seeing affected residents in East Hampton, New York. Patients generally experience a progressive decline in cognitive, psychiatric, and motor functions. The disease is fatal. In 1993 an interna- tional team of scientists discovered the gene that causes the disease. Despite years of intense research, no cures or treatments to delay the onset or prevent the progression of the disease are available. HD is caused by an inherited domi- Naoko Tanese, PhD, Associate Dean for Biomedical Sciences, and Director, Sackler nant mutation in the Huntingtin gene, Institute of Graduate Biomedical Sciences HTT. This means an offspring of a parent who carries a mutant HTT gene has a 50% chance of inheriting other cells and tissues intact. This referred to as protein folding. When the mutant gene. The mutation results indicates that some neurons are par- proteins misfold, they often lose their in an increased number of repeats ticularly sensitive to the toxic effects normal functions. Cells have developed (greater than 40) of the amino acid of mutant HTT. elaborate mechanisms to remove such glutamine in the encoded Huntingtin aberrant, misfolded proteins. This protein (HTT). The normal HTT protein has been protects the cells from potential implicated in many cellular functions. harmful effects of misfolded proteins. A normal HTT protein has between 7 However, we have an incomplete and 35 glutamines. Increased number understanding of how mutant HTT However, misfolded proteins can of glutamine repeats changes the causes the disease. A better under- accumulate over time and form property of the protein and renders standing of the functions of the irreversible aggregates that impair it toxic to cells. The HTT protein is normal and mutant HTT protein is cellular homeostasis. These aggregates present throughout the body and paramount, if effective therapies or are a hallmark of many neurodegen- throughout life. However, mutant HTT cures are to be developed. erative diseases. They are found in is toxic to select cells. Postmortem postmortem brain tissues of affected examination of the brains of affected Proteins made in cells maintain certain individuals. Age-associated diseases individuals shows massive cell loss in structures dictated by their biochemical such as Alzheimer’s disease, are certain parts of the brain, leaving and biophysical properties. This is linked to protein misfolding. HD is 16 PROFILE also considered a protein misfolding Since the functions of normal HTT and binding proteins linked to neuro - disease although many other mecha- the mechanisms by which its mutant degenerative diseases. Our results nisms are thought to play a role in the counterpart contributes to HD remain suggest HTT has a role in the formation disease pathogenesis. unclear, my lab began investigating of RNA-protein granules. the role of HTT in RNA metabolism. Decades of research have uncovered New imaging techniques have helped Unlike normal HTT, mutant HTT has a intriguing properties of different types us determine the location of the propensity to interact with one of protein aggregates, some of which normal HTT protein inside neurons. another through the increased repeat are RNA-protein granules found in sequence. At high concentrations, normal cells. Each granule appears to Strikingly, we discovered that HTT mutant HTT alters biophysical proper- have distinct properties and its forma- could be found near neuronal RNA ties of RNA-protein assemblies and tion is driven by specific sets of proteins granules. RNA granules are large RNA- shifts the equilibrium in favour of and RNA. Some granules are formed protein assemblies responsible for forming aggregates. in response to stress. This mechanism transporting RNA to specific locations serves to halt energy-consuming in the neuron. To determine whether Furthermore, a re cent study reported cellular activities, by sequestering HTT influences RNA localisation, we stable formation of RNA aggregates proteins involved in key biochemical reduced the level of normal HTT in containing repeat sequences. Collec- processes. Upon removal of the stress, neurons grown in a culture dish and tively, the findings suggest that granules disassemble and the released examined its effect on transport of mutant HTT together with repeat proteins resume their normal functions. RNA. We found that the reduction of sequence-containing RNA forms HTT in cells disrupts RNA localisation. granules that become converted to Interestingly, mutant proteins linked The result points to HTT contributing irreversible toxic aggregates over to several neurodegenerative diseases to the integrity of RNA granules during time. The development of chemical have been located within these types RNA transport. agents that prevent aggregation or of granules. They include mutant disrupt aggregates may serve to RNA binding proteins associated with New experiments in HTT reverse the toxicity associated with amyotrophic lateral sclerosis, spinal To further investigate cellular processes the mutant protein and RNA. Through muscular atrophy, and fragile X that HTT is involved in and how they understanding of how HTT supports syndrome. These RNA binding might differ in mutant HTT, we neurons with these functions, we proteins normally play a role in designed experiments to purify hope to reveal effective new targets RNA transport, translation of RNA normal and mutant HTT proteins from for therapeutic intervention. to make proteins, and formation of cells and tissues. We next identified RNA-protein complexes. proteins that interacted with each form of HTT. By identifying the func- Mutant RNA binding proteins, however, tions of the proteins that co-purified show altered biophysical properties. with HTT, we uncovered new functions They have increased propensity to for HTT. Analysis of the binding partners interact with one another and affect of HTT proteins revealed that both the formation and function of granules. normal and mutant HTT interact with Naoko Tanese, PhD There is increasing evidence that over proteins involved in RNA metabolism Associate Dean for Biomedical Sciences, time mutant RNA binding proteins in and protein synthesis. Director, Sackler Institute of Graduate these granules steadily accumulate Biomedical Sciences and become converted to irreversible We have thus uncovered new roles for New York University School of Medicine aggregates that are toxic to cells. normal and mutant HTT in RNA Tel: +1 212 263 8945 Neurons are vulnerable to aberrant metabolism. The findings have several [email protected] proteins that accumulate because implications for the development of https://med.nyu.edu/faculty/naoko-tanese neurons do not divide. Ultimately the HD. We have located mutant HTT in www.twitter.com/nyuschoolofmed machinery in the cell fails to remove neuronal granules, similar to those http://sackler.med.nyu.edu toxic proteins, causing cell death. associated with aforementioned RNA 17 HEALTH & SOCIAL CARE The diagnosis and treatment of cancer in the United States The vital work of the National Cancer Institute, part of the National Institutes of Health, is placed under the spotlight here by Open Access Government, including the dissemination of new findings on the diagnosis and treatment of cancer he National Cancer Institute, part of the National On top of this, the act provided additional founding t Institutes of Health, is the U.S. federal govern- establish 15 new cancer research centres, local control ment’s lead agency in coordinating research, programmes and an international cancer research Tproviding training and disseminating new findings on data bank. the diagnosis and treatment of cancer. Over the years, the NCI has established several major In 1937, President Franklin D Roosevelt signed the programmes to tackle cancer, including the Cancer National Cancer Act to support cancer research – the Information Service (1976), the Office of Cancer Sur- first time Congress had appropriated funds for a vivorship (1996) to study ways to enhance the length non-communicable disease. and quality of life for cancer survivors and the TARGET Initiative (2006) to identify the molecular characteris- The act established the National Cancer Institute as the tics of childhood cancers in order to design better federal government’s primary agency in coordinating treatments. grant funding for cancer research, providing training in diagnosis and treatment and disseminating the findings It has also worked with the National Human Genome of research carried out in the U.S. and other countries. Institute to launch the Cancer Genome Atlas, a project to systematically examine the genomic changes involved Thirty-four years later, the National Cancer Act of 1971 in human cancer. greatly expanded the role of the NCI, giving its director the broad authority to plan and develop an intensified There has been tremendous progress made. Over the and coordinated National Cancer Programme that past two decades, research has led to a 25% decline in included NCI and related initiatives, other research the rate of deaths from cancer. institutes, federal and non-federal programmes “in order to more effectively carry out the national effort However, there is still much to do. Nearly 40% of Amer- against cancer”. icans will be diagnosed with cancer in their lifetimes. Around 600,000 adults and 2,000 children die from The act also granted the NCI director access to the cancer in the US every year. president of the United States and required them to submit an annual budget directly to the Oval Office. The NCI is pushing ahead with a broad portfolio of Furthermore, it established the National Cancer Advi- research. In 2017-18, the institute’s total budget stood sory Board, made up of 18 distinguished scientists, at $5.67 billion, around 40% of which goes towards members of the public and ex-officio members of research grants. other government agencies, to advise the NCI on its programmes, along with the President’s Cancer Panel Current key initiatives include the Cancer Moonshot, to provide annual reports. an ambitious plan to accelerate a decade’s worth of 18 HEALTH & SOCIAL CARE NCI-backed research has made headlines in recent months. In June, it was reported that a novel approach to immunotherapy developed by NCI researchers had led to the complete regression of breast cancer in a patient who had been unresponsive to all other treatments. “Nearly 40% of Americans will be diagnosed with cancer in their lifetimes. Around 600,000 adults and 2,000 children die from cancer in the US every year.” The findings of the clinical trial, which was led by Dr Stephen A Rosenberg, chief of the surgery branch at the NCI’s Center for Cancer Research, were published in Nature Medicine. “We’ve developed a high-throughput method to identify mutations present in a cancer that are recognised by the immune system,” Dr Rosenberg says. “This research is experimental right now. But because this new approach to immunotherapy is dependent on research into five years through targeted grant fund- mutations, not on cancer type, it is in a sense a blueprint ing, supplements and where appropriate, partnerships we can use for the treatment of many types of cancer. with foundations, academia and the private sector. In 2016, Congress approved $1.8 billion over seven years “All cancers have mutations, and that’s what we’re to support the Cancer Moonshot. attacking with this immunotherapy. It is ironic that the very mutations that cause the cancer may prove to be The NCI also runs the Precision Medicine Initiative, the best targets to treat the cancer.” which focuses on four broad areas – new and expanded precision medicine clinical trials; overcoming The Center for Cancer Research is the largest division drug resistance to cancer treatments; developing new of the NCI intramural research programme and com- laboratory models for cancer research; and building prises nearly 250 groups conducting basic, translational and sharing a digital repository of data resulting from and clinical research. The CCR’s clinical programme is NCI-sponsored precision medicine clinical trials – with housed at the National Institutes of Health’s Clinical the aim of bringing precision medicine into everyday Center, the world’s largest hospital dedicated to clinical clinical practice. research. ■ Meanwhile, the National Clinical Trials Network (NCTN), the cornerstone of NCI’s clinical trials programme, brings together organisations and clinicians to conduct large-scale trials across the U.S. and Canada. These help to establish new standards of care, move new therapies toward FDA approval, test new approaches to radiation therapy and surgery and validate new biomarkers. The Open Access Government NCTN provides the infrastructure for NCI-funded [email protected] treatment, screening and diagnosis treatments at over www.openaccessgovernment.org 3,000 sites. www.twitter.com/OpenAccessGov 19 PROFILE Cancer immunotherapy therapy is here and now Stephanie K. Watkins PhD from Loyola University Chicago shares her views on cancer immunotherapy therapy – the concept of using the immune system to fight and destroy cancer cells he concept of using the immune trastuzumab and pembrolizumab. The therapy is that cancer cells constantly system to fight and destroy naked monoclonal antibody sticks to mutate or lose expression of the cancer cells has been a dream of the target Ag on the surface of tumour antigen – that antibody was designed Tclinicians since 1891 when Dr William cells and generates an immune to target and frequently become resis- Coley first injected a patient with an response by recruiting immune cells tant to the therapy. Therefore, the key inoperable bone cancer with strepto- to destroy the cell harbouring the to this therapy is choosing the coccal organisms and observed the antibody. A second mechanism uses appropriate target and monitoring regression of an aggressive, malignant the antibody to block Ags on cells in desensitisation. tumour. These first attempts were the tumour microenvironment. quite extraordinary, given how little Similar to monoclonal antibody was known or understood about the “The major advantage of immune- strategies, one of the most successful immune system at that time. Unfortu- based therapies is that they are very therapies across a spectrum of cancers nately, because of this lack of under- individualised for each patient and currently, is the use of immune check- standing, many clinicians ignored the tailored to “natural” protection against point inhibitors. T lymphocytes or T potential that these immune therapies tumours.” cells are a critical cell in the immune carried to cure cancer and the strategy system and are the primary cell fell by the wayside for many years. The blockage prevents tumours from responsible for targeting and destroy- growing or spreading by denying ing cells that are harmful to the body, Now that the field of immunology activation of the blocked Ag. The con- including virus-infected cells and has exploded and is accepted as a jugated monoclonal antibodies are tumour cells. In normal immune critical component across all areas of joined to a chemotherapy drug or responses, it is important to keep T medicine, scientists and clinicians are sometimes a radioactive particle. This cells under control and prevent them once again focused on utilising the type of monoclonal antibody is often from destroying healthy tissues, there- power of the immune sys tem to used to deliver a cytotoxic drug (the fore, when they are activated they up- eradicate cancers of all origins. chemotherapy or radioisotope agent) regulate receptors on the cell surface Immunotherapies today are highly directly to a tumour cell that is bearing that allows their functions to be quickly technologically advanced and target the target antigen. The directed deliv- turned subdued. These regulatory an array of properties of the immune ery lessens the destruction of normal receptors include PD-1 and CTLA-4. system. In this review, we will briefly healthy cells during the destruction of cover the main types of therapy used tumour cells. In cancer, when activated T cells infil- in the clinic. trate a tumour, many tumours express The bispecific monoclonal antibodies the ligands that bind to the regulatory Monoclonal antibodies are one class are drugs designed to target two dif- receptors and can turn T cells “off”. of immune therapies designed to ferent antigens, one on the tumour Therefore, the checkpoint inhibitors target specific antigen (Ag) expressed cell and one on the T cell, an immune are designed to bind to either the by tumour cells. Different types of cell capable of killing tumour cells and receptors or the ligand and prevent monoclonal antibodies include: naked, the antibody brings the two cells the interaction from eliminating the T conjugated and bispecific. The naked together, allowing the T cell to destroy cells anti-tumour functions. monoclonal antibodies consist of pop- the cancer cell. The largest hurdle to ular drugs, such as alemtuzumab, overcome with monoclonal antibody Commonly used drugs are the PD-1 20 PROFILE T (Provenge) and was approved by the FDA in 2010 for the treatment of metastatic prostate cancer. Provenge was a vaccine using dendritic cells (DC). DC is responsible for presenting antigen to T cells that are then stimu- lated to attack cancer cells bearing similar antigen. The original trial was conducted in 512 randomised patients and the vaccine was found to extend the median survival time 4.1 months. Electron microscopy image of immune cells, T cell, neutrophil, monocytes Dendritic cell coated with prostate specific Again, this was a small but important antigen step, paving the way for more advanced immune cell vaccines. individualised for each patient and inhibitors pembrolizumab and tailored to “natural” protection against nivolumab, PD-L1 inhibitors ate- In recent years, researchers have tumours. Many immune bases zolizumab, avelumab and durvalumab identified ways to make more effec- therapies, especially the adoptive T and CTLA-4 inhibitor ipilimumab. tive and potent immune cells for cell transfer therapies consist of a Ipilimumab was the first FDA approved patient delivery. The CAR T-cell therapy single infusion with only a few weeks immune-checkpoint drug for the was FDA approved for treatment of of follow up care, compared to treatment of melanoma and kidney children with acute lymphoblastic traditional chemotherapy approaches cancers. Within the last year, six more leukaemia (ALL) and adults with other which often last six months or more. drugs in this class have made approval lymphomas in 2017. CAR T-cell stands Cancer continues to evolve, but and the list continues to grow. Current for chimeric antigen receptor T cell. research and ongoing clinical trials are strategies are now working to combine These T cells are the patient’s own T making successful strides to employ these checkpoint inh ibitors with the cells that are genetically modified to new technologies to harness the use of small molecule drugs that can add an artificial receptor to their cell power of nature’s best medicine, also prevent T cell exhaustion, which surface that targets the CD-19 the immune system. happens in during chronic antigen molecule by cancer cells. The genetic stimulation, such as within a tumour. modifications promote the T cell to produce an abundance of inflamma- “Now that the field of immunology tory proteins, called cytokines and has exploded and is accepted as a often resulting in a “cytokine storm” critical component across all areas of shortly after patient administration. medicine, scientists and clinicians It’s approximated that 70-90% of are once again focused on utilising patient experience this short-term the power of the immune system to event due to the robust immune eradicate cancers of all origins.” response. Originally, the cytokine storm was somewhat feared as a neg- The third class of therapies making ative result of stimulating the immune tremendous strides in the clinic today system, but now with drugs, such Stephanie K. Watkins PhD are the cancer vaccines or adoptive T as tocilizumab, the duration and Department of Microbiology and Immunology cell transfer therapies. This therapy is intensity can be controlled, and the and Surgery, Loyola University Chicago the direct transfer of immune cells cytokine storm may be observed as a Tel: +1 708 327 3361 into a patient that is capable of either positive event indicating the initiation [email protected] directly destroying cancer cells or of an effective therapy. https://ssom.luc.edu/microbio/ boosting the internal immune response to fight cancer. The first vac- The major advantage of immune- cine of this type was called sipuleucel- based therapies is that they are very 21 HEALTH & SOCIAL CARE Muscular dystrophy: Present concerns and foreseen opportunities Cecilia Van Cauwenberghe from the TechVision Group at Frost & Sullivan provides a detailed analysis of the present concerns and foreseen opportunities around muscular dystrophy (MD) uscular dystrophies constitute a group of checkpoint inhibitors utilised in cancer therapy involve genetically dissimilar diseases related to the the release of a cascade of immune systems that accel- weakening and breakdown of skeletal erates muscle loss. Moreover, nutritional support Mmuscle. At present, nine main categories and over results are generally ineffective in these patients due thirty subtypes of muscular dystrophy have been to the fundamental molecular processes governing recognised, based on alterations in the structure cancer-associated muscle metabolism and the epige- and/or function of the dystrophin protein caused by netic processes conducting muscle wasting phenotype mutations in certain genes specifically impacting (Carr et al., 2017). muscle function (Saada et al., 2016). Sarcopenia is defined as low muscle function in the Despite the prevalence and the estimated economic presence of low muscle mass. Sarcopenia is mostly burden of over $795 billion associated with the whole associated with endocrine causes such as diabetes set of types and subtypes of muscular dystrophy, the mellitus and insufficient insulin-like growth factor 1, as underlying biology and pathogenesis remains poorly well as, decreased grow th hormone and male hypog- understood (Gumucio, 2017). Nevertheless, recent onadism, conveniently treated with insulin, testos- advances in omics-based science, including the advent terone and selective androgen and anti-myostatin of artificial intelligence (AI) learning methods contributing activin II receptor molecules (McKee et al., 2017). to the analysis and the correlation of genome, proteome, epigenome, metabolome and lipidome data, are Additional factors leading to sarcopenia are decreased significantly accelerating disease pattern identification physical activity, sudden weight loss, reduced blood under a precision medicine framework. An in-depth flow to muscles, loss of motor neuron units and lack of knowledge of the mechanisms involved in both normal vitamin D, generally treated with leucine-enriched physiological functioning and disease status is becoming essential amino acids and vitamin D, while increasing crucial for the development of efficient treatment aerobic exercise. strategies for muscular dystrophy. A collateral effect associated with muscular dystrophy Muscular dystrophies: A brief overview is myosteatosis, that is, the accumulation of patholog- Disease implications and collateral effects ical ectopic lipid with concomitant atrophy and fibrosis. Myopenia, a clinically relevant muscle wasting condition Myosteatosis mostly follows chronic rotator cuff associated with the impairment of muscle function due injuries. Scleraxis, a basic helix-loop-helix transcription to congenital or acquired causes including cachexia and factor required for the embryonic formation of tendon sarcopenia, may represent a life-threatening disorder. and the differentiation of tendon progenitor cells, is supposed to play an important role in adult tendon Cachexia is a multifactorial syndrome related to a variety adaptation as well, along with the progression and of conditions leading to inflammatory muscle mass consequences of myosteatosis on muscle metabolism loss, hence potentially resulting from multiple different and function. Although the pathways activated by disease causes and genetic variability. Cancer patients excess lipid are poorly understood, the myosteatosis are commonly affected by cachexia. Most immune process starts with an initial acute inflammatory phase 22 HEALTH & SOCIAL CARE due to a dysfunctional mitochondrial functioning Breakthrough genetic therapies targeting unable to oxidise lipid. As a result, a lipid is accumulated muscular dystrophy over time, leading to a chronic, persistent inflammatory The estimated prevalence of Duchenne’s and Becker’s condition causing increased oxidative stress, tissue muscular dystrophy (DBMD) in the United States is 1 atrophy and muscle dysfunction. in every 7,250 males aged 5-24 years (Romitti et al., 2015). Both diseases involve the loss of function of the Clinical approaches: The precision dystrophin gene, generally due to a disruption in the medicine era dystrophin protein reading frame. Therefore, an accu- Diagnosis and treatment opportunities in rate correction of the dystrophin gene via gene editing, modern medicine gene therapy or cell regeneration approaches would A recent focus in the field has centered on the ability constitute a noteworthy therapeutic solution. In fact, to recognise the genetic mutations related to each sub- recent approaches have been made intending to use type of muscular dystrophy, followed by the prospect recombinant adeno-associated viral (rAAVs) vectors of gene manipulation intending to reverse the disease and lentiviral vectors, as well as, sleeping beauty non- progression. Indeed, genetic modulation via DNA and viral transposons to host truncated highly functional oligonucleotides and gene editing technologies includ- microdystrophin or microutrophin genes into the ing clustered regularly interspaced short palendronic genome aiming to improve the dystrophin function. repeats (CRISPR) are expected to hold the great promise of a cure for muscular dystrophy (Morley and Anker, Additional advances have been made with the devel- 2017). The advent of precision medicine is significantly opment of DNA and RNA-based therapies, including paving the way for the development of novel smart oligonucleotides capable of interfering the splic- genomics-based early preventive strategies and poten- ing process to restore the dystrophin protein reading tial treatments for a plethora of severely underserved frame (Van Cauwenberghe, 2018). Indeed, the U.S. conditions, such as those associated with some type of Food and Drug Administration (FDA) approved muscular dystrophy. eteplirsen for the treatment of Duchene’s muscular Continued on page 25 23 TAILOR-MADE PROMOTION As part of our package of information services, Open Access Government are proud to present the option of a bespoke publication. Our ebooks can be used by you to target electronically to a targeted audience a specialised readership with informative using the latest digital publishing content. They can be 8, 12 or even 16 technology for ease of reading. pages promoting your profession and services. We have access to an ex tensive database of contacts within specialised areas, so Our production, editorial and design you can be confident that your message teams will work with you to identify and will be delivered to the right people at develop your message before delivering it the right time. Get in touch today to plan your communication strategy. Tel: 0843 504 4560 OPEN ACCESS www.openaccessgovernment.org GOVERNMENT HEALTH & SOCIAL CARE Continued from page 23 dystrophy (DMD). Gene editing approaches, more Further reading precisely CRISPR techniques, have been tested to genetically alter, enhance or inhibit specific genes 1 Carr, R.M., Enriquez-Hesles, E., Olson, R.L., Jatoi, A., Doles, J. and related to muscular dystrophy in human stem cells Fernandez-Zapico, M.E., 2017. Epigenetics of cancer-associated (Iyer, 2017). Although most results achieved via gene muscle catabolism. editing approaches have led to unintended mutations, 2 Gumucio, J., 2017. Mechanisms of Growth and Chronic Disorders of the synergy of this technology with human induced Musculotendinous Tissues. pluripotent stem cell (iPSC) therapies is still highly 3 Iyer, V., 2017. Growth Insights on the Global CRISPR/Cas9 Tools promising. Market, 2017 – A Disruptive Technology – Gene-editing Tools for Multiple Applied Industries. Frost & Sullivan Research Service, Growth “Myopenia, a clinically relevant muscle wasting Insights, K242. condition associated with the impairment of muscle 4 McKee, A., Morley, J.E., Matsumoto, A.M. and Vinik, A., 2017. Sarcope- function due to congenital or acquired causes nia: an endocrine disorder? Endocrine Practice, 23(9), pp.1143-1152. including cachexia and sarcopenia, may represent a 5 Morley, J.E. and Anker, S.D., 2017. Myopenia and precision (P4) med- life-threatening disorder.” icine. Journal of cachexia, sarcopenia and muscle, 8(6), pp.857-863. 6 Romitti, P.A., Zhu, Y., Puzhankara, S., James, K.A., Nabukera, S.K., Final remarks Zamba, G.K., Ciafaloni, E., Cunniff, C., Druschel, C.M., Mathews, K.D. Gene and cell therapies, including gene editing and and Matthews, D.J., 2015. Prevalence of Duchenne and Becker mus- stem cells technologies, synergistically combined with cular dystrophies in the United States. Pediatrics, 135(3), pp.513-521. data analytics and AI-based learning processes, consti- 7 Saada, Y.B., Dib, C., Lipinski, M. and Vassetzky, Y.S., 2016. Genome-and tute a powerful potential approach to efficiently treat cell-based strategies in therapy of muscular dystrophies. Biochemistry muscular dystrophy. Associated with a deficient struc- (Moscow), 81(7), pp.678-690. ture or function of the dystrophin gene protein, 8 Van Cauwenberghe, C., 2018. Innovations in RNA Interference and myopenia represents a therapeutic area that can be MicroRNA Therapies. Frost & Sullivan Research Service, Drug Discovery powerfully addressed under a precision medicine TechVision Opportunity Engine (TOE), D951/1C. approach. Although further efforts remain to be made, the use of a patient’s own genome, proteome, epigenome, metabolome and lipidome outputs as predictive and prognostic biomarkers for the adequate treatment and management of muscular dystrophy is making precision medicine a reality, propelling therapeutics discovery pathways through notable inno- vations in microRNA-based platforms, self-delivered RNA interference-based liposomes, anti-code thera- peutics, therapeutic ribonucleases, antisense drugs, RNA splicing modulation, exon skipping treatments and microRNA programming, among many other disruptive approaches. ■ Cecilia Van Cauwenberghe, PhD, MSc, BA Acknowledgements Associate Fellow and Senior Industry Analyst TechVision Group, Frost & Sullivan I would like to thank all contributors from industry [email protected] involved with the development and delivery of this article ww2.frost.com from the Te chVision Group at Frost & Sullivan. www.twitter.com/Frost_Sullivan 25 PROFILE Disease-associated myosteatosis in people with cancer: Can it be treated? athological fat infiltration into Myosteatosis is revealed in vivo by muscle is a feature of disease- computed tomography (CT) imaging induced muscle loss that signif- as muscle wi th low radiodensity com- Picantly associates with shorter survival bined with presence of intermuscular in people with cancer. Fat is associated adipose tissue. The evidence for a with skeletal muscles in the form of relationship between low muscle intra-myocellular lipid droplets within radiodensity and shorter survival in the cytoplasm of myocytes as well as people with cancer is building. Loss of intermuscular adipocytes. These lipid skeletal muscle mass appears to gen- stores are thought to provide fuels for erally occur with accumulation of adi- This slide shows a CT image from a cancer skeletal muscle contraction, however, pose tissue into muscle. We reported patient who underwent 16 weeks of first excess deposition of triglycerides that patients undergoing treatment line platinum doublet chemotherapy for lung cancer. Only the intramuscular within cells and organs that normally for lung cancer lost muscle mass and adipose tissue is shown in color contain only small amounts of fat concurrently gained intermuscular (such as liver, pancreas, skeletal and adipose tissue during treatment for cardiac muscle) is defined as steatosis. cancer, whereas patients who supple- mass and experienced a decline in Myosteatosis (steatosis of the muscle) mented their daily intake with fish oil intermuscular adipose tissue over the is a pathological phenomenon reflect- containing eicosapentaenoic acid and same time period. This intervention ing an impairment of synthesis and docosahexaenoic acid [EPA+DHA (2.2 also resulted in a greater response by elimination of triglyceride. g/day)] maintained or gained muscle the tumor to the drugs being usedo t To quantify different tissues for body composition analysis using computed tomography imaging, a bony landmark is used to consistently measure the same region of the body across patients. The 3rd lumbar vertebrae is an established landmark in body composition analysis that correlates with amount of whole body muscle and fat. Each tissue attenuates radiation in a specific way which is recognised by a software program to enable skeletal muscles and different types of adipose tissues to be identified. Each tissue of interest is then color coded (see legend). When more than one CT image exists in the patient record, tissue changes over the trajectory of the disease can be determined. This image presents 2 scans taken approx 6 months apart at the same region within the same patient. The marked decline in muscle and adipose tissue is evident, concurrent with deposition of adipose tissue into muscle 26 PROFILE An illustration of annotated CT images, and Illustration of Variation in Muscle Radiodensity accompanying histograms of radiation attenuation showing the percentages of total tissue cross-sectional area within the ranges of adipose tissue in paraspinal/psoas muscles is useful to understand the problem of myosteatosis. This illustration shows the percentages of total tissue cross-sectional area within the typical attenuation ranges determined for the respective tissues for 2 subjects. Subject 1 is a 63 year old male with muscle characteristics at the median values for male cancer patients with a diagnosis of solid tumor at our centre. For Subject 2 there is extensive macroscopic adipose tissue and less than half of the cross sectional area of his muscles falls within the normal attenuation range. Overall, Patient I has a greater proportion of fat and low attenuation muscle, than muscle with normal characteristics. Patient II is remarkable in several respects, including extensive visible fatty infiltration and extremely high proportion of total muscle area falling within a range of attenuation values generally recognized to be abnormally low (adapted from Aubrey et al 2014) treat the cancer. Therefore there may Using this as the rationale for the next suggests an improvement in patho- be multiple benefits of dietary fish oil step of this line of questioning, we logical features of myosteatosis by to the cancer patient undergoing have planned a clinical trial upon dietary EPA and DHA. If so demon- treatment. which to text the biological efficacy of strated, this work will provide critical fish oil to reverse cancer- associated translational knowledge required to To explore these observations that myosteatosis in a cancer population effectively plan treatment interven- cancer patients supplementing with known to exhibit myosteatosis, veri- tions that have significant potential to EPA+DHA experience an improvement fied by in vivo imaging of muscle impact the lives of people diagnosed in myosteatosis, we established a pre- features by CT scan. At the time of with cancer, a major cause of death clinical model to enable intervention diagnosis and treatment planning, globally. with EPA+DHA at various time points patients will be randomized and con- in the cancer trajectory. We used an sented to consume EPA+DHA (2.2 g rat model bearing the Ward colorectal per day) until day of surgery (at least tumor and treated in a manner that a 4 week period) or receive standard mimics standard clinical care for this of care (no intervention). Muscle from disease in humans with respect to the the subjects will be collected at the types of drugs used and the toxicities time of surgery and prepared for anal- they evoke. Using this model we have ysis. Analysis of the muscle tissue will demonstrated that the results align enable determination of differences Dr Vera Mazurak with our human data suggesting an in Triglyceride-fatty acid content (a University of Alberta improvement in muscle condition hallmark of myosteatosis). We expect www.afns.ualberta.ca/StaffProfiles/Aca- concurrent with a better response by that this research will verify the tanta- demicProfiles/Mazurak.aspx the tumor to the anti-cancer drugs. lizing evidence we have in hand that 27 PROFILE Duchenne muscular dystrophy (DMD): Correcting the dystrophin gene Dr Ahlke Heydemann, Associate Professor and Director of Medical School Curriculum at University of Illinois, Chicago explains Duchenne muscular dystrophy (DMD), focussing on the issue of correcting the dystrophin gene uchenne muscular dystrophy tant trait can be utilised to set a Utilising cells to reintroduce a wild-type (DMD) is an inherited progres- reasonably achievable goal for a highly dystrophin gene into diseased muscle sive disease that affects skele- beneficial and successful therapy. has been investigated for many years. Dtal, diaphragm and cardiac muscles. Recent progress has given new hope to The pathology initiates with muscle Treatments in the preclinical this particular therapy for MD. Stem weakness, particularly noticeable on and clinical trial pipeline cells (SC) can be harvested from a the leg muscles of the young – two to There are many promising treatments number of sources: embryonic (ESC) three-year-old – boys. The dystrophin in the preclinical and clinical trial ti ssues or induced (induced pluripo- gene is located on the X-chromosome; pipeline. These can be subdivided into tent stem cells) (iPSC) from adult tis- therefore, it is sex-linked and only boys overlapping categories. sues. These SCs have the potential to get the full disease. Women are carri- become permanently engrafted into ers and can develop cardiomyopathy • Inflammation/immune inhibitors. the host muscles, proliferate, express much later in life. As time goes on, the dystrophin and respond to injury. ESCs skeletal muscles continue to weaken, • Modulators of metabolism. have the benefit of being immune and corticosteroid treatments are privileged, meaning the host tissue will initiated, usually at around six years • The reestablishment of the dys- not reject the cells as foreign. However, of age. trophin glycoprotein complex with- obtaining the number of ESCs required out dystrophin and to treat a patient has been difficult. A few years later, night-time assisted Proliferating the ESCs in culture causes ventilation and then prophylactic • Gene correction. functional changes that impede their ACE inhibitors for the maintenance effectiveness in establishing themselves of respiratory and cardiac function, The gene correction strategy can be in the host tissue. respectively, are added to the treat- further subdivided as shown below. ment regimen. These combined treat- One of the benefits of iPSCs is that ments have extended the quality and Gene correction scientists can produce large numbers quantity of the patients’ lives, but more 1. Cell transplantation. without changing their effectiveness effective treatments or even cures are a. Stem cells for transplant. ESCs are usually still urgently required. Within MD, i. Embryonic. derived from normal donors and there is some relationship between the ii. Induced. therefore, contain and deliver the specific mutation in the dystrophin 1. From normal donors. intact dystrophin gene to all muscles gene and the protein levels of dys- 2. From the patient, corrected that the cells populate. iPSCs can be trophin and the severity of the disease. in vitro derived from a normal donor or the b. Muscle satellite cells. patient themselves. If derived from The mildest cases are classified as i. From normal donors. the patient, the genetic defect will Becker MD (BMD). These mild cases ii. From the patient, corrected in have to be corrected while the cells reveal that a relatively low expression vitro. are in culture. An additional step, level of dystrophin – only 20 to 40 % of 2. Premature stop codon read-through. but a highly effective one, and using normal levels – is required to establish 3. Exon skipping. the patient’s cells ensures that a a mild disease course. This very impor- 4. CRISPR/Cas. large immune response will not be 28 PROFILE therapeutically beneficial levels. Researchers are still perfecting this technique to produce more protein. The CRISPR system is also being inves- tigated for gene correction in isolated cells fro m DMD patients and for gene correction within the patient. The final stages of preclinical testing will soon be completed. The exon-skipping and CRISPR systems are largely patient specific. Therefore, each patient will require specific chemistries to guide the editing machinery. mounted upon transplantation. One through strategies. This approach is The further good news is that these of the most positive aspects of this based upon a fortuitous discovery genetic correction strategies can be stem cell transplantation approach is that some antibiotics impede bacte- utilised with other strategies that treat that it can be a true cure. If the cells rial proliferation by causing the the symptoms to provide the most engraft and repopulate the muscles protein-making machinery to ignore patient benefit with the lowest side- appropriately, they could survive and the bacterial stop codons, thereby, effects. Very importantly, transplanta- provide sufficient dystrophin for the making longer and less functional pro- tion, read-through and exon skipping life of the patient. teins. A subset of dystrophin muta- studies are currently being tested in tions in patients causes a premature patients for efficacy. In the near future, Muscle satellite cells (muscle resident stop codon, by the selective use of multiple options will be available for stem cells) are another source of cells antibiotic-like pharmaceuticals, the clinicians and their patients to combat that could potentially engraft all mammalian ribosomes will ignore this disease. muscle groups and be a true cure. the stop codon and continue making These cells are derived from adults the remainder of the dystrophin and are, therefore, more plentiful and protein, with just one amino acid tolerate proliferation in cell culture change, instead of no protein at all. very well and their use has fewer In addition, advanced generation ethical ramifications. The donor is a read-through pharmaceuticals have a normal volunteer or the patient them- much higher efficiency of ignoring selves, with the same considerations the stop codon then the original as mentioned above for the iPSCc. antibiotics, providing higher levels of Recent work identifies a procedure dystrophin expression. that fuses normal donor satellite cells with the patient’s satellite cells. This Recent news has highlighted the results in cells which express dys- success of exon-skipping strategies. Dr Ahlke Heydemann trophin and are immune privileged. This strategy is based upon aligning Associate Professor And, as mentioned above, the cells two synthetic nucleotide strands, with Director of Medical School Curriculum tolerate proliferation, so the clinicians specific sites of the native DNA which University of Illinois, Chicago can have a large number of cells avail- causes the normal mRNA processing Tel: +1 312 355 0259 able for transplantation. machinery to skip exons which con- [email protected] tain the mutation. So far, this strategy http://physiology.uic.edu/index.html Clinical trials are also being conducted has caused almost normal dystrophin upon premature stop codon read- protein to be expressed at close to 29 HEALTH & SOCIAL CARE Cannabis: One of the most thoroughly studied plants ever David Bearman, M.D., Executive VP of the American Academy of Cannabinoid Medicine details the research priorities for cannabis, one of the most thoroughly studied plants of all time annabis is one of the most thoroughly studied Cannabinoids and terpenes plants of all time. Its documented medical use Over the past three decades, we have been moving goes back to the first known materia medical, into an ever more sophisticated understanding of both Cthe Ping Ts’ao Ching, dated by Chinese oral tradition to the endocannabinoid system (ECS) and the therapeutic be written in 2637 BC. At the turn of the 19th to the constituents of the cannabis (aka hemp) plant. An 20th century, cannabis was the third most common increased focus is being placed on many of the other ingredient in physician prescriptions and over-the- 113 cannabinoids found in the plant beside THC and counter (OTC) medications, after opium and alcohol. CBD. Research is being done on THCa, CBDa, THCV, Cannabis was in the USP (United States Pharmacopeia) CBC, CBN, CBG and other cannabinoids. For instance, from the 1850s to 1942. the existing research shows CBC has anti-inflammatory and anti-cancer properties. In more contemporary times, there have been more than 25,000 articles printed in peer-reviewed medical Terpenes are the most common molecule in nature. journals on cannabis, cannabinoids and the endo- There are more than 200 terpenes in the plant and cannabinoid system, since 1995. Numerous human they have got the attention of researchers. Cannabis studies have been performed at four UC medical terpenes include B Caryophylin, Pinene, Humulene, schools under the administration of the California Myrcene, Linalool, Limonene and Nerolidol. Not only Medical Cannabis Research Center at UCSD Medical will more research be done on the role of these School. Many human studies were done on whole cannabinoids and terpenes, but studies have and will plant alcohol extracted cannabis in the UK from GW look at not only the THC/CBD ratios but also the thera- Pharmaceuticals. Their tincture of cannabis product, peutic contribution of many of the other constituents Nabixol, is approved for use in 24 countries including of the plant, such as those mentioned above. Canada, the UK and the European Union. Health Studies Allopathic physicians are experts in disease not health. The combination of historical medical use, modern Cannabis has been called a food, a vegetable and a research and clinical experience have demonstrated nutraceutical. The seeds are high in Omega 3 and many of cannabis’ therapeutic effects, including Omega 6 fatty acids and cannabis may decrease the analgesic, anti-inflammatory, anti-epileptic and migraine risk of certain cancers. We need to study what the daily relief. Because of government interference, whole minimum dose of cannabis should be recommended. cannabis plant studies in the U.S. are few. We are however beginning to see state and private money Medical conditions and cannabis treatment supplanting federal government funding of medical As to looking at cannabis’ therapeutic utility for specific cannabis research. Two new academic-based research disease entities, we have over 4,000 years of clinical centres have opened in California, one at UCI School use to suggest what conditions to look at. To date, of Medicine and another at UCLA School of Medicine. most of the modern studies have looked at the low This is in addition to the Medical Cannabis Research hanging fruit; treating nausea, epilepsy, pain and for Center at UCSD School of Medicine. appetite stimulation. A ground-breaking study on 30 HEALTH & SOCIAL CARE cannabis for post-traumatic stress disorder (PTSD) is Dose and THC/CBD ratio being carried out in Arizona right now with 76 military Researchers and clinicians are still trying to determine veterans by Dr Susan Sisely. With 22 American military what the appropriate dose of THC and CBD is, as well veterans committing suicide each day and the VA as what role, if any, other plant constituents play in ignoring the potential benefit of cannabis for treating treating the many medical conditions that respond PTSD, this is an enormously important study. favourably to cannabis. With the federal government sitting on their hands, it is important for state govern- “As to looking at cannabis’ therapeutic utility for ments and private interests to fund cannabis research specific disease entities, we have over 4,000 years that could prove to be critical to potentially life-extending of clinical use to suggest what conditions to look at. discoveries. To date, most of the studies have looked at the low hanging fruit; treating nausea, epilepsy, pain and for Endocannabinoid system (ECS) appetite stimulation. A ground-breaking study on Lastly, we need another article to cover the studies cannabis for post-traumatic stress disorder (PTSD) required to learn more about the ECS. As a clinician, I is being carried out in Arizona right now with 76 leave that article to basic science researchers. The ECS military veterans by Dr Susan Sisely.” plays a key role in neuromodulation and homeostasis. Because of the ECS’s impact on most organ systems, Another related area is ADD (attention deficit disorder) there are an enormous number of disease types which /ADHD (attention deficit hyperactivity disorder). are ripe for more research on cannabis’ therapeutic ADD/ADHD often has a genetic component however it value. These conditions include but are not limited to, can also be a co-morbid condition with PTSD. There neurodegenerative disease, autism spectrum disorder, have been well over 75 studies done on cannabis and bipolar disorder, autoimmune diseases, connective cannabinoids for the treatment of the symptoms of tissue disorders, gastrointestinal disorders, as well as the ADD/ADHD. Prominent researchers, such as Dr Danielle well-known conditions of migraine treatment, seizure Piomelli at UC Irvine have done ground-breaking work disorder, analgesia PTSD, ADD/ADHD and cancer. A on the benefits of cannabis and cannabinoids for treating better understanding of the ECS is giving us new this condition and more work continues. insight into the functioning of the human brain and immune system. Does cannabis “cure” cancer? The most important question to answer is, does I invite state, federal and private resources to help us cannabis cure cancer? Donald Abrams, MD, oncologist better understand the human body to develop better, and professor at UCSF School of Medicine, has said that more effective prevention and treatment of disease. ■ there is more than enough basic scientific evidence and anecdotal reports to justify doing double-blind studies to see if cannabis cures cancer. The first such human study was completed last year in the UK on glioblastoma (GBM). With a very low dose of a whole cannabis plant alcohol extract (25 mg. THC, 25 mg. CBD administered three times a day), the study docu- mented a 40% increase in lifespan from diagnosis to David Bearman, M.D. death for those receiving conventional treatment Executive VP of AACM plus tincture of cannabis as opposed to conventional American Academy of Cannabinoid Medicine treatment alone (330 days compared to 510 days). Tel: +1 (805) 961 9988 Clearly, more studies with higher doses of THC and [email protected] CBD need to be done not only on glioblastoma but also http://aacmsite.org/ on multiple types of cancer. www.twitter.com/aacm_info 31 HEALTH & SOCIAL CARE Acute respiratory distress syndrome – diagnostics and therapeutics Cecilia Van Cauwenberghe, from TechVision Group, Frost & Sullivan provides a detailed analysis of acute respiratory distress syndrome, focussing on the evolving diagnostics and therapeutics in the precision era of medicine ezoagli et al., 2017, investigated acute respira- parenchyma and pulmonary circulation accentuating tory distress syndrome (ARDS) epidemiology and the effects of positive pressure ventilation. This affection etiology, concluding that ARDS can be triggered is designated as pulmonary vascular dysfunction (PVD) Rby a broad spectrum of local and systemic factors. and it denotes the specific alteration of the vascular Pneumonia, extrapulmonary sepsis and aspiration are system in ARDS leading to an increase in pulmonary the most critical risk factors for ARDS, along with addi- arterial (PA) pressure and pulmonary vascular resistance tional demographic and environmental risk factors. (PVR) and right ventricular (RV) distress and potential death due to heart failure. This interaction involves a The acute lung injury prediction score (LIPS) is a model series of factors that contribute to an inefficient ventric- that introduces a series of risk factors and risk modi- ular ejection, which along with impaired pulmonary vas- fiers to predict patients’ predisposition to develop cular mechanics, increases both arterial elastance and ARDS by using routinely available clinical data even wave-reflection, additionally leading to RV afterload. before they are admitted to the intensive care unit (ICU). Bauman et al., 2015, validated the use of LIPS for Therapeutic intervention broadly recurs to selective early recognition of ventilated patients at high risk for pulmonary vasodilators, lung protective mechanical developing ARDS and mortality in ventilated surgical ventilation strategies involving prone positioning and critical care patients. According to the researchers, the open lung approach (OLA), to amend PVD by early identification enables ventilator and fluid man- enhancing functional lung volume. Nevertheless, ARDS agement optimisation strategies, thereby reducing the holds a high mortality rate mostly driven by pulmonary risk of developing ARDS and overall mortality. vascular interaction and RV afterload. Life-threatening interaction – pulmonary Advanced diagnostics and potential vascular dysfunction therapeutics Strongly characterised by diffuse alveolar and endothe- Next generation biomarkers lial damage, ARDS is indeed the most severe form of In the precision medicine era, discovery and validation acute respiratory failure. Wohlrab et al., 2018, empha- of biomarkers constitute an essential need to help sise in the impact of an increased pulmonary vascular ARDS patients to prevent lung injury severity by directly permeability and a loss of aerated lung tissue that lead conducting effective therapies. García-Laorden et al., to bilateral opacity, pulmonary edema, hypoxemia, 2017, have investigated the trajectory of many candi- increased venous admixture and decreased lung com- date biomarkers. pliance. As a result, patients with ARDS need supportive care in the ICU to maintain oxygenation and prevent Unfortunately, specific biomarkers for ARDS are diffi- even more adverse consequences. cult to find due to the complex and heterogeneous pathophysiology of the disease. Therefore, scientists Sipmann et al., 2018, focuses their investigations on are more focused on recognising combinations of bio- the heart-lung interactions present in ARDS because markers and clinical predictors reflecting different of the critical pathophysiological alterations in lung aspects of diffuse alveolar damage (DAD) such as 32 HEALTH & SOCIAL CARE epithelial damage, endothelial injury and/or inflamma- to facilitate alveolar liquid clearance, have been receiv- tion, more prone to be identified. ing increasing attention over the past decade. Lin et al., 2018, have deeply analysed the metabolomics Stem cell technology has also been proposed to of patients with ARDS between healthy people, aiming regenerate lung tissue while modulating inflammation to find metabolic markers with potential diagnostic via secrete growth factors and cytokines. A further values and prognosis. The authors found that caprylic approach can be carried out by implementing miRNAs, acid, azetidine, iminodiacetic acid and ornithine had a small non-coding RNAs involved in the post-transcrip- positive correlation with the ratio of the arterial partial tional regulation of various genes’ expression, as both pressure of oxygen to fraction of inspired oxygen biomarkers therapeutics, due to miRNAs may control (PaO2/FiO2). The researchers also uncovered near a several signalling pathways associated with the onset hundred of new metabolic pathways linked to these of ARDS. metabolites exhibiting significant statistical references to ARDS, which can be potentially used to judge the Acknowledgements acuteness and envisage the prognosis of ARDS. I would like to thank all contributors from industry involved with the development and delivery of this Receptor for advanced glycation end-products (RAGE) article and Frost & Sullivan’s staff from the TechVision has been reported as a promising biomarker of lung Group. ■ epithelium injury as a pattern recognition receptor. Angiopoietin-2 (Ang-2) and surfactant protein D (SP-D) Further reading play a key role in endothelial junctional integrity. Due Bauman, Z.M., Gassner, M.Y., Coughlin, M.A., Mahan, M. and Watras, J., to their levels are significantly altered in patients with 2015. Lung injury prediction score is useful in predicting acute respiratory ARDS, they can be used for diagnostics. Similarly, inter- distress syndrome and mortality in surgical critical care patients. Critical leukin-8 (IL-8) regulates neutrophils and monocytes care research and practice, 2015. chemotaxis in the lung, so that higher IL-8 concentra- García-Laorden, M.I., Lorente, J.A., Flores, C., Slutsky, A.S. and Villar, J., tions have predictive value in high-risk patients for 2017. Biomarkers for the acute respiratory distress syndrome: how to developing ARDS. make the diagnosis more precise. Annals of translational medicine, 5(14). Lin, S., Yue, X., Zhu, J., Lei, M., Wang, C. and Xu, F., 2018. 1064: Explore Therapeutic pipeline Potential Biomarkers of Acute Respiratory Distress Syndrome Through Despite promising ongoing clinical trials being under- Plasma Metabolomics. Critical Care Medicine, 46(1), p.516. gone, presently, there are no specific and effective Rezoagli, E., Fumagalli, R. and Bellani, G., 2017. Definition and epidemi- pharmacotherapies to address the ARDS challenge. ology of acute respiratory distress syndrome. Annals of translational Principal attempts are based on a combination of medicine, 5(14). therapies leveraging the advent of several adjacent Sipmann, F.S., Santos, A. and Tusman, G., 2018. Heart-lung interactions technologies including small molecules agonists and in acute respiratory distress syndrome: pathophysiology, detection and inhibitors, interferons, nano-peptides, stem cells and management strategies. Annals of translational medicine, 6(2). microRNAs (miRNAs), among other innovations. Wohlrab, P., Kraft, F., Tretter, V., Ullrich, R., Markstaller, K. and Klein, K.U., 2018. Recent advances in understanding acute respiratory distress Aerosolised beta2-adrenergic agonists (β2-agonists) syndrome. F1000Research, 7. have been suggested to prevent the development of ARDS. SB-681323 is a selective p38 alpha inhibitor that may potentially inhibit the inflammatory response by interfering with the mitogen-activated protein kinase (MAPK) pathway, hence preventing inflammatory cas- Cecilia Van Cauwenberghe, PhD, MSc, BA cade events. As responsible for the well-functioning of Associate fellow and senior industry analyst the endothelial barrier function, interferon beta-1a TechVision Group, Frost & Sullivan may prevent vascular leakage. Nano-peptides, such as [email protected] AP301, which activates the pulmonary epithelial and ww2.frost.com endothelial amiloride-sensitive sodium channel (ENaC) www.twitter.com/Frost_Sullivan 33 PROFILE Understanding the process of intravenous access Virginia M Stewart, MD outlines when intravenous access may be needed and how the skilful process should be undertaken atients coming to the Emergency Department (ED) with shortness of breath may have character- Pistics that impede intravenous (IV) access. Such characteristics may include hypotension, dialysis dependence, morbid obesity, history of diabetes, sickle cell disease, or IV drug use. One prospective observational study identified nearly 1 in every 9 to 10 adults coming to an urban ED had difficult venous access requiring 3 or more IV attempts.1 If peripheral IVs are not established, patients may need a central venous catheter placed for life-saving medications administered. In addition to requiring physician skill, central venous catheter insertion car- Figure 1: Short axis view of a peripheral vessel visualised with Colour Doppler (blue). The scale on the right of the screen demonstrates a total depth of 2.6 cm. A guide (white dots) in the centre ries a risk of complications including of the screen marks each 0.5cm of depth. Therefore the depth of the vessel is between 1-1.5cm infection, arterial puncture or an deep to the skin surface. aneurysm, and pneumothorax. Ultra- sound-guidance for peripheral IV veins are easy to locate. The brachial When considering vascular access, placement (UGPIV) has pr evented the artery is generally flanked by 2 smaller there is 2 views, a short and long axis need for central venous catheter veins and the median nerve. Anatom- view. Cannulation from the short axis placement in 85% of patients with ically, these structures are medial to is considered ‘out of plane’ since the difficult intravenous access.2 UGPIV has the insertion of the medial biceps needle is perpendicular to the probe. been performed by Emergency Medical tendon. This tendon is palpable in the A short axis approach ‘looks’ at a cross Technicians (EMTs) in prehospital antecubital fossa as the patient flexes section of the vessel. Long axis uses settings, as well as nurses and then extends the elbow. The basilic and ‘in plane’ approach with the needle physicians. Patients who have been vein is located medial to the brachial entering from the probe marker end, identified as having difficult access vessels. Generally, it is more superfi- and ‘looks’ along the length of the have higher patient satisfaction cial, larger, and does not have an vessel. Figure 1 identifies a vessel scores when ultrasound is used in accompanying artery or nerve at the using colour Doppler in the short axis peripheral IV access attempts.3 level of the antecubital fossa. As you view. Figure 2 demonstrates a long move proximally up the arm (towards axis view with a hyperechoic angio- Frequently, the large veins of the ante- the head) the basilic vein dives deeper catheter. Figure 3 is the same vessel cubital fossa are sufficient to place toward the humerus, and longer in long axis with the angiocatheter large bore peripheral IVs needed for angiocatheters may be required for placed. While both approaches may resuscitation. The brachial and basilic cannulation. be used for UGPIV placement, the 34 PROFILE depth from the skin surface should be noted. A common mistake is to use an angiocatheter that is too long or too short. A general rule of thumb is to use a catheter length that is more than twice the depth of the vessel to ensure at least half the catheter lies within the vein. Sterile ultrasound gel should be used, with a covered probe Figure 2: Long axis view of a peripheral Figure 4: Power Doppler (orange) confirms vessel. The hyperechoic needle is visualized to prevent infection. To prevent the placement of an intraosseus line within the approaching from the top left of the screen risk of multiple punctures, this author distal tibia. The bright white line of the tibia into the vessel lumen. cortex (in long axis view) is visualised at the advocates for first bouncing the top of the screen, with flow confirmation needle on the skin over the point of from a 10cc saline flush immediately distal (below) to the hyperechoic cortex. benefit for the short axis is the ability entry. The tissue should deform at the to identify target veins as well as top of the screen, and confirm the accompanying non-target (arteries needle is over the target vessel. Once the bony cortex in this adult tibia. If and nerve) structures. the skin is punctured, the needle tip is the line is improperly placed, the kept in view by angling the ultrasound blush of colour using Doppler would Identify the vein: remember probe until the target vessel is appear in the soft tissues. For further the two C’s punctured. information about UGPIV placement, The two C’s to remember for UGPIV visit: http://rmgultrasound.com/piv- access or for central venous cannula- To confirm placement, either a access/ tion are compression and colour (or ‘bubble study’ with agitated saline Power) Doppler. Veins are thinner- may be performed or Colour (or References: walled and more easily compressed Power) Doppler utilised to visualise 1 Fields, J.M., Piela, N.E., Au, A.K., Ku, B.S., Risk factors associated than arteries. This author advocates saline flow through the cannulated with difficult venous access in adult ED patients. Am J Emerg Med. for finding a vessel first in the short vessel. A vessel that is not properly 2014 Oct; 32(10):1179-82. plane, and compressing the vessel to cannulated will demonstrate extrava- 2 Au, A.K., Rotte, M.J., Grzybowski, R.J., Ku, B.S., Fields, J.M., ensure it is indeed a vein, rather than sation of saline around the vessel into Decrease in central venous catheter placement due to use of a less or non-compressible artery. the tissue before the tissue swells to ultrasound guidance for peripheral intravenous catheters. Colour or Power Doppler may be a degree which is palpable on the sur- Am J Emerg Med. 2012 Nov;30(9):1950-4. utilised to determine if the pulsatile face of the skin. Figure 4 demonstrates 3 Schoenfield, E., Shokoohi, H., Boniface, K. Ultrasound-guided flow is consistent with an artery or confirmation of intraosseous (IO) lines peripheral intravenous access in the emergency department: a vein. Colour Doppler uses red and utilise Power Doppler. A 10cc saline patient-centered survey. West J Emerg Med. 2011 Nov;12(4):475-7. blue to determine flow towards or flush is rapidly pushed through the away from the probe respectively. line, and flow is demonstrated beneath Power Doppler detects flow without concern for direction. Colour should not be relied on alone to determine arterial or venous flow due to the colour scale setting can be flipped or reversed, or aliasing can occur. Arte- Virginia M Stewart, MD rial flow is more pulsatile than venous. Forsythe Emergency Services, PA Venous flow may require distal aug- PO Box 25447 mentation (by squeezing the forearm Winston-Salem distal to the probe) to appreciate the NC27114 blush of colour. [email protected] Figure 3: In this long axis view of a peripheral www.fespagroup.com vessel the catheter has been threaded and is Once the target vein is identified, the seen within the lumen of the vessel. 35 RESEARCH & INNOVATION Mathematics: A powerful tool for understanding the world Dr Juan C. Meza, Division Director for the Division of Mathematical Sciences (DMS) at the National Science Foundation (NSF) reveals why mathematics is such a powerful tool for understanding the world around us n the article, “The Unreasonable Effectiveness of daunting, the idea is actually quite simple. The basis Mathematics in the Natural Sciences”, the well- for this technique relies on th e idea that many signals known physicist Eugene Wigner once wrote about (audio, video, images) have a structure that we can Ithe wide applicability of mathematics even beyond its take advantage of when they are first measured and own field. So, why is it that mathematics has proven then stored. By using mathematical algorithms, we can such a powerful tool for understanding the world reconstruct images based on far fewer measurements around us? than we had previously thought possible. One simple analogy is when we recognise a whole song by hearing For many people, mathematics research often seems just a few bars of the melody or recognise a picture esoteric, but the results inspire new ways of thinking from a few well-chosen features. and commonly lead to novel applications. Here at the National Science Foundation’ s (NSF) Division of Math- Using this technique, scanning is strikingly faster, result- ematical Sciences (DMS), we support research in math- ing in patients spending much less time inside MRI ematics and statistics, the research training of the next machines. That’s especially important for paediatric generation of mathematical scientists and a portfolio patients, where time inside an MRI must be restricted. of national research institutes. The speed-up also allows for lower costs per patient. An unexpected outcome The benefits are only now becoming widespread, but it One of the goals of DMS is to develop new mathematical was DMS-funded basic research that led to the new MRI theories, models and tools to help solve some of the technologies. Compressed sensing highlights the bene- most challenging problems in the physical, biological fits of interdisciplinary research, as researchers from and life sciences. This research ultimately has a signifi- three different mathematical fields – geometric analysis, cant impact on the United States’ health, security and statistics and computational math – and from astronomy economy. came together to work on this problem. It has been one of the great successes in the mathematical community, A clear example emerged last year. In 2017, the U.S. with a societal impact that is only just beginning. Food and Drug Administration approved two new mag- netic resonance imaging (MRI) devices that dramati- Driving US mathematics research cally speed up scanning of the body – between eight DMS is the largest supporter of mathematical sciences and 16 times faster than conventional methods. research in the United States and accounts for more Siemens’ technology (CS Card iac Cine) reveals movies than 60% of federally funded basic mathematics of the beating heart and GE’s technology (HyperSense) research, including studies in algebra, topology and allows rapid 3-D imaging of the brain. geometric analysis, number theory, applied mathemat- ics, analysis, combinatorics, probability and statistics, Both products make use of a mathematical technique computational mathematics and mathematical biology. known as compressed sensing, a breakthrough devel- We also support conferences and workshops and a oped ten years earlier by NSF-supported mathemati- portfolio of national mathematical sciences research cians. While the underlying mathematics can be institutes. 36 RESEARCH & INNOVATION NSF-Simons centers to search for the Rules of Life Image: © Northwestern University DMS’ six Mathematical Sciences Research Institutes run that supports discovery-driven scientific research in programmes for the research community and have a mathematics and the basic sciences – to create four new long history of bringing mathematicians together from Centers for Mathematics of Complex Biological Systems. around the world to share their work, which often leads to new collaborations. This $40 million programme is funded equally by NSF and the Simons Foundation and involves DMS and two Some of the activities supported by the institutes other divisions in NSF’s Biological Sciences Directorate: include programmes to discuss challenges in the devel- Integrative Organismal Systems and Molecular and opment of materials for quantum computing, machine Cellular Biosciences. learning applications for computer vision and data- driven methods for precision medicine to guide treat- The centres will apply mathematical approaches in the ment decisions – all of which have deep mathematical hopes of developing predictive frameworks for under- questions at their heart. standing the pathways from DNA within cells to organ- isms interacting in nature. Such findings have potential Bridging disciplines for both pure scientific discovery and for a wide range Another DMS guiding principle is collaboration with of applications, from agriculture to health. One of the other science disciplines to develop new mathematics. defining characteristics of the centers will be the close For example, biology is now more quantitative than ever and sustained collaborations between biologists and before because of new technologies like high-through- mathematical scientists leveraging their complementary put, next-generation sequencers and high-resolution expertise and diverse perspectives. imaging and microscopy techniques. Such technologies have led to an abundance of new data for biologists to DMS programmes span a wide range of energy and analyse, data that may answer fundamental biological security applications, as well. Some mathematicians and questions, as well as raise new ones. statisticians are working on developing mathematical models for modelling efficient and reliable electrical Building from that need is one of the most exciting power grid systems, while others work on mathematical activities emerging from DMS this year: a new partner- algorithms for detecting threats such as outbreaks of ship with the Simons Foundation – a private foundation epidemics like severe acute respiratory syndrome Continued on page 39 37 SUBSCRIBE FOR FREE Open Access Government is pleased to offer a FREE subscription service to all our products including our regular newsletters. We can offer you news and features focusing on a specific topic plus a monthly round-up. CLICK HERE TO SUBSCRIBE You can choose from a variety of newsletters from our selection of subject areas OPEN ACCESS www.openaccessgovernment.org GOVERNMENT RESEARCH & INNOVATION Sand Strings Continued from page 37 Image: © Jie Ren, Joshua Dijksman, Robert P. Behringer; Center for Nonlinear and Complex Systems, Duke University (SARS). Yet others look for hidden patterns in large Through the many such programmes and initiatives graphs (like the World Wide Web) that could indicate funded by DMS, new and exciting mathematics emerging threats. Mathematicians are even studying research is providing insights into some of the hardest ways to help manage and mitigate the aftermath of challenges society is facing today, from understanding natural disasters such as hurricanes. complex biology to deciphering the fundamental prop- erties necessary to build quantum computers – and The future of mathematics understanding their security implications. In addition to basic research, DMS also places a strong emphasis on training the next generation of mathe- While one cannot know where the next breakthrough maticians and statisticians. Through research fellow- in science or technology will emerge, mathematics will ships, we provide an opportunity for mathematical have been used to better understand or even predict sciences doctoral students to participate in internships it. Mathematics is essential to society and NSF’s Division at national laboratories, in industry and at other of Mathematical Sciences is positioned to support the approved facilities. needed mathematics that will help realise that new and better future. ■ Our Mathematical Sciences Graduate Internship fel- lowship program is aimed at students who are inter- ested in understanding the application of advanced mathematical and statistical techniques to real-world problems, regardless of whether the student plans to pursue an academic or non-academic career. In 2017, we placed 40 graduate students from 38 uni- D r Juan C. Meza versities in 10 national labs. All of the students were Division Director for the Division of able to apply the theoretical coursework they had Mathematical Sciences (DMS) learned in school to real-world problems like improving National Science Foundation (NSF) computational meshes for simulations, deblurring www.nsf.gov/div/index.jsp?div=DMS images and machine learning. www.twitter.com/NSF 39 PROFILE The natural world – Why field studies matter Thomas L. Fleischner, Ph. D, Executive Director of the Natural History Institute discusses the critical importance of direct engagement with the natural world ost major leaps in under- standing the complex work- ings of the natural world have beenM discerned by naturalists, in the field, engaged in careful observation of plants, animals, and their interac- tions in natural settings. Experimental manipulations, laboratory-based inquiries, and theoretical models often yield exciting and important information. But frequently, such studies represent attempts to sharpen insights that came initially from the direct observation and description at the core of natural history – “the practice of intentional, focused attentiveness to the more- works is more urgent than ever. But working group – representing a broad than-human world, guided by honesty the startling fact is that fewer and diversity of academic institutions and and accuracy.“ fewer biologists have the opportunity other NGOs – focused on the decline to develop the skills of field biology of field studies in biology education. The unifying theory of modern biolog- and natural history. Over the past This project was supported by the ical science – evolution through few decades, academic field studies U.S. National Science Foundation, and natural selection – was famously have diminished on both sides of the coordinated through the Natural developed independently by two Atlantic, as institutions and funding History Institute. astute field naturalists, Charles Darwin agencies have privileged theory over and Alfred Russel Wallace. Only direct empirical field studies. The benefits of study field study of real organisms in real The value of field study is vast: field landscapes offered a clear enough The American conservationist Aldo experiences not only contribute view into the phenomena of nature Leopold lamented the loss of field to better science, but also create for this unifying theory to be revealed. studies in biology education more than better scientists, citizens, and people, As the renowned ecologist Paul 70 years ago – and the situation has thereby substantially affecting the Dayton has noted: “There is simply no only grown more critical. Biologists human-nature relationships that form substitute for actually experiencing with the skills to identify plants and the basis for sustainability. nature, to see, smell, and listen to the animals have become the exception integrated pattern that nature offers rather than the rule. How can we Observing nature is the touchstone an open mind.” recognise human impacts on biodi- for understanding how life works, and versity if we can’t recognise the thus field studies serve quite literally Today, in the grip of climate change species that comprise it? as the grounding for the biological and the sixth mass extinction, our sciences. At the same time, field need for understanding how nature I’ve had the honour of directing a experiences often force observers to 40 PROFILE question and to re-evaluate their component of every scientist’s training. Accommodating study assumptions about how the natural Collectively, these factors contribute world operates. Field education also promotes devel- to a significant decline in field study opment of place-based understanding. opportunities for students and lack of Accordingly, field observations can Students who engage in field experi- pedagogical guidance for instructors lead to re-calibration of research ences have greater opportunity to interested in conducting field courses. strategies for exploring biological cultivate the critical connections to At many institutions, instructors inter- phenomena, explanations for which real places that transform abstract ested in providing field experiences are often subsequently tested using concepts into tangible realities. This must negotiate a complex suite of information collected by observa- outcome extends to the cultural, financial, logistical, legal, and attitudi- tional approaches in the field. Field social, and political settings in which nal hurdles. observations reveal patterns, and field studies occur. A sense of place these often lead to development of can be a powerful motivator for learn- Sometimes, something as simple as formal hypotheses. Theoretical models ing and stewardship and thus individ- the lack of a vehicle for transporting are only as solid as the field natural uals who become strongly connected students is what denies them field history foundations on which they rest. to a specific setting, tend to become study opportunities. Over time, these more effective advocates for all ele- hurdles may sap the energy and Field-based education is particularly ments of that environment. morale of even the most dedicated critical to the biological sciences, instructors, thereby reinforcing the providing fundamental training for key On an individual level, field studies cycle of decline for courses that include disciplines such as behaviour, ecology, often spark a “sense of wonder” that a field component. evolution, systematics, and conserva- can launch students on a path of tion science. Field studies underlie the discovery-based science, resulting in More than ever, the world needs the conceptual and technical bases for life-long commitment to careers in passion, insight, and wisdom that these disciplines and are required to natural, environmental, and medical come from field studies. Academic ensure their healthy growth. science. Field experiences – in partic- institutions must recognise that field ular residential and other immersive experiences are more crucial, not less, Now, as society struggles to respond experiences – also provide unparal- in the 21st century, and work to appropriately to losses of biodiversity, leled opportunities for development encourage, rather than obstruct, field range shifts due to climate change, and of intra- and inter-personal skills that education. Funding agencies have an emergence of new human pathogens, are critical to effective leadership. important role to play by supporting the decline in opportunities for field There is also empirical evidence that this critical foundation of learning study means that subsequent gener- field courses contribute to improved how nature works. ations of biologists will be increasingly academic performance and cognitive divorced from the primary setting – learning in undergraduate biology the natural environment – in which students. the phenomena that they study occu r. Challenges to study As the capacity to modify biological Higher education has changed dra- systems expands – from genomes to matically since Aldo Leopold wrote ecosystems to global cycles – it is about the importance of field studies Thomas L. Fleischner, Ph. D imperative that scientists and the in the 1930s. Institutional challenges Executive Director broader public can critically evaluate to field studies include decreasing Natural History Institute the outcomes of these changes in the financial resources and increasing 126 N. Marina St. context of complex natural settings. regulatory concerns. Institutions, Prescott, Arizona 86301 USA Within academia, this need also presuming high costs, fearing legal (Faculty Emeritus, Prescott College) applies to the educators charged with liability issues, too often construct [email protected] training future generations of problem administrative obstacles to faculty www.naturalhistoryinstitute.org solvers. Field studies are an essential offering field experiences for students. 41 PROFILE Physics: Optical microscopy in 3D Dr Chunqiang Li, PhD from the Physics Department at University of Texas at El Paso explains the fascinating area of physics, optical microscopy in 3D eeing is believing.” Of course, we must validate what we see “ as a full picture. Living in a 3D Sworld, dynamic information obtained from 3D space will provide much more enriched information than that from individual 2D snapshots. Two- photon excitation has the advantages of reduced photobleaching, photo- damage and background signal sup- pression compared with one-photon excitation and has been widely used in biomedical research, particularly for in vivo imaging. Laser scanning two-photon fluorescence microscopes are the workhorse. These commercially Fig. 1 Temporal focusing two-photon microscope with a pulse shaper setup. available microscopes typically can acquire two dimensional (2D) images in the range of one to one hundred can obtain wide-field 2D images with- sion (GVD) of the femtosecond laser images/second by raster scanning the out scanning laser beams. Based on pulses could lead to the displacement laser beam in a sequential manner. the success of this technique, several of the plane of the temporal focus, Typically, the laser beam scanning is groups have adopted temporal focus- along the optical axis of the objective the bottleneck of acquitting high- ing to image cellular dynamics in thick lens, yielding z-scanning as a function speed imaging. tissues. Since it does not require scan- of GVD. Femtosecond laser pulse ning the laser beam, it could reach shaping is a technique that spreads In the last decade, several groups 1000 frames/second 2D imaging femtosecond laser pulse spectrum in have demonstrated temporal focusing speed with an amplified femtosecond space, then modulates each wave- as a way of implementing two-photon laser system as the light source. length component with a spatial light microscopy for wide-field 2D imaging, modulator (SLM) to arbitrarily shape without scanning the laser beam. In a In many applications, especially in live an ultrafast pulse. Hence, pulse shap- temporal focusing two-photon micro- animal imaging, it is necessary to ing could electrically control the GVD scope, the focal region is a light sheet acquire information in all three of the femtosecond laser pulse with- with a diameter around a few hun- dimensions. To achieve 3D volumetric out any mechanical motion, which dred micrometres, depending on the imaging, most modalities still need to could further control the z-scanning in focal length of lenses and femtosec- mechanically move the sample stage the temporal focusing two-photon ond laser pulses. which only reach its or the objective lens to acquire depth microscope. Therefore, the goal of our shortest temporal profile at focal information (z-scanning). In the tem- project is to integrate pulse shaping region. Therefore, when using a CCD poral focusing two-photon micro- into temporal focusing two-photon camera as a 2D detector, this tempo- scope, it has been demonstrated that microscopy to achieve 3D volumetric ral focusing two-photon microscope changing the group velocity disper- imaging without mechanical scanning. 42 PROFILE slightly shifted away from a geometric focal plane in the range of ±10 µm, the single fluorophore image becomes blurry. When this shift is larger, the single fluorophore image has the characteristics of concentric rings with peak intensity in the outermost ring and the central lobe becomes blurred as shown in the second to fourth row in Fig. 2. Overall, we integrated ultrafast laser pulse shaping with the temporal focusing two-photon microscopy and achieved a high-speed 3D imaging Fig. 2 Temporal focal plane shift by varying GVD. Series of fluorescent images of microspheres at different z positions (z= -10 to 80 µm) after the temporal focal plane is shifted at z=0, 20, 30, method. This 3D imaging system and 40 µm planes with varying GVD. requires neither laser beam steering nor sample mechanical scanning. The depth scanning is achieved by control- Figure 1 illustrates a schematic setup create the desired radio frequency ling the femtosecond laser spectrum. of the temporal focusing two-photon wave that controls the GVD of the The dependence of scanning depth microscope. To achieve higher imaging femtosecond laser pulse. on the applied electronic signals speeds, a high peak power laser is which can be tuned at a millisecond needed. Therefore, a chirped-pulse Our microscope demonstrated the timescale. Its high-speed 3D imaging amplifier (CPA) is added after the capability of shifting the temporal capability was demonstrated by imag- Ti:Sapphire laser to achieve high peak focal plane via pulse shaping. We ing fluorescence microspheres in a power (>1 uJ/pulse) at a repetition rate applied different voltages on the arbi- volume of 100×100×80 µm3. of more than 1 kHz. The incident trary function generator and the z angle of the grating is adjusted to position of the sample was scanned ensure the central frequency follows by moving the 3D sample stage with x the optical axis and propagates and y positions fixed and finally, a flu- through the 4f setup, which comprises orescence image was acquired at the collimating lens, relay lenses and each z position. This varying voltage the objective lens. Since the spectrum function induced GVD on the laser of femtosecond laser pulses has been spectrum and changed the temporal spread out spatially by the grating, the focal plane, as shown in Figure 2. This next step is to add a pulse shaper shifting of the temporal focal plane by (dash box in Figure 1) to use acoustic applied GVD depends on several waves to control the dispersion of the parameters, such as laser spectral Dr Chunqiang Li, PhD femtosecond laser pulses in the spec- width and the numerical aperture of Physics Department tral domain to achieve scan-less 3D the objective lens. The temporal focal University of Texas at El Paso volumetric imaging. The spatial light plane was shifted to z= 60 µm plane by Tel: +1 915 747 7537 modulator (an acousto-opto modula- applying a voltage of 10.2 V. This sep- [email protected] tor, AOM) is located at the 1f location aration of the temporal focal plane https://science.utep.edu/photonics/ to the left of the first collimating lens. from the geometric focal plane has a The AOM is driven by a radio fre- negative effect on the image quality. quency arbitrary wave generator to When the temporal focal plane is 43 RESEARCH & INNOVATION Image: © Mikephotos | Dreamstime.com | Dreamstime.com Image: © Mikephotos Microbes and the rigour of space flight William B. Miller, Jr., M.D. argues that without the planning to do so, we have launched microbial life from this planet t was the greatest car ad ever conceived. A red Tesla the solar system. And no one seems to understand Roadster was launched into space with a jaunty that particles of those micrometeorites will ricochet off spaceman mannequin at the wheel. As it streaks the car and mannequin and carry bits and pieces of it Iaround our solar system at speeds of seven miles per wherever they go. And no one has noted that on every second, its dashboard screen reads a playful, ‘Don’t minuscule bit, there will a new set of travelling com- panic’. Initial press coverage was fawning. The biggest panions. Wherever those particles go, associated question was, “Is this art or advertising?” It was never microbes will now circulate with those particles, some mentioned that the car and its mannequin are loaded of which will travel outward for light years. with microbes. There hadn’t even been any real attempt to clean it prior to launch. No big deal. It’s just It is the same for all the NASA spacecraft that have ever floating in space and won’t impact a planet for a million been launched. To NASA’s credit, they have tried to be years or more. careful. NASA has been rightfully concerned about the possibility of sending our planetary life out into space. However, its elliptical orbit around the Sun has it cross- To that end, they enacted rigorous ‘clean’ rooms. Prior ing Mars orbit every 18.8 months. It will often get close. to launch, vehicles were carefully scrubbed to get rid No one seems to care that this craft will gradually of any lurking microbes. When our spacecraft was deteriora te over time from the impact of innumerable launched, they were thought to be sterile. Unfortunately, micrometeorites during its endless loops throughout what NASA believed to be true, was not. It is now under- 44 RESEARCH & INNOVATION stood that the culture techniques that NASA relied Although the milestones of the Voyager craft are being upon to determine sterility were utterly insufficient. minutely detailed, NASA astronomers remain com- pletely silent about the most portent ous aspect of this In our contemporary era, there are new tools of genetic Voyager mission. That silence is not entirely surprising assessment that permit our identification of a much since, until the Tesla car launch, the Voyager mission wider range of microorganisms than in prior decades. represents the most egregious example of unintended In fact, it is now known that fewer than 10% of all consequences in human history. microbes can be cultured in the standard manner that NASA was diligently applying. Therefore , the tests that Though this event receives no attention, it is NASA relied upon to issue their declarations of sterility immensely more significant than any war in human were unfortunately completely inaccurate. Although history, or any ideology, or all our art and culture. With- the NASA spacecraft were culture negative upon out planning to do so, we have launched microbial life launch, they were abounding with covert microbial life. from this planet. Now, for endless eons, that tenacious life will be propelled outward into deep space. Every- Furthermore, we now know that many microbes can where Voyager goes, life will be shed. It is the same, withstand every rigour of space flight. In the vacuum but even more so, for the supremely egotistical Tesla of space, with its absolute cold and bursts of destruc- in space. Both are instances of singular technical tive radiation, humans would instantly die. Yet, some achievement and delinquent government oversight. microbes do not, nor do singular small animals, called Tardigrades. These incredibly resilient microscopic There is a theory of the origin of life that suggests that eight-legged creatures can withstand all the extremes it began on Earth as an instance of Panspermia. In of space. We know that this is true since some of them effect, life on this planet began elsewhere, finding a have even survived re-entry back to our planet from home here and thriving. Now, without explicit intent, other space flights. both Voyager spacecrafts and the Tesla advertisement have begun the process of seeding of life throughout It is these exact findings that inform us that single the Cosmos. In our uniformed hubris, we have become most important event in our entire human history is an unintentional agency of Panspermia. Now, in a direct currently transpiring. This unheralded event is the sense, we have become a Cosmic invasive species. passage of the Voyager 1 and 2 spacecrafts beyond our solar system and exiting into interstellar space. What Let it be our earnest hope that we will be forgiven. ■ makes this passage so momentous is that both crafts carry life. Dr Bill Miller had been a physician in academic and private practice for over thirty years. He is the author of The Microcosm As originally envisioned, the mission of the Voyager Within: Evolution and Extinction in the Hologenome. Dr Miller is spacecraft was to study the outer planets of our solar an internationally recognised evolutionary biologist and an system. In this regard, that mission has been highly expert on the emerging science of the microbiome. He is the successful. The Voyager craft left Earth in 1977, arrived author/co-author of numerous academic papers on the micro- at Jupiter in 1979 and then passed by Jupiter, Saturn biome and evolution, serves as guest editor of a major academic and Uranus, to arrive at Neptune by 1989. Important biology journal and is co-editor of a forthcoming textbook on physical discoveries were catalogued at each planet, developmental and evolutionary biology. Connect with him on such as the magnetospheres of Uranus and Neptune. Twitter, @billmillermd. By mission design, there was never any possibility of return. Instead, the craft was tasked towards an endless continuation into deep space. William B. Miller, Jr., M.D. Now, Voyager 1 is over 13 billion miles from Earth, with Author, Physician Voyager 2 close behind. Currently, they are just at the Tel: +1 602 463 5236 margin of the heliosphere which is the large zone influ- [email protected] enced by our Sun. Thereafter, interstellar space looms www.themicrocosmwithin.com/ and the Sun’s influence rapidly fades. www.twitter.com/billmillermd 45 PROFILE Pesticides: A contributing factor to the increase in asthma? Pamela J. Lein at the University of California, Davis discusses the evidence suggesting that pesticides are risk factors for asthma sthma is a chronic inflammatory Occupational exposures associated tified safe levels of OPs as those that lung disease, characterised by with the production, distribution and do not inhibit acetylcholinesterase. episodic and reversible bron- application of OPs occur primarily via Achoconstriction (contraction of the dermal absorption, with more limited Case reports published in the 1960’s smooth muscles that line the airways), exposure via inhalation. The general provided the first indication t hat excessive secretion of mucus in the population is exposed to OPs via exposures to OPs at levels that do not airways and airway hyperreactivity ingestion of food and water contami- cause cholinergic crisis may trigger (an exaggerated reaction of airway nated with OPs and by dermal and asthma in adults. Subsequent cross- smooth muscle to contractile stimuli). inhalational exposure to pesticide sectional studies of farmers and their All of these effects interfere with drift and “overspray”. The latter is not families, farmworkers and commer- breathing. an insignificant source of exposure as cial pesticide applicators in multiple extensive OP contamination has been countries around the world provided Worldwide asthma prevalence and documented in the air, homes and further evidence that occupational severity has incr eased markedly over urine from pregnant women and exposures to OP pesticides are asso- the past two decades, especially in children living in communities near ciated with adult-onset asthma. urban settings. Many hypotheses have agricultural fields sprayed with OPs been proposed to explain the increased More recent epidemiologic data asthma in urban residents, including OPs inhibit the enzyme acetylcholine - suggest that not only occupational exposure to allergens, air pollution, sterase, which functions to inactivate exposures, but also exposures to differences in healthcare and stress. the neurotransmitter acetylcholine. environmentally relevant levels of However, an environmental factor Acetylcholinesterase inhibition signif- OPs, such as might be experienced by associated with agricultural asthma icantly increases acetylcholine levels the general public, are associated with that is beginning to receive increased at the synaptic junction between increased risk of asthma and asthmatic attention in the context of urban nerves that secrete acetylcholine and symptoms in adults and adolescents. asthma is exposure to organophos- their target tissues, causing excessive OP-induced asthma may not be limited phorus pesticides (OPs). stimulation of target tissues. to these age groups, as indicated by emerging data from the Center for the OPs are the most widely used class of Acetylcholinesterase activity is func- Health Assessment of Mothers and pesticides worldwide and are applied tionally important in not only insects, Children of Salinas (CHAMACOS), the extensively in not only agricultural but but also humans. It is well established longest-running longitudinal birth also in suburban and urban settings that OPs cause neurotoxicity in humans cohort study of pesticide effects on to control insects. Although residential by inhibiting this enzyme, a medical children’s health, which has been uses of OPs are being phased out in condition referred to as the choliner- studying children in a farmworker the United States and many European gic crisis. Acute exposures to OPs that community in the Salinas Valley of countries, OPs are still used heavily in inhibit acetylcholinesterase by more northern California. Data from the agricultural, industrial and commercial than 80-90% of control levels can CHAMACOS study suggests that OP settings and OPs are widely detected cause death in humans, typically by exposures during pregnancy and the in the general human population in inhibiting the respiratory centres in first year of life, as determined by all countries in which this has been the brain that control breathing. Thus, analysis of urinary OP metabolites in assessed. many regulatory agencies have iden- pregnant women and their infants, 46 PROFILE persisted for at least seven days after a single injection of the OP. Further studies in the guinea pig model suggest that OPs cause airway hyperreactivity by interfering with neural mechanisms that normally function to limit the release of acetylcholine from airway nerves onto airway smooth muscle. This effectively increases the amount of acetylcholine available to cause contraction of the airway smooth muscle. How OPs cause dysfunction of airway nerves remains an outstanding question, although preliminary data suggest that the mechanism may vary depending on the allergic status of the individual. Answering this question will be critical for identifying suscepti- ble subpopulations and for designing more effective therapeutic interven- tions for preventing or reversing OP-induced airway hyperreactivity. More immediately, these findings raise significant questions regarding Farm worker spraying pesticide treatment on fruit garden the use of acetylcholinesterase activity as a point of departure for regulatory action. Furthermore, these are associated with respiratory symp- Importantly, OP-induced airway findings suggest the possibility that toms in children at five and seven hyperreactivity is observed at levels the increased prevalence of asthma is years of age. that do not inhibit acetylcholine - related less to the insects that we live sterase. Several different OPs, including with than to the chemicals we use to While systematic reviews of the chlorpyrifos, parathion and diazinon, kill them. published epidemiologic literature can induce airway hyperreactivity in generally support an association guinea pigs following subcutaneous between OP pesticide exposure and injection, a route of exposure that asthma, it is difficult to establish a mimics dermal exposure in humans. cause-effect relationship based on In contrast, pyrethroids, a class of human data. This is due in large part pesticides structurally and mechanis- to the fact that it is extremely chal- tically distinct from OPs, do not induce lenging to accurately quantify OP airway hyperreactivity in guinea pigs, Pamela J. Lein exposure in humans. Thus, studies in suggesting that the airway response Professor animal models are critical for deter- to OPs is not a generalised property of University of California, Davis mining whether OPs are causally all pesticides. Tel: +1 530 752 1970 linked to asthma. The animal studies [email protected] published to date support the hypoth- Interestingly, the effect of OPs on http://www.vetmed.ucdavis.edu/lein-lab/ esis that OPs directly cause airway airway hyperreactivity was not evident hyperreactivity, a key symptom of immediately after exposure, but rather asthma. were manifest 24 hours later and 47 RESEARCH & INNOVATION How developmental biology changes our lives Shyh-Jye Lee (Jeff), Ph. D, President of the Taiwanese Society of Developmental Biology (TSDB) explains the way in which developmental biology impacts upon our lives evelopmental biology (DB) is an expansion of stage embryos have the full potential to become all types traditional embryology, which studies the of adult cells that are called “totipotency”. The totipo- development of a single-cell fertilised egg to a tency is gradually lost in later stage embryos, but they Dmulticellular free-living organism. Today, DB research still retain “pluripotency” to become multiple types of cells. covers beyond embryogenesis to include growth, Eventually, embryonic cells limit their developmental sexual maturation and ageing. potential to one specific type of cells. However, we know that even terminal differentiated somatic cells DB affects our life in many aspects. One of the key contain the same genome as that of a fertilised egg. issue related to our life and the sustention of species is the control of fertility and infertility. The understanding Theoretically, it can be totipotent if properly repro- of oestrous cycle and the development of sexual grammed back to the original state. Although the organs and gametes helps us control conception and astounding generation of Dolly Sheep proves the prin- increase fertility. Birth control pills and condoms are ciple by somatic nuclear transplantation experiments, both effective tools for population control. The devel- low success rate and unhealthiness of cloned animals opment of in vitro fertilisation (IVF, i.e. test-tube baby) imply that reprogramming the differentiated genome technology is another good example to show how DB to its default state is not reached by using this method. research can change our lives. The desire of having their own baby was often a dream that never came Many animals, like planarians, salamanders and true for infertile couples. zebrafish can replace missing body parts. In contrast, mammals only have a limited regenerative ability in But since the development of IVF and other assisted tissues and organ-like skin epithelial layers, hair and reproductive technologies, many couples regain their liver. This may lead to severe health problems like hope to have biological babies. The success of IVF in fibrosis, accumulation of extracellular matrix proteins mammals, including human, was based on the basic like collagens in heart and other organs. Heart injuries understanding of fertilisation mechanisms of marine often lead to scars and subsequent fibrosis. Fibrosis invertebrates like sea urchins. From those studies, we results in the stiffness of heart, impaired function and appreciate the importance and regulation of ionic eventually heart failure. flows during fertilisation. By manipulating those factors along with others, scientists gradually broke The studies of fibrosis prevention and resolution have through the IVF barriers in mice, human and other attracted the attention of medical professionals, as larger mammals. IVF is thus one of the most fascinating well as DB researchers. DB researchers often use stories of how DB research can improve the wellbeing animal models capable of regeneration to understand of human life itself. how the regeneration is induced and accomplished. They are now more eager to apply the gained knowl- How could a single-cell fertilised egg develop into a edge to screen drugs or devise tools or strategies to multicellular functional adult is a key fundamental repair injure tissues or organs in mammals and human question asked by developmental biologists. Throughout that have been established in a new discipline called centuries of research, we understand that cells in early- “regenerative medicine”. 48 RESEARCH & INNOVATION During development, a group of cells called stem cells not only can become other types of cells, but they can renew themselves to keep their stemness. The most competent stem cells are embryonic stem cells (ESCs). ESCs are cells from the inner cell mass of a blastocyst. They contain pluripotency that allows them to be induced into many other types of cells in vivo or in vitro and is potentially a great cell source to be cultured to tissues, or even organs to be used in regenerative medicine. “Developmental biology (DB) is an expansion of traditional embryology, which studies the Shyh-Jye Lee (Jeff), Ph.D. development of a single-cell fertilised egg to a President multicellular free-living organism. Nowadays, the DB research covers beyond embryogenesis to include drug screening as well. However, we still have a long growth, sexual maturation and ageing.” way to go and proper animal models are still needed. However, it is unavoidable to destroy a blastocyst while One of the most exciting discoveries in biology lately is collecting ESCs. It becomes a major hurdle that prevents the invention of CRISPR/Cas9 technology, which allows the practical use of ESCs due to ethical and religious much more convenient targeted genome editing in reasons. Terminal differentiated somatic cells still cells and organism levels. DB researchers quickly apply retain the same genome as that of fertilised eggs. this technology to edit genomes of different model Triumphantly, we now can reprogram somatic cells like systems, as well as for IPSCs. It is then of great potential fibroblast cells to become stem cells called inducible to correct human genetic diseases with known muta- pluripotent stem cells (IPSCs). Using IPSCs different tion(s) using CRISPR/Cas9 if it is proven to be safe and types of cells, including blood, neuronal cells, muscle effective in the future. cells, germ cells and others have been created in vitro. The next challenge will be how to consistently produce Overall, although most DB research still focuses on the those cells to be reliably used in regenerative medicine. basic regulations of developmental processes, devel- opmental biologists are prompt to apply their findings IPSCs may also push the development of medicine to for practical use in both medicine and agriculture. the next level. Traditionally, the development of drugs So far, many great discoveries have been made that relies heavily on the use of immotile cell lines and have affected our lives, but I can only name a few here. animal models, mainly mice. However, only less than To go further, we will need more efforts from 1% of drugs tested in clinical trials are approved. The DB researchers, along with continuing support from failure of drug testing can be for a variety of reasons. governments, the private sector and the public. ■ The suitability of screening model is certainly one of the issues. Although mice resemble human in many ways, they are not human. Even in humans, there are Shyh-Jye Lee (Jeff), Ph.D. variations between different people. President Taiwanese Society of Developmental Biology (TSDB) In addition, drugs entered the market are suitable for Director, Research Center for Developmental Biology and Regenerative most people that may not fit you well. Therefore, the Medicine, National Taiwan University idea of “precision medicine” emerges. The IPSCs may Tel: +886 2 3366 1736 fit in the precision medicine nicely. We can use patient- [email protected] derived IPSCs for drug testing before administrating to [email protected] patients. We can also use human-derived IPSCs for www.tsdb.org.tw/en 49 PROFILE Rediscovering observations of the environmental factors affecting tissue regeneration in aquatic species Graciela A. Unguez, PhD, Professor of Biology and student Bahiyyih Mitchell at New Mexico State University explore the environmental factors affecting tissue regeneration in aquatic species hat controls the regenera- Sternopygus macrurus. S. macrurus is a tion of entire body parts highly regenerative species and and organs in some ani- our lab has exploited this property to mals,W even multiple times in adult- characterise the differentiation of myo- hood? This “million-dollar” question genic cells in response to repeated tail has fuelled the curiosity of many amputations, the effect of neural input scientists for centuries. Today, the on the differentiation of myogenically- number of both terrestrial and aquatic derived cell types and the activation of species tested for their response to myogenic stem cells to restore original injury continuously grow, expanding skeletal muscle and muscle-derived the comparative analysis of regenera- electrogenic tissue lost3-6. tion capacities throughout the animal kingdom. Surprisingly, we recently performed an experiment in which 12 adult fish At the same time, the availability of had their tails amputated, but none of molecular approaches and tools to the fish regenerated a blastema as manipulate genomic sequences has expected even two weeks after ampu- driven the focus of scientific studies tation. These fish had been kept in a towards elucidating the genetic basis room adjacent to the main aquaria of regeneration processes. This has led room. Upon return to their original to a growing identification of distinct tanks in the main aquaria, these fish molecular switches and signaling began regenerating their tails. This pathways that activate or inhibit stem observation led us to hypothesize that Figure 1: Experimental lab setup to modify external lighting conditions. cell progenitors and other cellular decreases in light exposure negatively 1-2 Top Row: Fish in the Control group were mechanisms of tissue regeneration . affected tail regeneration in S. macru- housed in individual tanks and had no rus. S. macrurus fish (n=5) were then changes in ambient light exposure. However, and perhaps unintentionally, placed in either constant darkness Bottom Row: Fish in the Restricted Lighting the emphasis on establishing model conditions or on a control 12hr- or “dark” group were housed in individual tanks and their exposure to light was systems amenable to genetic manipu- on/12hr-off light cycle condition greatly reduced by covering their tanks lation under controlled lab conditions (Figure 1) and regeneration blastema with thick black plastic bags. has led many of us to overlook and/or length measured seven and 14 days underestimate the environmental post-amputation. tions at seven and fourteen days after effects on regeneration. tail amputation (Figure 2). Quantita- In general, regeneration blastemas tion of cell proliferation in regenera- A case in point is the effect of artificial from fish kept in restricted light or tion blastemas under control and light exposure on tail regeneration “dark” conditions appeared smaller dark conditions using the 5-ethynyl-2’- of the gymnotiform electric fish than those in control lighting condi- deoxyuridine (EdU) labelling assay 50 PROFILE showed mean lower numbers of EdU-positive cells in blastemas from fish kept in dark, compared to that of fish in control lighting conditions. These observations led us to our redis- covery of a study published in 19777 on stunted forelimbs of newts Triturus (Notophthalamus) viridescens when these were kept in constant darkness following limb amputation. Specifically, animals exposed to continuous light reached the regeneration stage four to five days before those who were kept in total darkness. Moreover, the differ- ence in regeneration rate was first Figure 2: Light restriction leads to smaller regeneration blastemas. Images of partial S. macrurus evident in the moderate early stage; it tails 2 weeks after tail amputation under control and restricted light (i.e., “dark”) conditions. then increased during subsequent stages and the difference persisted their predicted function in the mech- 8 Young, H. E., Bailey, C. F., & Dalley, B. K. (1983). Environmental- during the observation period – obser- anisms of tissue regeneration in less conditions prerequisite for complete limb regeneration in the vations similar to those in our study of controlled environmental conditions. postmetamorphic adult land-phase salamander, Ambystoma. S. macrurus. Anatomical Record, 206(3), 289-294. References “Today, the number of both terrestrial 1 Juan WC and Hong W (2016). Targeting the Hippo Signaling Acknowledgement: This research was supported by NIH grant and aquatic species tested for their Pathway for Tissue Regeneration and Cancer Therapy. Genes 7, U54CA132383, NSF INSPIRE Award CNS-1248109 and HHMI response to injury continuously grow, 55 doi:10.3390/genes7090055. Science Education Program, Grant 52008103. expanding the comparative analysis of 2 Tanaka EM (2016). The molecular and cellular choreography of regeneration capacities throughout appendage regeneration. Cell 165, 1598-1608. the animal kingdom.” 3 Patterson, J. M., & Zakon, H. H. (1993). Bromodeoxyuridine labeling reveals a class of satellite-like cells within the electric In 1983, a study by Young et al8 also organ. Journal of Neurobiology, 24(5), 660-674. doi: reported that restricted lighting con- 10.1002/neu.480240510. ditions could retard regeneration in 4 Unguez GA and Zakon HH. (2002). Skeletal muscle transformation the adult salamander, Ambystoma. into electric organ in S. macrurus depends on innervation These two studies are not cited in (https://www.ncbi.nlm.nih.gov/pubmed/12382266) . J Neurobiol. the numerous papers dissecting the 53:391-402. genetic and molecular factors of 5 Unguez, G. A. (2013). Electric fish: new insights into conserved regeneration processes under con- processes of adult tissue regeneration. Journal of Experimental trolled lab conditions. Whether or not Biology, 216(13), 2478-2486. doi: 10.1242/jeb.082396. Graciela A. Unguez, PhD changes in environmental lighting act 6 Weber, C. M., Marti ndale, M. Q., Tapscott, S. J., & Unguez, G. A. Professor of Biology through any of the currently known (2012). Activation of Pax7-Positive Cells in a Non-Contractile Department of Biology pathways or regulatory protein fac- Tissue Contributes to Regeneration of Myogenic Tissues in the New Mexico State University tors that activate or inhibit regenera- Electric Fish S. macrurus. Plos One, 7(5). doi: Tel: +1 575 646 7963 tion is currently unknown. Certainly, 10.1371/journal.pone.0036819. [email protected] of more importance is whether or not 7 Maier, C.E., & Singer, M. (1977). The Effect of Light on Forelimb the molecular switches and signalling Regeneration in the Newt. Journal of Experimental Zoology, pathways of current interest retain 202(2), 241-244. doi: 10.1002 /jez.1402020213. 51 ENVIRONMENT Promoting polar science in the United States The work of the Office of Polar Programs (OPP), part of the National Science Foundation (NSF), is examined here by Open Access Government ithin the National Science Foundation (NSF), International Thwaites Glacier collaboration the Office of Polar Programs (OPP) exists to In other recent news, we learn that the collapse of the promote innovative and creative scientific Thwaites Glacier in West Antarctica could affect global Wresearch that concerns the polar regions. They achieve sea levels significantly. In April, the National Science this by catalysing fundamental understanding and Foundation (NSF) and the United Kingdom’s Natural discovery of polar systems and their global interactions Environment Research Council (NERC) announces that to educate the United States and to advance the welfare teams of scientists in various U.S. institutions will of everybody. deploy to Antarctica to collect the data required to find out if the glacier could begin to collapse during the Science, Technology, Engineering and Mathematics next few decades or centuries. (STEM) engagement and workforce development (edu- cation & people) are very much a part of OPP’s remit, This is part of a new $25 million research collaboration, as they aim to undertake their duties in a collaborative which will continue until 2021 and we discover that The and sustainable manner. OPP works with a wide array Thwaites Glacier already drains an area that is similar of partners, including native Arctic communities and to the size of Britain or the state of Florida, which Alaskan residents from the polar regions, as well as accounts for around 4% of global sea level rise. local, state, federal and international educational and research agencies and institutions. “Satellites show the Thwaites region is changing rapidly,” says William Easterling, NSF assistant director Ice stream draining Greenland Ice Sheet for Geosciences. “To answer the key questions of how One of the many examples of research highlighted on much and how quickly sea level will change requires OPP’s website is all about a study which shows that a scientists on the ground with sophisticated equipment ribbon of ice more than 600 km long that drains collecting the data we need to measure rates of ice- around 12% of the gigantic Greenland Ice Sheet which volume or ice-mass change. The challenges of conduct- has been smaller than it is today, a new study explains. ing fieldwork of this scope and scale in such remote We find out that the loss of ice from the Northeast locations are enormous. The only practical way for Greenland Ice Stream (NEGIS) took place during the nations to do this is to work collaboratively, each warm Holocene period, and during a time preceding bringing scientific and logistical resources to enable the last glacial maximum that is thought to be very cold complex and comprehensive field studies”, he adds. one, the researchers argue. The Office of Polar Programs manages the U.S. Antarctic “There are some parts of the ice sheet that are relatively Program, which will support the collaboration’s stable and others that show evidence of very rapid researchers and provide U.S. logistics for the project’s retreating – a pattern we’re seeing today as well as vital work. “The fate of the Thwaites Glacier is one the thousands of years ago,” says Anders Carlson, from big unknowns in Antarctic science,” says Duncan Wing- Oregon State University, who is a co-author of the ham, NERC’s chief executive. “We currently do not know study. “Some of it relates to bed topography – when the enough about the likelihood, timing and magnitude of bed is below sea level, it stabilises that part of the ice the collapse of West Antarctic glaciers such as Thwaites sheet. In low spots, it is unstable”, he adds.1 to be able to plan accordingly. NERC and NSF, working 52 ENVIRONMENT together, are uniquely placed to attempt to reduce the In closing, it’s worth just saying that these two examples scientific uncertainty about these unknowns, providing illustrate the Office of Polar Programs clear aim to pro- answers to one of the most important questions facing mote, “creative and innovative scientific research…in us about global sea level rise”, he adds. and about the polar regions, catalysing fundamental discovery and understanding of polar systems and “Within the National Science Foundation (NSF), the their global interactions to…advance the welfare of all Office of Polar Programs (OPP) exists to promote people.”3 ■ innovative and creative scientific research that concerns the polar regions. They achieve this by References catalysing fundamental understanding and discovery 1 https://www.nsf.gov/news/news_summ.jsp?cntn_id=245563&org= of polar systems and their global interactions to OPP&from=newsField educate the United States and to advance the 2 https://www.nsf.gov/news/news_summ.jsp?cntn_id=245261&org= welfare of everybody.” OPP&from=news 3 https://www. nsf.gov/div/index.jsp?div=OPP This is the largest joint project undertaken by the two nations in Antarctica in more than 70 years and includes about 100 scientists from research institutes in both countries alongside those other nations, includ- ing Germany, Sweden, South Korea, New Zealand and Finland. Kelly Falkner, director of NSF’s Office of Polar Programs, underlines that the U.S. Antarctic program has: “decades of experience in supporting large-scale international research initiatives – from building the world’s largest neutrino detector at the South Pole to Open Access Government supporting ice-core and sediment drilling projects that [email protected] provide glimpses into the thawing and freezing of www.openaccessgovernment.org Antarctica over timescales of millions of years.”2 www.twitter.com/OpenAccessGov 53 PROFILE The Antarctic notothenioid fishes: An especially interesting and unique marine species flock Arthur L. DeVries, from the University of Illinois provides a comprehensive insight into a unique marine species flock, the Antarctic notothenioid fishes t one time the Antarctic Ocean waters of the sub-Antarctic islands column and are neutrally buoyant was home to a temperate fish and the Patagonian region of South even though they lack a swim bladder. fauna which included sharks, America. They have achieved neutral buoyancy raysA and bony fishes (teleosts). About by reducing mineralisation of their 20 million years ago the Antarctic waters When the waters surrounding the skeletons and scales and accumulat- began to cool and all the temperate Antarctic continent began freezing – a ing lipids which are less dense than fishes died out, except for a bottom- novel trait evolved in some of the seawater. The smelt accumulates sacs dwelling fish that probably looked like progeny of the notothenioid ancestor of clear lipid under its skin and a northern hemisphere sculpin. This – which permitted them to avoid between its dorsal vertebral spines. hypothetical ancestor gave rise to a freezing; this trait was a blood-born Neutral buoyancy adaptations allow group of closely related fishes that glycoprotein which had antifreeze these two species to cruise through survived the cooling waters, which properties. This antifreeze glycopro- the water column expending energy today are known as the notothenioid tein (AFGPs) lowered its blood freezing only for directional swimming rather fishes: (a sub order Notothenioidei point a few tenths of a degree below than swimming to counteract sinking. nested within the modern bony fishes the freezing point of seawater (-1.9°C). (Perciforms). Some of the shared The antifreeze trait allowed them to Channichthyids, often called crocodile features of this group are the lack of a survive and diversify into many fishes because of their large mouths swim bladder making them negatively species which filled the ecological as adults are sit and wait predators buoyant in seawater, paired pelvic and niches vacated by the extinction of the and can gulp and swallow a fish half pectoral fins positioned one above the temperate fish fauna. Presently, there their size. The most amazing trait other and just distal of the opercula are a variety of body morphs. Some of found in this family is the lack of red and mostly benthic species. the nototheniids and harpagiferids blood cells and hence hemoglobin the resemble north temperate bottom oxygen transport pigment. Oxygen This suborder includes eight families dwelling thorny sculpins (Cottids). taken up at the gills is transported most of which are found in the South- only as dissolved oxygen in their ern Ocean south of the Antarctic con- Other species of the nototheniid hemoglobinless blood. vergence. Members of five of the eight family are like smelt and salmonids in families are primarily confined to the body form with a fusiform shape. The However, they have evolved adapta- narrow shelf region of the Antarctic nototheniid, Trematomus borch- tions to partly overcome the lack of continent. The families include the grevinki inhabits the waters at the hemoglobin such as larger gills for a Nototheniidae, Channichthyidae, underside of the fast ice and finds larger gas exchange surface to absorb Bathydraconidae, Artedidraconidae refuge in the platelet layer and has a oxygen, a larger blood volume with a and Harpagiferidae. They make up body form similar to a codfish. The larger heart and the absence of scales about 90% of the fish biomass of the two nototheniid fishes, Pleura- which allows some gas exchange shelf and the populations of some of gramma antarctica (Antarctic smelt) through the thin skin. Despite these the species are huge. The other three and giant Antarctic toothfish, Dissos- adaptations, they do not tolerate families (fig 1) are confined to the tichus mawsoni inhabit the water stress like their red-blooded relatives 54 PROFILE Adaptive Radiation of Antarctic Notothenioid Fishes ! Major groups of fish taxa disappeared at ~40 mya. Basal taxa Endemic Antarctic taxa ! Rise of the Non-Antarctic notothenioid fishes : ! ~45% of all species in Southern Ocean; 90-95% of fish individuals on continental shelf. AFGP appears Figure 1. Cladogram of Antarctic fishes of the Suborder Notothenioidei and characteristics of the group and are therefore at a physiological The notothenioid group is an excellent genomic changes that gave rise to disadvantage relative to the other example of a marine species flock. them. This marine species flock is like notothenioids. That is, a closely related clade of the African Rift cichlids which also arose species that arose from a common from a common ancestor and evolved However, they have been able to sur- ancestor and underwent an adaptive into hundreds of species which exhibit vive for millions of years because the radiation that gave rise to a variety of morphological, behavioural and repro- cold Antarctic Ocean contains more species with unique morphological ductive differences and utilise different oxygen than warm temperate waters and physiological characteristics that ecological niches in the fresh water because oxygen solubility is greater in allowed them to successfully invade lakes. cold water than warm water. The and fill most of the underutilised eco- presence of one species of the chan- logical niches that were vacated by the nichthyid species in 12°C waters of extinct temperate fauna. Because Tierra del Fuego exemplifies the cre- they are closely related the similarities ativity of evolution as this one species and differences in some of their bio- can tolerate temperatures well above chemical, physiological and morpho- those ice fish species endemic to the logical traits can be more easily Antarctic Ocean which fail to survive compared without having to deal with Arthur L. DeVries at temperatures higher than +6°C. a phylogenetic signal that would be Department of Animal Biology, Although this South American fish present if they originated from unre- University of Illinois appears to exist near it physiological lated ancestors. Tel: +1 217 333 4245 limit, it does attest to its evolutionary [email protected] success despite having to compete Thus, a clearer picture can be gleaned with many coexisting red blooded from comparative studies of their species, such as salmonids and other morphological, biochemical, physio- non-Antarctic fish species. logical adaptations and the underlying 55 ENVIRONMENT Ocean sciences: Advancing the frontiers of knowledge The activities of the Division of Ocean Sciences (OCE), a section of the National Science Foundation (NSF), in advancing the frontiers of knowledge around ocean sciences, are reviewed here by Open Access Government he Division of Ocean Sciences (OCE) is a section of NSF experiments on giant kelp the National Science Foundation (NSF) in the U.S. In recent news from OCE, we discover that a giant kelp that strongly supports research, infrastructure can grow two feet a day and reach nearly 150 feet in andT education to further understanding of the global length – in one growing season. Researchers affiliated oceans and ocean basins, including their interactions with the NSF) Santa Barbara Coastal (SBC) Long-Term with the integrated Earth system and human beings. Ecological Research (LTER) site aimed to find out how giant kelp can maintain their impressive growth in OCE’s activities provide essential knowledge for seasons when nitrate all but vanishes. addressing many of the U.S.’s most pressing challenges in the area of earth processes. OCE advocates collabo- Details of their findings on one of the fastest-growing ration in the field and encourages the development of organisms on Earth appeared in June 2018 in the a diverse scientific and educational community, at journal, Limnology and Oceanography Letters. “This home and abroad. report provides an explanation for how giant kelp in Southern California is able to persist and grow when Working in partnership with the U.S. ocean sciences nitrate concentrations in coastal waters are extremely academic community, OCE directs funding towards low,” says David Garrison, a program director in NSF’s advancing the frontiers of knowledge, enhancing the LTER program, which funded the study. public’s understanding of ocean sciences and developing the next generation of researchers. “It turned out that kelp consistently showed no prefer- ence, and used urea at equal rates as ammonium,” While OCE represents this community in the Federal lead author Jason Smith of the University of California, context, they coordinate with international partners in Santa Barbara (UCSB) explains. “Our results suggest areas such as funding for research and managing that there’s enough urea available to sustain kelp infrastructure. OCE also takes part in the development growth when levels of ammonium and nitrate are low.” of policy by means of a number of forums and pro- grammes in the U.S. and further afield. Having said that, calculating a rate of use for the 56 ENVIRONMENT various compounds provided just some of the answer, Dispersants to clean up oil spills we are told. Finally, other news worth exploring concerns the NSF’s research with the Woods Hole Oceanographic Institu- “We performed a set of controlled experiments on kelp tion (WHOI), which discovered that sunlight chemically tissue to prove that the urea molecule itself enters the alters crude oil floating on the surface of the sea within tissue,” Smith adds. “We’re the first to document for any a matter of days or hours. seaweed that the whole urea molecule is consumed, which greatly expands the known physiology of giant “It’s been thought that sunlight has a negligible impact kelp and the kinds of nitrogen forms the plant can use.”1 on the effectiveness of dispersants,” explains Collin Ward, a scientist at WHOI and lead author of the study. The impact of hurricanes on coastal “Our findings show that sunlight is a primary factor that ecosystems controls how well dispersants perform. And because In other news, we learn that scientists have set out to photochemical changes happen fast, they limit the chronicle how two decades of hurricanes have affected window of opportunity to apply dispersants effectively.” North Carolina’s Neuse River, the second-largest estuary in the U.S. The NSF supports this fascinating area of Henrietta Edmonds, a program director in NSF’s Division research through its Biological Oceanography and of Ocean Sciences, which funded the research adds, Chemical Oceanography programs, which included a “This study shows how important it is to do basic rapid response grant following 2016’s Hurricane Matthew. research on the chemical reactions that take place in the environment. The results will help us learn how to “OCE’s activities provide essential knowledge for effectively respond to oil spills.”3 addressing many of the U.S.’s most pressing challenges in the area of earth processes. OCE Final remarks advocates collaboration in the field and encourages The above examples of research into the ocean sciences the development of a diverse scientific and reveal exactly how OCE directs funding into areas that educational community, at home and abroad.” advance “the frontiers of knowledge”, develop “the next generation of researchers” and enhance “the public’s “One manifestation of climate change may be a higher understanding of ocean sciences.”4 It also fits in with frequency of storms,” says David Garrison, a program the wider aim of the NSF to “support basic research director in NSF’s Division of Ocean Sciences. “This study and people to create knowledge that transforms the provides valuable insights into how coastal estuaries future.”5 ■ will be affected.” References Hans Paerl, a scientist at the University of North Carolina 1 https://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=245489& at Chapel Hill adds: “Understanding how an increase in org=OCE&from=news extreme events such as hurricanes affects coastal 2 https://www.nsf.gov/discoveries/disc_summ.jsp?cntn_id=245304& ecosystems is critical to preparing for a stormier future.” org=OCE&from=news 3 https://www.nsf.gov/news/news_summ.jsp?cntn_id=245099&org= Understanding how coastal ecosystems respond to OCE&from=news hurricanes and other major storms, including nor’east- 4 https://www.nsf.gov/geo/oce/about.jsp ers and severe thunderstorms, says Paerl, “is important 5 https://www.nsf.gov/about/ at a time when such extreme weather events are becoming more frequent and intense.” This perspective examines the effects of hurricanes on estuaries, also indicates that the increased CO in coastal waters could impact upon the climate. “The Open Access Government impacts of these infrequent but significant pulses of [email protected] nutrients into sensitive coastal ecosystems have been www.openaccessgovernment.org mostly unknown,” Paerl underlines.2 www.twitter.com/OpenAccessGov 57 PROFILE Oceans heated by volcanic ridges and seamounts Dr Karen Bemis from Department of Marine and Coastal Sciences, Rutgers, The State University of New Jersey gives a fascinating explanation of how oceans are heated by volcanic ridges and seamounts ave you ever wondered what controls the temperature and the chemistry of the deep Hocean? If you are interested in climate change, you should. Many factors, including dense surface waters that sink to the depths, can affect the deep ocean temperature and chemistry. One of the most surprising and spectacular controls on deep ocean temperature and chemistry are the volcanic hot springs that line the mid- oceanic ridges and cap seamounts providing chemosynthetic energy to support fantastic ecosystems. These hot springs transfer sufficient heat and chemicals into the ocean to affect the deep ocean circulation patterns, Figure 1. Black smoker on top of Grotto vent in the Main Endeavour Field on the Juan de Fuca the ocean chemistry (for example, the Ridge. Video frame taken on July 9, 2011, at 04:41 GMT courtesy of Ocean Network Canada dissolved Fe content), and the biomass productivity of the ocean. (1) standing how seafloor hydrothermal the orientation of the fan. This results In volcanic systems under the ocean, venting works and to quantifying the in information on the amount and seawater infiltrates deeply into the amount of magmatic heat transferred phase of backscattered sound from fractured crust warming up due to into the ocean over time. (2) The Cabled every point within a 50m x 50m x 50m heat from magma and reacting with Observatory Vent Imaging Sonar, known volume, creating an image of plumes the crustal rocks. This altered hot as COVIS, detects and measures such rising from hot springs within that seawater rises back to the seafloor fluxes and their spatial distribution region of seafloor. Detailed waveform forming hot springs. Some of the hot using a multi-beam sonar from a information is combined with the water forms and exits from sulfide stationary platform to measure observed plume geometry to infer chimneys, creating rising plumes. backscatter and phase variations vertical variations in rising speed and Other hot water mixes with cold within a 3D volume. (3) the overall heat transferred. COVIS seawater below the seafloor and also operates in an alternate mode exists through cracks in the seafloor COVIS emits sound which is scattered which produces a map of hot spring and porous sulfide deposits forming by particles and rapid turbulent incidence on the seafloor over a lower temperature distributed deposits changes in temperature; COVIS records 50m x 50m area. and supporting extensive communities the amount and locations of back - of microbes and animals. scattered sound. Because COVIS is a In 2010, a joint team of scientists and multi-beam instrument, each ping of engineers from Rutgers, The State Measuring the heat flux transferred sound covers a fan-shaped area; University of New Jersey, and the by such fluids is critical to both under- mechanical rotation is used to control University of Washington worked with 58 PROFILE Cabled Array node in the ASHES vent field in the caldera of Axial Volcano, which erupted in 1998, 2011 and 2015. (6) The COVIS scientists and engi- neers are hoping to observe changes in heat and the distribution of hot springs during a volcanic eruption. References 1 - German, C. R., Casciotti, K. A., Dutay, J.-C., Heimbürger, L. E., Jenkins, W. J., Mills, R. A., Obata, H., Schlitzer, R., Tagliabue, A., Turner, D. R., and Whitby, H. (2016). Hydrothermal impacts on trace element and isotope ocean biogeochemistry. Phil. Trans. R. Soc. A, 374(2081), 20160035. 2 - Bemis, K., Lowell, R., and Farough, A. (2012). Diffuse flow on and around hydrothermal vents at mid-ocean ridges, Oceanography, 25(1), 182-191, http://dx.doi.org/10.5670/oceanog.2012.16. Figure 2. COVIS was lowered into the ocean in September 2010 over the Juan de Fuca Ridge from the R/V Thompson. Photo taken by Peter Rona who headed the project until his death in 2014 3 - Bemis, K. G., Silver, D., Xu. G., Light, R., Jackson, D., Jones, C., Ozer, S., Liu, L., The path to COVIS: a review of acoustic imaging of hydrothermal plumes. Deep Sea Reseach Part II: Topical Ocean Networks Canada to attach the very low rates of even tiny earth- Studies in Oceanography, 121, 159-176, doi:10.1016/j.dsr2. COVIS to their underwater cabled quakes. (5) Researchers suspect that 2015.06.002, 2015. observatory which extend to sites on heat transfer rates would be higher 4 - Xu, G., K. Bemis, and D. Jackson (2017), Sounding the black the northern part of the Juan de Fuca during times of greater earthquake or smoker plumes, Eos, 98, https://doi.org/10.1029/2017EO086289. Ridge, more than 100 km off the coast volcanic activity. Published on 10 November 2017. of British Columbia. (4) From 2010 to 5 - Xu, G., Jackson, D. R., Bemis. K. G., and Rona, P. A., Time series 2015, COVIS monitored the heat After extensive refurbishing, COVIS is measurement of hydrothermal heat flux at the Grotto mound, transferred by a small hydrothermal soon to be installed in a new location Endeavour Segment, Juan de Fuca Ridge, Earth and Planetary vent called Grotto Vent. During this for monitoring heat from seafloor hot Science Letters, 404, 220-231, 2014. period, the average heat transfer rate springs: COVIS will be connected to 6 - Chadwick, W. W., Jr, J. B. Paduan, D. A. Clague, B. M. Dreyer, S. of 20 MW changed little reflecting the US National Science Foundation's G. Merle, A. M. Bobbitt, D. W. Caress, B. T. Philip, D. S. Kelley, and S. L. Nooner (2016), Voluminous eruption from a zoned magma body after an increase in supply rate at Axial Seamount, Geophys. Res. Lett., 43, 12,063-12,070, doi:10.1002/2016GL 071327. Figure 3. Example image from COVIS data at noon on Oct. 22, 2012. Blue-green colours highlight the plumes rising above the seafloor (light brown) Dr Karen Bemis while yellow-red-blacks Department of Marine and Coastal Sciences highlight areas of intense diffuse output. Black lines are Rutgers, The State University of New Jersey lines of constant seafloor Tel: +1 848 932 3384 depth. All distances (and heights) are relative to COVIS’s [email protected] location. COVIS data https://marine.rutgers.edu/main/ downloaded from Ocean Networks Canada; bathymetry from Dave Clague at MBARI 59 PROFILE Recognising the important role of biodiversity Pamela S. Soltis, Director, University of Florida Biodiversity Institute, reveals the key work being done in the U.S. to respond to the ‘biodiversity crisis’ iodiversity refers to the extraordinary variety of life on Earth. While widely accepted Bthat natural biological diversity is fundamental to a healthy, sustainable planet and that its loss has negative impact on human well-being (for example, see Science magazine, July 2014), the connections between biodiversity, ecosystem function and services that contribute to human well-being – from the flow of fresh water to pollination of crops – are less well understood. Ecological economists note the effect of invasive species (>$120 billion annually in the U.S. alone) and have begun to quantify the economic benefit of ecosystem services, but less is known about the impact of lost ecosystem services on Why biodiversity matters More recently, the International Plat- other aspects of both environmental Recognising the important role of bio- form on Biodiversity and Ecosystem and human well-being. diversity in the biological and socio- Services (IPBES), with 118 member logical health of the planet, the U.N. nations and modelled after the Global responses to societal problems declared 2010 the “Year of Biodiver- Intergovernmental Panel on Climate arising from both loss and alterations sity” and 2011-2020 the “Decade on Change (IPCC), has begun assessing of biodiversity suffer from insufficient Biodiversity” to focus attention on the the scientific and social knowledge of information and inadequate policies accelera ting loss of biodiversity in the Earth’s biological diversity and how for sustainable use of natural face of human population growth, environmental change will impact resources, in part, due to the slow rate landscape modification and climate ecosystems and human so cieties. at which biodiversity data are gathered change. In 2011, the U.S. President’s Like IPCC, the IPBES does not conduct and the difficulty in accessing the Council of Advisors on Science and primary research but assesses knowl- information once it is available. Con- Technology called for improved edge and attempts to influence poli- sequently, much of the diversity of accounting of ecosystem services and cies aimed at protecting ecosystems our planet is likely to disappear before greater protection of environmental and pursuing sustainable economic it can be discovered and understood. capital, citing the need for further growth. This “biodiversity crisis” – that is, the biodiversity science and application of loss of biodiversity and its attendant informatics to enhance our under- The recent establishment in the U.S. consequences – creates both the standing of ecosystem services and of NEON (the National Ecological necessity and the opportunity for a develop an appropriate policy to Observatory Network) is beginning to new type of response. protect them. provide extensive environmental data 60 PROFILE and baseline ecological monitoring at ate and lead large-scale, collaborative biodiversity collections – that is, the select sites across the country, with biological surveys to document and integrated database that shares biodi- fully operating data streams from monitor biodiversity on a global scale; versity data for the nation’s natural nearly all sites now in place. Current (2) Conduct collaborative and interdis- history specimens. iDigBio currently and future assessment targets include ciplinary research on biodiversity, with serves 110 million specimen records, the impact of declines in pollinator an emphasis on the use of big data; representing approximately 300 mil- populations on food production, inva- and (3) Translate biodiversity science lion of the estimated 1-2 billion speci- sive species and habitat degradation, to solve major societal problems. mens i n U.S. collections. This growing all topics that will threaten food secu- resource is driving innovations in rity during the coming century and are “The UF Biodiversity Institute has management, analysis and interpreta- relevant to agencies such as the U.S. already established strong links to tion of biodiversity data, both in the Department of Agriculture, which data science, informatics, computer U.S. and globally, with a promise to governs not only food production, but science and engineering, as well address problems ranging from food also forestry in the U.S. Despite an as to specialists in environmental security to invasive species to the increased awareness, more integrated, law, agricultural economics, climate response of species to climate change. accessible science and technology plat- science, land use and human forms are needed to leverage novel population growth.” In a recent series of articles on the planetary data, models and tools to UF Biodiversity Institute, we have create and link knowledge to policy. The UF Biodiversity Institute is addressed the resources of iDigBio, the exploring the world's past and present global need for innovative biodiversity The University of Florida (UF) biological diversity at scales from training programmes for students and Biodiversity Institute molecules to ecosystems and the practitioners to take advantage of The University of Florida (UF) Biodiver- relationship of biodiversity to climate ongoing developments in data avail- sity Institut e was launched in 2016 to change and to healthy and sustainable ability and use, as well as the economic bring together scientists, social scien- natural and human environments. value of ecosystem services. tists and policy experts to address crit- Institute scientists conduct synthetic ical societal issues of the 21st century research using data from all relevant related to biodiversity: invasive sources to address fundamental species, emerging pathogens, climate problems in biodiversity science and change and food security, to name a solve pressing societal problems. few. This interdisciplinary institute is Newly synthesised knowledge from accelerating synthetic research on the institute is available to individuals biological diversity to serve stakehold- and organisations seeking validated ers in Florida (a biodiversity hotspot) biodiversity information. and globally through efforts to understand and manage biodiversity, The UF Biodiversity Institute has develop relevant conservation, educa- already established strong links to Pamela S. Soltis tional and outreach programmes and data science, informatics, computer Director shape policy to protect and enhance science and engineering, as well as to University of Florida Biodiversity Institute environmental capital. specialists in environmental law, agri- University of Florida cultural economics, climate science, Gainesville, Florida 32611, USA The Mission of the UF Biodiversity land use and human population Tel: +1 352 273 1964 Institute is to conduct high-quality growth. The institute benefits from [email protected] research and develop programmes to strong ties to iDigBio, the U.S. national https://biodiversity.institute.ufl.edu/ advance three primary goals: (1) Initi- coordinating centre for digitisation of 61 ENERGY First EU TF Magnet undergoes cold testing Fusion energy: Making history Laban Coblentz, Head of Communication at ITER explains his thoughts on how history is being made when it comes to the exciting world of fusion energy ast November, the ITER fusion project – 35 coun- understood. A few grammes of hydrogen in two forms tries collaboratively building the most world’s most – deuterium and tritium – are injected into a large, complex machine – reached the 50% mark in “total doughnut-shaped vacuum chamber. The hydrogen gas constructionL work scope through First Plasma.” Nearly is superheated to form an ionized plasma, its atoms 800 publications and media outlets in more than 40 separated into positively charged nuclei and negatively countries hailed this milestone. Scientists, government charged electrons. At temperatures approaching 150 ministers and industry CEOs congratulated each other million °C, the charged particles are moving fast on the joint progress to date. enough that when they collide, they overcome their natural repulsion and fuse. Adhering to E=mc2, a minis- Which feature captures the significance of this accom- cule portion of mass is converted to a massive release plishment? Is it ITER’s ground-breaking science and of energy. engineering? The multinational project management required? The potential impact of fusion energy on ITER’s engineering has also been largely validated in society? Perhaps it is a combination of the three? past tokamak reactors. Multiple sets of superconduct- ing electromagnets – cylindrical, round, D-shaped and Part one: The science and engineering more – create an invisible magnetic cage that confines The physics of magnetic confinement fusion is well the charged particles of the plasma away from the 62 ENERGY metal chamber walls. Only the neutrons, which have no charge, escape the plasma to convert their immense kinetic energy into heat. These behaviours have been demonstrated in smaller machines, as have most of the cryogenics, vacuum systems, robotics and power electronics in the ITER design. What sets ITER apart is the combination of scale and precision required. Each of ITER’s main magnets weighs several hundred tonnes; some have dimensions as large as 25 metres; yet the intense magnetic fields they generate must be cross-woven so intricately that charged hydrogen nuclei – sized at roughly 10-15 metres – cannot escape. Components so large they must be fabricated in shipyards will be positioned with the delicacy of a watchmaker. Japanese TF Coil Case “The physics of magnetic confinement fusion is well Babel that begins with no one speaking the same understood. A few grammes of hydrogen in two language, connecting through the common vocabulary forms – deuterium and tritium – are injected into a of mathematics, physics and three-dimensional CAD large, doughnut-shaped vacuum chamber. The drawings. hydrogen gas is superheated to form an ionized plasma, its atoms separated into positively charged Yet this is not lunacy. As the ITER Director-General, nuclei and negatively charged electrons.” Bernard Bigot, said recently: “No country or organisation could do this alone. By choosing to build this machine in These extremes are driving a host of innovations and an integrated way, we have made our success interde- firsts, from fabrication techniques to new materials, pendent. Our project is built on this condition: if our part- instrumentation and tools. They are required by ITER’s nerships perform well, each partner contributes its mission: to demonstrate the feasibility of fusion energy expertise, we all learn from each other, the interfaces are on a commercial scale, by creating for the first time on well-managed, the project succeeds, and everyone wins.” Earth the conditions necessary for a “burning plasma,” Multinational project management at ITER – systems in which the plasma heating is largely self-generated: engineering, risk management, configuration control – in brief, to create a star on earth. is a herculean effort; but in this crucible, new models for cross-border collaboration are being forged. Part two: Multinational project management As if the complexity of a full-scale tokamak were not Consider one example: In December 2017, Japan cele- demanding enough, the ITER Agreement stipulates brated the completion of ITER’s first toroidal magnet that each member will contribute most of its financial case: at first glance, merely an oddly shaped, giant support “in-kind,” in the form of hardware. In other piece of steel. But the devil is in the details: the words, the million-plus ITER components being manu- 16-meter case, fabricated in sections by Mitsubishi and factured across the globe, in Japanese factories, Amer- Hyundai, successfully achieved tolerances of less than ican laboratories, Indian foundries, Korean industrial 1 millimetre. In January it was shipped to Italy, where a plants, Chinese workshops, Russian shipyards, Euro- 310-tonne magnet, containing more than 5 kilometres pean innovation centres – must be fitted together into of niobium-tin superconductor manufactured in China, a single, functional device: a sort of reverse Tower of Europe, Russia and the United States, will fit snugly into 63 ENERGY First Sub Sector Assembly Tool 90% complete the case. When finished, the component will be fusion roadmap of every country involved. Gargan- received at the ITER worksite in southern France, tuan, audacious, hellishly complex, yet elegant in the where an 800-tonne, Korean-made assembly tool – simplicity of its civilisation-changing goal: ITER seeks to standing 10 stories tall, arms outstretched like a enable the human animal to harness the power of the mechanical angel’s wings – will cradle it gently, together heavens. Safe, environmentally friendly and with abun- with a European-made sector of vacuum vessel and a dant supplies of fuel available to every country, fusion Korean-made ultra-thin silver-plated thermal shield; energy aims to transform the socio-political landscape. and will slowly, ponderously merge the pieces together to form a single, unified tokamak section. The stakes are high for humankind. ■ To quote Bigot again: “The future of fusion – like the future of science – is partnership.” Almost from its inception, magnetic confinement fusion has been uniquely collaborative. In 1968, when Russian scien- tists announced that their T-3 Tokamak had achieved plasma temperatures of 10 million degrees, their next action defied precedent: they invited a team fro m the United Kingdom, their Cold War enemies, to work with them at the Kurchatov Institute to verify and build Laban Coblentz together on this breakthrough. From that point Head of Communication forward, fusion has been a globally collaborative ITER R&D effort. Tel: +33 4 42 17 66 12 [email protected] This is the genius of ITER: the study of a controlled www.iter.org burning plasma is the convergent next step in the www.twitter.com/iterorg 64 PROFILE Physics: Plasma-Jet-Driven Magneto-Inertial Fusion (PJMIF) Professor Y. C. Francis Thio and Dr. F. Douglas Witherspoon of HyperJet Fusion Corporation, USA share their expert views on physics, with a focus on Plasma-Jet-Driven Magneto-Inertial Fusion (PJMIF) n the previous article in this series1, we reported on the plasma physics reasoning showing there is a sweet Ispot in the fusion parameter space with a density of the burning plasma intermediate between the two extremes typified by the two conven- tional approaches to fusion, namely magnetic confinement fusion (MCF) and inertial confinement fusion (ICF). A new class of modern fusion approaches, magneto-inertial fusion (MIF), designed to exploit this interme- diate density regime has emerged over the last two decades, thanks to MIF uses a material shell the stewardship provided by NASA, (liner) to compress a magnetised plasma target to DOE Fusion Energy Sciences (FES), create fusion reactions. DOE National Nuclear Security Admin- istration (NNSA) and the Advanced Research Project Agency for Energy (ARPA-E). tion of the broad principles of MIF, velocities up to about 100 km/s are without regards to the particular choice launched from the periphery of the The parameter space of MIF is very of liners and targets. Our pursuit at vessel, which has a radius of about 3 broad. MIF covers a density range present focuses on the use of hyper- m. The plasma jets merge at a radius for the burning plasma from 1024 sonic plasma jets as the main driver of about 1.5 m to form a plasma liner deuterium-tritium ions per m3 to 1029 due to its several attractive attributes that continues to converge towards per m3. In terms of the implosion that may enable rapid progress in our the centre and compresses the pre- velocity, it ranges from 1 km/s to more quest. The fusion approach is called formed magnetised target plasma than 100 km/s. The liner may be solid, Plasma-Jet-Driven Magneto-Inertial- down to a diameter of approximately liquid or gaseous. The many combina- Fusion (PJMIF)2,3. Los Alamos National 1 cm when fusion burn occurs in the tions of the key parameters for the Laboratory is our partner in this devel- target. The fusion burn lasts for about target and the liners give rise to a rich opment, together with several univer- 0.3 µs resulting in a micro-explosion and potentially large portfolio for MIF, sities and institutions. and a burst of energy. Because the presenting ample opportunities for efficiency of the plasma guns may be innovations in the field. In PJMIF, a magnetised target plasma as high as 50% or more, the fusion is first formed at the centre of an gain needed for a practical fusion At HyperJet Fusion Corporation, our otherwise vacuum spherical vessel. A power plant may be as low as 20 or goal is to develop economical fusion spherical array of hypersonic plasma less. A thick liquid wall (FLiBe for power, through a systematic exploita- jets, up to perhaps 600 in total, with example, approximately 1 m thick) 65 PROFILE contained between two concentric adiabatic, the timescale for the loss of spherical walls is used as a blanket to heat from the target plasma (its ther- absorb the fusion neutrons, trans- mal timescale) should be greater than forming their kinetic energy into heat 50 to 100 µs, which is a challengingly and to breed tritium by an exothermic long thermal timescale for the density nuclear transmutation to feed the and size of the magnetised plasma fusion reactor. The liquid wall also targets currently known. Initial target serves as a coolant in a heat plasma diameter much larger than 10 exchanger to extract the heat from cm may be required to match the the fusion reactor to generate electric- thermal timescale to the implosion ity. Each pulse of the fusion burn pro- velocity, increasing the overall cost of duces about 500 MJ of energy. If the the reactor. Furthermore, the implosion pulse is repeated at 1 Hz, approxi- produces debris, leading to low shot mately 500 MW of average thermal rate and high cost per shot during R&D. power is produced. Because the cost of recycling the plasma guns and the Diagnostic access to the target plasma first wall is relatively low, the PJMIF is also challenging, due to the opacity reactor vision allows for the guns and of the liner to most diagnostics. These the first wall to be replaced and recy- factors tend to limit the rate of progress cled after approximately every 20 mil- in R&D. Hardware destruction makes lion shots (~7 months)4. implementing solid-liner driven MIF as an economical, repetitively pulsed, Why are plasma liners and commercial fusion reactor a real PJMIF among other choices challenge. of liners (solid, liquid) and drivers (z-pinches, lases) for Liquid-liner driven MIF uses a liquid MIF? metal vortex to compress a magne- Solid-liner MIF typically employs a tised target plasma. The liquid liner is hollow cylindrical aluminium shell imploded by pistons driven by very an even larger initial magnetised with a diameter of ~10 cm, thickness low-cost compressed gas in a plasma target, resulting in a larger of ~1 mm and ~30 cm long. The favourably distributed configuration. cost for the reactor. The liquid liner advantages of the solid liner are that The liner is non-destructive and is directly faces the fusing plasma, cre- the technology of imploding a solid capable of high shot rate and doubles ating the potential for severe disrup- liner is relatively matured, the liner is as a protective blanket against the tion and a mix of the liquid vortex with extremely compact and has a high fusion neutrons and a tritium breed- the imploding plasma and as such, Mach number and the implosion can ing blanket, as well as a primary-loop both may be highly detrimental to the be made to follow a low adiab at, lead- coolant in a heat exchanger for the fusion burn. Similar to the solid liner, ing to high hydrodynamic efficiency. extraction of the fusion energy for diagnostic access to the target plasma With a modest a radial convergence, electricity generation. Rotation of the during R&D is also challenging due to the implosion is also hydrodynamically liquid liner in a vortex further sta- the opacity of the liner to most diag- stable. bilises the implosion against hydrody- nostics. The lower density of the namic instability. The liquid liner is target plasma necessitated by its However, the solid liner is imploded at also massive and is capable of provid- larger size may lead to plasma insta- a relatively low velocity of about 5 ing long plasma containment time bilities that cause a turbulent and km/s to 10 km/s. The implosion time during fusion burn. However, the anomalously high rate of thermal is thus about 5 to 10 µs, with a plasma implosion velocity is limited to about losses, further exacerbating the density of about 1024-26 per m3. For the 2 km/s or less, even slower than in the adverse consequences of the low heating of the target plasma to be case of the solid liner, thus requiring implosion velocity. 66 PROFILE The immediate near-term objective of our research: to form a spherically imploding plasma liner (by merging 60 plasma jets) that will be used to compress a magnetized target plasma to fusion The PLX facility at Los Alamos National conditions. The cutaway Laboratory for investigating the basic physics spherical vacuum chamber is of jet merging to form a plasma liner. 2.7 m in diameter. Figure courtesy of HyperV Technologies Corp. In PJMIF, implosion can be accom- appropriate plasma accelerators 2 Y. C. F. Thio et al., “Magnetized Target Fusion in a Spheroidal Ge- plished with suitably high velocity (guns) to deliver plasma jets with the ometry with Standoff Drivers,” in Current Trends in International from 50 km/s to over 100 km/s with required density, velocity, Mach Fusion Research – Proc. 2nd International Symposium (NRC the implosion energy and momentum number and precision in mass, veloc- Canada, Ottawa, 1999), p. 113. generated in a distributed manner. ity and launch synchronisation, to 3 S. C. Hsu et al., “Spherically Imploding Plasma Liners as a Standoff The high implosion velocity over- form a plasma liner with suitable uni- Driver for Magnetoinertial Fusion,” IEEE Trans. Plasma Sci. 40, comes target heat loss with relatively formity to limit the amplitude of 1287 (2012). small targets. It allows high-density hydrodynamic instabilities and devel- 4 Y. C. F. Thio et al., “Nuclear Fusion Blast and Electrode Lifetimes targets thus avoiding plasma instabil- oping the magnetised target plasma in a PJMIF Reactor,” Bull. Amer. Phys. Soc. 62, 396 (2017). ities that may lead to anomalously with the required high density. high thermal losses. The plasma guns are relatively inexpensive. Like the An attractive feature of the PJMIF liquid liner, it produces no hardware concept is that its component tech- debris, thus enabling high repetition nologies have near-term commercial rate and low cost per shot for com- spin-offs including the making of mercial fusion power plant, as well as metallic powders for additive manu- high shot rate during R&D to provide facturing, thermal spray and medical high data rate for rapid resolution of isotopes, as well as the processing of scientific and technological issues. nuclear wastes. The spatial and temporal scales of the implosion and the open geometry In the next article, we will report on allow convenient access for diagnos- the state of the development of the Dr Y. C. Francis Thio tics. Because of these attributes, rapid PJMIF approach. Dr F. Douglas Witherspoon progress at relatively low costs in R&D HyperJet Fusion Corporation is possible. Its main disadvantage is References Tel: +1 (703) 378 4882 that being the newest fusion 1 Y. C. Francis Thio and F. Douglas Witherspoon, Open Access Gov- [email protected] approach, it is at a very early stage of ernment, November 8, 2017. https://www.openaccessgovern- www.hyperjetfusion.com development. Technically, the main ment.org/entrepreneurial-opportunities-fusion-energy-developm challenges are the development of the ent/39604/. 67 AGRICULTURE The research priorities for the cereals and oilseeds sector Tim Isaac, Head of Arable at the Agriculture and Horticulture Development Board shares his thoughts on research into the cereals & oilseeds sector hen it comes to the cereals and oilseeds validating indicators of soil biology and soil health in sector, there are a variety of programmes research trials and integrating a far-reaching knowledge and tools AHDB has put together to enable exchange programme throughout the five-year pro- theW delivery of key objectives. gramme. The £1 million project is part of the AHDB GREATsoils programme, complementing a £1.5 million AHDB has three core research areas in cereals and initiative looking at soil structure. oilseeds comprising: In addition to longer-term research, AHDB has to be 1. Understanding the genetic potential of new cereal able to respond and move quickly in an ever-changing and oilseeds varieties, the recommended lists; environment. Issues can suddenly occur which require a rapid response to provide new information to inform 2. Understanding soil health and plant nutrition and; the industry across the supply chain. This may include a new disease outbreak, loss of important products, or 3. Crop protection, to evaluate new methods of monitor- changes in quality requirements by end users, usually ing, prevention and control of crop pests and diseases. as a consequence of changes in legislation. These three areas provide outcomes in their own right, Understanding plant pests, weed and disease epi- but together they provide a valuable resource for inte- demics, including challenges associated with new grated crop management based on robust independent threats, resistance and a reduction in agrochemicals to information. AHDB, through its links to the research manage them is a situation which requires a systems community, growers and end users, can providen a approach. Research tends to focus on individual com- important linkage to ensure innovative research ideas ponents, which is important to understand, but the can be tried and tested for the benefit of the whole practical cost-effective solutions require a whole farm industry. approach based on crop rotations over several years. Confidence in the independent evaluation of new AHDB, with its expertise both in applied research and varieties is a good example, leading to faster uptake of an understanding of growers’ businesses, is in a good new varieties with good quality benefits to the end position to help farmers deal with future challenges. user and better agronomic and disease resistance to the farmer. Its Farm Excellence Platform inspires the industry to improve performance and succeed through farmer-to- As part of AHDB’s soils research, AHDB and the British farmer knowledge exchange. For the arable sector, Beet Research Organisation (BBRO) announced an this includes Strategic Farms, Monitor Farms, Arable ambitious new research partnership to develop practi- Business Groups and technical events across the UK. cal soil biology management guidance, worth £1 million. The five-year partnership looks to improve on-farm Monitor Farms bring together groups of like-minded understanding of soil health by benchmarking current farmers who wish to improve their businesses by shar- academic and industry knowledge, developing and ing performance information and best practice around 68 AGRICULTURE a nationwide network of host farms. AHDB organises The Agriculture and Horticulture Development Board and facilitates the meetings for farmers, who own and (AHDB) is a statutory levy board, funded by farmers, operate the scheme – by farmers, for farmers. Monitor growers and others in the supply chain and managed Farms also incorporate the use of AHDB’s benchmarking as an independent organisation (independent of both tool, Farmbench, throughout their three-year term to commercial industry and of government). AHDB’s pur- track and improve performance. pose is to inspire our farmers, growers and the industry to succeed in a rapidly changing world. Our vision is for A key connection between research and knowledge a world-class food and farming industry inspired by and exchange is where knowledge gaps are identified in on- competing with the best. farm ac tivity and fed back to the research community for further analysis and guidance. For example, the sig- This is summarised in AHDB’s four core priorities: nificant rise in interest in no-till establishment systems led to a three-month review published in April 2018 – • Inspiring British farming and growing to be more AHDB was also able to conclude that there is insuffi- competitive and resilient; cient evidence to change autumn nitrogen guidance for no-tilled cereal and cover crops. • Accelerating innovation and productivity growth through coordinated R&D and knowledge exchange; Other knowledge gaps can be addressed on a farm. Some Monitor Farmers are investigating how different • Helping the industry understand and deliver what spring barley varieties perform under different condi- consumers will trust and buy and; tions. Different varieties from across northern Europe are being grown on farms across the UK alongside more • Delivering thought leadership and horizon scanning. ■ conventional options. The aims are twofold – firstly to look at the resilience of different varieties in different conditions and secondly to challenge growers to get the most out of their crops. These are just a few examples of the huge range of Tim Isaac work that AHDB is doing to inspire British farmers to Head of Arable be more competitive and resilient in light of the Agriculture and Horticulture Development Board changes that lay ahead. They clearly demonstrate that Tel: +44(0)24 7 669 2051 the key to achieving this is by accelerating innovation [email protected] and productivity growth through coordinated R&D and https://ahdb.org.uk/ knowledge exchange. www.twitter.com/TheAHDB 69 PROFILE Water, temperature and crop productivity research Prof Robert Aiken, research crop scientist at Northwest Research—Extension Center tells us about his fascinating research into water and temperature, including the extent to which they limit crop productivity lanting an agricultural crop requires a degree of optimism. In the semi-arid region of PKansas, which I study, water and tem- perature frequently limit crop produc- tivity. These components of weather, along with sunshine and relative humidity, comprise the weather- related risks which limit the productiv- ity of the crop just planted. As an agricultural scientist, I query the climate scientists: Are there periodic behaviours in weather patterns? Are there long-distance signals indicating wetting and drying trends? Is long- term weather forecasting feasible? If Figure 1: The in-sample predictive ability for wheat yield variation of multiple regression based on the NINO_3 surface temperatures of the Equatorial Pacific is compared against observed yield so, accurate forecasts can inform the variation for wheat yield in Kansas counties W of the 99th Meridian. Observed variation represents optimism required to plant that crop, variation after removal of a linear historic trend (1970 – 2007 period) as normalised by dividing by the standard deviation of the time series for each county. infusing an additional hope that the bet has been hedged. “There is an opportunity to develop High Plains. Louis Baumhardt, a USDA- ing between values of -4 and 4 to indi- climate-informed decision-support for ARS soil scientist and his colleagues cate drying (negative) and wetting cropping systems in the U.S. central found a degree of association (positive) conditions. We compared High Plains.” between ENSO patterns and winter wheat yields, reported for counties3 in wheat yields in the Texas Panhandle1. Kansas (1970 through 2007) against Seeking information about weather Does this ENSO signal convey informa- monthly SPEI values, after removing forecasting skill, I learned about tion about wheat productivity further linear historic trends attributed to ‘teleconnections’ at recent American north, in the central U.S. High Plains? improved genetics and production Meteorological Association meetings. technologies. The El Nino-Southern Oscillation We know that winter wheat is vulner- (ENSO) phenomena serves as an able to drought conditions; wheat can A moderate relationship (R2 = 0.41)4 example. Warming and cooling trends also respond positively to wet condi- emerged for wheat yields reported for in the surface waters of the equatorial tions, though subject to disease counties in W Kansas, indicating posi- Pacific Ocean impact fisheries and impacts2. The Standardized Precipita- tive effects of weather conditions in rainfall in coastal Peru. Indeed, ENSO tion-Evapotranspiration Indicator February, March and April. A weaker trends impact the productivity of (SPEI) provides a metric for wetting relationship (R2 = 0.25) resulted for winter wheat growing in the Texas and drying conditions, generally vary- counties in sub-humid E Kansas, 70 PROFILE References 1 Baumhardt, R.L. S.A. Mauget, R.C. Schwartz and O.R. Jones. 2016. El Nino Southern Oscillation effects on dryland crop production in the Texas High Plains. Agron. J. 108:736-744). 2 Aiken, R., X. Lin and Z. Zambreski. 2017. Winter wheat yield responses to climate variation in the U. S. Central Great Plains. ASABE Paper No. 1701661 DOI: https://doi.org/10.13031/aim.201701661 3 National Agricultural Statistics Service 4 ‘R’ squared (R2) indicates the fraction of observed variation which can be accounted for by a regression relationship. Figure 2: Regression coefficients of the NINO_3 multiple regression model is shown in relation to corresponding time lag (months prior to a September planting period for winter wheat in Kansas). Positive coefficient values for a given time lag indicate a positive association with expected wheat yields for that lag interval; negative coefficient values indicate a negative association. indicating both positive (October, ductivity in W Kansas related to equa- February, April) and negative (August, torial Pacific Ocean surface tempera- December, May, June) relationships tures in preceding years? We tested with the SPEI metric. This regression the null form of this hypothesis using analysis quantified the relationship of multiple regression for W Kansas winter wheat productivity to weather county yield reports and monthly variation during the growing season. ENSO data for the 24-month period However, the utility of forecasting skill prior to wheat planting (September, a depends on the information available year prior to harvest). We found a prior to planting decisions. positive result. A moderately strong relationship (R2 = 0.53) resulted from “Are there periodic behaviours in regression analysis (Figure 1). Interest- weather patterns? Are there long- ingly, the strongest influences were distance signals indicating wetting and ENSO values 18- and 16-months prior drying trends? Is long-term weather to the wheat planting period (Figure 2). Prof Robert Aiken forecasting feasible? If so, accurate This indicates that complex patterns in Research crop scientist forecasts can inform the optimism equatorial Pacific Ocean temperatures Northwest Research—Extension Center required to plant that crop, infusing an can convey information which is Tel: +1 785 462 6281 additional hope that the bet has been pertinent to subsequent winter wheat [email protected] hedged.” yields in W Kansas. There is an oppor- https://www.northwest.k-state.edu/ tunity to develop climate-informed Thus, we evaluated a hypothesized decision-support for cropping systems ENSO signal: is winter wheat grain pro- in the U.S. central High Plains. 71 PROFILE Genomics of thermotolerance – helping beef cattle adapt to the climate change Developing genomic tools for increased thermotolerance in beef cattle is imperative, says University of Florida’s Associate Professor Raluca Mateescu Climate change and beef cattle Heat stress is the principal factor limiting production of animal protein and negatively affecting the health and welfare of cattle in subtropical and tropical regions. Detrimental effects on livestock productivity asso- ciated with heat stress are expected to intensify and expand into currently temperate zones upon the realisation of predicted climate change (Figure 1). The I ntergovernmental Panel on Cli- mate Change (IPCC), which includes more than 1,300 scientists from the Figure 1: Projected Temperature Change. Warming is projected for all parts of the nation during this century. In the next few decades, this warming will be roughly 2°F to 4°F in most areas. By the United States and other countries, end of the century, U.S. warming is projected to correspond closely to the level of global emissions: forecasts a temperature rise of 2.5 to roughly 3°F to 5°F under lower emissions scenarios (B1) involving substantial reductions in emissions, and 5°F to 10°F for higher emissions scenarios (A2) that assume continued increases in 10 degrees Fahrenheit over the next emissions. (Figure source: NOAA NCDC / CICS-NC) century. Most animal-producing areas in the US are predicted to experience cattle are more severely affected by but tend to have slower growth, lower extreme summer conditions and by heat stress than beef cattle, their con- fertility and meat quality as they have 2100, average temperatures in the US finement and intensive production not been as intensively selected for are projected to increase 2° to 6°C, systems make climate control via these traits as specialised Bos taurus depending on the emissions scenario housing design and management breeds. Use of genomic tools to pro- and climate model applied. The interventions feasible. Beef cattle, duce an animal with superior ability for number of days with maximum particularly those in the cow-calf seg- both thermal adaptation and food pro- temperatures above 32°C (90°F) is ment, are typically reared in extensive duction represents an energy-efficient expected to increase. The SE and SW systems with limited opportunities for sustainable approach to meet the areas of the US currently average 60 controlling environmental stress challenge of global climate change. such days per year but is projected to (Figure 2). Genetic improvement is experience at least 150 such days a one of few feasible strategies for What is thermoregulation? year by the end of the century. ensuring adequate and sustainable Thermoregulation is a process in which production of beef protein in an environmental information provokes Importance of genomics for increasingly hot world. Substantial an appropriate response (e.g., vaso- improved thermotolerance differences in thermal tolerance exist constriction, panting), to maintain Development of effective strategies to among breeds and among animals body temperature within the narrow improve the ability to cope with heat within breeds indicative of opportuni- range necessary for optimal cellular stress is imperative to enhance the ties for selective improvement. For and molecular function. This is accom- productivity of the US livestock indus- example, Bos indicus cattle exhibit plished by jointly regulating heat try and secure global food supplies. increased resistance to many environ- production and heat loss. Beef cattle Although swine, poultry and dairy mental stressors relative to Bos taurus, regulate internal heat production (by 72 PROFILE data will be integrated to identify chromosomal regions associated with regulation of body temperature. We will use this information to develop tools to be used in selection and management programs designed to mitigate the effect of heat stress in indicine-influenced beef cattle popu- lations that predominate in hot and humid regions of the US and globally. In depth knowledge of the genomic variants with major effect on thermal regulation and the maturation of tech- nologies for gene, editing means that thermotolerance genes can be rapidly introduced into thermally-sensitive Figure 2: Bos Indicus cattle are naturally adapted to survive in tropical and breeds such as Angus, Simmental, and subtropical environments Holstein to allow producers to exploit modulating basal metabolic rate indicus influenced cattle, in particular, genetic lines of cattle selected for high through thyroid hormone actions and Brangus (Brahman x Angus). In com- productivity with minimal disruption changing feed intake, growth, lactation, parison to straight Bos taurus popula- by heat stress. Development of ‘the and physical activity) and heat tions, we expect that the major genetic cow of the future’ with high productiv- exchange with the environment variants controlling thermal tolerance ity and resistant to heat stress will be (by increasing blood flow to the skin, will be segregating in these indicine- realised through the use of genomic and increasing evaporative heat influenced populations due to the selection within indicine-influenced loss through sweating, panting and length of time since divergence of the breeds and through the application of behavioural wetting of the skin). two subspecies, natural adaptation to gene editing technologies that allow Hyperthermia results when these different environments, and exposure genetic variants conferring thermal adjustments are not able to mitigate to an artificial selection of different tolerance to be rapidly incorporated the environmental heat stress and intensities and with different objec- into non-adapted breeds. body temperature increases. Improve- tives. Our goal is to discover genetic ments in production, such as increased variants responsible for thermal growth rate, lead to increased tolerance and use this knowledge to metabolic heat production and exacer- develop genomic tools to improve bate the problem of thermoregulation. thermal tolerance in cattle popula- Thus, for example, there is a negative tions at risk of exposure to heat stress. genetic correlation between milk yield and ability to regulate body tempera- Our research will use a system biology ture during heat stress in dairy cattle. approach by integrating genomics Unless accompanied by changes that and phenomics with additional -omics Raluca Mateescu increase heat loss capacity, im prove- data to understand the genetic archi- Associate Professor of Quantitative ments in production make animals tecture of thermal tolerance. Frequent Genetics & Genomics more susceptible to hyperthermia body temperature measurements, Graduate Program Director during heat stress. skin temperature, and perspiration Mateescu’s Animal Genetics and Genomics Lab rate in free ranging cattle will be Tel: +1 352 392 2367 Genomics for climate smart beef recorded during heat stre ss on 2,000 [email protected] The strategy we are undertaking is to Brangus heifers genotyped with the www.ralucamateescu.com reveal the genetic architecture of traits 250K functional SNP chip. Phenomics defining thermal tolerance using Bos for thermal tolerance and genomic 73 AGRICULTURE Advancing open access and open data in higher education Jaime Adams and Anne Mims Adrian, PhD shares their views on advancing open access and open data in higher education very year, the U.S. Government provides billions ing situation. To explore the issue further, a consortium of dollars to U.S. universities to conduct scientific of universities from around the world known as Presi- research. In 2013, the U.S. Government began dents United to Solve Hunger – or PUSH – conducted a Ethe process to increase public access to the results of study assessing open access and open data policies and research funded by the federal government, to ensure practices. these results were made available to the American taxpayer. Opening research results may lead to many “Opportunities for new knowledge, more informed advancements, including accelerating scientific discov- decisions, predictions and innovations are created ery, stimulating innovation, reducing duplication of when data collected throughout the research effort and enhancing economic growth and job creation. process are shared. Open data policies that balance the requirements from funders and researchers on As the U.S. Government continues to fine-tune open standards and practices are needed for successful access requirements, many universities are finding and effective data exchange and use.” themselves at a crossroads. U.S. universities often receive funding from various sources including the U.S. Open data practices are currently driven by funders’ Government. Many funders are instituting open data requirements, yet very few universities have policies and requirements, which often vary creating a very challeng- procedures to address these requirements. Scientific 74 AGRICULTURE Universities (APLU) released the Public Access Working Group Report committing to a set of shared principles and minimal levels of standardisation across institutions and agencies to ensure access to publicly funded research. “Open data practices are currently driven by funders’ requirements, yet very few universities have policies and procedures to address these requirements. Scientific disciplines like biomedicine, veterinary medicine and pharmacy have established standards and repositories open to the research community but lack the infrastructure to freely share research data with the public.” Opportunities for new knowledge, more informed decisions, predictions and innovations are created when data collected throughout the research process disciplines like biomedicine, veterinary medicine and are shared. Open data policies that balance the pharmacy have established standards and repositories requirements from funders and researchers on stan- open to the research community but lack the infrastruc- dards and practices are needed for successful and ture to freely share research data with the public. effective data exchange and use. ■ In a recent PUSH study, no PUSH member universities have open data policies and only 15% have open access policies. Many participants believe that clarity must be given to data ownership before developing open data policies. This report , released in June 2018, also provided several recommendations to advance open data implementation to include greater alignment between funders’ expectations and universities’ capa- Jaime Adams bilities, by including costs of sharing and maintaining Senior Advisor for Internati onal Affairs data sets in project budgets and delineating standards Office of the Chief Scientist, Office of the Secretary and protocols. U.S. Department of Agriculture Tel: +1 202 617 4747 In a separate Global Open Data for Agriculture and [email protected] Nutrition ( GODAN ) study , researchers found that www.usda.gov funders recognise that cost and lack of infrastructure www.twitter.com/usda and standards are preventing data to be shared in ways that are free, accessible, interoperable and re-useable. Anne Mims Adrian, PhD PUSH Open Data Project Manager In both studies, it is evident that there is a growing Auburn University need for standards, common language (ontologies) Tel: +1 (334) 844 4000 and protocols to make data discoverable and useable. [email protected] In November 2017, the Association of American Univer- www.auburn.edu sities (AAU) and Association of Public and Land-grant www.twitter.com/auburnu 75 PROFILE Woody breast: A hard problem for the poultry industry Dr Macdonald Wick, Associate Professor at The Ohio State University’s Department of Animal Sciences explains why Woody Breast is a hard problem for the poultry industry everal decades of selective breeding have changed the genetics of chickens, with breed- ersS selecting for faster growth, ever- increasing body weights, but more specifically, increased breast muscle (P. major) meat to carcass ratios (breast muscle yield). This has resulted in the generation of ‘broiler’ chickens – genet- ically designed for meat production. Optimisation in genetics and nutrition have contributed to affordable and plentiful poultry. In 2016, over 15 million metric tonnes of broiler meat were consumed in the US and nearly 90 million tonnes worldwide. However, this success has not been without costs – both for the birds themselves and consumers. hemorrhagic/inflammatory lesions Wooden breast was first described in and loss of vasculature (pale/yellow live broilers as extremely stiff breast In addition to systemic challenges, colour). Microscopic similarities include muscles that could be detected by these genetic and rearing strategies, polyphasic degeneration, perivascular palpation. The phenotypic hardness have contributed to correlated necrosis and infiltration of connective of wooden breast is associated with increases in developmental breast and fat tissue. varying degrees of firmness, pale muscle abnormalities (myopathies). colour, surface haemorrhaging and These myopathies result in decreased Muscle development – or ‘myogenesis’ white striping. The hemorrhagic consumer acceptability. The two most – is a complex yet tightly regulated lesions and diffuse, hardened areas, important myopathies currently chal- temporal and spatially specific process when examined histologically, exhibit lenging the poultry industry are white in poultry that begins with the embryo polyphasic degeneration, perivascular striping and wooden breast. Studies while still in the egg. Precursors to necrosis, interstitial inflammation, have reported a strong correlation muscle cells, known as myoblasts, perivenular infiltration of T lympho- between white striping and wooden migrate and fuse together to form cytes with the infiltration of connec- breast. It has been argued that acceler- fibres known as myotubes, which sub- tive tissue and fat. Hypoxic conditions ated growth, breast muscle yield, with sequently differentiate into mature limit the regenerative capacity of the accompanying impaired vascular- muscle fibres. The molecular/cellular muscle fibres by favouring the ity are predisposing factors to all three mechanisms induced by the genetic replacement of degenerated muscle anomalies. Macro- and microscopic selection for the increased growth fibres with lipid and fibrotic tissue. characterisations of white striping and ratio of a single muscle, the P. major, Various potential contributing factors wooden breast have striking similari- remains unresolved but it is likely that to wooden breast have been identi- ties, including mild to severe edema it lies at the root of the myopathies. fied, such as localised muscular 76 PROFILE hypoxia, oxidative stress within the teomic and statistical modelling to mechanisms behind muscle problems affected muscle and increased levels elucidate the molecular mechanisms in poultry. These studies will eventually of intracellular calcium. underlying poultry muscle growth and lead to the establishment of biomark- development to elucidate the molecu- ers for future breeding strategies that Not surprisingly, these anomalies can lar/cellular mechanisms of white strip- balance welfare with the economic have a significant impact on consumer ing and wooden breast. These studies value of meat products. acceptability, most notably through are focused on various influences – visual, white striping and textural, both genetic and environmental – that For example, recent reports describe wooden breast, changes. With white affect poultry muscle development, as the macroscopic changes associated striping, the surface of the breast well as the post-slaughter conditions with WB ontogeny in the development muscle exhibits white strips of fat that directly affect meat quality with of a ranking system and the contribu- tissue. In the case of wooden breast, particular emphasis on meat process- tion of growth parameters in the there is an increase in compression ing characteristics. determination of rank wooden breast force and shear force using Allo- severity. Results suggest that physical Kramer, Warner-Bratzler shear force “In 2016, over 15 million metric measurements inherent to selection analyses. As such, these affected tonnes of broiler meat were consumed for high-yielding broiler genotypes breast muscles are often downgraded in the US and nearly 90 million tonnes are contributing to the occurrence or even condemned. The potential worldwide. However, this success has and severity of both white striping economic loss due to downgrading not been without costs – both for the and wooden breast. These studies are was previously offset by the continued birds themselves and consumers.” leading to a ranking system to gains in growth and breast muscle describe the ontogeny of wooden yields and management practices New information is emerging, using breast and a model relating the rank which minimised the predisposition combined morphological and quanti- probabilities to the severity of the for the myopathies. Unfortunately, tative transcriptomic strategies in myopathy, based on physical mea- since the initial description of these which the P. major of broiler chickens surements during the post-hatch anomalies, the industry has experi- were evaluated for the changes in growth period with the potential enced a rapid increase in the percent- muscle-specific transcription factors development of an economic model age of affected broilers within a given and the morphology of the breast to simultaneously optimise bird’s flock, as high as 90%. muscle every other day post hatch welfare and the economic return of until market weight to elucidate the poultry operations. There is ample data to support an myogenic signals and proteins associ- association between white striping ated with the progression of white and wooden breast, with nearly all stripping and woody breast. The data reported cases of a wooden breast supports the notion that white striping having some degree of white striping. is a harbinger of wooden breast and In addition, the onset and severity of that nutrition can play a role in reduc- each anomaly is influenced by: Geno- ing the onset of wooden breast. That type (high > standard breast yield), is, reducing growth rates can delay the gender (males > females), growth rate onset of myopathies. (fast > slow), diet (high > low energy), Dr Macdonald Wick P. major breast muscle weight (heavy In conclusion, the demand for inexpen- Associate Professor > light) and slaughter weight (heavy > sive, affordable poultry meat has Department of Animal Sciences, light). Again, the cause and effect rela- pushed chickens and turkeys to The Ohio State University tionships underlying this association their physiological limits – impacting Tel: +1 614 292 7516 have not been reported. the welfare and muscular health of the [email protected] birds, as well as the quality of their https://ansci.osu.edu/our-people/macdon- Many studies are underway, using meat. Studies are underway in an ald-wick combinations of transcriptomic, pro- attempt to unravel the biological 77 EDUCATION & YOUNG PEOPLE What next for children and young people with speech, language and communication needs? Mary Hartshorne, I CAN’s Head of Evidence shares her thoughts on the report Bercow: Ten Years On and the next steps for children and young people with speech, language and communication needs any reports are criticised as spending too much time admiring a problem and not enough time doing something about it. In MMarch 2018, I CAN, the children’s communication charity and the Royal College of Speech and Language Thera- pists (RCSLT) launched the Bercow: Ten Years On report, an independent review of provision for children and young people with speech, language and commu- nication needs (SLCN) in England. The report found a fractured system failing thousands of children and young people by not identifying their needs early enough or providing adequate levels of support. It’s not a new problem. So, if we’ve all been guilty of ‘admiring the problem’ before, now is really the time for action. Action is needed because the findings of this report matter. They matter for the two or three children in every classroom who have developmental language disorder (DLD): a condition where children have prob- Mary Hartshorne, Head of Evidence lems understanding and/or using spoken language, but where there is no obvious reason for these difficul- ties – no hearing problem or physical disability that difficulties are highly prevalent in the youth offending explains them. Around half of these children go unno- population. But this does not have to be the case, ticed in primary schools and because good language with the right support; children with DLD can do well skills underpin the ability to learn to read, to learn and academically, socially and emotionally. to develop socially and emotionally, this can have a drastic impact. We have the evidence for this: just 15% In taking action, thousands of children and young of pupils DLD achieved the expected standard in people with DLD will get this support. To, ensure that the reading, writing and mathematics at the end of primary report will not just stay on the shelf, quickly becoming school compared with 61% of all pupils, likewise only out-of-date as governments come and go; there is both 20% of pupils with DLD gained grade 4/C or above in a ‘top-down’ and ‘bottom-up’ approach to change. English and maths at GCSE, compared with 63.9% of all pupils. There is also a much higher risk of mental From the top, strategic recommendations demand health issues in children and young people with DLD, change from national and local leadership. The report increased risk of behaviour difficulties and language asks for systemic change, which considers the impor- 78 EDUCATION & YOUNG PEOPLE How people can act locally, to support the strategic recommendations Top-down Bottom-up Strategic recommendations www.bercow10yearson.com/supportingchange Ofsted should ensure that training for Use our information sheet and PowerPoint presentation inspectors should ensure a focus on SLCN, for primary or secondary schools to share information about including specific advice on how schools progress in spoken language and the impact of SLCN support assess and monitor progress in the spoken with Ofsted inspectors. language. NHS England and the Department for Use our prevalence information to share information with Education should fund a programme of people responsible for commissioning SLCN support. Talk training for local commissioners on about local prevalence or about the numbers of children with commissioning for SLCN. SLCN in your school or college. Local area SEND reviews should consider the Look out for your LA SEND inspection here and take up the evidence from this review for effective joint invitation to meet with inspectors when they inspect your commissioning of support for SLCN. local SEND services. Use our information sheet for advice about questions you can ask and ideas for useful information to share. tance of speech, language and communication in As far as possible, the calls to action support recom- children and young people’s development and asks for mendations both top-down and bottom-up – here are SLCN to be embedded within government policies. So, just a few examples of how this works: for example, where the government is taking steps to change mental health provision, this should recognise I CAN and RCSLT have committed to reporting on the link with SLCN; current plans for reforming early progress one year on; in the meantime, there are career support for newly qualified teachers should things that you can do. You can sign a petition asking include training in SLCN; commissioners o f SLCN for the government to respond to the review at services need to understand about effective ways of https://petition.parliament.uk/petitions/215643. supporting children and young people with SLCN. Visit www.bercow10yearson.com/supportingchange The bottom-up approach draws from the evidence and find out how you can act and watch out for the presented to the review. As well as challenges and progress report in 2019. ■ issues, the review also found many examples of inno- vative, effective practice. Based on these, a series of calls to action encourages everyone to take bold first steps to make change happen: school staff, early years Mary Hartshorne practitioners, speech and language therapists, parents Head of Evidence and young people themselves. Accompanying the report I CAN is a website www.bercow10yearson.com/supporting- Tel: +44 (0)20 7843 2510 change, which is full of practical resources: information [email protected] sheets, top tips, email templates, presentations and www.ican.org.uk guidance to support people in doing this. www.twitter.com/ICANcharity 79 PROFILE Language development: Learning from what children say Mabel L. Rice, Distinguished Professor of Advanced Studies at the University of Kansas argues that children’s utterances provide valuable clues about how their language develops and hallmark areas of grammar weaknesses in those with Specific Language Impairment (SLI) hen we want to learn a sider a six-year-old boy, Stevie, whose “little word” that can be omitted with- certain language, we have language is immature for his age. He out hampering communication. many kinds of reference does not know the names of colours, materialsW to consult, benchmarked to which is a limitation in a classroom Although most speakers of English the adult language system. In contrast, with colour-coded spaces and signs. use the rules that apply to the use of children’s grammar has not yet been For example, an adult tries to teach auxiliary DO, they rarely know the fully documented. An important him the names of the colours “red,” structure of the underlying rules and source of information in this area of “blue,” “green” and “yellow,” using are highly unlikely to explain the rules study is what children say. Early stud- simple blocks and toy objects and to their children, in contra st to ies were done by parent scientists, repeatedly asking “what colour is this?” the ways parents often focus on the keeping diaries of what their child This approach is pursued for several names of colours. Instead, parents said. In 1973, Roger Brown realised the months, with no apparent success. may sense that a six-year-old’s gram- value of new technologies for record- One day, Stevie asks the adult, with mar is “immature” if such forms are ing speech with portable devices for genuine bewilderment, “Why you call omitted, although they are unaware the purpose of studying children’s that red?” of exactly what is missing. early language in detail; he reported the outcomes in a benchmark book1 What clues are provided by his ques- “Language appears late in children and established new scientific meth- tion? On the content level, Stevie is with Specific Language Impairment ods for recording child utterances. perplexed about using a word to refer (SLI), although other developmental to the hue of an object, or that this is benchmarks follow age expectations. Language appears late in children with a meaningful way to differentiate The causes of delayed language Specific Language Impairment (SLI), objects (although he certainly knows acquisition are unknown.” although other developmental bench- about broken objects, dirty objects marks follow age expectations. The and his versus my objects). Stevie Advances in linguistic theory in the causes of delayed language acquisi- subsequently works this out on his early 1990s identified systematic ways tion are unknown. The details in what own, without continued prompting in which young children learn the prop- children say provide valuable clues and with pride in his accomplishment. erty of grammar known as “finiteness about weaknesses in their linguistic marking”2. In English, a set of forms system. Informative dimensions are However, his more significant prob- mark finiteness: Auxiliary DO in ques- what they talk about (i.e., content) and lem with language is less apparent tions (but main verb DO is different the sentence structures they use (i.e., and is at the level of sentence struc- grammatically), copula and auxiliary linguistic form). ture. His sentence: “Why ___ you call BE, past tense -ed, or a default to the that red?”, is missing the required aux- citation form of the verb for irregular For example, during the preschool iliary DO (the italicised capitalisation past tense (“run” instead of ”ran”) and years, children learn the names of conveys the citation form that would third person singular -s, as in “walks”3. colours. This can take longer than include the words “do”, “does,” and In the case of children with SLI, a stage expected for children with SLI. Con- “did”). This is often thought of as a of omission of these forms is likely to 80 PROFILE why you call that red? persist into adolescence, long after though it is a required element of a 6 Rice ML, Zubrick SR, Taylor CL, Hoffman L, Gayan J. Longitudinal unaffected children have mastered it4. well-formed sentence. Perhaps Stevie’s study of language and speech of twins at 4 and 6 years: Twinning This part of the grammar has served as question reminds us that the most effects decrease; zygosity effects disappear; and heritability a reliable clinical marker of children obvious “error” is not necessarily the increases. J Speech Lang Hear Res. 2018;61:79-83. with SLI5 with high heritability6,7. only error or the most important one to 7 Dale PS, Rice ML, Rimfeld K, Hayiou-Thomas ME. Grammar clinical note. Our sense of what to notice is marker yields substantial heritability for language impairments in Stevie’s question reveals the need for affected by our knowledge of where to 16-year-old twins. Journal of Speech , Language, and Hearing understanding two distinct dimensions look, even for something as common- Research. 2018;61:66-78. required for language acquisition: 1. place as children’s language. Children’s conceptual development as a basis for language concepts References expressed in words and 2. The ways in 1 Brown R. A first language: The early stages. Cambridge, MA: which grammar works with linguistic Harvard University Press; 1973. constructs such as tense marking, sub- 2 Quirk R, Greenbaum S, Leech G, Svartvik J. A comprehensive ject/verb agreement and word order grammar of the English language. New York: Longman, Inc.; 1985. requirements, such as the insertion of 3 Wexler K. Optional infinitives, head movement and the economy auxiliary DO in Wh- questions. of derivations. In: Lightfoot D, Hornstein N, eds. Verb movement. Cambridge, England: Cambridge University Press; 1994:305-350. Mabel L. Rice Although the meaning part may be 4 Rice ML, Hoffman L, Wexler K. Judgments of omitted BE and DO Distinguished Professor of more intuitively obvious and more likely in questions as extended finiteness clinical markers of specific Advanced Studies to be overtly taught, for most children language impairment (SLI) to 15 years: A study of growth and University of Kansas no explicit teaching is needed for learn- asymptote. Journal of Speech, Language, and Hearing Research. Tel: +1 785 864 4570 ing grammar. Yet, for children with SLI, 2009;52:1417-1433. [email protected] the requirement to mark finiteness is 5 Tager-Flusberg H, Cooper J. Present and future possibilities for not readily learned and instead contin- defining a phenotype for specific language impairment. J Speech ues to be treated as optional, even Lang Hear Res. 1999;42:1275-1278. 81 BLOCKCHAIN INNOVATION The current status of blockchain technologies Marta Pierkarska, Director of Developer Ecosystem at Hyperledger reveals her thoughts on the current status of blockchain technologies e are midway through 2018 and it seems healthcare and the government. In fact, the need for a everyone has bought into blockchain. But collaboration platform was so high that we have Whave they really? launched Public Sector and Healthcare Working Groups. When we go to staple industry conferences, it definitely The working groups reflect a significant shift in thinking feels like there is not a single person in the world that from those getting deeper into the deployment process. has not heard about blockchain. At Hyperledger, we While developing Proofs of Concept, enterprises are proud and grateful to get public and social media believed that one can simply do it alone. That there can attention. We have almost 45,000 Twitter followers and be one blockchain per company and the technologist a webinar series where our community can learn, on a can develop ways for the ledgers to talk to each other. monthly basis, about blockchain and our frameworks. However, blockchain is a Peer-to-Peer network. To scale and make use of its full benefits peers, or nodes should “Governments, while struggling to regulate come from different parties. This means evolving from cryptocurrencies and ICOs, are absolutely bought “blockchain is a decentralised database system” to into the blockchain space. Today, there are 203 “blockchain is a distributed record of data” mindset. The different initiatives around the world implementing shift has led to the creation of a number of consortia in solutions in different governments.” various domains since the beginning of 2018. Some examples: we.trade, developed by nine different banks; Thankfully, though, we also get invited to speak at TReDS, a similar platform in India; the Intelligent Health- conferences that are not industry specific. That’s where care Network for claims management in healthcare and we learn that not everyone is crazy about blockchain. Realtor® Association Blockchain, which created regional Many have often never even heard about it! From big repositories of activity of their 1,200 members. This aim to small, there is a whole world outside of our echo for collaboration and modularity shows a new level of chamber. They ask: “what is blockchain?” and “how is maturity in the space. it different from a database?”, “can I have a blockc hain where I don’t share any information with anyone?” and, Not everyone is crazy about blockchain though. Many of course, “what is the killer app for blockchain?” are still looking to understand the return on investment in the blockchain space. Or are still looking at how to It is good to step out of the comfort zone. It challenges choose the right technologies – ones that will scale with us to look from the outside and ask: “what is the adoption time – and for the right use cases. Is it better to use a of blockchain in enterprises today?” sniper approach and target a small number of big proj- ects or a machine gun one: blockchain everything and Hyperledger has now reached almost 250 members, see what sticks? Which of the solutions implemented showing how much interest there is in enterprise today will stand the test of users and time? Frustration blockchain applications. If you belong to the Innovators when experimenting with blockchain is unavoidable. on the Rogers’ Diffusion Curve, then 2018 is a year of Departments spent money on horizon 2 projects, but deployment. We see enterprises going live with their only a few of them can move to horizon 1. Even then it platforms in the supply chain, financial technologies, requires more financial engagement. 82 BLOCKCHAIN INNOVATION Blockchain will not solve all our problems and will not interest and increasing adoption. Still, there remains a be valuable in all industries. All sectors are facing chal- huge demand for education. Not only on what lenges around security, as well as the usability of the blockchain is, but also how to share data through a newly developed DLT-based projects. While blockchain blockchain, while preserving the most important IP in is being used for security updates in The Internet of enterprises and PI in the case of individuals. As with any Things (IoT) or a better voting mechanism, it also brings new technology, the demand is there but supply new attack vectors. Questions arise about how we eval- remains scarce. But we are getting there. ■ uate smart contracts, how we ensure the consensus cannot be broken, what information should be stored on a blockchain and how. On the usability front, there is a need for better user interfaces and the integration tools to encourage a wider adoption. The maturing market is starting to ask the right ques- tions and new industries are adopting the technology. Governments, while struggling to regulate cryptocurren- cies and ICOs, are absolutely bought into the blockchain Marta Pierkarska space. Today, there are 203 different initiatives around Director of Developer Ecosystem the world implementing solutions in different govern- Hyperledger ments. In art and music for IP protection and proof of [email protected] provenance, in shipping and logistics for a bill of lading www.hyperledger.org or in education for certification storage, there is growing www.twitter.com/hyperledger 83 CANADA Educational philosophy and theory: Priorities and new directions for research The editorial team of Philosophical Inquiry in Education, Bruce Maxwell, Lauren Bialystok, Kevin McDonough and David Waddington, outline their views on promising new directions for research in educational philosophy and theory ike philosophy itself, the field of educational Analysis of the language of education. What began as philosophy is notoriously difficult to define even, a project to clarify fundamental questions about edu- if not especially, for the very people working in it. cation (e.g., what is an educated person?) by clarifying LOther areas of educational research are more straight- the meaning of words, the quest for coherence in the forwardly delineated in terms of a characteristic object language of educati on is now more likely to consist in of inquiry. Researchers in mathematics education, for subjecting to critical scrutiny terms that have gained example, investigate matters relating to how that sub- currency in educational discourse (e.g., constructivism, ject is taught and learned in schools and researchers in brain-based education). teacher education study the acquisition of professional competencies among new and experienced teachers. Critical pedagogy. Drawing on intellectual currents in the social sciences and humanities such as critical race What unifies scholarship in educational philosophy and theory, Marxism and postmodernism, this approach to theory is something more abstract: a commitment to a educational philosophy applies a critical lens to educa- particular mode of inquiry. Philosophers of education tional questions to unmask forms of identity-based tend to explore fundamental questions that touch on discrimination and other social injustices perpetrated meaning, value and purpose in education and pursue by educational institutions. the answers to such questions using the tools of critical inquiry and argumentation. Politics and ethics of education. Primarily concerned with how educational philosophy can contribute to During the early years of its history as a distinct area of public debates around policy and ethics, thinkers asso- scholarship, expounding and developing what great ciated with this approach gravitate towards two broad thinkers of the past had to say about education was the issues: the proper aims of citizenship education in bread and butter of educational philosophy. This orien- liberal democratic societies (autonomy? patriotism? tation was largely driven by the demands of teacher civic engagement?) or the ethical analysis of policy education programmes, which generally considered options and other ethically laden questions facing that exposure to the “classics” was an essential part of teachers, educational leaders and parents. Such ques- the professional socialisation of future teachers. As tions include school choice, banning religious clothing teacher education has evolved in recent decades, the in schools and “zero tolerance” disciplinary policies. philosophy of education has changed with it. “Modern” educational philosophy has coalesced into four dis- History of educational thought. The philosophers of cernible thematic areas which, taken together, embrace education who continue in this tradition are inclined to the research activities of the vast majority of scholars reinvent the history of educational ideas as a dialogue who identify as philosophers of education. between education’s past and present, either by seek- ing to uncover insights from the work of philosophers Roughly in the order that they emerged historically of the past that can shed new light on contemporary from the 1960s on, these areas are: educational questions or by turning to such writings to 84 CANADA retrieve valuable ways of thinking about education that Paralleling a similar development in mainstream philos- have been lost or forgotten. ophy, a second promising direction for research in the philosophy of education involves a new appreciation Prognosticating about the future of any field of scholarly of how the philosophical perspective can be enriched inquiry inevitably involves making uncertain distinctions through greater integration with empirical work. In the between passing trends and stable tendencies. The phi- past, philosophers of education were largely expected losophy of education, like other areas of the humanities, to engage primarily with the work of other philosophers is highly subject to both occasional enthusiasms for and to eschew empirical inquiry. particular authors and peaks of interest in issues deter- mined by the ambient political climate. As editors of Today, we find philosophers of education increasingly Philosophical Inquiry in Education, a philosophy of attentive to how appropriately designed empirical education journal with a deliberately open and inclusive studies can complement the traditional activities of editorial policy, we are regularly exposed to new work conceptual analysis and social critique. The finest emanating from all four of the thematic areas described recent example of this approach may be Paula McAvoy above. From this vantage point, we see two recent shifts and Diana Hess’s investigations into teaching about in scholarly activity that already show signs of shaping controversial issues in schools, which has won acco- the contours of research in educational philosophy lades for breathing new life into old debates about and theory. teacher neutrality. ■ The first of these is assigning greater importance to public engagement. Bringing to bear a philosophical perspective on current educational issues has always been a concern in work on educational policy and ethics. However, recent years have seen philosophers of education being more pragmatic in the choice of questions to address and finding ways to write about Bruce Maxwell, PhD ethical and policy issues that can make educational Associate Professor of Education philosophy accessible to decision makers and educa- Co-editor of Philosophical Inquiry in Educati on tors. Two notable recent examples are Amy Shuffelton University of Quebec Trois-Rivières and Bryan Warnick’s work on gun violence in schools [email protected] and Doris Santoro’s work on teacher burnout. https://uqtr.academia.edu/BMaxwell 85 Featured ebook Respectful Relations: Enacting Reconciliation in Canadian Universities What role are Canadian universities taking in reconciliation? The mission of a university is to provide education within an environment that fosters curiosity, creativity, and research. Universities provide students with opportunities to engage in critical thinking, explore new ways of analyzing information, and make room for new intellectual growth as students question all that they have been taught and all that they know. It would seem that universities would offer an ideal place to begin work on reconciliation and yet universities continue to face tensions and challenges when attempting to address the Truth and Reconciliation Commission (TRC’s) calls to action. To read the digital ebook www.brocku.ca PROFILE Reconciliation in a higher education context: Tensions and challenges Dawn Zinga, Associate Professor and Chair at the Department of Child and Youth Studies at Brock University explores reconciliation in a higher education context, by detailing the tensions and challenges in this area n August 2017, I wrote about how expressed. The university’s response underscores the difference between a Canadian institutes of higher edu- to Recommendation 28 was to ensure surface response to the calls to action cation were taking up the Truth and that all law students were provided and meaningful action. IReconciliation Commission’s calls to with opportunities to better under- action. Almost a year later, higher stand Indigenous peoples and the “The conundrum facing higher education contexts continue to face law by weaving Indigenous content education is how to proceed to address tensions and challenges in addressing throughout the law curriculum. How- the calls when institutions are having those calls to action. There has been ever, in practice, there appear to be difficulty being able to recognise how much talk of how to address the calls challenges with the implementation of the very structures of the institutions and some policy changes, but it is clear significant changes. Angelique Eagle- are getting in the way.” that there are a lot of tensions and Woman was hired by Lakehead Univer- challenges around the implementation sity as the first female Indigenous law Universities and colleges are strug- of any changes. Lakehead University school dean in 2016 but resigned citing gling to address the calls to action and offers an example of how those systemic discrimination and racism in to understand what reconciliation tensions and challenges can be 2018. This unfortunate situation means. Indigenous scholars Marie 88 PROFILE Battiste, Jan Hare, Jackie Ottman and Jackie Ottman also spoke to the claims of cultural inclusion or returns Dwayne Donald spoke eloquently at hidden curriculum and unconscious to pathologising Indigenous students the 2018 Congress of the Humanities codes that are triggered by attempts and scholars. and Social Sciences about reconcilia- to meaningfully address the TRC. She tion within a higher education context. stated that while the Royal Commis- Reconciliation requires an examina- Each of them remained committed to sion on Aboriginal Peoples issued its tion and understanding of what has the conviction expressed by the Com- report in October 1996 and offered happened and how current structures, mission that education will be pivotal over 400 recommendations, the TRC’s systems and attitudes/biases that are in putting Canada on the road to rec- 94 calls to action has engendered a conscious or unconscious continue to onciliation. Battiste spoke about the more lasting response. However, she uphold colonialism and Eurocentrism. importance of decolonising and how warns that the weight of addressing University mission statements can everyone has been “marinated in those calls to action within higher include commitments to Indigenisa- Eurocentrism” and that the tenets of education contexts could not be left tion but without a meaningful exami- Eurocentrism that are characterised to Indigenous students and scholars nation of what that term means and by superiority, hegemony and a to do all the heavy lifting, but that an appreciation that decolonisation is monopoly over all other knowledge non-indigenous students and scholars the first step and that such commit- systems, stand in the way of reconcil- needed to walk alongside and share ments will fail to produce any signifi- iation. Battiste speaks about cognitive the weight and the work. Jan Hare cant change, other than putting a new imperialism and how every Canadian agreed with her colleagues and calls face on a continued inability to engage student has been a victim and benefi- for a continued commitment to in reconciliation. ciary of the same education system reconciliation that is grounded in an that has exposed them in Eurocen- understanding of everyone’s roles and trism and cognitive imperialism. responsibilities. These act as some of the greatest barriers to reconciliation and the “Universities and colleges are serve to blind people to the colonialism struggling to address the calls to embedded throughout education at action and to understand what all levels. reconciliation means.” Dwayne Donald agrees that it is diffi- The conundrum facing higher educa- cult to accomplish much when the tion is how to proceed to address the very institution that claims to want to calls when institutions are having diffi- take steps towards reconciliation gets culty being able to recognise how the in the way when tensions arise. He very structures of the institutions are argues that part of the problem is the getting in the way. Most institutions are Dawn Zinga tendency within higher education con- implementing policies and directives, Professor texts to take shortcuts by attempting but not doing the hard work of explor- Department of Child and Youth Studies to make changes without examining ing what it will mean to actually imple- Brock University the embedded colonialism. When ment those policies and directives. The Tel: +1 905 688 5550 ext. 3152 change is implemented in those end result is window dressing without [email protected] contexts, tensions quickly rise and the any meaningful change or a resur- https://brocku.ca/social-sciences/depart- response to those tensions is to gence of colonialism and a return to ments-and-centres/child-and-youth-studies reassert “colonial terrain”. the status quo that hides behind 89 CANADA The role of research in Canada for the future of ageing Dr Yves Joanette, Scientific Director at the CIHR Institute of Aging explores how Canada’s researchers are meeting the needs of an ageing population, now and in the future he world’s population is ageing. The World Health Our first step was to establish an Institute of Aging as Organization projects that the number of people part of the Canadian Institutes of Health Research in of over 60 will double by 2050. Dr Margaret Chan, 2000. I’ve had the privilege of serving as Scientific Direc- Tformer Director General of WHO noted it is not enough tor of the CIHR Institute of Aging since 2011 and our that people are living longer lives, we need to ensure mission is to support research, to promote functionally these extra years are healthy, meaningful and dignified. healthy ageing and to address causes, prevention, screening, diagnosis, treatment, support systems and As Scientific Director of CIHR’s Institute of Aging, I palliation for those complex health challenges that can couldn’t agree more. We want to make sure that these be present in older individuals. extra years are functionally healthy, that older people continue to lead meaningful lives and that they are “This increased lifespan results from the excellent treated with the utmost dignity and respect. quality of life in Canada. It also results from access to high-quality healthcare and the success of our In Canada, we reached a major demographic inversion public health programmes. To adjust to this in 2016. For the first time, the number of Canadians aged demographic change, it also means that we need 65 and older surpassed the number of Canadians aged to change our social programmes and attitudes 14 and under. That trend is expected to continue with towards older people.” one in four Canadians expected to be aged 65 or over by 2036, thus bringing Canada among the super-aged To provide critical data on the determinants of countries. functionally healthy ageing, we fund the Canadian Lon- gitudinal Study on Aging (CLSA). This cross-Canada The fastest growing segment of our senior population research platform involves more than 50,000 Canadi- is the ‘oldest old’ – or people 85 years old and more, with ans, aged 45 to 85, who will be followed for 20 years. centenarians being the most rapidly growing group. CLSA will provide data and biological samples for Canadian researchers to help identify the determi- This increased lifespan results from the excellent nants of a functionally healthy ageing, from the most quality of life in Canada. It also results from access to basic biological to the most social aspects, including high-quality healthcare and the success of our public work and retirement trajectories. health programmes. To adjust to this demographic change, it also means that we need to change our social The CLSA team recently released a first baseline report. programmes and attitudes towards older people. It represents the most comprehensive picture of the health of Canadians over age 45 ever produced. On the In Canada, we have long anticipated this demographic bright side, almost 90% of participants rated their health change and from a research perspective, we have as good to excellent. At the same time, the report worked to establish the infrastructure needed to carry revealed potential challenges. Only 25% of participants out collaborative research among researchers and reach recommended amounts of physical activity. 38% institutions within Canada and internationally. of participants reported having to provide care to 90 CANADA others. And among retired participants, 25% reported Overall, we want to celebrate and help older adults to health reasons as a factor in their decision to retire. participate fully in their communities and to contribute their skills and wisdom to their families, friends and “In Canada, we reached a major demographic fellow citizens. ■ inversion in 2016. For the first time, the number of Canadians aged 65 and older surpassed the number of Canadians aged 14 and under. That trend is expected to continue with one in four Canadians expected to be aged 65 or over by 2036, thus bringing Canada among the super-aged countries.” Finally, loneliness and social isolation, particularly among women, was identified as a concern. If we want to break down barriers that prevent older adults from continuing to work or otherwise lead fulfilling lives, we will also have to embrace new technologies in ways Dr Yves Joanette that will support the mobility and independence of Scientific Director older people. CIHR Institute of Aging Tel: +1 613 954 1968 As we look forward to the future, the Institute of Aging [email protected] is committed to creating a world that supports health www.cihr-irsc.gc.ca/e/8671.html and wellness throughout the trajectory of ageing. www.twitter.com/CIHR_IRSC 91 PROFILE Physical activity and ageing: Recommendations that will translate into greater practice Isabelle J. Dionne, Professor at Université deSherbrooke provides a compelling analysis of physical activity (PA) and ageing, focussing on how to develop recommendations that will translate into greater practice hysical activity (PA) is a key recommendations. Learning from importance of doing it but also on behaviour in the determination exercise physiology and performance what to do based on the specific of health and quality of life. studies, we know that depending on health needs of an individual. PDespite massive public health strate- the exercise type (aerobics, resistance), gies and clear recommendations, modalities (number of repetitions or The specific case of Type 2 physical inactivity remains elevated in duration of bouts) and intensity (per- diabetes developed countries. Increasing the centage of maximum capacity – heart Type 2 diabetes (T2D) remains a major levels of physical activity depends rate, maximum oxygen consumption, chronic disease in Canada and clinical upon innovative and effective avenues percentage of maximum strength), we practices need to be revisited for both of PA promotion. can generate specific metabolic and prevention and management. For functional adaptations. Hence, specific instance, gains in muscle mass are still Physical activity and ageing exercise recommendations coeuld b promoted to be associated with The overall objective of the Canada developed to minimise the risk of improvements in insulin sensitivity. Research Chair is to improve older developing diseases such as T2D or Nevertheless, we found that a small in adults’ quality of life and health by disability in older individuals who have size, but high-quality muscle mass determining the best exercise modal- been identified to be at risk. seems beneficial to cardiovascular ities, accompanied or not by nutri- risk factors, such as blood lipids and tional interventions, to prevent or Within the past 10 years, the Faculty glucose metabolism. Surprisingly, we delay T2D or disability (loss of physical of Physical Activity Sciences, together even showed that during exercise, function). Indeed, the ageing of the with the Research Centre on Aging, muscle mass loss was beneficial for population and the greater preva- has developed a strong expertise in insulin sensitivity, possibly through lence of obesity at all ages leads to conducting large exercise trials with improvements in inflammation and major health issues, among which tight control of the intervention and a quality. My work thus supports to Type 2 diabetes (T2D) and physical wide array of clinical areas, which is explore creative strategies where disability have important clinical impli- instrumental in developing exercise weight loss would be accompanied by cations. Both conditions could be pre- recommendations. Research in this changes in muscle mass quality, vented by the development of specific area is especially timely since the high instead of absolute gains and exam- exercise recommendations. prevalence of physical inactivity and ine how it would impact metabolic disuse in older adults has led to impairments, especially those that will While the Canadian Society for Exercise numerous health problems. In paral- have been determined to increase the Physiology guidelines promotes a min- lel, a surge of research on adherence risk of T2D in older women with a imum of physical activity participation to physical exercise in all populations family history of it. to improve health in the general popu- focusses on making older adults, lation: they do not target precise med- among others, to adopt an active On the other hand, the level of exer- ical conditions or affected populations lifestyle. It thus appears timely to cise remains low in adults with health who may benefit from more specific intensify research not only on the risk and in diabetic patients. In our 92 PROFILE research, in that sense, appears as one highly pertinent avenue. In this line, the Faculty of Physical Activity Sci- ences has recently launched the first Doctorate Program in Physical Activity Sciences that is interdisciplinary in nature. We are confident that this type of training will support the training of future researchers who are more open to addressing physical inactivity and its health complications through a wider spectrum of approaches and the most appropriate methodology. The ultimate goal Our research will inform clinical guide- lines through creative exercise recom- mendations, both from a prescription (type, intensity) and contextual (setting, environment) standpoints. My research lab, older women tend to reduce exer- ommendations, by adding key pieces will improve exercise efficiency, adher- cise practice, even after having been of advice related to the context of ence and maintenance, leading to a supervised for several months and exercise practice for older adults. decreased overall risk of developing having experienced tangible benefits. T2D and related disability, thus We thus intend to extend exercise The need for interdisciplinarity contributing to improve older women’s recommendations to the context of research health. practice and recently began studying In this context, the importance of exercise adherence using more eco- interdisciplinary research has become logical approaches (i.e. living lab). For evident. Numerous contemporary instance, my team and I have devel- health problems can be blamed on oped an interest in why people strug- physical inactivity (a level of physical gle with engagement and compliance activity of moderate and vigorous in exercise programmes, despite wide intensity that is below recommenda- education strategies. We thus con- tions) and sedentarity (many seden- ducted studies pertaining to personal tary activities such as TV watching, and contextual factors of exercise computer-based activities, reading, practice to determine how to increase etc.). This applies to several popula- exercise programmes adherence and tions (children, adults and elderly) in compliance over time. We determined various contexts (leisure, school, that adherence to exercise pro- w orking environment, long-term care Isabelle J. Dionne grammes is greater outdoors than facilities, etc.). Professor indoors, with equivalent physiological Université deSherbrooke responses. These results are impor- Altogether, these complex problems Tel: +1 (819) 821 8000 *63721 tant because we also showed that cur- call for more comprehensive strate- [email protected] rent exercise participation is the best gies supported by a large array of per- www.usherbrooke.ca/fasap/personnel/ predictor of health in older adults, spectives (physiological adaptations, professeurs/dionne/ independent of past participation or contraindications, motivation, health not. These results allow refining rec- education, etc.). Interdisciplinary 93 CANADA Why Canada urgently needs a national strategy to tackle the diabetes epidemic Kimberley Hanson, Director of Federal Affairs at Diabetes Canada argues that the country urgently needs a national strategy to tackle the diabetes epidemic n Canada today, one in three Canadians lives with Alarmingly, diabetes is on the rise the world over and prediabetes or diabetes. In some communities that Canada is faring worse than many OECD (Organization rate soars above 60%. Canadians under 20 years of for Economic Co-operation and Development) countries. Iage now face a 50% chance of developing the disease in Globally, the number of adults living with diabetes has their lifetime. For Indigenous Canadians, that risk is 80%. quadrupled since 1980, from just over 100 million to more than 400 million according to the World Health If we continue with the status quo, the direct costs to Organization. The International Diabetes Federation our healthcare system will top $5 billion per year lists Canada in the bottom third of OECD countries for within a decade and the indirect costs will be triple diabetes prevalence. Diabetes or prediabetes now that. And the human suffering involved is incalculable. affect 11 million of the 33 million Canadians and yet, millions still don’t know they have it. But first, a quick refresher on the disease: Diabetes is a metabolic disorder in which the body either cannot It’s time for an urgent change. This is not an epidemic produce insulin or cannot properly use the insulin it that will be addressed by personal willpower and produces. Insulin is a hormone that the body needs to shame. To blame and stigmatise those living with Type use blood sugar as an energy source. The two main 2 diabetes for their disease is not only unhelpful, it is a types of diabetes are Type 1 – an auto-immune condition vast oversimplification. Type 2 diabetes is caused by a that often develops in childhood – and Type 2, which complex array of factors including genetics, lifestyle occurs when the body doesn’t make enough insulin or and environmental factors such as poverty, reduced use properly that which it does make. access to clean drinking water, food insecurity and a disease-promoting food and physical environment. In addition, there’s a precursor condition known as Issues of health inequality are at the core of the prediabetes, when blood glucose levels are higher than diabetes epidemic and addressing this epidemic is normal but not yet high enough to be diagnosed with wholly reliant on addressing health inequities. Type 2 diabetes. Nearly 50% of those with prediabetes will go on to develop Type 2 diabetes if nothing is done. To really turn the tide of the diabetes tsunami, we need a nation-wide approach and in 2018, Diabetes Canada Diabetes can cause serious and life-threatening is developing just that. We’re building on a successful complications. People with diabetes account for “90-90-90” model implemented in the global HIV/AIDS 30% of the strokes, 40% of heart attacks, 50% of kidney community and adapting it to tackle diabetes in Canada. failure requiring dialysis and 70% of amputations in Canada each year. The life expectancy of a person with Implementing such an approach would mean that, in diabetes is shortened by an average of 13 years. In time, 100% of Canadians would live in an environment 2012, the disease directly caused 1.5 million deaths that does not promote the development of diabetes; worldwide and elevated blood glucose levels linked to 90% of Canadians would know whether they’re at risk diabetes were responsible for an additional 2.2 million of, or living with, diabetes; 90% of those with predia- deaths that year. betes or diabetes would be engaged in appropriate 94 CANADA treatment and support to avoid developing diabetes Desmond Tutu once said: “There comes a point where or its complications and, in consequence, 90% of them we need to stop just pulling people out of the river. We would be achieving improved health outcomes. need to go upstream and find out why they’re falling in.” When it comes to the millions upon millions of We know from research that when someone with pre- Canadians who already have or are well on their way diabetes who makes moderate lifestyle adjustments to developing diabetes and its many complications, the (losing 5-10% of their body weight, for example), they time to move upstream and fix the problem is now. are 60% less likely to develop the disease. That could With guidance and input from hundreds of experts, in mean that if we increase risk awareness and then 2018 Diabetes Canada plans to chart a path to doing provide adequate support, we could help 3.5 million just that. ■ Canadians make meaningful changes to avoid or significantly delay developing diabetes. A coordinated approach to diabetes could translate into preventing diabetes in millions of Canadians who are currently on track to develop it. Millions of Canadi- ans with diabetes who are at risk of developing serious Kimberley Hanson complications like blindness, kidney failure or amputa- Director of Federal Affairs tion would see that risk reduced. And significant time Diabetes Canada and money would be saved or used more efficiently by www.diabetes.ca our health-care system. www.twitter.com/DiabetesCanada 95 INDEX B Brock University – Faculty of Social Sciences ...... 86-89, OBC D Department of Animal Biology – University of Illinois ...... 54-55 Department of Animal Sciences ...... 76-77 Department of Biology – New Mexico State University ...... 50-51. Department of Emergency Medicine – BRIPPED Project ...... 34-35 Department of Surgery and Microbiology and Immunology ...... 20-21 Department of Pharmacotherapy and Translational Research ...... 10-13 Dole Human Development Center ...... 80-81 F Faculty of Physical Activity Sciences ...... 92-93 L Los Alamos National Laboratory ...... 65-67 M Mateescu’s Animal Genetics and Genomics Lab ...... 72-73 N Natural History Institute ...... 40-41 New York University School of Medicine ...... IFC, 16-17 Northwest Research – Extension Center ...... 70-71 P Physics Department ...... 42-43 R Rutgers, The State University of New Jersey ...... 58-59 U UC Davis Department of Molecular Biosciences ...... 46-47 University of Alberta ...... 26-27 University of Florida ...... 60-61 University of Illinois, Chicago ...... 28-29 96 NEWS, VIEWS AND OPINION www.openaccessgovernment.org acts as a platform for discussion and debate providing news and topical features with cutting edge policy analysis. We welcome contact from all experts with an interest in making an editorial contribution, and from those with an opinion to express. CONTACT [email protected] OPEN ACCESS www.openaccessgovernment.org GOVERNMENT Department of Child & Youth Studies Child and Youth Studies (CHYS) is one of the most popular programs at Brock. Students learn from a broad-based approach that considers the individual child or youth within the context of the family, school, peer group and community. With interdisciplinary roots in psychology, education, sociology, cultural studies and criminology, the degree gives academic background to pursue a wide variety of careers or to pursue further studies in a Master's program and the new transdisciplinary PhD program. CHYS will be hosting a multidisciplinary conference on conceptualizing children and youth October 11-13, 2017. Watch the CHYS website for more details: https://brocku.ca/social-sciences/departments-and-centres/child-and-youth-studies www.brocku.ca