Research Outreach Issue 103 by Research Outreach

The outreach quarterly connecting science with society ISSN 2517-7028 ISSUE 103

FEATURING RESEARCH FROM:

University of Illinois, University of the Pacific, The European CanCer Organisation (ECCO), The Princess Margaret Cancer Centre, McGill University, Harvard Medical School, University of Toronto, Northwestern University, Feinberg School of Medicine, University of Cologne, British Columbia Childrenâ&#x20AC;&#x2122;s Hospital, University of California, University of Glasgow, Western University, St. Johnâ&#x20AC;&#x2122;s College University of Manitoba, University Research Features 3 of Konstanz, University of South Dakota, UCLA, University of Massachusetts Dartmouth and the Pfleger Institute of Environmental Research (PIER), University of Minnesota.

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WELCOME TO ISSUE 103

Research covers so many diverse areas. From fertility, cancer treatments and hearing damage to gender equality in the green economy, the range of subjects covered by the researchers featured in this issue of Research Outreach is testament to the diversity of work being conducted around the world. We also hear from two Thought Leaders within Health research who share their insights with us. Professor Rhian Touyz is the Director of the Institute of Cardiovascular and Medical Sciences (ICAMS) at the University of Glasgow. She discusses the institute’s goal with us, outlining the vital research conducted there and the vision for the future. The European CanCer Organisation (ECCO) aims to raise awareness and improve prevention, diagnosis, treatment and care of cancer patients. Birgit Beger, CEO of ECCO, outlines the role of the organisation, its influence so far and, more importantly, the future of cancer care. With such a varied array of subject to choose from, I hope you enjoy learning more about the extraordinary work of the researchers we feature.

THIS ISSUE Published by: Research Outreach Publisher: Simon Jones Editorial Director: Emma Feloy emma@researchoutreach.org Operations Director: Alastair Cook audience@researchoutreach.org Editor: Hannah Fraser hannah@researchoutreach.org Designer: Craig Turl Project Managers: Kate Cooper (Senior) kate@researchoutreach.org Tobias Jones tobias@researchoutreach.org Ben Phillips ben@researchoutreach.org James Harwood james@researchoutreach.org Contributors: Patrick Bawn, Alex Davey, Ingrid Fadelli, Siobhan Fairgreaves, Rachel Goddard, Anna Jones, Dee Lawlor, Alistair Lee, Barney Leeke, Karen O’Hanlon Cohrt, Emily Porter, Victoria Stanley Tsui, Rebecca White. /ResearchOutreach /ResOutreach

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CONTENTS 06

NEW HOPE FOR MUSCULAR DYSTROPHY TREATMENT Dr Ahlke Heydemann Developing new and more effective treatments based on existing drug FTY720. EXTENDING THE HALF‑LIFE OF THERAPEUTIC PEPTIDES Dr Mamoun Alhamadsheh Developing new treatments for diseases caused by protein aggregation, including Alzheimer’s disease ECCO: IMPROVING OUTCOMES FOR ALL CANCER PATIENTS IN EUROPE THROUGH MULTIDISCIPLINARITY Birgit Beger Connecting the European cancer community by leveraging knowledge. COMPUTATIONAL METHODS OF RESEARCHING CANCER TREATMENTS Dr Benjamin Haibe-Kains Developing machine learning tools and databases to help understand cancer. SWIMMING AGAINST THE STREAM: MODERN-DAY CHALLENGES TO MALE REPRODUCTIVE HEALTH Dr Bernard Robaire Exposing the impact of age, health and exposure to chemicals on male fertility. A CAREER IN CANCER Dr Bruce Zetter Seeking treatments for highly aggressive, metastatic cancers and mentoring students.

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HELPING PATIENTS PUT THEIR BEST FOOT FORWARD Dr Gillian Hawker Developing standardised patient assessment criteria for knee surgery. LET’S HEAR IT FOR THE PROTEOME Dr Jeffrey Savas Understanding the effects of loud noise upon the molecular workings of the inner ear. UNRAVELLING THE CELLULAR MECHANISM OF SPINAL MUSCULAR ATROPHY: FROM GENE AND MODIFIERS TO THERAPY Dr Brunhilde Wirth Using advanced genetics to better understand spinal muscular atrophy.

A SHINING LIGHT IN THE FIGHT AGAINST CHILDHOOD LEUKAEMIA? Dr C. James Lim Unravelling the mechanisms of acquired chemotherapy resistance in childhood cancer. FLUOXETINE (PROZAC) USE IN CHILDREN: WORKING TOWARDS A CUSTOMISED APPROACH Dr Mari Golub Looking at the behavioural effects of fluoxetine (Prozac) on brain development. HIGH PRESSURE TALK WITH PROFESSOR RHIAN TOUYZ Professor Rhian Touyz Discovering mechanisms of cardiovascular disease at the Institute of Cardiovascular and Medical Science.

I am proud of the trans-national, transgenerational, trans-disciplinary research team building I have been involved in. PROFESSOR DIANA BRYDON Page 58

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HOW TO PROMOTE GENDER EQUITY IN THE GREEN ECONOMY Dr Bipasha Baruah Examining the reasons for inequality in the emerging green economy. GLOBALISATION THROUGH A POST-COLONIALIST LENS: UNDERSTANDING OUR PAST IS KEY TO OUR PRESENT Professor Diana Brydon We must learn from the past in order to ask better questions in the future. A FASCINATION WITH VIOLENCE: APPETITIVE AGGRESSION IN MALES AND FEMALES Dr Danie Meyer-Parlapanis & Dr Mareike Augsburger Studying the effects of violencerelated trauma on appetitive aggression.

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EMERGING FORMS OF METROPOLITAN GOVERNANCE IN LATIN AMERICA Dr Raul Acosta Garcia Investigating the efforts of grassroots activists in Guadalajara, Mexico

A SUSTAINABLE APPROACH TO ENVIRONMENTAL MANAGEMENT Dr Meghann Jarchow Varied factors affect the current functioning and management of the Upper Missouri River.

FROM BEER TO BRAINS HOW YEAST MOLECULAR GENETICS PROVE THE IMPORTANCE OF INTRONS Dr Tracy Johnson Investigating the way in which cells synthesise, splice, and process RNA.

INTO THE DEEP UNDERSTANDING SWORDFISH ECOPHYSIOLOGY Dr Diego Bernal Explaining how swordfish can move from warm to cool water without negative effects. OPEN-SOURCE BIOINFORMATIC SOLUTIONS FOR ‘BIG DATA’ ANALYSIS Drs Tim Griffin and Pratik Jagtap Developing workflows on an open source platform for the analysis of multi-omic data. COMMUNICATION The changing perception of climate change.

RESEARCH AREAS

Health & Medicine

Behavioural Sciences

Biology

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Health & Medicine ︱ Dr Ahlke Heydemann

New hope for muscular dystrophy treatment Muscular dystrophy (MD) is a family of genetic diseases which cause muscular weakness. Their severity varies but all are progressive and many are ultimately terminal. Until now, therapy options have been purely palliative, treating only the symptoms of MD. Dr Ahlke Heydemann of the University of Illinois at Chicago is developing new and more effective treatments. Her current work focuses on a drug – FTY720 – which has shown great potential in animal models and is already licensed for use in the treatment of other human diseases.

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ffecting just over one in a thousand people, muscular dystrophy (MD) is the most widespread lethal genetic disease of humans. Causing muscle weakness and wasting, sufferers become increasingly disabled as the disease progresses. If the heart or respiratory system is affected, the condition may be terminal. There are about 60 different forms of muscular dystrophy, ranging from the most common Duchenne MD, which often causes death by the age of thirty, to rarer, more slowlyprogressing or later-onset forms. All types of MD are caused by mutations in genes implicated in muscle structure and function. For instance, Duchenne

MD is caused by a mutation in the gene encoding the protein dystrophin, which helps hold muscle cells together, giving them strength. Errors in such genes result in muscle weakness, damage and inflammation, although the severity and speed of disease progression can vary considerably between different mutations. Dystrophin is actually part of a complex of molecules situated in the membrane encircling muscle cells. Other members of the complex include proteins called sarcoglycans, and mutations in sarcoglycan genes cause another type of MD, limb-girdle MD, which begins in the muscles of the shoulder and pelvis.

Sarcoglycans

Dystroglycans Sarcolemma

Dystrophin nNOS

Actin

Figure 1. The dystrophin glycoprotein complex at the muscle cell membrane – also known as the sarcolemma. Many muscular dystrophy causing mutations occur in the proteins depicted here. In this article mutations in dystrophin and γ-sarcoglycan are discussed. When mutations occur in these two proteins disease progression is similar. This disease progression is diagramed in Figure 2. Redrawn from Roberts et al, Biochemical and Functional comparisons of mdx and Sgcg (-/-) muscular dystrophy mouse models. Biomed Res Int 2015; 1314362.

DYING FOR A TREATMENT One thing all forms of MD have in common is a lack of effective treatment. Current therapies, often reliant upon steroids, can lessen the symptoms but are unable to slow disease progression. They also come with many unwanted side effects. Dr Heydemann is one of a number of researchers looking at new methods of treating the causes of MD. One promising avenue lies in reinforcing the muscle cell membrane in the absence of dystrophin or one of the sarcoglycans. “If we can restore as little as twenty percent of the function of dystrophin, for instance, others have seen real functional benefits for patients,” says Dr Heydemann.

inflammation in the debilitating autoimmune disease, multiple sclerosis (MS). Fingolimod – which is marketed under the trade name Gilenya – appears to interact with membrane-bound receptors called the sphingosine1-phosphate receptors, which are involved in many crucial biological processes, including immune responses. Fingolimod binds to the receptors by mimicking its substrate, sphingosine-

– and has already found significant effects upon disease progression in three different types of muscle: skeletal muscle, which controls limb movements; heart muscle; and the diaphragm, which facilitates breathing. A MULTI-FUNCTIONAL MOLECULE Dr Heydemann has documented that fingolimod has at least three separate mechanisms of action against MD. Firstly, it initiates molecular changes which support the membrane surrounding muscle cells. This strengthens the muscles. Secondly, as in MS, fingolimod reduces the chronic inflammation caused by infiltration of the body’s own immune response. Thirdly, it prevents fibrosis, a build-up of inflexible connective tissue which impedes muscle function by preventing the tissue from contracting. Crucially, fibrosis also hinders muscle relaxation, which is vital for the correct functioning of muscles,

One thing all forms of MD have in common is a lack of effective treatment

Her current work focuses on a drug called FTY720 or ‘fingolimod’, already licensed for treatment of chronic

1-phosphate. In doing so, it triggers a reduction in the permeability of the cell membrane and strengthens it against damage. Dr Heydemann is testing fingolimod in genetically engineered strains of laboratory mice bred to have and exhibit the symptoms of limb-girdle MD type 2C – a fully lethal disease in humans

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Dr Heydemann’s mouse studies have shown that just a three-week treatment with fingolimod dramatically inhibits fibrosis in all three muscle types studied. Ultimately, these changes produce measurable and potentially lifechanging improvements in the function of the heart and diaphragm. However, treatment must be initiated early: it does not yet appear possible to reverse the changes caused by MD, but only to prevent progression from occurring. Fingolimod is a promising new option for MD treatment: it has few side effects and, being already approved in many countries for MS treatment, it should be possible to move quickly to the stage of clinical trials. Furthermore, the mechanisms by which it fights MD are entirely separate from that of the steroid drugs usually used to treat the disease’s symptoms. This means that the two therapies can be used together in a coordinated approach to produce highly beneficial outcomes for patients. In fact, as Dr Heydemann puts it: “The real advantage of the long list of therapies that are now being developed for MD is that patient-specific co-therapies can be formulated.” These target multiple points in the disease progression and limit side effects by minimising the dosage of any one treatment. MORE QUESTIONS THAN ANSWERS Dr Heydemann’s work into fingolimod continues: so far it has raised almost more questions than it has answered! She now aims to fine-tune the dosage and treatment regime to maximise benefits in her MD mice, as well as investigating any other potential benefits it might have beyond reducing fibrosis and strengthening the muscle membrane. Crucially, she intends to

Figure 2. Disease progression follows a well-documented path for dystrophin and γ-sarcoglycan mutations, although faster in the dystrophin mutant mice and humans than in the γ-sarcoglycan mutant mice and humans. Normal muscle progresses through the stages until non-remodelling fibrotic scar tissue is formed within the muscles.

Normal, healthy muscle

Membrane damage, immune infiltrate

DISEASE PROGRESSION

including the heart and diaphragm. Fibrosis also hinders damaged muscle tissue from regenerating, and impedes the delivery of treatments to affected muscles.

Degeneration/regeneration

Necrosis/apoptosis

Myocytes replaced by fibroblasts

Fibrosis/scar

investigate exactly how fingolimod works, including the highly complex cascade of cellular and molecular signals that are brought to play downstream of the sphingosine-1-phosphate receptors. Intriguingly, initial studies have shown that fingolimod can cause cells to increase production of certain sarcoglycans, suggesting it may be able to re-establish parts of the dystrophin

There are many reasons to be optimistic regarding the imminently available therapies for muscular dystrophy

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complex. She is also investigating how fingolimod interacts with existing steroid treatments to produce further improvements in patient health. And she is studying a new ‘super-healing’ strain of mouse in which MD symptoms, particularly fibrosis, are diminished. MD research is an exciting field to work in, with so many potential treatments coming to light that it is difficult to attract enough patients to take part in clinical trials for all of them. As Dr Heydemann herself concludes: “There are many good reasons … to be very optimistic regarding the imminently available therapies for muscular dystrophy.”

Behind the Bench Dr Ahlke Heydemann

E: ahlkeh@uic.edu T: +1 312 355 0259 W: http://physiology.uic.edu/faculty/index.html?fac=ahlkeheydemann&cat=active MORE INFO: musculardystrophyuk.org mdaeurope.org

Research Objectives Dr Heydemann’s research focuses on identifying new and more effective treatments for Muscular Dystrophy. In particular, she and her research team have identified an immune inhibitor that significantly decreases pathology in mouse models of Muscular Dystrophy. Funding National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Q&A

How did you get involved in muscular dystrophy research? After my very basic science PhD, I was determined to work on something more clinically applicable. I had met Dr McNally years earlier and found her work highly intriguing and I could easily see how her lab’s work would benefit patients. After discussing a few potential projects, we agreed upon my doing a post-doc in her lab. The passion to help the patients quickly became instilled in me. What is fibrosis and what is its significance in muscular dystrophy? Fibrosis is an internal scar. The scar behaves differently in different tissues and organs. In muscle, the key detrimental facts regarding scars are that: scars do not contract; scars impede natural healing; scars do not let therapies through to the diseased cells; and in cardiac muscles scars do not propagate the contraction impulse. In healthy damaged muscles,

Collaborators Dr Maria Siemionow, professor in UIC’s Department of Orthopaedic surgery. Together Drs Heydemann and Siemionow are analysing genetically corrected muscle stem cell transplants into mdx mice. Bio Dr Heydemann received her undergraduate degree from the University of Maryland and her PhD from the University of Chicago. She later went on to work as a post-doc with Elizabeth M McNally at the

scars remodel, break down, and the muscle heals itself. Muscles in a muscular dystrophy patient lose this ability to remodel and heal themselves. Why would a drug used to treat multiple sclerosis also be beneficial in the treatment of muscular dystrophy? After the initial muscle damage caused by muscular dystrophy, the immune system enters the muscles to clean up the dead tissue debris. After repeated cycles of cleaning up debris the immune system actually creates more muscle damage. This chronic inflammation is pathogenic. In multiple sclerosis FTY720 helps the patients by keeping the immune cells away from the damaged tissues. We initially tested if FTY720 would do the same – reduce chronic inflammation – for the MD mice. We found that FTY720 did this and, thankfully, so much more.

University of Chicago until 2011, when she became an Assistant Professor at the University of Illinois at Chicago. Contact Ahlke Heydemann, PhD Associate Professor University of Illinois, Chicago COMRB 2035, MC 901 835 South Wolcott Ave. Chicago, IL 60612-7352 USA

How important are animal models in your research? Animal models, in particular the mouse model, are critically important for the MD research community. The tremendous advances we are currently making are only possible because of the mouse models of the diseases. What do your results mean for sufferers of muscular dystrophy? FTY720 will require additional preclinical testing. We still have to establish the optimum dose and delivery timings for mice and then extrapolate that to the patients. Luckily, we can utilise the known safe dose from the multiple sclerosis patients to inform our decision. I feel once these last hurdles are surpassed a large number of young muscular dystrophy patients can begin to have healthier longer lives.

I feel once these last hurdles are surpassed a large number of young muscular dystrophy patients can begin to have healthier longer lives

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Health & Medicine ︱ Dr Mamoun Alhamadsheh

Extending the half‑life of therapeutic peptides Dr Mamoun Alhamadsheh is Associate Professor at the University of the Pacific, Thomas J. Long School of Pharmacy and Health Sciences, California. He heads a multi-disciplinary team working in the field of proteinprotein interactions. Their research is focused on the development of new treatments for diseases caused by protein aggregation, including Alzheimer’s disease and transthyretin amyloidosis. Their current work in peptide conjugation is showing great promise. After publishing their work in the prestigious journals PNAS and Nature Chemical Biology, the team are now about to embark on exciting new clinical trials to evaluate the efficacy of a new therapy for a form of heart disease caused by transthyretin amyloidosis.

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myloidosis is a group of rare but serious conditions caused when deposits of damaged proteins known as amyloid fibrils, accumulate around tissues and organs. Over time these accumulations interrupt the normal function of the organ and in advanced cases can cause organ failure. Cardiac amyloidosis, which is commonly caused by aggregation of immunoglobulin light chain (AL) or transthyretin (TTR), is a main contributor of morbidity and mortality in patients with amyloidosis. TTR amyloidosis (ATTR) is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. Clinically, ATTR presents as: (i) a cardiomyopathy (ATTR-CM) which is an infiltrative, restrictive cardiomyopathy characterised by progressive

Above: The AG10 analogue-peptide conjugate can bind reversibly to the thyroxine binding sites of endogenous human TTR (shown as ribbon diagram with transparent surface). This will increase the in vivo half-life of peptides by protecting against proteases and by decreasing glomerular filtration. Importantly, due to its reversible binding to TTR, the binding affinity of the peptide conjugate to its target receptor would not be adversely affected.

This ability to extend the life of peptides will have future applications in the imaging and treatment of tumours left and right heart failure, or (ii) a peripheral polyneuropathy (ATTR-PN), a neurodegenerative disease affecting sensorimotor and autonomic functions. TTR is a transport protein secreted by the liver. It is found in the serum and the cerebrospinal fluid and named after its function in transporting thyroxine and retinol (vitamin A). TTR is coded for by the TTR gene, and a faulty copy of this gene can lead to misfolding of the TTR protein. This structural change leads to the protein aggregation and the creation of the amyloid fibrils. The build-up of these TTR amyloid fibrils in the heart leads to ATTR-CM. There is currently no cure for ATTR-CM. Alhamadsheh’s team (in collaboration with Stanford University) developed a small molecule, called AG10, that stabilises TTR against amyloidoisis. AG10 is currently being developed by as a therapeutic agent for ATTR-CM.

THERAPEUTIC PEPTIDES Peptides are essential for carrying out vital biological functions. A peptide is smaller than a protein – peptides are made of up to 50 amino acids (over 50 amino acids gives you a protein). It has long been known that peptides (e.g. insulin) have great utility in therapeutics. Some of their advantages include binding with high selectivity – making them effective and reliable. Many peptides are made inside the body, so the immune system does not attack them and there is little chance of rejection. They are easy to synthesise in the lab and, compared to large proteins, are capable of crossing the cell membrane, meaning they can deliver treatments straight into the cell. One of the downfalls of peptides is that they have a poor pharmacokinetic profile – that means that do not circulate in the body for a long time. The half-life of a peptide is usually

Above: TTR acts as a “Rock” that protects the peptide “Paper” from degradation by the protease “Scissors”.

between two and 30 minutes, after which they are quickly filtered out by the kidneys. This means that any treatment they carry only has a very short time to reach the part of the body where it is required. To compensate for this short window of activity, peptide treatments are often administered in high and frequent doses. This obviously has an impact on the patient experience and increases the cost of treatment. A NOVEL APPROACH TO INCREASE THE THERAPEUTIC POTENTIAL OF PEPTIDES The in vivo half-life of holo-RBP (a protein that carries vitamin A in the blood) is around three hours. However, when holo-RBP is bound to TTR (our

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Dr Mamoun Alhamadsheh and his team at the University of the Pacific, Thomas J. Long School of Pharmacy and Health Sciences, California.

transport protein that we discussed previously), the in vivo half-life of holoRBP is increased threefold. Inspired by this, Dr Alhamadsheh and his team have focused their efforts on an analogue of the TTR binder described above, AG10. The team repurposed this AG10 analogue and conjugated it to a number of peptides, which allows the peptides to be carried by TTR in blood. The binding to TTR is what provides potent and reliable stability for the peptides against degradation and clearance by the kidneys. By improving the half-life of these peptides, the effectiveness and its ability to be active in the body is also improved. By optimising the harnessing and protection provided by TTR for these peptide conjugates, the team aim to enhance the pharmacokinetic properties of therapeuticÂ peptides. As this technique involves a simple conjugation reaction, it is reliable,

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The team aim to have a safe, effective treatment available to TTR cardiomyopathy patients in the near future predictable, and reversible. There is hope that this ability to extend the life of peptides will have future applications as therapy for metabolic diseases and as well as in the imaging and treatment of tumours. The team envision that their findings will be able to help extend the in vivo half-life of other molecules including proteins, oligonucleotides, oligosaccharides and liposomes, and will also have applications in the development and delivery of imaging agents and other small molecule drugs. THE FUTURE AG10 is more effective in stabilising TTR in human serum than other molecules in clinical trials. AG10 passed a number of toxicity studies in animals and can

be given orally. Clinical trials for this game-changing new molecule (AG10) has just started, focusing on patients with cardiomyopathy (ATTR-CM) a disease of the heart muscle. The trials will be run by Dr Alhamadshehâ&#x20AC;&#x2122;s new company Eidos Therapeutics, which was established in 2016, along with co-founder Dr Isabella Graef. By starting a company that focuses purely on their new-found molecule, the Eidos team aim to have a safe, effective treatment available to patients in the near future. Alhamadshehâ&#x20AC;&#x2122;s team is also using their newly developed technology to extend the in vivo half-life of a number of peptides.

Behind the Bench Dr Alhamadsheh

Dr Wabel Albusairi

E: malhamadsheh@PACIFIC.EDU T: + 1 209 946 3164 W: http://alhamadshehlab.org/

Research Objectives Dr Alhamadsheh’s research combines synthetic organic chemistry with biochemistry and molecular biology to study protein-protein interactions. The team are particularly interested in developing chemical tools and therapeutic agents for protein aggregation diseases such as Alzheimer’s disease and Transthyretin Amyloidosis. Funding National Institutes of Health (NIH) Collaborators • Dr Miki Park, University of the Pacific

Q&A

What have been the most significant challenges you have faced in conducting this research so far? In addition to TTR, there are more than 4,000 proteins in human serum. Finding a molecule that has high binding affinity and selectivity for TTR in serum was not an easy task. We started working on TTR in 2008 and we were the first group to perform a highthroughput screening (we screened the binding of 120,000 molecules) for TTR binders. The information and insights we gained from the best hits from the screen were used to develop AG10. Your new technique has tremendous therapeutic potential. Could you talk us through its advantages? Besides maintaining the potency of peptides, our strategy has several advantages over traditional halflife extension approaches. (i) Our approach involves a simple chemical conjugation of peptides, and the

• Dr William Chan, University of the Pacific Bio Dr Alhamadsheh is Professor of Pharmaceutical Chemistry at University of the Pacific. He received his BS in pharmacy from JUST in Jordan and his PhD in organic chemistry from University of Toledo. He completed his postdoctoral studies in chemical biology at Stanford University. He is cofounder of Eidos Therapeutics. Dr Wabel Albusairi is Assistant Professor of Pharmaceutics at Kuwait University. She received her products are homogeneous and can be easily characterised and purified. (ii) Our peptide conjugates would be stable products that do not require refrigeration. This would decrease the cost of production and storage of peptide conjugates. (iii) Because of the smaller size of our peptide conjugates, we anticipate it to be able to penetrate solid tumours efficiently and they also would unlikely cause an immunogenic response. What other potential applications are there for AG10? Treatment for TTR polyneuropathy and conjugating AG10 analogues to peptides to increases the half-life of peptides. We envision that our approach could potentially be applicable for enhancing in vivo half-life of proteins, oligonucleotides, oligosaccharides, liposomes, imaging

MPharm in pharmacy at the University of Manchester, UK, and PhD in drug targeting and delivery in Dr Alhamdsheh’s lab at University of the Pacific. Contact Mamoun Alhamadsheh, PhD Associate Professor of Pharmaceutical Chemistry Thomas J. Long School of Pharmacy and Health Sciences 3601 Pacific Avenue Stockton, CA 95211 USA

agents and small molecule drugs. This should broaden the scope and utility of our approach. Your research opens up new possibilities for creating peptides for many diseases and even imaging and diagnostic agents. What are the next steps for your research and for developing peptide therapeutics further? Continue working on the half-life extension technology. We are interested in applying our technology to improve the half-life and lower toxicity of anticancer agents. This would allow less frequent dosing and better safety profiles for cancer patients which would decrease production cost and increase clinical success rate.

Clinical trials for this game-changing new molecule (AG10) has just started, focusing on patients with cardiomyopathy

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Thought Leader

ECCO: Improving outcomes for all cancer patients in Europe through multidisciplinarity The European CanCer Organisation (ECCO) is a not-for-profit federation that exists to uphold the right of all European cancer patients to the best possible treatment and care, promoting interaction between all organisations involved in cancer at European level. ECCO aims to raise awareness and improve prevention, diagnosis, treatment and care of cancer patients. CEO of ECCO Birgit Beger spoke with us at Research Outreach to discuss their work and more in greater detail.

ccording to the World Health Organization, cancer causes 20% of deaths in the European Region. With more than 3 million new cases and 1.7 million deaths each year, cancer is the most important cause of death and morbidity in Europe after cardiovascular diseases. But what about the lucky survivors and the care and treatment they need to recover? How can we ensure that patients have access to the best possible treatment and care? How can care for cancer patients be improved across Europe? These are the many questions and key focuses for the European CanCer Organisation (ECCO). ECCO connects the European cancer community by leveraging knowledge,

the organisation in a way that ensures the fulfilment of its vision and core purpose. What are ECCO’s core principles in terms of history, heritage and background, and which areas of cancer research are you currently looking into? ECCO was established in 1981 to unite all healthcare professionals in oncology with the aim to improve health outcomes for all patients. Being a federation of European Associations, ECCO needs to bridge together different professional traditions and cultures like those of surgeons, radiologists, medical oncologists, pathologists, pharmacists, researchers, nurses, psychologists etc. ECCO is a patient centric organisation that involves a close and early collaboration with 15

Our research greatly reflects the debate on quality cancer care. For selected tumour types, ECCO has produced ‘Essential Requirements for Quality Cancer Care’ (ERQCCs). These provide oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high-quality care throughout the patient journey. How influential has ECCO been on cancer research since it was first established? ECCO is contributing to cancer research through several avenues. Firstly, ECCO has organised scientific congresses for its members. For example, ECCO organises a joint symposium for the European

ECCO’s vision is to improve outcomes for all cancer patients in Europe through multidisciplinarity promoting education and building awareness. ECCO also plays an important role in engaging with policymakers to promote the interests of cancer patients, research as well all other members of the oncocommunity. We caught up with ECCO’s CEO, Birgit Beger, who outlines the role of the organisation, its influence so far and, more importantly, the future of cancer care. Hey Birgit! Could you tell us what your role involves as the CEO of ECCO? Being CEO of ECCO is a very exciting and enriching task where I learn every day. As CEO, I implement the decisions of our members and help to sustain and develop

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European patients’ organisation in all ECCO’s activities. ECCO’s vision is to improve outcomes for all cancer patients in Europe through multidisciplinarity. There is no golden standard: recommendations can lead the way to improve each health care system by providing a toolbox for change. Our core values are the following: • Patient Centricity • Commitment to Science • Cohesiveness • Inclusiveness • Equality and Fairness • Openness and Transparency

Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR). Secondly, ECCO is a founding member of the Alliance of Biomedical Research in Europe, which represents a unique initiative of leading European medical societies that together include more than 400,000 researchers and health professionals. In this context, ECCO assisted in advocating for the establishment of the European Commission’s Scientific Panel for Health (SPH).

Thirdly, ECCO is a longstanding partner of the Joint Research Centre, which provides the European Union with scientific knowledge when formulating policies and legislation. Lastly, ECCO also sets its own focus on cancer research, by providing feedback to the European Commission to its consultation on the Advisory group report for the Horizon 2020 Societal Challenge on health, demographic change and well-being. From a more personal perspective, are there any achievements you are particularly proud of? ECCO looks back to a heritage of extensive engagement of its members and a series of 18 very successful congresses bringing science and research forward and being a cornerstone in scientific progress by representing inter alia latest clinical trial data. Devising a strategic renewal in 2013/2014, ECCO has decided to put more focus on oncopolicy, i.e., marrying science and policy to help improve the outlook of oncology. In addition to this, we have set new priorities for policy and advocacy, uniting our members in fresh positions in respect to, not only quality cancer care, but also access to innovation, integration of care, as well as emerging oncology workforce issues. Where there is a grand debate concerning the future of cancer care, ECCO intends to help its members to be present, articulate, and advocate for the interest of best quality patient care and outcomes. What impact does ECCOâ&#x20AC;&#x2122;s link to

the European Journal of Cancer have on communicating cancer research between fellow researchers, and the public? The beauty of The European Journal of Cancer is its true spirit of multidisciplinary enquiry and reflection. It ensures a real coming together of researchers in clinical practice from a great variety of fields. The abstracts of the ECCO Congress have always been part of the publications in the European Journal of Cancer (EJC). This allows fellow researchers to connect in between the congresses and stay up-to date with the latest research. ECCO tries to bridge the world of fellow

researchers, healthcare providers in oncology and the broader public on burning topics in oncology. Our latest paper sets out that access to innovation is about more than pharmaceuticals alone. It challenges our own professions to identify potential areas of inefficient or outdated practice and treatment. It also brings the use of real world data to the heart of the access debate. These and more act as an example of how ECCO would like to bring about awareness and change into cancer research and beyond. In September next year, ECCO will be holding its 2018 European Cancer Summit in Vienna â&#x20AC;&#x201C; What is the significance of this and what influence

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do events like these have on installing a community movement in cancer research? With ECCO’s strategic renewal, the format of our congresses was redesigned. The ECCO 2017 Congress in Amsterdam in January 2017 showed the many innovative concepts in bringing research, science and policy closer together. The ECCO 2018 European Cancer Summit takes place in Vienna, Austria on 7–9th September 2018. It aims at taking the congress to a higher level, namely to a summit where worldwide leaders from the cancer healthcare, patient advocacy and stakeholder communities come together in a unique multidisciplinary forum. The idea is to complete the summit with the agreement of consensus resolutions by leaders in cancer policy, which will shape oncopolicy in health care systems across Europe. To connect science with real life, outcome research forms a decisive part, i.e., using real-world data to observe how new treatments and diagnostic modalities have performed in cancer care delivery. Health economics of cancer care is another topic, which is highly connected with outcome research and cannot be surpassed in any oncology debate today. Lastly, ECCO aims to focus on the patient voice to determine an agreed vision for guiding and supporting patients through diagnosis, treatment and follow-up in a world facing an ageing population, increasing survivorship and a technological revolution in e-health resources. Do you think cancer research receives as much funding and attention as it should? From a European perspective, the European Commission sees cancer

Birgit Beger, ECCO CEO

priority list of the current Commission. However, we are delighted that a new EU ‘Joint Action’, following CanCon and aiming to implement the CanCon European Guide on Quality Improvement in Comprehensive Cancer Control,

research. This reflects the demographic changes and the increase of cancer incidences, but also the growing success in treating cancer, which provides strong motivation among politicians to invest in cancer research. However, the more

Our research greatly reflects the debate on quality cancer care: what are the elements required to deliver high quality cancer care for all patients in Europe? research and cancer control still as an important topic, though health policy overall does not seem to be high on the

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will start in 2018. The EU’s research programme, Horizon 2020, has also set aside substantive resources for cancer

research advances, the more it becomes apparent how many gaps there are still to close before science is anywhere

Thought Leader near mastering cancer. Though there is the firm belief among researchers that cancer will be curable, there needs to be more research into the varieties of cancer we discover. The perception and understanding of cancer has become much more differentiated and will have to become even more so to help advance with therapies delivering best health outcomes.

Vytenis Andriukaitis, Commissioner for Health and Food Safety, speaking at the ECCO 2017 European Cancer Congress

Although your name has a European focus in its title, do you extend your research outreach to collaborate with other countries internationally? ECCO has longstanding relationships with the American Society of Clinical Oncology (ASCO) and with the Japan Society of Clinical Oncology (JSCO) including via joint sessions at each other’s congresses. Established in 1999, ECCO has been coorganising the Methods in Clinical Cancer Research (MCCR) Workshop, which is an educational programme that introduces junior clinical oncologists in any oncology subspecialty to the principles of good clinical trial design. The workshop is the product of co-operation between ECCO, the American Association for Cancer Research (AACR), European Organisation for Research and Treatment of Cancer (EORTC) and the European Society for Medical Oncology (ESMO). The junior clinical oncologists not only come from all specialties, but also from all over the world, which makes the workshop an international and inspiring event. Beyond this, ECCO also strives to cooperate more on a policy level. For example, the question of protocols for clinical trials, clinical trial data and ethical questions are of international relevance and therefore, a joint approach is highly desirable. ECCO is also involved as a contributing member of the Union for International Cancer Control (UICC) and aims at being an active partner internationally wherever there is common ground for the development of policy, for example via the World Cancer Declaration. Which direction would you like to see cancer research going in the future and how will ECCO’s leadership strategy play into this? Given the dimensions addressed above,

the growing importance of cancer research, and the global co-operation needs, ECCO’s role of fostering multidisciplinary throughout the European region, but not stopping at this, is the right way forward. One large task is to deal correctly with data. The means of our age, electronic tools and systems seem to offer endless opportunities if the society manages to harness them in an ethical and legally correct manner. One of the challenges that remains today is the integration of data generated in one component of healthcare delivery into the wider healthcare IT system, so that in terms of providing good patient care, a more seamless record can be shared across all three fields of primary, secondary and social care. For cancer research, the need to collect data as well as to share results from clinical trials, independent of whether they are positive, negative or inclusive, is decisive. Despite the establishment of Cancer Registries and European Reference Networks, there are still many steps ahead before

the challenge of data is managed appropriately in cancer research. • For more information about ECCO, their upcoming events or the European Journal of Cancer, please visit ECCO’s website at www.ecco-org.eu.

Contact Birgit Beger CEO ECCO - the European CanCer Organisation Avenue E. Mounier 83 B-1200 Brussels, Belgium E: birgit.beger@ecco-org.eu T: +32 2 775 02 01 W: http://www.ecco-org.eu/

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Health & Medicine ︱ Dr Benjamin Haibe-Kains

Computational methods of researching cancer treatments T Artificial Intelligence (AI) and machine learning algorithms have the potential to bring substantial advances in the fields of research exploring complex diseases and trying to identify effective treatments. Dr Benjamin Haibe-Kains, working at The Princess Margaret Cancer Centre in Toronto, has spent over a decade developing machine learning tools and databases that could help scientists gain a better understanding of different sub-types of cancer and their response to pharmacological treatments, in order to identify more effective drugs for individual patients.

he computational analysis of big data is set to bring huge advances in terms of the methods used to carry out medical and basic research. A number of researchers worldwide have already started developing algorithms that can analyse large amounts of biological and medical data, identifying new hypotheses for future investigation. A particular field of medical research that could highly benefit from the use of machine learning algorithms is that of exploring cancer genomics and trying to determine the best treatments for different subtypes of the disease. THE VALUE AND CHALLENGES OF BIG DATA Throughout the years, scientists have collected vast amounts of data from experiments aiming to achieve a better understanding of the molecular dynamics behind complex diseases. However, the complexity of such data makes it difficult for human researchers to run in-depth analyses and extract the relevant information. This is where the use of high performance computers, coupled with the right programs could be of great help. In the last decades, computer scientists have worked hard to develop machine learning algorithms – programs allowing machines to quickly analyse large amounts of data and “learn” models useful to identify the relevant pieces of information and make predictions. These algorithms can then be leveraged to develop artificial intelligence (AI) tools that can assist humans to analyse data that are beyond our reach. As they become increasingly advanced and sophisticated, AI tools are opening up a new world of possibilities for big data analysis, by transforming the way in which studies and investigations are conducted, leading to important discoveries in a much shorter time.

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ARTIFICIAL INTELLIGENCE AND CANCER RESEARCH Artificial Intelligence and their underlying machine learning algorithms could be of particular value for research exploring complex diseases, when trying to identify effective pharmacological treatments for them. Cancer, one of the leading causes of death worldwide, is a perfect example of this. Scientists have not yet been able to identify a systematic treatment for cancer that is successful in curing the disease in many of its most aggressive subtypes. Cancer derives from an uncontrolled division of abnormal cells in a given part of the body, which can invade and destroy surrounding healthy tissue and organs. It is an extremely complex disease, with more than 200 subtypes, each of which is often diagnosed and treated differently. As cancer arises from aberrations in the genomic materials of the cells, scientists have developed sophisticated profiling technologies to measure these aberrations and use them to personalise therapies. Still, the most common treatments for cancer are chemotherapy, using drugs to kill the most proliferative cells, and radiotherapy, using high energy X-rays. These treatments can sometimes be successful in reducing or eradicating cancerous cells, yet they can be highly toxic and are not tailored toward the specific set of genomic aberrations that make each tumour unique.

genomics to improve prediction of patient survival and response to therapies. During his graduate training at the Université Libre de Bruxelles in Belgium, he worked on developing predictors of survival in breast cancer patients based on high dimensional gene expression (messenger RNA) data. He continued his research as a postdoctoral fellow at the Dana-Farber Cancer Institute/Harvard School of Public Health, leveraging a large collection of data to develop “gene expression signatures” to robustly identify molecular subtypes of breast and ovarian cancers. Using large collections of cancer molecular data and machine learning algorithms, Dr Haibe-Kains and his collaborators identified several “prognostic biomarkers”, that are

recognised that, due to the high costs of clinical trials, the existing clinical data related to given treatment and cancer subtypes were extremely scarce. Given that machine learning usually requires a large sample size to avoid artefactual discoveries, it was time to investigate “preclinical models”, which are cancer cells derived from patient tumours that one can replicate infinitely. These models therefore provide a fantastic advantage compared to clinical trials as the same cancer cells can be tested with multiple therapies to assess which one is the most efficient, something impossible to do with patients. Dr Haibe-Kains’ laboratory invested most of its resources in compiling and curating the largest anticancer drug screens in preclinical models. Such screens contain not only the genomic make-up of the cancer cells, but also the way these cells react to chemical treatments; these complex data are referred to as pharmacogenomics. These efforts resulted in the development of PharmacoDB1, a web-application allowing researchers to quickly access the pharmacogenomic data to investigate the possible associations between genomic aberrations and drug response.

Dr Benjamin Haibe-Kains explores the potential of machine learning algorithms, bioinformatics and computational genomics to improve prediction of cancer patients’ survival and response to therapies

Artificial Intelligence tools could assist researchers by analysing the complex genomic make-up of each individual tumour to develop accurate predictors of treatment response. This would in turn help to identify more effective treatments for individual patients, a major step towards personalised medicine. COMPUTATIONAL METHODS FOR CANCER RESEARCH Throughout his career, Dr Benjamin Haibe-Kains has explored the potential of machine learning algorithms, bioinformatics and computational

computational models using specific molecular features to predict the probability of survival of cancer patients treated with standard-of-care treatments. He says: “Amongst many discoveries, my research unravelled the landscape of cancer pathway activities associated with patients’ survival in each of the molecular subtypes, allowing me to further improve my molecular prognostic models.” EFFECTIVE TREATMENTS FOR INDIVIDUAL PATIENTS In 2012, Dr Haibe-Kains started his own independent laboratory, broadening his field of research to explore ways in which machine learning algorithms could be used to predict therapy response in patients. With big players like IBM announcing its Watson initiative to develop AI to assist oncologists in their treatment decision process, it was an exciting opportunity for Dr Haibe-Kains to extend the biomarker discovery beyond patients’ survival, and to make personalised medicine a reality. However, Dr Haibe-Kains and his team quickly

As part of his current research, Dr Haibe-Kains is testing machine learning algorithms on the database, to try and pinpoint predictors of treatment reaction. Paired with the right machine learning algorithms, PharmacoDB could be used to develop an AI tool assisting in selection of the most effective treatments for each individual cancer patient. Dr Haibe-Kains’ laboratory also leveraged these valuable data to address another important issue in cancer research: how to classify drugs based on their mechanism of action? Although biologists, chemists and pharmacologists teamed up to develop a large portfolio of drugs with high anticancer potential, it is unclear for many of these drugs how they actually inhibit the growth of cancer cells. Dr Haibe-Kains and his team developed the Drug Network Fusion (DNF), a

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new technique integrating multiple pharmacogenomic data to design a comprehensive drug similarity map (or taxonomy). DNF allows researchers to assess the similarity between a drug with unknown mechanism of action with well-characterised drugs, therefore providing an efficient tool to identify potential new indications for approved or experimental drugs (a process called “drug repurposing”). As more pharmacogenomic data becomes available and machine learning algorithms are further improved, databases such as PharmacoDB could become extremely valuable resources. A NEW ERA FOR RESEARCH If developed and used correctly, the use of machine learning and AI tools in

basic and translational cancer research could mark the beginning of a new era for personalised medicine, characterised by quick and advanced data analysis,

Dr Haibe-Kains’ approach to research is highly collaborative and multidisciplinary, merging the expertise of scientists from a number of different fields. In future,

Application of artificial intelligence in basic and translational cancer research could mark the beginning of a new era for personalised medicine which was previously unattainable. Dr Haibe-Kains’ work is a perfect example of this, as he has introduced computational methods that could speed up cancer research significantly, by analysing large datasets and identifying predictors of treatment response.

the computational methods developed by him might lead to ground-breaking discoveries, which could inform oncologists on how to select the most effective treatments for individual cancer patients in clinical settings.

1 http://pharmacodb.pmgenomics.ca/ 2 PharmacoGx: An R package for analysis of large pharmacogenomic datasets. Smirnov P, Safikhani Z, El-Hachem N, Wang D, She A, Olsen C, Freeman M, Selby H, Gendoo DM, Grossman P, Beck AH, Aerts HJ, Lupien M, Goldenberg A, Haibe-Kains B. Bioinformatics. 2015 Dec 9. 3 PharmacoDB: an integrative database for mining in vitro anticancer drug screening studies. Smirnov P, Kofia V, Maru A, Freeman M, Ho C, El-Hachem N, Adam GA, Baalawi W, Safikhani Z, Haibe-Kains B. Nucleic Acids Res. 2017 Oct 9, gkx911. 4 Integrative cancer pharmacogenomics to infer large-scale drug taxonomy. El-Hachem N, Gendoo DM, Soltan Ghoraie L, Safikhani Z, Smirnov P, Chung C, Deng K, Fang A, Birkwood E, Ho C, Isserlin R, Bader G, Goldenberg A, Haibe-Kains B. Cancer Res. 2017 Mar 17 5 Gene isoforms as expression-based biomarkers predictive of drug response in vitro. Safikhani Z, Smirnov P, Thu KL, Silvester J, Lupien M, Mak TW, Cescon D, Haibe-Kains B. Nat Commun 2017 oct, in press.

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Behind the Bench Dr Benjamin Haibe-Kains

E: benjamin.haibe.kains@utoronto.ca T: +1 416 581 8626 W: http://www.pmgenomics.ca/bhklab/ https://www.linkedin.com/in/benhaibekains/ https://twitter.com/bhaibeka Research Objectives Dr Haibe-Kains’ research focuses on the computational integration of high dimensional molecular data to simultaneously analyse multiple facets of carcinogenesis. Funding Princess Margaret Cancer Foundation, Canadian Institutes of Health Research, Terry Fox Research Institute, Stand Up To Cancer Canada, Cancer Research Society, Natural Sciences and Engineering Research Council of Canada, Canadian Cancer

Q&A

When and how did you first start being interested in computational models to be used in cancer genomics research? When I did my bachelor in Computer Science, I was interested in the development of Artificial Intelligence in robotics. In the early 2000s, AI robotics was still in its infancy and the applications were still limited. This is when my former supervisor at the Université Libre de Bruxelles, Prof Gianluca Bontempi advised me to consider bioinformatics, a booming field in need of researchers with expertise in machine learning. I followed his advice and started a PhD under a co-supervision with Dr Christos Sotiriou, a breast cancer oncologist at the Institut Jules Bordet. This is how I started using computational models in cancer genomics research. So far, how effective have the machine learning tools developed by you been in improving biomarker discovery and drug selection from pharmacogenomic data? My lab was definitively not the first to tackle these important challenges. However, we built on our previous experience in meta-analysis of large compendium of gene expression data to develop computational platforms for pharmacogenomic data analysis. PharmacoGx2 and PharmacoDB3 are open-source and freely available

Research Society, Ministry of Economic Development/Ministry of Research and Innovation of Ontario, Ontario Institute for Cancer Research Bio Dr Benjamin Haibe-Kains is Scientist at the Princess Margaret Cancer Centre and Assistant Professor in the Medical Biophysics and Computer Science departments of the University of Toronto (Canada). He earned his PhD in Bioinformatics at the Université Libre de Bruxelles (Belgium), before conducting a

for the scientific community. With these large amounts of pharmacogenomic data in hand, we applied machine learning techniques to better classify drugs (DNF4) and discover new biomarkers predictive of drug response in cancer cell lines5. Even though these discoveries will have to undergo further validation before their translation into clinic, they show that machine learning can yield promising results with potential clinical relevance. How long do you believe it might take to start witnessing a major introduction of AI technology within medical settings? Not long, probably a few years from now. As more hospitals have the patients’ electronic health records connected to the experimental data derived from their tumour materials, we will finally have access to the large, high quality data required for AI to show its full potential for biomedical applications. Recognising that large cohorts of patients and derived materials are necessary to make major discoveries and build the new generation of AI-based tools in the clinic, hospitals are joining forces, and even pharmaceutical companies have started to share more and more data related to clinical trials. These are the necessary steps we must take to unleash the power of AI for personalised medicine. In the years to come, what role do you feel AI will have in terms of research and innovation within the medical field? It is hard to predict the roles of AI in the future of medicine; the applications are close to limitless. It will help patients

postdoctoral fellowship at the Dana-Farber Cancer Institute and Harvard School of Public Health (USA). Contact Benjamin Haibe-Kains, PhD Princess Margaret Cancer Research Tower, Floor 11, Room 310 101 College Street Toronto ON M5G 1L7 Canada

better schedule the series of medical appointments involved in the treatment of complex diseases such as cancer. It will help hospitals better monitor their performance, and ensure the highest standards of safety, diagnosis accuracy and treatment efficacy. The mining of data from wearable devices will allow continuous monitoring and patients to be more proactive when symptoms arise. And of course, AI will enable new discoveries, further expanding our knowledge of cancer and other diseases. Limitless. What are your plans for future research? First, I want to validate our first discoveries – predictors of drug response and new drugs predicted to be efficacious in aggressive cancer types – in animal studies to get them close to clinical applications. The Princess Margaret Cancer Centre enjoys a strong drug development group, which will be key in this endeavour. Second, I want to make our pharmacogenomic platforms tools of choice for hospitals and pharmaceutical companies, to further facilitate data sharing and large-scale computational analysis. Finally, I want to integrate molecular data with imaging data, both pathological and radiological images, to predict the best course of treatments and better follow the patients over time. Our first application of deep learning on radiological images is promising, supporting this line of research for future clinical applications.

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Health & Medicine ︱ Dr Bernard Robaire

Swimming against the stream: modern-day challenges to male reproductive health The effects of a mother’s age, health and habits upon her offspring are well documented. However, far less attention has been paid to fathers. Dr Bernard Robaire, Professor at McGill University, Montréal, Canada, believes male reproductive health may be just as important for future generations as that of females, with a father’s age, health and exposure to chemicals all having an impact on the quality and genetic makeup of his sperm – and ultimately the fitness of his children.

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omen today are showered with advice regarding their reproductive health and the health of their future children. Some of the stories you hear typically include: ‘older mothers are more at risk of fetal abnormalities’; ‘don’t drink alcohol, smoke, or eat soft cheese during pregnancy’; ‘take folic acid when you’re trying to conceive’; ‘avoid exposure to chemicals such as pesticides’, etc. This is all good advice, of course, but how about the fathers – do they get off scot-free? Well, not for much longer! Dr Bernard Robaire’s research is set to overturn the predominant view that a man’s age, health and habits have little impact upon his future offspring. Bad news for fathers-to-be, perhaps, but good news for the accuracy of reproductive health guidelines.

LITTLE SWIMMERS Unlike a woman’s eggs, which are all present in her body at birth and released gradually throughout her lifetime, sperm – the carriers of genetic information from the male parent – are continuously produced throughout a man’s life – at a rate of about 1000 every time his heart beats. The male sex organs, the testes, are filled with coiled tubes called ‘seminiferous tubules’ – which are lined with sperm stem cells

As sperm mature they pass through the tubules and are stored until they are ready to be released. It was previously thought that their constant manufacture rendered sperm relatively immune to the kind of damage that can accumulate in a woman’s eggs over her lifetime. However, Dr Robaire’s research and that of his colleagues have shown that this is not the case. Exposure to drugs (therapeutic or otherwise), smoking, environmental chemicals,

Sperm are continuously produced throughout a man’s life – at a rate of about 1000 every time his heart beats that divide to produce sperm – and sperm nurse cells (‘Sertoli cells’), which regulate the process, under the control of sex hormones such as testosterone.

and conditions such as obesity, are now known to have negative effects on a man’s sperm, and, therefore, his children, and these effects may cumulate with age.

Dr Robaire’s research aims to find out exactly how these effects are manifested. His team members are investigating how the components of the male reproductive system, and the different processes involved – hormone production and reception, sperm production, maturation and storage – are impacted by a range of possible environmental factors, and are looking to characterise the molecular mechanisms that mediate these effects. THE AGE EFFECT In today’s society, men and women alike are increasingly delaying parenthood until later in life. Now it seems that this may not be such a good plan. Dr Robaire’s animal studies have shown that the progeny of older male rats have lower weights and are more likely to die in the neonatal period than those of younger fathers. When their sperm were examined, the

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offspring of the older rats were found to have greater levels of damage to their genetic material, DNA. In humans, older men are reported to have testes containing slower sperm, and a higher proportion of these are abnormal. They also show higher rates of infertility, and their partners take longer to get pregnant and are more likely to miscarry. Increasing numbers of studies have linked paternal age with higher rates of diseases with a complex genetic component, such as autism, ADHD, schizophrenia, and bipolar disorder. There is mounting evidence linking paternal age with chromosomal and genetic changes in offspring, increasing the risk of breast cancer, heart defects, and developmental, behavioural and neurological disorders. Furthermore, dominant genetic disorders such as achondroplasia, the most common form of dwarfism, are shown to be more common in the children of older fathers. These genetic changes have been connected to deficits in the cellular mechanisms for repairing damaged DNA, which are essential in cells undergoing genetic recombination such as sperm cells. Dr Robaire’s research has, in turn, linked these failings to defects in the body’s defence against oxidative stress, which can cause mutations in the genetic material. His studies in mice even suggest a possible preventative measure – an

Testis section of a three-month-old mouse showing seminiferous tubules at various spermatogenic stages highlighted using acrosome marker (red) lectin PNA from Arachis hypogaea (peanut), with immunofluorescent markers for vimentin in Sertoli cells (green), and ZBTB16 in spermatogonia (magenta). These markers were quantified using Imaris® to determine the mean number of positive cells per tubule for select spermatogenic stages, and compared between different mice.

instance, older or younger than 45 years – Dr Robaire hopes to conduct more nuanced analyses in both human and animal models, which will enable him

Older men are reported to have testes containing slower sperm, and a higher proportion of these are abnormal antioxidant molecule – which seems to halt the losses associated with increased oxidative stress during ageing. His current grant, supported by the Canadian Institute of Gender and Health under the Canadian Institutes of Health Research, brings together a team of researchers with complementary expertise, aiming to explore the whole spectrum of impacts male ageing has and to quantify the risks in terms of sperm quality and children’s health. While most previous studies have simply divided their participants into two groups – for

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to track declines in fertility and perhaps pinpoint a threshold above which risks are significantly increased. He aims to tease out whether the genetic effects of age result from changes in the sperm stem cells themselves, in the environment provided by the seminiferous tubule, or both. INESCAPABLE IMPACTS? Although age is a highly significant factor, male fertility is also impacted by environmental chemicals, particularly the so-called ‘endocrine disrupters’ which disturb the balance of hormones throughout the human body. Chemicals

such as pesticides, fertilisers, flame retardants and plasticisers can all leach into our environment and, even at minute quantities, have toxic effects – particularly at certain stages of development. For instance, brominated flame retardants from soft furnishings accumulate in the household dust that we are exposed to every day. Dr Robaire is working with a wide-ranging team at McGill University to understand more about the risks these chemicals pose, their mechanism of action, and to develop safer alternatives and precautionary standards and policies to protect our reproductive health. With an ageing population and increasing rates of delayed parenthood, Dr Robaire and his colleagues’ research into all aspects of male fertility will facilitate reproductive counselling and suggest changes men can make now, to promote the health of their children and decrease the impact of disease on future generations.

Behind the Bench Dr Bernard Robaire

E: bernard.robaire@mcgill.ca T: +1 514 398 3630 W: http://www.medicine.mcgill.ca/pharma/robairelab/

Research Objectives Dr Robaire’s research interests focus on male-mediated reproductive toxicology, ageing of the male reproductive system, mechanisms of androgen actions, and the structure, function, and regulation of the epididymis. Funding Canadian Institutes of Health Research (CIHR) Collaborators Dr Robaire has collaborated with a

Q&A

Why do you think men’s reproductive health has been so little investigated compared to women’s? There are probably many factors. For example, the fact that men can continue to have children, even into old age, while women lose the ability to have children after menopause has given the impression that good sperm keep on being made throughout life. The traditional concept that the reproductive burden lies with women, not men, is likely a social factor that has weighed in. The complexity of understanding the ongoing process of sperm production is also likely to have played a role. The fact that most investigators in the field of reproduction were men in the past may have played a role too, but I do not think that this is the case today.

wide range of colleagues but most notably with Dr Barbara Hales for animal studies on male-mediated reproductive toxicology and Dr Peter Chan for clinical studies. Bio Bernard Robaire received his BA from UCLA and his PhD from McGill University. After a postdoctoral fellowship at Johns Hopkins University, he returned to McGill to take up a joint appointment in the Departments of Pharmacology & Therapeutics and of Obstetrics & Gynaecology where he

How does the population of sperm in a man’s testes change as he gets older? There is a debate as to whether the number of sperm produced actually decreases with age, but there is little doubt that the quality of sperm does go down as men age. By quality I include sperm motility, their appearance and the integrity of their DNA and its packaging. Do you think sperm quality declines linearly, or declines suddenly after a certain age? All the studies to date indicate that this is a steady, slow process – there is no indication of a rapid change at a particular age.

has remained and is currently a James McGill Professor. Contact Dr Bernard Robaire, PhD, FRSC James McGill Professor Departments of Pharmacology and Therapeutics and of Obstetrics and Gynecology McGill University 3655 Promenade Sir William Osler room 104 Montréal QC Canada H3G1Y6

Is there a relationship between the different factors that affect sperm quality? For instance, does the effect of chemicals on sperm cumulate as men age? Few studies have looked at a combination of factors such as age, obesity, or exposure to chemicals that could affect sperm. However, there is no reason to think that these would not be cumulative. If you were hoping to father children, what would be the most important thing you could do now to protect their future health? Do not smoke! Keep your weight down. Have your kids at a younger age, preferably before 35.

There is little doubt that the quality of sperm (motility, appearance and DNA integrity) does go down as men age

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Health & Medicine ︱ Dr Bruce Zetter

A career in cancer Dr Bruce Zetter is the Charles Nowiszewski Professor of Cancer Biology at Harvard Medical School. He is known internationally as an expert on cancer biology, diagnosis and treatment. He currently works to find treatments for highly aggressive, metastatic cancers and also serves as an advocate for young scientists and for improved relationships between academia and industry.

r Bruce Zetter started out over forty years ago as a graduate student in microbiology, but technological advances in studying cancer cells, along with increased funding for cancer research, encouraged him to switch disciplines and turn to the study of this deadly disease. Then at the Massachusetts Institute of Technology in Cambridge, MA, the lab he was working in was just getting started in investigating cancer, so he made the switch from studying bacterial cells to cancer cells, and has been driving this research forward ever since. DECLARING WAR ON CANCER Cancer is the name for a group of diseases which involve abnormal cell growth and proliferation. Fortunately, many tumours are benign and are unable to spread to other parts of the body. However, through a process called metastasis, cancerous tumours have the

turned to finding treatments for the most aggressive, metastatic forms of cancer. DRUGS AND DELIVERY Drug resistance in cancers is another major problem that Dr Zetter and his colleagues have turned their attention to in recent years. Many frontline treatments have had their efficacy diminished by the rapid development of drug resistance, so the team is identifying biomarkers (proteins expressed on the cell surface) that can help screen patients for resistance and even be used as targeting tools to direct other drugs towards resistant cells. In searching for these effective drugs, Dr Zetter has identified that some drugs are particularly effective on the most aggressive cancers, but less so on milder versions of the disease. Several of these selective drugs have been previously approved as anti-parasitic,

Science – both academic and otherwise – remains a career that will continue to enthral, engage and financially support the coming generations of scientists potential to invade other tissues and organs. The majority of deaths from cancer are due to this process rather than the primary cancer, so it is clear that targeting this feature of tumours is important in managing cancer-related mortality. Dr Zetter’s work has focused on precisely this feature of cancers, identifying a variety of proteins which are implicated in tumour progression and metastatic potential. This has resulted in the development of tests for biomarkers that are useful in cancer diagnosis, prognosis, recurrence monitoring and in determining responsiveness to particular therapeutic agents. More recently, his work has

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suggesting some commonality between the treatment of parasites and metastatic tumour cells. Poor solubility of some compounds means not all are suitable for administration in cancer treatment though. However, Dr Zetter has worked with medicinal chemists such as Dr Lijun Sun to devise new versions which can be given to patients with very advanced cancers and few treatment options. This attitude of collaboration to bring effective products to patients is a feature of Dr Zetter’s career to date. Successful partnerships have been forged with bioengineers to develop novel delivery mechanisms for innovative cancer treatments. Nanoparticles capable of

delivering a payload of RNA molecules, which would usually be degraded by the body long before reaching the target tumour, are helping the team to treat tumours in animal models which were impossible just a few years ago. These RNA molecules are used either as gene silencers to turn off cancercausing and -promoting genes, or to replace tumour-suppressing functionality lost during the evolution of the tumour. The team’s latest work has successfully delivered the tumour-supressing gene PTEN (Phosphatase and tensin homolog, a protein which inhibits the pathway controlling many aspects of cell growth and proliferation) to an active tumour site via intravenous injection. Expressing this gene in the tumour represses tumour growth, allowing the animal to survive much longer. It has the potential to be coupled with gene silencing techniques to further improve efficacy. MENTORING THE YOUNG This work has made Dr Zetter internationally recognised as a leading expert on cancer research and drug development, but laboratory-based investigations are just a part of his role as a scientific authority in this area. Over the course of his career, Dr Zetter has found the time to write grants, patents and opinion pieces; teach and direct university courses; advise legislators and act as an expert witness in court cases; and run all the research at a large institution in the shape of Boston Children’s Hospital. Putting his knowledge and experience to good use now means that Dr Zetter is engaged in a mentoring role for young investigators. “We are in a challenging time for academic medicine. Funding is, for now, harder to come by, papers seem to be harder to get published, and respect for science among the public appears to be eroding,” as he puts it, adding that this is potentially leading to a deficit of academics to train the next generation of scientists. His approach to combatting this is to meet with young scientists, individually or in groups, to share his belief that “talk of the sky falling is exaggerated and science – both academic and otherwise – remains a career that will continue to enthral, engage and financially support

the coming generations of scientists.” After many years of experience, he sums it up simply: “I personally couldn’t envision a better career choice.” STARTING UP AND SPINNING OUT It is not just young scientists who need this kind of clear and positive thinking. Starting a new biotech company is a complex and risky endeavour, a fact which

Dr Zetter knows only too well from his early experiences with entrepreneurial colleagues and newly formed companies. A steady and experienced hand to guide them around the pitfalls is almost essential for anyone starting out. Over the years Dr Zetter has become one such influence and he now assists others to find their feet. In the process, he

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Working with collaborators Omid Farokhzad and Jinjun Shi at Brigham and Women’s Hospital in Boston, Dr Zetter has been able to restore tumour suppressor activity to tumours by delivering tumour suppressor messenger RNA by intravenous delivery into experimental animals. Unlike most therapies which seek to block a cancer-causing gene, this approach restores tumour cells to a suppressed state, more similar to normal cells. The graphic depicts the messenger RNA delivery in the context of a “message in a bottle” that is delivered to the tumour by the blood stream. Image credit: Kristin Johnson.

mRNA-nanoparticles

Tumour

Blood vessel

has become passionate about ensuring that research in academic environments eventually finds its way to patients in the form of effective treatments. This process often involves small biotech companies, so Dr Zetter educates academic investigators on how they can make their work more attractive to companies, helps them find commercial partners and works with the companies to ensure the partnership stays on track. Over the years he has counselled dozens of young entrepreneurs while also serving as an advisor to more than 40 biotech companies. He particularly likes to help young companies avoid the pitfalls that commonly occur in the first few years of their existence.

MAKING RESEARCH RELEVANT This isn’t just about making sure research is profitable: “This is all about ensuring that potential disease cures don’t languish on the lab bench top but get sent out

There remain significant challenges in developing treatments for cancer, but with the progress that has been made in recent years Dr Zetter strikes a positive note. As these new therapies and combinations of therapies come out of the lab, perhaps the biggest challenge is how to ensure they reach patients. From progression through clinical trials to ensuring that physicians have up-to-date information on which treatments are most effective for specific cancers and stages, there is a key role for good communicators and facilitators. Dr Zetter has proved to be one such breed of scientist, able to push forward groundbreaking research while simultaneously helping others to realise their full potential.

This is all about ensuring that potential disease cures don’t languish on the lab bench top but get sent out the door to a company that knows how to develop them and eventually reach patients in the clinic

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the door to a company that knows how to develop them and eventually reach patients in the clinic.” Dr Zetter finds this aspect of his role immensely satisfying, and believes that it has benefitted patients just as much as the research that has taken place in his own lab.

Behind the Bench Dr Bruce Zetter

E: Bruce.Zetter@childrens.harvard.edu T: +1 6179192331 /bruce-zetter-7a9b4a8 W: www.politico.com/agenda/story/2016/04/biden-cancer-moonshot-needs-to-fix-000109

Research Objectives Dr Zetter has dedicated his research career to finding the means by which tumours spread to distant sites, looking to uncover methods to predict this occurrence and treat the metastases once they arise.

• Michael Rogers PhD (Boston Children’s Hospital, Harvard Medical School) • Jinjun Shi PhD (Brigham and Women’s Hospital, Harvard Medical School) • Lijun Sun PhD (Harvard Medical School, Beth Israel Deaconess Medical Center)

Funding National Institutes of Health (NIH)

Bio Dr Bruce Zetter is the Charles Nowiszewski Professor of Cancer Biology at Harvard Medical School. He is known internationally as an expert on cancer biology, diagnosis and treatment. He currently works to find treatments for highly aggressive, metastatic cancers. He also serves as an advocate

Collaborators • Omid Farokhzad MD (Harvard Medical School, Brigham and Women’s Hospital) • Marsha Moses PHD (Boston Children’s Hospital, Harvard Medical School

Q&A

Why is targeting tumour metastasis so important? Quite simply, of the patients who die of cancer, 90% succumb to the consequences of their metastases, not from their primary tumour. The biggest challenge in cancer treatment is to find a way to extend the lives of patients with widespread metastases. What is your lab currently focussing on? We are very interested in trying to find treatments to late-stage metastatic cancers, particularly from the types of cancers that are hardest to treat. By the time a cancer reaches this late stage, it may be very different from the initial cancer, so we have tried to find new therapies that selectively target these highly aggressive latestage cancers. Once we find them, the next problem is to find ways to deliver these therapies preferentially to the tumour, wherever it may be. This is why we are collaborating with bioengineers such as Drs Omid Farkhzad and Jinjun Shi to devise nanoscale delivery systems that can bring our new drugs directly to the metastatic sites. We are currently working on ways to simultaneously

block cancer-promoting genes, while restoring tumour suppressor genes to the same cells at the tumour site. What is the most important aspect of developing a scientific career? I don’t think this has ever changed. The key to a successful scientific career is to focus first on your science. It sounds simple, but today’s scientists have so many competing obligations (funding, teaching, service to their institutions, family, etc.), that they sometimes need to be reminded to keep the science first and everything else will follow. The reason we all chose this career was because we love science. We should never lose sight of that. What would be your advice to someone considering starting a biotech company? A. Focus on the ultimate goal. It’s not actually the technology that is the most important thing, it’s what you want that technology to do. There may ultimately be other ways to accomplish the same goal. B. Know your strengths. If you’re a scientist, find the best business partners that you can. Too many small companies fail when the scientists try to run the business side. C. Expect the unexpected. Every small company

for young scientists and for improved academic-industry relationships. Contact Dr Bruce Zetter Boston Children’s Hospital/Harvard Medical School 300 Longwood Ave Boston, MA 02115 USA

has a major crisis early on with the technology, the funding or the people. Being flexible is the key to getting past these valleys. How do you see the future of cancer treatment developing in five to ten years? Over a long career in cancer research, I have seen countless trends, and no doubt will see many more. I’ve learned to let them play out over time before getting too excited. Yet there is clearly accelerated progress right now – greater than any time I can remember. We have moved now to combining many different kinds of cancer treatment for the same patient – sometimes all at once and sometimes one after another. With combinations of approaches, we sometimes see much stronger responses, but sometimes we see much stronger toxicity. Today, we combine these approaches in an almost random way. To me, the key to the future of cancer treatment is to find ways to predict which combinations will work on each patient. Let’s call it “rational combination therapy”. It will require some new ideas and some very serious computing power but I think it is the key to our greater success in treating challenging cancers over the next decade.

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Health & Medicine ︱ Dr Gillian Hawker

Helping patients put their best foot forward Dr Gillian Hawker of the University of Toronto is helping potential knee replacement patients to make informed decisions about their health. As an increasing number of us require joint replacement, Dr Hawker seeks to make sure that only those who are best suited will undergo surgery. By developing standardised patient assessment criteria for knee surgery, Dr Hawker is striving to make the most of precious health care resources and create better conversations between patients and consultants.

nee osteoarthritis is very common and the numbers affected are on the rise. For some people with osteoarthritis, non-surgical therapies may be insufficient to manage the pain and functional limitations caused by their knees and joint replacement surgery may be recommended. Research undertaken by Dr Gillian Hawker of the University of Toronto seeks to improve the outcomes of this increasingly common surgery. More than 1.2 million knee replacement surgeries are conducted across the world in a single year and worryingly, the rates of Joint Replacement Surgery (JRS) are on the rise. Lengthening lifespans and obesity are two of the most likely culprits of this increase, but it has also been found that patients are seeking surgery earlier in the course of their disease, raising concerns that JRS may be becoming overused. People aged between 20 and 59 have

JRS recipients are dissatisfied with the results of their surgery. Dr Hawker aims to ensure that only patients who are suitable candidates for knee replacement receive the surgery and has conducted extensive research into determining criteria to aid decision making. APPROPRIATENESS CRITERIA By liaising with patients and orthopaedic surgeons, Dr Hawker and colleagues were able to establish four criteria for deliberation when considering knee replacement. These are: despite appropriate non-surgical treatment, patient’s joint symptoms are negatively impacting quality of life; patient is ready, willing and able to undergo surgery; patient has realistic surgical expectations; and the likelihood of patient benefit from JRS is greater than the risks. The question

The importance of collaborative decision making when considering knee replacement surgery cannot be overstated seen the biggest increase in rates of knee replacement surgery. This is an unsettling trend as a second knee replacement later in life, known as revision surgery, is less likely to be successful and much more costly. Furthermore, research has shown that though largely successful, 15–30% of

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is, how best to evaluate these criteria, and can they predict at surgical consult whether or not the patient will benefit from surgery? This is the focus of her current research. Findings from this study will help patients and their physicians make informed healthcare decisions.

Candidates for this current study have been recruited from one of two large joint surgery clinics in Alberta, Canada. To be included in the study patients must have symptoms due to arthritis of the knee, be aged 30 or above and have undergone referral to a surgeon. Each patient that agreed to participate in the study was assessed using the appropriateness criteria before they saw the consulting surgeon. This information was not shared with the surgeon. After being seen by the surgeon, the latter indicated if surgery had been recommended and, if so, whether or not the patient had realistic expectations of knee replacement. The surgery then continued as arranged. In order to evaluate the effectiveness of the surgery, Dr Hawker and the team interviewed patients at six and twelve

months post-surgery. During these interviews patients were asked about their knee pain, physical function, and whether or not their expectations of knee replacement had been met. One of the major challenges of the study was defining, from patient responses, whether knee replacement had been of benefit to the patient. As different people have different expectations of surgery, as well as different levels of acceptable pain, it was necessary to prioritise some factors over others. Pain is one of the major factors which triggers people with arthritis to undergo surgery. Reduced level of pain was therefore used as the primary measure of benefit. Patients must express that their pain was “much” or “somewhat” improved, as well as being “very” or “somewhat” satisfied with the results in order to

be considered as having benefited from surgery. Alternative definitions of benefit are also being considered. While the attitudes and experiences of patients is extremely important, the decision to operate ultimately falls at the feet of the surgeon. Dr Hawker and her team intend to use the data collected in this study to finalise their appropriateness criteria and use them to develop tools to aid surgeons in their decision making. MAKING GOOD DECISIONS Though earlier work has helped develop aids to support patients in the decisions they make leading up to surgery, surgeons have not previously experienced similar attention. Consistency is important in making healthcare decisions and Dr Hawker found that, “Participants agreed that

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surgeons did not consistently discuss/ assess all of the appropriateness criteria that were identified.â&#x20AC;? Dr Hawker and colleagues have also found that health care funders and hospital administrators would like a greater level of transparency about the selection criteria that surgeons apply. Having criteria by which to reliably identify those patients most likely to benefit from surgery could be used by surgeons alongside their patients, could help them make better informed decisions and help reduce the

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Dr Hawker seeks to emphasise the importance of helping patients make their own informed healthcare decisions number of patients who experience a suboptimal surgical result. The financial implications of the increasing number of surgeries are also an important consideration. Within the study area of Alberta, Canada more than $800 million are spent each year solely on knee replacement surgeries. The importance

of collaborative decision making when considering knee replacement surgery cannot be overstated. With significant human and financial implications, it seems clear that helping patients and surgeons to make better decisions together will benefit everyone.

Behind the Bench Dr Gillian Hawker

E: gillian.hawker@wchospital.ca T: +1 416 323 7722 W: http://ihpme.utoronto.ca/faculty/gillian-hawker/

Research Objectives Dr Hawker has established a record of academic excellence in the field of osteoarthritis (OA) outcomes. A predominant theme of her research is the appropriate use of hip and knee joint replacement surgery for OA. Joint replacement surgery reduces pain and disability in people with hip and knee arthritis. Her work has a broad impact, important in understanding the roles of arthritis severity, other health conditions, patient preferences, and sex/gender and physician bias in determining rates of use of joint replacement surgery. Funding Canadian Institutes for Health Research (CIHR)

Q&A

Will the development of this tool allow patients and surgeons to contribute equally to decisions about healthcare? No, surgeons and potentially the health care system will always be able to trump a patient’s decision to have surgery when they won’t benefit from it, but patients who understand their likelihood of a good outcome with surgery will hopefully make better decisions. How important do you think is the psychological readiness of the patient for surgery, compared with the physical suitability? Both are important, but I think we have undervalued the importance of psychological readiness – in our prior work, patients talked about this a lot… And in research we clearly find that the ‘optimists’ and ‘copers’ are more likely to adhere to their post-operative rehabilitation, etc – so it matters!

Collaborators Deborah Marshall, University of Calgary; Tom Noseworthy, University of Calgary; Eric Bohm, Concordia Hip and Knee Institute, University of Manitoba; Michael Dunbar, Dalhousie University; Peter Faris, Alberta Health Services; Allyson Jones, University of Alberta; Bheeshma Ravi, University of Toronto; Linda Woodhouse, University of Alberta

articles and received a number of honours for her research, including the Canadian Rheumatology Association Distinguished Investigator Award in 2011. Contact Dr Gillian Hawker Women’s College Hospital 190 Elizabeth Street, Suite RFE 3-805 Toronto, ON M5G 2C4

Bio Dr Gillian Hawker is the Sir John and Lady Eaton Professor and chair of the Department of Medicine at the University of Toronto, where she is also a rheumatologist and clinician scientist at Women’s College Hospital, University of Toronto. Dr Hawker has published over 240 peer-reviewed

Do you find that patients are becoming more interested in understanding all their healthcare options before commencing surgery? Patients are definitely more engaged in their health care decisions period… not just for surgery. They are way more likely now than a decade ago to arrive at their doctor’s office having done their own investigation into the treatment options – our job now is to help them decipher the good evidence based information from the bad stuff – with respect to knee replacement however, people are also wanting more from the surgery than in the past – whereas previously folks wanted surgery mainly to be able to do their basic activities of daily living, now folks are wanting ALSO to be able to exercise, travel, do sports – much more vigorous high impact activities that knee surgery wasn’t designed for. As lifespans lengthen, are higher rates of revision surgery sadly inevitable, regardless of primary surgery success or failure? Yes and no… if we reduce need for the

first surgery, that will help a lot – knee osteoarthritis is very much impacted by our weight – reducing body weight and maintaining a healthy weight along with keeping physically active would go a long way to reducing the number of people who require a first joint replacement. With respect to the second or revision surgery, again, guidance for people who receive a first knee replacement about what will enable the prosthesis to last longer or need revision sooner can be helpful. You were honoured by The Arthritis Society of Canada with a Queen’s Jubilee Medal in 2013 for your continued contributions to osteoarthritis research. What has been the highlight of your career? I am fortunate to have had many highlights – the many successes of my trainees over the years for sure is amazing… especially those who are now going on to establish their own careers focused on improving the lives of people with osteoarthritis.

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Health & Medicine ︱ Dr Jeffrey Savas

Let’s hear it for the proteome Hearing loss is one of the most common sensory impairments, affecting 250 million people worldwide. The causes of deafness, such as exposure to loud noise, are relatively well known, but exactly how they result in hearing loss remains unclear. Dr Jeffrey Savas, Assistant Professor of Neurology at Northwestern University, Feinberg School of Medicine, USA, heads up a lab dedicated to understanding neurological conditions, including deafness, at the molecular and genetic level. His current project focuses on the effects of loud noise upon protein molecules and synapses in the inner ear.

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n a world dominated by verbal communication, deafness or even partial hearing loss can be debilitating. Hearing impairment is one of the most common sensory disabilities, affecting one in five adults in the US: four times as many people as MS, spinal cord injury, stroke, epilepsy, Parkinson’s and Huntington’s diseases combined. TURN DOWN THE VOLUME The most common cause of hearing loss is exposure to excessively loud noise, a situation faced by millions of people daily in the course of their work. A key target, then, for deafness research is to determine exactly how noise causes hearing damage at the cellular and molecular level, and therefore how its effects can be minimised, treated, or even prevented.

The work of Dr Savas’s lab focuses on the role of the ‘proteome,’ the total complement of protein types found in any given cell or tissue, in a range of neurodevelopmental and neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s, as well as hearing impairment. By identifying differences between the protein complement of healthy and diseased tissues, he aims to pinpoint potential protein targets that contribute to these conditions. Dr Savas describes this work as, “Searching for hidden proteomes that can guide us into previously underappreciated and largely uncharted areas of neuroscience.” CRITICAL MASS Dr Savas’s investigations centre on an analytical technique, mass spectrometry-based proteomics, which is becoming increasingly prevalent in bioscience research. The method can identify and quantify the individual molecules present in complex mixtures based on minute differences in their mass, and can simultaneously analyse thousands of molecules in just a few hours. Dr Savas calls this first step “generating a protein parts list”. Using mass spectrometry, he can identify the proteins present in a healthy inner ear, and then go on to study what happens to those proteins when hearing is impaired by exposure to high levels of noise. His team’s research involves subjecting mice (which, being mammals, have inner ears analogous in basic structure to humans) to varying levels of noise, and then extracting their main hearing organ – a spiral, snail-shaped structure called the cochlea – to undergo mass spectrometry. This will determine

Above: Fluorescent image of immunostained mouse cochlea after noise exposure (Myo7a = red, CtBP2=green, GluR2=blue). Image credit: Miguel Ramirez.

Above: Fluorescent image of mouse cochlea expressing GFP in hair cells. Image credit: Ann C. Y. Wong.

A key advancement for deafness research is to determine exactly how noise causes hearing damage at the proteomic level which proteins in the cochlea change in concentration or structure after being subjected to damaging noise causing temporary or permanent hearing loss. It is clear from the research so far that loud noise causes substantial changes to a surprisingly large number of cochlear proteins. Furthermore, of the thousands of proteins measured in the mouse cochlea, Dr Savas’s team identified a small number which changed significantly in abundance depending on the level of noise exposure. Interestingly, many more of these were found to increase in response to noise rather than decrease, and many of them were associated with structures known as proteasomes, collections of enzymes involved in breaking down proteins. This indicates that loud noise stimulates pathways within the cochlea which cause protein degradation. Key signalling proteins were also enhanced, some of them as noise progressed from temporarily- to permanently-damaging levels. All of these proteins provide potential targets for further investigation.

SPLITTING HAIRS However, to decipher the causes of noise-induced hearing loss in detail, Dr Savas needs to know where the important proteins are localised within the cochlea, a complex organ comprising several different types of cells. He has now made progress towards isolating and purifying these cell types, in particular the tiny inner ear hair cells that actually perceive sound when it enters the cochlea, so that mass spectrometry can, for the first time ever, determine protein composition. Although hundreds of proteins were more abundant in hair cells than in the rest of the ear, including some found only in the hair cells and nowhere else, many of these are at very low absolute concentrations, making them very difficult to isolate and characterise. Dr Savas’s lab are exploring different methods and designing a targeted mass spectrometry analysis protocol to accurately quantify such small numbers of molecules, many of which may be critical to both hearing and balance. Already, they have found a set of thirty,

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previously-undetected proteins linked to deafness and significantly enriched within cochlea hair cells – suggesting potential targets for genetic studies into deafness. The lab’s current research focuses on determining how their newly-identified cochlear proteins are affected by moderate noise resulting in temporary hearing loss, a process which appears

them. Dr Savas now aims to explore the functions of Nrxn and Nlgn and how they may contribute to stabilising cochlear synapses to hopefully prevent hearing loss. This is ground-breaking research and the inner ear proteome generated in the Savas lab – although the most comprehensive ever developed –

An understanding of the inner ear proteome will accelerate our understanding of how the ear works in healthy and pathological conditions to be critically linked to changes occurring at the junctions, known as ‘synapses’, between hair cells and nerves. Two proteins in particular – Nrxn and Nlgn – have been identified as playing key roles in maintaining these synapses and regulating signals across

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remains incomplete. In a project funded by the US National Institutes of Health (NIH), Dr Savas will continue to explore the role of the proteins responsive to noise in the mouse ear, and to measure those found at very low abundances, ultimately generating a ‘protein

Above: Fluorescent image of mouse cochlea hair cells. Image credit: Chelsee Strojny.

expression atlas’ of the mammalian ear. Proteins do not, he says “function in isolation … we aim to identify groups of co-regulated proteins to accelerate our understanding of noise-induced hearing loss”. Certain drugs are already known to protect against noise-induced hearing loss, and Dr Savas hopes to be able to compare the proteome of mouse ears treated or untreated with these drugs, to explore their mechanism of action. Working with clinical or industrial partners, this could lead to therapeutic strategies to protect inner ear hair cells and synapses. Dr Savas believes his first draft of the inner ear proteome is set to accelerate the whole field of research into hearing loss and, he says, “kick start the development of effective therapeutics to eventually treat and prevent noise-induced hearing loss”.

Behind the Bench Dr Jeffrey Savas

E: jeffrey.savas@northwestern.edu T: +1 312 503 3089 W: http://www.savaslab.com W: http://www.feinberg.northwestern.edu/research/news/people/faculty/j-Savas.html

Research Objectives Dr Savas’ work focuses on noiseinduced hearing loss and the effect that noise has on cochlear synaptic proteins. He is particularly interested in translating his results into treatment or prevention methods. Funding National Institutes of Health (NIH) Collaborators • Lab members: • Post-Doctoral Fellow: Nopporn Jongkamonwiwat, PhD • PhD student: Miguel Ramirez

Q&A

Could you briefly describe the structure of the inner ear and the importance of its different components in your work? Sound enters the outer ear, is transmitted through the middle ear, and is converted to fluid pressure waves at the cochlear oval window. In the cochlea, pressure variations are distributed by frequency along the length of the basilar membrane. Vibration of this membrane stimulates the hair cells through shearing forces in their stereocilia that trigger neural signals that are transmitted to the auditory neurons across specialised synapses at their base. While hair cells, and spiral ganglion neurons are certainly central cellular players in the process of hearing, the cochlea contains many other cells that provide physical and chemical support. Has hearing loss received enough study over the years compared to other neurological conditions? No. For example, the 2017 NIH Budget

• Collaborators: • Allen F. Ryan, PhD, UC San Diego School of Medicine, La Jolla, CA 92093 • Joris de Wit, PhD, VIB and KU Leuven, Leuven, Belgium Bio Jeffrey Savas received a Bachelor of Science in Biochemistry and Molecular Biology at the University of California, Santa Cruz and his PhD from New York University School of Medicine. He completed his postdoctoral training at The Scripps Research Institute in La Jolla. The Savas Lab opened at

Northwestern University in February of 2015. Contact Jeffrey N Savas, PhD Northwestern University Ward Building Room 12-102 303 E Chicago Avenue Chicago IL 60611 USA

of the National Institute of Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) were both more than three times that of the National Institute on Deafness and Other Communication Disorders (NIDCD). One of the major reasons for this difference in the level of funding is that deafness, while significantly lowering the quality of life, does not kill.

those driven by gene mutations like cancer or autism, studying changes at the level of changes in the DNA sequence is essential. However, in the case of noise-induced hearing loss, caused by acute synaptic excitotoxicity, stress, and physical damage, studying changes in the actual cellular machinery is a much more relevant measure.

You use mice as models for humans in your work. How can you tell what a mouse is hearing? Good question. We use an approach called Auditory brainstem response (ABR). In ABR audiometry, we place a tiny microphone into the mouse’s ear, provide stimulating sounds at increasing intensities, and simultaneously measure the neuronal responses emanating from the cochlea all the way to the brain with a recording electrode.

How could the results of your research be translated into actual treatments for, or protection against, hearing loss? Recent data show that those synaptic contacts formed between inner ear hair cells and auditory nerve fibres are the most noise sensitive elements in the cochlea. Prolonged exposure to moderate levels of noise causes a dissociation of the pre- and post-synaptic membranes. We have identified those proteins that physically bridge these synapses and are actively working to identify molecules that can stabilise these interactions and prevent noise-induced synapse loss.

Why did you choose to study the proteome rather than the genome? What can the proteome tell us that the genome cannot? In some biomedical contexts such as

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Health & Medicine ︱ Dr Brunhilde Wirth

Unravelling the cellular mechanism of spinal muscular atrophy: from gene and modifiers to therapy Spinal muscular atrophy (SMA) is a common neuromuscular disease characterised by weakness and wasting of muscles. People with the most severe form of the disease are unable to sit or walk and die within the first two years of life. Although the genetics of SMA are well understood, the cellular mechanisms involved are unclear and there is currently no cure. Professor Dr Brunhilde Wirth at the University of Cologne is using advanced genetics to discover SMA protective modifiers and various animal models to unravel the cellular mechanisms responsible for SMA and networks of protection, with the ultimate goal of developing novel therapeutics.

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here are currently ~50,000 people living with SMA in Europe and the USA and, in the European population, one in every 35 people is a carrier of the disease. SMA is characterised by the progressive loss of motor neurons – specialised nerve cells that innervate muscle and stimulate contraction – and impaired neuromuscular junctions – the synapses between motor neurons and muscle cells. In patients with SMA, the muscles are under stimulated and so they weaken and waste away in a process called atrophy. SURVIVAL MOTOR NEURON People with SMA have a deficit of a vital protein called “survival motor neuron” (SMN). SMN is produced by all body cells and is important for their survival. However, motor neurons require fifty times more SMN than any other cell type. Most individuals with SMA have inherited two absent copies of the SMN1 gene (the gene responsible for SMN production) from their parents.

Neuromuscular junction of a SMA mouse at postnatal day ten

Humans have an almost identical second copy of the SMN gene, called SMN2. This gene also produces SMN protein but, due to a problem with the splicing process, only 10% of the protein is functional. In SMA-affected individuals, SMN2 is the only source of SMN, so its copy number (humans can have between one and six copies) affects the severity of disease. For example, patients with two absent SMN1 genes and only two copies of SMN2 will usually have the most severe form of SMA (type I). These babies will develop symptoms before six months of age, will never be able to sit or walk, will be dependent on respiratory and nutritional support, and have a life expectancy of usually less than two years. People with two absent SMN1 genes but three copies of SMN2 usually have an intermediate SMA and learn to sit but never to walk. Those with two absent SMN1 genes and four to six copies of SMN2 usually have a mild

Dr Wirth’s research highlights the power of protective modifiers to unveil the cellular mechanisms and develop novel therapies for SMA form of the disease (type III or IV). Onset of symptoms is not until later in childhood or adulthood and patients are able to sit and walk despite some muscle weakness. PHYNOTYPICALLY DISCORDANT FAMILIES TEACH US A LOT In rare families, relatives of SMAaffected individuals may have no SMA symptoms despite carrying two absent SMN1 genes together with three or four SMN2 copies, a combination that would usually cause SMA. This suggests there are other factors involved in determining the severity of SMA.

By using advanced technologies to study the genes and proteins of family members in these SMA-discordant families, Professor Wirth has identified two proteins that act as SMA protective modifiers: Plastin 3 (PLS3) and Neurocalcin Delta (NCALD). Family members with two absent SMN1 genes who are unaffected by SMA produce much more PLS3 than their affected relatives. Conversely, unaffected family members with two absent SMN1 genes produce much less NCALD than their affected counterparts. Both high PLS3 and low NCALD levels have been shown to

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Cell body Nucleus

Above: Neuromuscular junction at postnatal day 21

protect against disease symptoms. For example, in one SMA-discordant family, in which two absent SMN1 genes and only four copies of SMN2 usually resulted in type III disease, low NCALD levels protected five family members across four generations. The protective effects of high PLS3 and low NCALD have been corroborated by Prof Wirth’s group using animal models of SMA, including mice, worms and zebrafish. Here, high levels of PLS3 or low levels of NCALD were shown to reduce disease symptoms. Using these same animal models, the group also showed that both PLS3 and NCALD protect against SMA by restoring endocytosis – a process that is essential for recycling the synaptic vesicles involved in transmission of nerve impulses across the neuromuscular junctions, which is impaired in SMA. FROM GENE TO THERAPY Having identified PLS3 and NCALD as protective modifiers, Prof Wirth’s group began to explore whether regulating production of these proteins could be used as a therapeutic strategy to treat SMA. The group used mouse models with either high PLS3 or low NCALD in combination with a low dose of SMN antisense oligonucleotides (ASOs), small molecules that increase SMN levels by targeting its production by the SMN2 gene. Both approaches dramatically reduced SMA symptoms. Strikingly, small amounts of SMN-ASOs in combination with low PLS3 increased animal survival from 14 days to over 250 days. This situation is comparable to severely affected type I SMA patients, where ASO therapy increases SMN production but not enough to cure the

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Dendrite

Nerve ending

Myelin

Axon

Motor neurons are the most polarised cells in our body with axons longer than one metre

People with the severe form of SMA need a combinatorial therapy and a systemic increase of SMN in every single cell disease. In this instance, a combined therapy with a second agent, such as PLS3 or NCALD, could constitute a long term therapeutic option. The first SMN ASO-based therapy (Spinraza) was recently FDA- and EMAapproved. Since the Wirth group have shown that a low dose of SMN-ASOs in combination with high PLS3 or low NCALD protects against even the most severe type of SMA in mice, regulation of these proteins could be used in combinatorial therapies with Spinraza to increase treatment efficacy. Prof Wirth’s research highlights the power of protective modifiers to unveil

the cellular mechanisms and develop novel therapies for SMA. The group are developing and using a number of different methods and technologies to identify the genetic cause of unsolved motor neuron disorders and to understand the genetic, biochemical, cellular and pathological basis of these disorders. They are also generating and using mouse models, zebrafish and, most recently, Drosophila (fruit fly) models as well as induced pluripotent stem cells to unveil the disease pathomechanism. Prof Wirth is now extending her research to search for the molecular cause of osteoporosis.

Behind the Bench Dr Brunhilde Wirth

E: brunhilde.wirth@uk-koeln.de T: +49 221 478 86464 W: http://humangenetik.uk-koeln.de

Research Objectives Professor Wirth’s research focuses on the genetic and molecular roots of neuromuscular disorders. Her team have a particular interest in translating their results into improved therapeutic methods. Funding DFG, EU, SMA-Europe, CMMC Collaborators • Prof Matthias Hammerschmidt (Biocenter, Cologne) • Dr Natalia Kononenko (CECAD, Cologne) • Dr Jay Gopalakrishnan (CMMC, Cologne)

Q&A

Does SMN deficit affect cells other than motor neurons? SMN has a housekeeping function in snRNP biogenesis and splicing. Therefore, when SMN falls below a certain threshold, every single cell is affected. Engineered SMA mice with two absent mouse SMN genes and two human SMN2 genes develop a severe SMA, similar to people with type I SMA. In addition, these mice show impairment of almost every single organ that has been analysed so far. It is therefore very likely that people with type I SMA and only two SMN2 copies also require more SMN in every single cell and not only in motor neurons to maintain their function lifelong. Why is only 10% of SMN produced by the SMN2 gene functional? SMN2 is an evolutionary recentlyoccurred duplication of SMN1 and human-specific. The two SMN genes differ by only five nucleotides. Each SMN gene has eight important DNA pieces (exons) and seven less

• Prof Thomas Gillingwater (Univ. Edinburgh) • Dr Frank Bennett (IONIS Pharmaceutical, Carlsbad) • Prof Anja Niehoff (German Sport University, Cologne) • Prof Anne Hart (Brown University, Rhode Island) Bio Professor Dr B. Wirth received her Diploma in Biology and certificate in Applied Genetics from University Bucharest, and her PhD from University Bonn. After a postdoc at the Imperial Cancer Research Fund Laboratories in London, she became a group leader at the Institute of Human Genetics important DNA pieces (introns). From DNA to protein an intermediate product (RNA) is generated, in which the introns are removed (spliced). In SMN2 this splicing process is impaired due to one different nucleotide in exon 7. When exon 7 is lacking, the SMN protein is unstable and rapidly degraded. Instead 10% of SMN2 RNA carrying exon 7 produces a SMN protein identical with the one produced by the SMN1 gene. Do people with mild SMA (types III and IV) live relatively normal lives? People with type III and IV have no reduced life expectancy, but muscle weakness. It is very likely that, if presymptomatically-treated with Spinraza or any other drug able to increase SMN levels, these people will be cured. Therefore, SMA needs to be included in neonatal screening in Europe. Current presymptomatic clinical studies with Spinraza show the highest impact. In cases of people with type I SMA, an increase of SMN amount will most likely turn them into a type II or III. For these populations, we will need a combinatorial treatment using the knowledge of our independent protective modifiers.

in Bonn. In 2006 she received the Venia legendi in Human Genetics and became certified in Human Genetics. In 2003 she was appointed as full professor and chair of the newly founded Institute of Human Genetics, University of Cologne. Contact Professor Dr Brunhilde Wirth Chair Institute of Human Genetics University of Cologne Kerpener Str. 34 50931 Cologne Germany

How are SMA-discordant families identified? In the past, when we tried to identify the SMA-causing gene, we collected all family members for linkage (segregation) analysis. Shortly after Dr Melki identified the SMN1 gene in 1995, we analysed these unusual families, in whom affected and unaffected carried identical markers on chromosome 5 where the SMN1 was found. To our surprise, the unaffected showed the same absence of both SMN1 genes and identical copies of SMN2 as the affected siblings. At first, we even doubted whether SMN1 was the SMA-causative gene, but then more and more small mutations in SMN1 were identified strengthening the role of SMN1 in SMA. How can production of PLS3 and NCALD be regulated in patients? Unfortunately, we neither understand why in some individuals PLS3 is upregulated nor why NCALD is downregulated. We have some interesting hypotheses and are working on them to unravel the underlying genetic mechanisms, but it will need a lot of sophisticated work.

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Health & Medicine ︱ Dr C. James Lim

A shining light in the fight against childhood leukaemia? Dr C. James Lim, PhD, is an Associate Professor at the Department of Pediatrics, University of British Columbia, as well as Investigator at the Michael Cuccione Childhood Cancer Research Program at British Columbia Children’s Hospital, Vancouver, Canada. His research group aims to unravel the mechanisms underlying acquired resistance to chemotherapy in childhood malignancies, with the goal of identifying new treatment strategies to improve the odds for children fighting this disease.

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eukocytes (or white blood cells) represent the body’s first line of defence against infection, and an effective immune response depends largely on the timely mobilisation of sufficient leukocytes to inflamed tissues.

Leukocyte targeting to infection sites is orchestrated by a group of cell adhesion receptor proteins that are present on leukocyte surfaces. The α4-integrins represent one group of cell adhesion receptors that are highly expressed by leukocytes, and the role of integrins in leukocyte adhesion, migration and resistance to chemotherapy has been the focus of Dr Lim’s research. Leukocyte targeting is fine-tuned via an intricate balance in the interactions between these cells and the environment

from which they originate, namely the bone marrow stroma. The stroma generates signalling cues and growth factors for blood cell formation (a process called haematopoiesis) in all types of blood cells, e.g., red blood cells and platelets, in the bone marrow. ALL OUT OF CONTROL Failures in the processes that regulate leukocyte targeting can lead to leukaemia and other immune diseases. Leukaemia refers to a group of blood cancers that often begin in the bone marrow, and are characterised by very high numbers of lymphoblasts, essentially abnormal and underdeveloped white blood cells. Dr Lim’s research group focuses on the most common type of childhood cancer,

Dr Lim preparing samples to image on the microscope

acute lymphoblastic leukaemia (ALL). Dr Lim points out that although treatment outcomes are very good for childhood leukaemia – with a success rate of about 85% – there is concern for the remaining 15% of cases that relapse with drug-resistant forms. Treatmentresistant relapsed leukaemia remains the leading cause for childhood disease-related mortality.

The group made a breakthrough in 2013, when they illustrated that the α4-integrins play a critical role in chemoresistance in ALL. Their findings corroborated with

role for α4-integrins in CAM-DR in ALL. In a series of elegant experiments, the group then showed that expression of a conserved region (known as a peptide motif) common to all α-integrins was sufficient to promote CAM-DR in ALL cells, and this process involves the coordinate influx of calcium into and the efflux of doxorubicin out of the cells. In essence, a process initiated by cell adhesion via α-integrins enhances the removal of doxorubicin from the cells via molecular pumps, effectively reducing the drug’s dosage within the tumour cell and its efficacy.

In 2013, the group was the first to illustrate that the α4-integrins play a critical role in chemoresistance in ALL

INTEGRINS IN CHEMORESISTANCE A small number of cancerous cells that don’t succumb to initial chemotherapeutic intervention may persist as minimal residual disease. These incalcitrant cells represent the most likely starting point for relapsed cancers, which tend to be multidrug-resistant in a manner not limited to the agents used in initial chemotherapy. Dr Lim’s group examines differences in cellular signalling between healthy and tumour cells in order to find clues about how chemoresistance gains a foothold, and how exactly the α4-integrins are involved in that process.

studies from other research groups showing that interactions between integrins and associated proteins were implicated in enhancing tumour cell prosurvival signalling and chemoresistance, in a process known as cell adhesionmediated drug resistance (CAM‑DR). Dr Lim’s group first compared the response to chemotherapy in ALL lymphoblasts that either express α4integrins, or are engineered not to. When exposed to the widely used chemotherapeutic, doxorubicin, leukaemic cells expressing α4-integrins and adherent to the integrin substrate were more resistant to elimination by doxorubicin compared to those without α4-integrins, thereby supporting a direct

The discovery by Dr Lim’s group that CAM-DR is not limited to a particular integrin or type of leukaemia provides hope that future attempts to target CAMDR with new therapeutic agents will not only improve treatment outcomes for leukaemia, but a broad spectrum of blood cancers. ENLISTING THE IMMUNE SYSTEM The chemotherapeutic toolbox is rather

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versatile today, and Dr Lim reminds us that “not all anti-cancer drugs are created equal.” Here, he is referring to the fact that certain drugs, including doxorubicin, don’t just kill tumour cells, but also stimulate the immune system to recognise and eliminate cancer cells in a sophisticated process known as immunogenic cell death (ICD). A key feature of ICD is the presentation of a protein called calreticulin on the surface of cells treated with drugs that stimulate ICD. This cell surface calreticulin then serves as an ‘eat me’ signal for macrophages, a type of specialised white blood cell, to engulf and destroy cancer cells in a process known as phagocytosis. SOLVING THE ‘EAT ME’ MYSTERY Researchers investigating ICD were fascinated by how calreticulin, which is normally restricted to one particular compartment inside the cell (the ER or endoplasmic reticulum), reaches the cell surface during ICD. Dr Lim’s research group shed some light on this mystery when they discovered that calreticulin, released from the ER during periods of drug-induced ER stress, moves through the cytosolic compartment prior to its appearance on the cell surface. While in the cytosol, calreticulin can interact with the cytosolic part of α-integrins, and this interaction only occurs when integrins are activated, either by cell adhesion or upon stimulation with integrin agonists. This means that when integrins are activated, they bind calreticulin, thus trapping it inside the cell, and the ‘eat me’ signal (cell surface calreticulin) is reduced. This finding, reported in a 2016 publication, is the first to demonstrate a direct role for integrins and cell adhesion in diminishing the likelihood of ICD, and have implications in our understanding of effective immunotherapy. TARGETING THE TUMOUR MICROENVIRONMENT Once leukaemia has developed, its continuous growth and ability to metastasise (or spread) depends on interactions between the leukaemic cells and their surrounding cellular environment, often called the tumour microenvironment (TME). Within the TME, the bone marrow stroma represents a niche for leukaemic cells to interact with microenvironmental factors (e.g., cell

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Colours: green - leukaemia cells (lymphoblasts); red - F4/80 labeled macrophages; blue - nucleus Image shows leukaemia cells (green) phagocytosed/engulfed by macrophages (red). The leukaemia cells were previously treated with a chemotherapeutic to induce immunogenic cell death. Photo credit: Dr C-C Liu, UBC

adhesion factors such as integrins, which promote their survival and contribute to drug resistance). The findings from Dr Lim’s group to date support the notion of the TME being a safe haven for cancer cells, and highlight the TME as a promising target for the therapeutic intervention of leukaemia. UNANSWERED QUESTIONS Based on Dr Lim’s findings to date, it is conceivable that blocking integrin

activity of immune cells to seek and detect foreign invaders such as bacterial pathogens. Given the obvious importance of immuno-surveillance, novel strategies that can selectively target α4-integrin signalling in the context of CAM-DR are preferable over complete α4-integrin inhibition. The exact source of the protective signals that allow tumour cells to acquire chemoresistance is not yet known, but it is likely that the bone marrow stroma

Some chemotherapeutic drugs, including doxorubicin, don’t just kill tumour cells, they also stimulate the immune system to eliminate cancer cells in a sophisticated process known as immunogenic cell death function might increase the ‘eat me’ signal to potentiate the effect of chemotherapeutic drugs that induce ICD. Targeting α4-integrin function with neutralising antibodies can be an effective therapeutic strategy. However, as Dr Lim points out, complete abrogation of α4 function can lead to potentially fatal outcomes. This is due to the suppression of immuno-surveillance, the coordinated

harbours these protective stimuli in the form of adhesion substrates and other immune mediators that promote integrin activation. Future work in Dr Lim’s group aims to shed more light on the identity of these stimuli. This research could provide further insight into the potential of integrin signalling as a novel therapeutic target for the treatment of childhood leukaemia and other malignancies.

Behind the Bench Dr C. James Lim

E: cjlim@mail.ubc.ca T: +1 604 875 2000 x 4795 W: http://bcchr.ca/our-research/researchers/results/details/chinten-james-lim

Research Objectives Dr Lim’s work focuses on understanding the effect of integrins, a group of cell adhesion receptor proteins, on the development of chemoresistance in acute lymphoblastic leukaemia, the most common form of childhood cancer. Funding • Canadian Institutes of Health Research (CIHR) • Natural Sciences and Engineering Research Council of Canada (NSERC) • Michael Cuccione Foundation

Bio Dr Lim is an Associate Professor with the Dept of Pediatrics, University of British Columbia. His lab is located at the BC Children’s Hospital Research Institute, where he studies the tumour– immune microenvironment and how their interactions influence treatment efficacy. The major focus is evaluating how cell adhesion via integrins and integrin associated proteins provides cell survival cues that diminishes the effectiveness of certain chemotherapeutics.

Are integrin mutations known to be a feature of ALL or other blood cancers? In general, mutated integrins is not a feature associated with malignancies. The roles associated with integrin function in tumour cells are not unlike their roles in normal cells. However, increased expression of certain integrins will likely impact upon treatment response and metastasis. In leukaemias and other blood cancers, increased expression of α4-integrins is a feature of minimal residual disease and a prognostic indicator of poor treatment outcomes. How far away do you think we are from seeing new anti-cancer drugs targeting the integrins? Due to the fact that integrins are cell surface receptors and therefore readily targetable, a number of integrin therapeutics are in various stages of clinical trials, with some already in clinical use. The majority of these biologics take the form of inhibitory or neutralising antibodies, facilitating the specific targeting of any one of the many forms of integrins expressed in various cells and

Key Publications Liu et al (2016) α-Integrin Expression and Function Modulates Presentation of Cell Surface Calreticulin. Cell Death Dis. 7:e2268. PMID:27310876 Liu et al (2013) The Membrane Proximal KxGFFKR Motif of α-Integrin Mediates Chemoresistance. Mol. Cell. Biol. 33:433445. PMID:24001772

Collaborators • BC Children’s Hospital Biobank (https:// bcchr.ca/biobank/home)

Q&A

Contact C James Lim, PhD Associate Professor, UBC Dept of Pediatrics, 3092-950 West 28th Ave Vancouver, BC V5Z 4H4 Canada

tissues. For leukaemias and other blood malignancies, pre-clinical studies show that neutralising the adhesive function of α4-integrins can enhance the susceptibility of tumour cells to chemotherapy, while also mobilising those cells that are ‘hiding’ within the bone marrow stroma and other tumour microenvironmental niches. How likely are we to see resistance to integrin-targeting chemotherapies? I believe the goal for therapeutically targeting integrins in leukaemia is to mobilise the cells from the tumourmicroenvironment to achieve effective chemotherapy, thus minimising the occurrence of the residual tumour cells. It is the residual tumour cells that become chemoresistant upon relapse, so the clinical aim will be to minimise minimal residual disease. Resistance to the integrin therapeutic in itself is unlikely. However, the expression of specific integrins within the tumour cells may shift to ones not being targeted, facilitating CAM-DR from another integrin instead. What would be your biggest concern about treating cancer via integrin targeting? The majority of biologics targeting integrins

prevent the adhesion of the cells to target tissues. It is important, in the context of chemotherapy, that integrin antagonists not only prevent cell adhesion, but also prevent the integrins from becoming activated. As implied from our studies on the effect of integrins on ICD (presented as surface calreticulin), certain antibodies may neutralise the cellular adhesive function while activating the integrins (with nothing to adhere to but the antibodies). In this context, we may undermine the immune-stimulating effects of drugs that induce ICD. Do you expect that integrin-targeting therapies will work for everyone, or are we likely to see groups of patients that won’t respond? It is unlikely to be a ‘one size fits all’ form of therapeutic as the various makeup of the integrins within the types of malignancies may dictate response. In addition, on-going monitoring of the tumour cell biology will be required to determine whether shifts in the types of integrins expressed are seen.

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Health & Medicine ď¸ą Dr Mari Golub

Fluoxetine (Prozac) use in children: working towards a customised approach

Dr Mari Golub from the Environmental Toxicology Department at the University of California at Davis, has recently completed a five-year research project looking at the behavioural effects of fluoxetine (Prozac) on brain development. Her findings, which have so far been published in eight academic papers, supplement information on the safety of fluoxetine use in children, and show for the first time that an individualâ&#x20AC;&#x2122;s genetic make-up can influence their reactiveness to the drug.

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luoxetine therapy has been used to treat children with Major Depressive Disorder (MDD) and Obsessive Compulsive Disorder (OCD) for over 14 years in the USA, and its use has recently been expanded to other behaviour disorders, including Attention Deficit Hyperactivity Disorder (ADHD), anxiety and autism. The drug, which has been used in adults since 1987, was approved

for use in children by the US Food & Drug Administration (FDA) in 2003, following a 19-week clinical trial in children. Apart from the findings of this trial, and those from a later toxicology study in rats, experiments evaluating the safety of fluoxetine use in children are limited. Dr Golub’s work has focused on the potential adverse effects of fluoxetine on brain development, using the juvenile rhesus

More startling, and entirely new, was the observation that behavioural responses to fluoxetine were influenced by variations in the monkeys’ genes

monkey as a model. Monkeys were given a dose of fluoxetine each day for two years before the onset of puberty. The dose used was selected because it produced comparable levels of fluoxetine and its metabolites in the monkeys’ blood serum as found in the blood serum of children successfully treated with the recommended dose of 20 mg per day. The monkeys were assessed for growth, impulsivity, activity, sleep, social interaction, attention and emotional response, after one and two years of dosing. RESPONSES: BEHAVIOURAL AND BIOLOGICAL The results showed that monkeys treated with fluoxetine had poor sustained attention, were more impulsive, had more disrupted sleep and displayed more social interaction compared to vehicle-treated controls (counterparts who received a sham preparation with no active ingredient). These results confirmed some previously described effects of fluoxetine in adults and children. More startling, and entirely new, was the observation that behavioural responses to fluoxetine were influenced by variations in the monkeys’ genes, and the identification of several metabolic biomarkers of response to fluoxetine. DRUG-GENE INTERACTIONS Fluoxetine belongs to a group of drugs known as selective serotonin uptake inhibitors (SSRIs). SSRIs are believed to work by blocking reabsorption of the neurotransmitter serotonin into the presynaptic cell, thus increasing the level of extracellular serotonin available to bind to the post-synaptic receptor. Regulating the level of extracellular serotonin helps neurons to transmit messages, resulting in a more stable mood. Under normal circumstances, serotonin levels are intrinsically regulated. Monoamine oxidase A (MAOA) is a protein that catalyses the degradation of amines, such as serotonin. The amount of MAOA produced by an individual can vary depending on their genetic make-up.

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When shown pictures with different affective content, the monkeys with low-MAOA genotypes had fewer emotional responses when they were treated with fluoxetine. Reprinted from Golub MS et al. Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions. Eur Neuropsychopharmacol. 2016 Dec;26(12):1920-1929.

In Dr Golub’s study, the monkeys’ genetic make-up was characterised to establish for each individual whether they had versions of the gene that produced higher or lower levels of MAOA. Using this information, Dr Golub has shown, for the first time, that genetic variation between individual monkeys can influence their responsiveness to fluoxetine. This was most significant when looking at emotional responsiveness. Monkeys treated with fluoxetine who produced low levels of MAOA were less emotionally reactive than their vehicletreated counterparts. Genes also affected aspects of other behaviours. For example, social invitations and initiations were greater in treated monkeys with the high MAOA version of the gene, whilst grooming was enhanced in treated pairs with the low MAOA version. CORRELATING BIOMARKERS WITH BEHAVIOURS The outcome of fluoxetine treatment can be uncertain for patients. In a recent clinical trial, around 57% of children with MDD or OCD were found to respond to fluoxetine (compared to 33% who were treated with a placebo). Prolonged dosing is often the only way to determine

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The biomarkers were correlated with impulsivity – a behavioural test affected by fluoxetine after one year of treatment whether the treatment will work. Clearly, it would be more advantageous if clinicians could predict how their patients might respond to fluoxetine before recommending it as a course of treatment, and the results of Dr Golub’s study could be a first step towards the development of such precision medicine. Precision medicine seeks to use biomarkers to optimise the use of drugs such as fluoxetine in individual patients. With this in mind, Dr Golub looked for metabolites that appeared in the blood serum, cerebrospinal fluid and fibroblasts (skin cells) of monkeys after one year of treatment with fluoxetine. To understand whether these biomarkers of fluoxetine response predicted behavioural effects, the biomarkers were correlated with impulsivity – a behavioural test affected by fluoxetine after one year of treatment. The MAOA genotype of the subjects was also included in the analysis to define

individual response. Several metabolic pathways that were influenced by fluoxetine treatment were identified through the course of the study, including some which were also influenced by MAOA genotype and associated with the impulsivity measure. Continued research in this area could yield potentially useful biomarkers for predicting response to fluoxetine in young patients. At its completion, this five-year study has advanced our understanding of the effects of fluoxetine treatment on juvenile brain development, helping to maintain safe and effective use of this therapy, and provided a glimpse of future treatment options that may be available to children with mood and behavioural disorders.

Behind the Bench Dr Mari S. Golub

E: msgolub@ucdavis.edu T: +1 916 205 9892 W: http://www.cnprc.ucdavis.edu/mari-golub/ W: http://etox.ucdavis.edu/directory/adjunct-professors/golub-mari/ Research Objectives Dr Golub’s research has focused on the effects of drugs, toxicants and poor nutrition on brain development using the rhesus monkey model. Her most recent project assessed the effects of fluoxetine (Prozac) on brain development. Funding • HD065862 – this grant supported research to supplement information on the safety of fluoxetine for children by using a juvenile non-human primate model • OD011107 – this grant supports the facility and staffing of the California National Primate Research Center

Q&A

Why were juvenile rhesus monkeys chosen as a model to study human brain development? Non-human primates, like humans, have a prolonged period of development between infancy and puberty. During this time, which we call childhood, the brain continues to develop higher cognitive abilities and acquire experiences that will guide the individual in the future. For this reason, the effects of psychoactive drugs on children are most appropriately studied in non-human primates.

Dr Golub with her great-nephew Alex, who has been a source of inspiration for her research

• OD010962 – this grant supported the genotyping of infants, to study genetic sensitivity to the drug Collaborators • Christoph Turck, Max Planck Institute of Psychiatry •C saba Leranth, Yale University • Richard Sherwood, University of Missouri • Casey Hogrefe, University of California at Davis •A licia Bulleri, University of California at Davis Bio Mari Golub received graduate degrees in psychology, pharmacology and toxicology

What motivated you to research the possible adverse effects of fluoxetine treatment in children? After fluoxetine was approved for children, an increase in suicidal thinking was reported in young people. This alarmed the medical community and activated biomedical researchers like myself to investigate the side effects of this drug in children versus adults. Also, our family has a young member with autism who had been prescribed psychoactive drugs. When I spoke to his mother, she described her concern about using the drugs and the value of more information on their safety. What other genetic variations could interact with fluoxetine treatment? Researchers are studying several genes for interaction with fluoxetine in adults, and also in transgenic mice. Prominent among these is the gene for the serotonin transporter (SERT). Monkeys will continue to be valuable for this research as they share many polymorphisms with humans, including SERT polymorphisms.

from University of Michigan and the University of California. Over a 40-year career at the University of California at Davis she has conducted studies of adverse effects on brain development in animal models including poor nutrition, drugs and toxicants. Contact Mari S. Golub, Ph.D., DABT CNPRC, Neuroscience and Behavior Unit University of California at Davis One Shields Ave, Davis, CA 95616 USA

When will we see the use of precision medicine in prescribing drugs such as fluoxetine? Our monkey subjects were not selected for any of the behavioural disorders that occur in children, like depression, anxiety, ADHD or autism. We hope that our study will encourage physicians to look into a possible role of MAOA polymorphisms in response to treatment in children. Only at that point will we have contributed to the use of precision medicine in childhood fluoxetine therapy. As you near retirement, what have been the highlights of your career in developmental neurotoxicology research? When I began studying psychopharmacology in the 1960’s, this class of drugs was just being developed and coming into widespread use. Our fluoxetine study in non-human primates was a fitting conclusion of my research in this area.

This study has advanced our understanding of the effects of fluoxetine treatment on juvenille brain development

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Thought Leader

High pressure talk with Professor Rhian Touyz At the Institute of Cardiovascular and Medical Science (ICAMS) at the University of Glasgow, world-renowned researchers are dedicated to discovering mechanisms of cardiovascular disease (CVD) in their quest to advance new treatments and to develop improved prevention, management and diagnostic strategies. Professor Rhian Touyz takes an innovative new approach to preventing CVD by conducting extensive research into other intricately linked critical conditions. She spoke with us at Research Outreach to discuss the institute’s aim, outlining the vital research and vision for the future.

rofessor Rhian Touyz is the Director of the Institute of Cardiovascular and Medical Sciences (ICAMS) at the University of Glasgow, the British Heart Foundation (BHF) Chair of Cardiovascular Medicine and Director of the ICAMS BHF Award of Research Excellence. She specialises in hypertension, abnormally high blood pressure which increases the risk of heart attacks, strokes, kidney failure and cognitive decline (dementia). Her mission is to help enhance human health through her research into the causes of cardiovascular disease.

of Research Excellence in Vascular Bioscience and Medicine. The BHF Research Excellence Award represents an outstanding achievement, recognising the calibre of expertise in pioneering cardiovascular research here at ICAMS. It’s very competitive and in the last round of applications, there were thirteen applications from the UK, of which six institutions were awarded, including: Oxford, Cambridge, Kings, Imperial, Edinburgh, and Glasgow. We are very proud to be part of these big-name institutions, especially given the high level of competition

Research Outreach caught up with Prof Touyz to talk about the latest ICAMS research and her role as leader in the 400-member institute. Here she discusses the development of her fascination with hypertension as one of the key causes of CVD and provides an insight into the organisation’s excellent contribution to cardiovascular research. She also discusses her earlier career and shares her hopes for the future.

Our institute focuses on cardiovascular research, specifically cardiovascular diseases. The diseases we focus on relate to heart disease, especially heart failure and ischemic heart disease or heart attacks. We conduct research in pulmonary hypertension, hypertension or high blood pressure, along with diabetes and metabolic disease as it is implied in cardiovascular disease. In addition to this, we have a very strong programme in stroke research and kidney failure because these pathologies are also intricately linked to cardiovascular disease. Those are our main areas of research in terms of disease processes, and alongside this, we also research the basic science that feeds into the mechanisms of these diseases, such as: molecular biology, cell biology, redox biology, experimental models, physiology, genetics, proteomics, imaging, and electrophysiology. Taking our research and discoveries from the laboratory to the patients and population is a major goal, and as such, we have a very strong programme on ‘healthy lifestyle’ and cardiovascular protection, enabling us to interact very closely with doctors in the hospitals.

Hi Rhian! Can you tell us more about the relationship between the Institute of Cardiovascular and Medical Sciences (ICAMS) and the British Heart Foundation Glasgow Cardiovascular Research Centre? The Institute of Cardiovascular Medical Sciences is a research-intensive institute that focuses on cardiovascular research, both basic and clinical, in the College of Medical, Veterinary and Life Sciences within the university. In 2014, ICAMS was recognised by the BHF as a Centre of Research Excellence, where it was successfully awarded a highly competitive grant. Through the award, ICAMS established the BHF Centre

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Could you provide us with more detail as to what hypertension is? Some people often get confused and they think hypertension means anxiety or high stress levels but essentially, hypertension means high blood pressure or high pressure in the blood vessels. Every time the heart beats, it contracts and then relaxes, allowing the pressure to be pushed along the vessel so that the blood vessels can drive the blood flow, supplying all the tissues and organs with nutrients, especially oxygen. If that pressure gets too high, it can cause damage to the blood vessels and organs. I always say that the best way of thinking about this is if you consider a hose pipe with a tap at the end. If you turn the tap on and the water flows through the hose pipe, then this can be viewed as a healthy working flow. But if you constrict the hose pipe, or make the lumen or inside of the hose pipe narrower, the pressure naturally must increase to allow for water to flow through, and that’s exactly what happens with hypertension. The heart is the tap in this analogy; it must pump harder to make the blood flow through the vessels when the pressure is higher, and this is what causes damage to the kidneys, heart, brain and other organs. Are there any recent breakthroughs or interesting projects that you’re particularly excited about? Yes, there’s a lot of exciting work going on. Our institute has greatly contributed and made a substantial impact to new treatments and clinical guidelines for heart failure, stroke, diabetes and hypertension. In fact, there was an enormous amount of publicity recently from one of our researchers who showed that cycling exercises are particularly important for

Imaging arteries with fluorescent probes using high powered specialised microscopes allows researchers to detect proteins and cells that regulate vascular function

I believe we’re going to see big advances in using new technologies and methods to understand the fundamental processes of cardiovascular disease maintaining cardiovascular health. I’m embarrassed to say I don’t cycle myself but I think that this research will make me and many others start. We have conducted a vast amount of research on statins and how they influence cardiovascular and cardiometabolic disease, especially in relation to the treatment of diabetes. These new breakthroughs will be published later this year. My personal interest, at the basic science level is to examine how small blood vessels undergo damage and

inflammation, and also how that may play a role in the injuries that underlie most cardiovascular diseases. What impact has the BHF GCRC had on cardiovascular medicine since it was established? The BHF GCRC has played a very important role in several large clinical trials related to hypertension, heart failure and to statins or treatment of high cholesterol. We were very instrumental in some of the earliest studies in the field several years ago, and these have really impacted clinical cardiovascular medicine. Ultimately, those trials were

influential in the change to guidelines for clinical practice. Also, the research work conducted in Glasgow has historically played a major role in the management of stroke, and in setting up a stroke unit that has effectively improved the outcomes for stroke patients. In fact, Glasgow has generally played a very important role in neurological disorders. For example, the universal Glasgow Coma Scale, devised right here by our neurologists, is the most common scoring system used to describe the level of consciousness in a person following a traumatic brain injury.

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The wonderful Touyz lab – comprised of dedicated young researchers, students, post doctoral fellows and technicians. This is a truly international lab with staff from Brazil, Poland, Greece, France, UK, Canada, South Africa and Sweden

Can your research significantly change the outcome of a stroke? Well, we do know for example, that one of the biggest ways to prevent stroke is by maintaining normal blood pressure. Hypertension is a major cause of stroke, and so if we can control hypertension, then we can prevent stroke by about 20–40%, and that’s been well proven. Our scientists and clinical researchers have discovered a treatment called thrombolysis, otherwise known as thrombolytic therapy, which is a treatment to dissolve dangerous clots in blood vessels, improve blood flow, and prevent damage to tissues and organs. They discovered that the sooner you complete thrombolytic treatment, the greater the chance of survival for stroke patients. One of our stroke specialist doctors has also played a very important role in the establishment of a stroke unit, in terms of when the patient comes in, what should be done and how the stroke unit should be organised effectively – this makes

a greater difference to the outcomes for stroke patients. As well as being the director, you are a clinician scientist carrying out research into hypertension, with an active role in patient care. How do you find the time to balance each of these positions? To be honest, it is demanding and challenging. Although, I am very fortunate because I have a great network of wonderful supportive staff along with an outstanding PA who helps run everything. Hence it boils down to great team work. I am truly blessed because I thoroughly enjoy every aspect of my work – from the leadership to the discovery science as well as mentoring students to treating patients. In terms of balancing my leadership, clinical, and research role, it all comes down to effective time management and prioritising the work that really needs to get done. These skills allow me to carry out these roles successfully.

That sounds like a good recipe. What initially triggered your interest in hypertension research? My interest in hypertension research goes back many years ago to when I was a medical student on a hospital ward and I witnessed a very young man have a terrible stroke. He essentially became a quadriplegic, (a person affected by paralysis of all four limbs). I asked the consultant at the time, why did this young man have a stroke and change from being healthy to totally incapacitated? The consultant said, “This patient had severely high blood pressure and had that blood pressure been controlled, the stroke could have most likely been prevented”. At that time, I asked, “What are the causes of high blood pressure?” with the reply that, “We don’t know exactly what the causes of high blood pressure are”. Therefore, my interest all stems from this first-hand experience. I became intrigued to try to discover the causes of hypertension, and since then, I have specialised in that field. I’m very interested in trying to understand what causes high blood pressure, as we already know that if you prevent hypertension or properly control blood pressure, other conditions directly linked to cardiovascular disease can be prevented. By preventing patients from getting strokes, heart failure, heart attacks, atrial fibrillation, dementia, or becoming dependent upon on dialysis, where they can’t work anymore and where they spend a lot of time in hospital, we would have a much healthier population; from a public and economic health point of view, this is much more attractive. That’s why I’m so committed to this research and study to try to prevent it or at least better manage it. So you’re now based in Scotland, but were originally from South Africa, and have worked across North America – do you find that attitudes to cardiovascular disease differ in each region? Cardiovascular disease is a really important

Modern medicine of the near future will focus on treatment of the specific disease characteristics of each individual patient using a personalised or precision medicine approach

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Thought Leader I think this is all going to become much clearer in the years ahead, and hopefully modern medicine of the near future will focus on treatment of the specific disease characteristics of each individual patient using a personalised or precision medicine approach. I also believe that we might see the emergence of different methods in the way we treat patients. Maybe we’ll use different strategies, rather than using drugs as we know them today. We may use things like nanotechnology, enabling more sophisticated diagnostic opportunities and yielding improved treatment. Essentially, new technologies and new approaches will advance over the next few years, along with the development of a greater understanding about the very fundamentals of disease processes. Finally, we may even see more management and treatment done within the home, where patients and doctors will be ‘hooked up’ through mobile apps and other technologies.

Prof Touyz – a clinician scientist – working at the bench and the bedside

cause of both morbidity and death across the whole world. We used to believe that it was only in the more developed western world that this was a problem. However, today we now know that globally, cardiovascular disease is the major cause of morbidity and death. We believe this is down to the fact that cardiovascular disease, especially hypertension, causes strokes, heart failure, kidney disease, and even vascular dementia.

In North America for example, patients tend to assume more responsibility for their own health and medical situations. Whereas here in Scotland, patients give most of the decision-making responsibility to the doctors. Of course, this is just from my personal observations and experiences. At the end of the day, it’s really important that patients get the best medical care that is appropriate for their particular disease.

In terms of the attitudes of the professionals, I think today everybody appreciates that cardiovascular disease is a medical priority that needs attention. In each region I’ve worked in, I found that the focus on prevention is very important, especially in terms of lifestyle modifications. Although, in Canada, South Africa and here in Scotland, some of the treatment protocols are a little bit different.

How do you think cardiovascular research will develop during the next decade? I think we’re at the start of a very exciting time for cardiovascular research; in fact, for all biomedical research. I believe we’re going to see big advances in using new technologies and methods to understand the fundamental processes of cardiovascular disease. For example, we talk about precision medicine today, understanding the exact genetic makeups in each individual patient, in terms of protein, metabolism and fats that can contribute to the formation of diseases.

Of course, while all patients are appreciative of good medical care, there are a few notable difference in patient attitudes across the different regions.

• For more information about the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, please visit their website at www.gla.ac.uk/ researchinstitutes/icams/

Professor Rhian M Touyz British Heart Foundation (BHF) Chair in Cardiovascular Medicine Director - Institute of Cardiovascular & Medical Sciences BHF Glasgow Cardiovascular Research Centre University of Glasgow 126 University Place Glasgow G12 8TA, UK E: Rhian.Touyz@glasgow.ac.uk T: + 44 (0)141 330 7775/7774 W: www.gla.ac.uk/ researchinstitutes/icams

The University of Glasgow, Charity Number : SC004401

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Behavioural Sciences ︱ Dr Bipasha Baruah

How to promote gender equity in the green economy The realities of climate change have prompted many nations to strive for greener industries. This includes the development of new technologies which are less carbon-intensive, and the overhaul of sectors such as energy and transportation where women are traditionally poorly represented in the workforce. As the green economy develops, thousands of jobs will be created, but it is unlikely that women will have equal access to these opportunities. Dr Bipasha Baruah, Professor and Canada Research Chair in Global Women’s Issues, Western University, Canada, examines the reasons for this inequality.

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ountries around the world are trying to make their economies less carbon-intensive by creating new green jobs, developing less polluting technologies, and by retrofitting existing sectors such as forestry, agriculture, tourism, manufacturing, water and waste management, construction, transportation and energy production (ILO, 2011). A gendered analysis of such green growth and development strategies reveals two blind spots. First, women are known to have weaker access to new technologies almost everywhere in the world (Hafkin and Huyer, 2006) so there are likely to be unequal access issues inherent in the transition to low-carbon economies. Second, it is well-established not only that 70 percent of the world’s poorest 1.3 billion people are women and children but also that women are already very poorly represented globally in some of the sectors that are critical to the green economy. Women account for nine percent of the global workforce in construction, 12 percent in engineering, 15 percent in financial and business services, and 24 percent in manufacturing. Women have also long been marginalised in the energy sector, where they constitute less than six percent of technical staff and below one percent of top managers (UN Women, 2012). Without appropriately targeted training, education, apprenticeships, employment placement, financial tools and supportive social policies, transitioning to a green economy may exacerbate existing gender inequities and hinder global human development goals. Dr Bipasha Baruah provides recommendations for optimising women’s

employment in four sectors that are critical for the Canadian and global green economy, namely, energy, manufacturing, construction and transportation. HIGHLIGHTING INEQUALITIES More than 50 percent of university students in Canada are women. So is half the labour force. But women remain severely underrepresented in sectors that are going to witness dramatic growth in the transition to a green economy. For example, only 25 percent of those employed in clean energy, 23 percent in transportation, 12 percent in construction, and 28 percent in manufacturing are women. Within these sectors, women are much more likely to be employed in lowerpaid clerical and administrative positions than in high-skilled technical or managerial positions. Most green initiatives in Canada have been driven by the private sector, municipalities and provincial governments. The federal government has, at least until very recently, not played an active role in framing and implementing effective policies to enable the transition to a low-carbon economy. Despite growing evidence of the potential for the green economy to generate a much larger volume of employment than the “brown” (fossil-fuel based) economy, even organisations committed to advocating for equity and social justice in environmental sustainability in Canada have never specifically addressed gender inequity.

just 23 percent of engineering graduates aged 25–34 (Hango, 2013). Since workers are likely to transition from jobs in the “brown” economy (which is heavily male dominated) to the “green,” it is inevitable that women will also be underrepresented in green jobs unless gender equity in employment is planned and implemented proactively. Recent media reports confirm this trend, indicating, for example, that laid-off oil and gas workers in Alberta are beginning to find employment in the clean energy sector (Bickis, 2016). The conversation about gender equity or social justice (more broadly) in Canada’s green economy is at best incipient and tokenistic. Raising awareness is therefore urgent and critical. Canada performs better than the OECD average for the gender employment gap (6.1 percent compared to 11.7 percent), but the gender wage gap in Canada is above the OECD average (19 percent compared to 15.5 percent). Not only does Canada have a bigger gender wage gap than other OECD countries, but women are also severely underrepresented in all high-growth green sectors (Thirgood et al. 2017).

vehicles and the expansion of public transportation systems. The barriers and opportunities women face in energy, transportation, construction and manufacturing are similar because they are all non-traditional occupations for women. Our research points to three major challenges for women in these fields: lack of information about employment, gender bias and gender stereotyping, and masculinist work cultures and working conditions. Women encounter both “sticky floors and glass ceilings” in these fields. In other words, careers may never get off the ground because of persistent and confining stereotypes of feminised roles. And the absence of role models and genderbalanced initiatives makes moving up the ranks more challenging for women. OFFERING SOLUTIONS We need targeted goals, monitoring and enforcement to improve women’s access to jobs in the growing green economy. Much of the workforce in low-carbon construction, manufacturing and transportation will come from the fossil-fuel dependent versions of these sectors. We must start planning for equity in the “brown” versions of these sectors if we expect to see any changes in the green economy. Careers in these fields must be targeted more specifically to women and girls through avenues such as recruitment sessions and employment fairs. Girls must be introduced at an early age to the potential in these fields. Encouraging young women to study science, technology, engineering and math (STEM) is critical since most technical jobs in these sectors require STEM training.

Without appropriately targeted training, education, employment, and financial and social opportunities, transitioning to a green economy may exacerbate existing gender inequities and hinder global human development goals

STICKY FLOORS AND GLASS CEILINGS Most future green job creation in Canada will be in occupations in which women are currently underrepresented, such as engineering and the skilled trades. A Statistics Canada study found that in 2007, women only accounted for one to two percent of completions in apprenticeship training in major trade groups (McMullen et al. 2010). Another report published by Statistics Canada shows that in 2011, women comprised

It is estimated that 200,000 new jobs will be created in the Canadian construction industry over the next decade but women only account for four percent of new registrants in the construction trades (Status of Women, 2017). There is also presently an estimated shortfall of 20,000 employees in manufacturing that could be filled more easily if women were part of the manufacturing workforce in larger numbers. New green jobs in manufacturing will be linked to the use of clean processing techniques and pollution control equipment. The transportation sector will also contribute substantially to green employment through new infrastructure, fuel-efficient

Apprenticeships are often a requirement before a worker can secure full-time employment in these fields. Women have difficulty completing apprenticeships because the processes for entering them remain highly informal and unregulated. Additionally, many apprenticeships are either unpaid or pay a nominal stipend. This is also a major barrier for many

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workers. Having the opportunity to learn a trade while supporting a family is crucial in breaking down barriers many poorly represented groups, including women, face in accessing skilled employment. Fair and equitable access to paid apprenticeships is critical for promoting equity in green jobs. Since women are already underrepresented in key sectors of the green economy, growth in these sectors may further exclude women if proactive measures are not adopted. Based on women’s current patterns of participation in jobs and training in these sectors, almost none of the skilled green jobs created in the next ten years, would go to women. This highlights the dire need for equity programmes and goals that are monitored and enforced. Canada needs all stakeholders – government, civil society organisations, corporations, trade unions, labour associations, public policy institutes and think-tanks – to work together to ensure equity in access to employment in the green economy.

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The barriers and opportunities women face in energy, transportation, construction and manufacturing are similar because they are all non-traditional occupations for women ... women encounter both “sticky floors and glass ceilings” in these fields REFERENCES Bickis, I. 2016. http://www. huffingtonpost.ca/2016/01/27/oil-andgas-career-change_n_9089360.html Hafkin, Nancy and Sophia Huyer. 2006. https://www.amazon.ca/CinderellaCyberella-Empowering-KnowledgeSociety/dp/1565492196 Hango, D. 2013. http://www.statcan. gc.ca/pub/75-006-x/2013001/ article/11874-eng.htm ILO. 2011. http://www.ilo.org/wcmsp5/ groups/public/@ed_emp/@emp_ent/ documents/publication/wcms_152065. pdf McMullen, K., J. Gilmore and C. Le Petit.

2010. http://www.statcan.gc.ca/pub/81004-x/2010001/article/11151-eng.htm Status of Women Canada. 2017. http://www.swc-cfc.gc.ca/rc-cr/bc-cb/ index-en.html Thirgood, J., McFatridge, S., Marcano, M. and J. van Ymeren. 2017. https://mowatcentre.ca/decent-work-inthe-green-economy/ UN Women. 2012. http://www.unwomen. org/en/news/stories/2012/6/fastforwarding-women-s-leadership-in-thegreen-economy

Behind the Bench Dr Bipasha Baruah E: baruah@uwo.ca

Lawson Hall 3244 The University of Western Ontario 1151 Richmond Street London, Ontario Canada N6A 5B8 Bio Bipasha Baruah is the Canada Research Chair in Global Women’s Issues and a tenured full professor in the Department of Women’s Studies and Feminist Research at Western University. Dr Baruah conducts

Q&A

What are the major reasons for women’s underrepresentation in STEM fields? I would say that there are three major reasons for women’s underrepresentation in STEM fields. First, there is systemic misperception and devaluation of women’s scientific and technical abilities. Women in technical fields are deemed less competent than men even when they are better qualified than their male peers. Second, public policies and corporate policies to enable equity in training and employment in STEM are either very weak or absent in many contexts. And finally, the persistence of patriarchal social norms and assumptions about breadwinning and caregiving make it difficult for women to assert themselves at par with men in these fields.

Q&A

How can we enable more women to succeed in these fields? It is extremely important for governments to create policy frameworks to ensure gender equity in STEM employment. We see promising results in countries that have done this. Brazil, for example, has succeeded in enabling women’s

T: +1 (519) 661 2111 (ext. 86316) W: http://publish.uwo.ca/~bbaruah/

interdisciplinary research on gender, development and globalisation; women and work; and social, political and economic inequality. Collaborators Sandra Biskupski-Mujanovic, a PhD student in Women’s Studies and Feminist Research at Western University, provided very able assistance on this research project.

substantial participation in STEM through progressive social policies that include state-funded tuition and scholarship awards at the undergraduate and graduate level. Equity and access policies that have been adopted by other countries are often linear and positivist. They do not seek any special privileges for women and simply demand that everyone receive consideration without discrimination based on sex. They are inadequate because they fail to address the wide range of social and institutional factors that prevent women from succeeding, and because they do not demand preferential hiring and promoting practices to correct historical and current inequalities. More comprehensive and finely-tuned state and corporate policies that take structural constraints into consideration will optimise women’s entry into and advancement in STEM fields. Are similar patterns seen worldwide with regard to the marginalisation of women in certain industries? The professional STEM community in OECD countries may not be optimally leveraging the message that these fields are prestigious and socially important. By contrast, much larger numbers of middleclass women study engineering and other technical fields in emerging economies

Funding Social Sciences and Humanities Research Council of Canada (SSHRC) Research Objectives Dr Baruah’s research programme is aimed broadly at understanding how to ensure that a global green economy will be more gender equitable and socially just than its fossil-fuel based predecessor.

like Brazil, India and China, at least partially because they are perceived as well-paid high-status occupations. In 1998, women accounted for 43.3 percent of engineers in Russia. By 2002, that number had dropped to 40.9 percent. And the numbers have continued to further decline. I use the Russian example not to advocate a return to Soviet-style central planning but rather to emphasise the value of state initiatives aimed at improving representation and removing barriers for career advancement for women in STEM fields. The Baltic nations of Estonia, Latvia, and Lithuania, which were formerly part of the USSR but joined the EU in the 1990s, revealed similar patterns of comparably high but declining rates of participation by women in engineering and technology fields. Female professional and technical workers in Estonia still outnumber men two to one. Estonia offers significant tuition incentives to draw high-school graduates into fields such as engineering. The World Economic Forum still identifies Estonia as the country with the highest percapita number of female engineers, even though, as in Russia, the numbers of women joining the field in Estonia have declined over the 1990s and 2000s.

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Behavioural Sciences ︱ Professor Diana Brydon

Globalisation through a post-colonialist lens: understanding our past is key to our present

Professor Diana Brydon is a leading research scholar, working at the intersections of globalisation and post-colonial cultural studies. Through her work, we can see how processes of globalisation have changed many aspects of our daily lives. She frames her study of concepts such as autonomy, community and democracy with the understanding that the history of colonialism is still entangled in contemporary research and knowledge systems: central to her work is the belief that we must learn from the past in order to ask better questions in the future.

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hat exactly is globalisation and how does it work? Globalisation is best understood as a process by which people and societies become increasingly integrated or interconnected. Technology is at the heart of this process but so are imaginaries, the unexamined ways through which people make sense of their changing world, establish their values and tell their stories. As a result, globalisation is characterised by both frictions and flows, new sensitivities to risks, and changing understandings of home. The development of the internet, portable communication devices (phones and tablets) and the twentieth century development of air travel have enabled significant changes to the ways we connect. A vital part of this relates to speed. Applications such as Skype

have the potential to transform the experiences of immigrants: a loved one living thousands of miles away can be contacted as easily as someone living in the same town. It is as participants of such processes that we find Professor Diana

and advance the study of globalisation and cultural practices in order to broaden trans-cultural understanding, challenging all the time the Eurocentrism and methodological nationalism of many disciplinary practices which have until

Indigenous voices have been silenced in the historical record [and] Indigenous groups are woefully under-represented by scholars in academic institutions Brydon’s contributions so illuminating; throughout her academic career she has challenged the notion that globalisation is solely a homogenising and economic force. Her research goals are to evaluate

this point excluded and marginalised women, cultural and ethnic minorities and Indigenous Peoples. THE ROLE OF THE IMAGINATION IN CONTEMPORARY LIFE Professor Brydon’s belief that the history and continuing impact of colonialism show us the many ways in which the research imagination has shaped the daily lives of people throughout the world is at the root of her work. She looks to literature, in particular, for insights into the ways individuals and communities negotiate belonging during times of change. Since her early research on the nature of Australian expatriate fiction, Brydon’s work has studied the mobilities of people and ideas across borders of various kinds. Research into Canadian settler colonialism is involving her in a very current dialogue about Canadian culture, history, and possible futures. Her country is rethinking its colonial past and her city is the home of a new national centre of learning, the Canadian Museum for Human Rights, established in Winnipeg in 2014, with its mission statement to ‘build […] a new era of global human rights leadership’ and take visitors ‘on a journey to erase barriers and create meaningful, lasting change.’ This suggests a sea change in thought and a desire to not just bring people together now, but to make sense of how existing cultural rifts came to be, and how they might be healed. Much of Brydon’s research which has aimed to penetrate the entanglement of Canada’s colonialist history within global systems has been done through collaboration with scholars, creators and

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Brydon with colleagues Dr Roberto Bezerra da Silva (Federal University of Rio de Janeiro) and Dr Vanderlei Jose Zacchi (Federal University of Sergipe) posing with guides during their visit to the Escola Nacional Florestan Fernandes - Movimento dos Trabalhadores Rurais Sem Terra (MST)

Top: April 27, 2015, the 2014 John M. Bowman Memorial Winnipeg Rh Institute Foundation Award was presented to Dr Brydon at a ceremony at the University of Manitoba Above: Following the Bowman ceremony, Dr Brydon delivered a lecture: “Canada in the World Today: Insights from the Humanities”.

students, highlighting the importance of an interdisciplinary approach to postcolonial studies. By shining a light on the literature of colonised peoples, she presents the world with a new resource by which to better understand – and learn to respect – the perspectives of others. In placing Canadian literature in settler colonial, post-colonial and international contexts, Brydon has also advocated for the study of Canadian literature with postcolonial reading strategies and decolonising imperatives. Her current research examines how speculative fictions from around the world enable readers to imagine a future beyond the limits of the present. COLONIALISM AND RESEARCH PRACTICES The forces that led to globalisation may be reaching their limits. By its act of ‘shrinking’ the world, colonialism has since the fifteenth century oppressed and eradicated minority cultural practices and groups while also preserving records that may be consulted with new sets of questions posed from the perspectives of the previously colonised. The legacies of such globalising processes in the twenty-first century include institutionalised misogyny and racism, a dearth of opportunities for young people and a widespread societal

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Her work is highly relevant in a world that is becoming increasingly uncomfortable with its past and anxious about its future ignorance of Indigenous culture. There has been positive action more recently; active resistance to such oppression led to the United Nations Declaration of the Rights of Indigenous Peoples in 2007, which not only affirms that any doctrine advocating the superiority of any peoples based on culture or ethnicity is socially unjust but acknowledges that the suffering of Indigenous Peoples historically has prevented themselves and their cultures from developing in accordance with their own needs and interests. It is time to listen to their stories and attend to their visions of the future. Indigenous voices have been silenced in the historical record. In addition, Indigenous groups are woefully underrepresented by scholars in academic institutions. As Brydon’s research has pointed out though, it is these voices that are critical to coming to terms with what it means to be, for example ‘Canadian’, today. Indigenous story-telling is changing the literary landscape and shifting understandings of land. Brydon’s research has consistently advocated

for increased transnational and transcultural engagement in cultural studies, arguing that Indigenous resurgence, multiculturalism and globalisation can best be understood through contextualisation of their entanglements at local, national and global scales. IMAGINING OTHERWISE Professor Diana Brydon has been a force in post-colonial studies of globalisation and Canadian and international culture, grappling throughout her career with the idea that our understanding of history and the world today can only be improved by acknowledging and considering previously (and often still) marginalised perspectives. Her work is highly relevant in a world that is becoming increasingly uncomfortable with its past and anxious about its future. Our best chance at co-existing in our progressively integrated society is tied up with our willingness to reflect on our past and listen to the stories we have been previously unable to hear.

I am proud of the trans-national, transgenerational, trans-disciplinary research team building I have been involved in

Behind the Bench

Prof Diana Brydon

E: Diana.Brydon@umanitoba.ca T: +1 204 474 8109 W: https://dianabrydon.com/ St. John’s College University of Manitoba, 92 Dysart Rd., Winnipeg, MB, R3T 2M5 Canada Bio Diana Brydon (BA and MA University of Toronto, PhD Australian National University) took up the Tier 1 Canada Research Chair in Globalization and Cultural Studies at the University of Manitoba in 2006. Elected to the Royal Society of Canada in 2008, she won the Bowman Research Award in 2015, and received an honorary doctorate from Linnaeus University, Sweden, in 2016.

Q&A

Your research has consistently strived for a global understanding of the past and the present; why do you think this is so important now, in 2018? We still only have a partial view of our history: that of the victors. The seeds of the challenges we face were sown many years ago and are now looming so large we can no longer ignore them. A lack of respect for other living beings, human and non-human, is now bearing fruit in rising seas, water shortages, desertification, and the social unrest they cause. I have turned to fiction and poetry seeking answers to the question of why people put up with the way things are and how, when they don’t, they can create a more just world. You have recently completed a partnership project working on Developing Transnational Literacies with colleagues from Sao Paulo University, Brazil. Can you tell us briefly about the objectives of this research partnership? We aimed to create a reciprocal dialogue between scholars working in Brazil and Canada. So much history

Research Objectives Professor Brydon’s research aims to improve understanding of how globalisation and culture interact and what humanities-based study can contribute to meeting global challenges. Funding Dr Brydon’s research is supported by the Canada Research Chairs Program. Additional funding received from: the Social Sciences and Humanities Research Council of Canada, the Aid to Scholarly Publications Program (CFHSS), the Canada Foundation for Innovation, the Province of Manitoba, the University of Manitoba, the Humanities Research

and so many stereotypes separate us. Our goal was to learn more about each other’s countries and the different challenges we face in teaching English language and literature as a route toward engaged critical thinking in global times. Our focus fell on the challenge of decolonising both English studies and teaching practices. For us, transnational literacy involves relearning how to learn, questioning what counts as knowledge, and the relations between knowledge and privilege. For example, we visited the National School run by the Landless Workers Movement outside Sao Paulo to learn more about their initiatives. How far do you think research practices have changed with regards to post-colonialist/feminist readings since you began your career in the 1970s? Enormous progress has been made. When I began my doctoral research, I was warned I would never get a job if I worked in these areas. Both fields have benefitted from the development of analyses of the structures of power, within and beyond the academy, that have prevented the contributions of women and the colonised from being taken seriously. The activism of social justice advocates continues to make

Institute (ANU), the Concurrences Centre in Colonial and Postcolonial Studies (Linnaeus University), and the Ford Foundation. Collaborators Brydon thanks research collaborators William D. Coleman, Marta Dvorák, Gunlög Fur and Peter Forsgren, Irena Makaryk, Lynn Mario Menezes de Souza and Walkyria Monte Mór, Jan Aart Scholte, and Helen Tiffin and graduate student research assistants: Ademola Adesola, Chigbo Arthur Anyaduba, Ifeoluwapo Adeniyi, Vanessa Almeida Nunes, Jeremy Strong, and Melanie Dennis Unrau.

a difference. The full challenge of decolonisation, changing those inequitable structures inherited from the past, remains before us but we now have a better understanding of what meeting that challenge may involve. Some of your publications have been described as game-changing and seminal; what work are you personally most proud of? I am proud of the trans-national, trans-generational, trans-disciplinary research team building I have been involved in, training new generations of scholars, and learning with others how to think beyond the borders of the training we ourselves received. Those partnerships don’t end when the research funding is over. Each of my publications, individual and collective, emerged from a moment in time that seemed to require that particular intervention. Most of my work continues to ask questions deriving from the “Globalisation and Autonomy” project, especially those set out in Renegotiating Community: Interdisciplinary Perspectives, Global Contexts, and further explored in subsequent articles and books. But it is always my latest project about which I am most excited.

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Behavioural Sciences ︱ Dr Danie Meyer-Parlapanis & Dr Mareike Augsburger

A fascination with violence:

appetitive aggression in males and females Exposure to violence during childhood or at later stages of life can result in severe trauma, mental health issues, and in some instances, appetitive aggression, an acquired fascination by or pleasure in violence. Under the leadership of Prof Dr Thomas Elbert, Dr Danie Meyer-Parlapanis and her co-author Dr Mareike Augsburger, from the University of Konstanz in Germany and the University of Zurich in Switzerland respectively, have been studying the effects of violence-related trauma on the appetitive aggression of male and female individuals, carrying out research on a sample of war combatants.

uman beings have been found to be traumatised or adversely affected by victimisation and by the witnessing of violent acts. However, some seem to find the perpetration of aggression appealing, developing a form of ‘bloodlust’. It is possible that this pleasure in violence, named appetitive aggression, is part of our species’ natural spectrum of behaviours, but it also appears to be affected or accentuated by particular life experiences. While studies have found exposure to childhood violence to be the main driver for ongoing aggression, recent research on war combatants has revealed that high exposure to violence in adulthood can be associated with greater levels of appetitive aggression. Importantly, these studies have focused on the role of sex in the development of appetitive aggression, shining a light on its previously overlooked prevalence in females. THE STUDY OF APPETITIVE AGGRESSION During childhood or at later stages of life, human beings might unavoidably be exposed to violence, whether in the role of witnesses, victims, or perpetrators. The results and consequences of this exposure can be varied, including mental health and behavioural issues, such as posttraumatic stress disorder (PTSD), depression, anxiety, and addiction, as

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well as the development of appetitive aggression. Appetitive aggression is a form of biologically-driven aggressive behaviour that does not serve the purpose of resisting a threat, but implies finding a certain pleasure in the observation or perpetration of violence. At a biological level, appetitive aggression is accompanied by a surge in adrenaline, as well as the release of cortisol and endorphins, hormones that have a variety of physiological functions, some of which include pain alleviation and euphoria. A typical example is the aggressive disposition associated with hunting, resulting in bloodlust and taking pleasure in ‘the kill’. Enhanced appetitive aggression has been found to reinforce the cycle of violence, leading to a positive feedback loop in which an individual repeatedly seeks out acts of violence to feel a degree of pleasure or satisfaction. Exposure to contexts in which human beings repeatedly perpetrate acts of violence against one another, such as domestic violence, organised crime, or armed conflicts, can increase the likelihood of appetitive aggression. Drs Meyer-Parlapanis and Augsburger have carried out extensive research into the effects of exposure to different forms of violence throughout the lifespan, with a particular focus on sex similarities and differences in the development of appetitive aggression.

Images taken by Dr Danie Meyer-Parlapanis during field work in Burundi

They found that exposure to war and armed conflicts resulted in an increased likelihood for the experience of appetitive aggression, with all combatants displaying substantially

combatants, investigating potential sex similarities and differences in the observed post-war lust for violence. In contrast to observations collected on non-combatant samples, the researchers found no difference in the level of appetitive aggression displayed by combatants of different sexes. This suggests that all individuals, regardless of their sex, can display both mental health complications and an increase in appetitive aggression after being repeatedly exposed to acts of violence.

The researchers found no difference in the level of appetitive aggression displayed by combatants of different sex

LUST FOR VIOLENCE IN WAR COMBATANTS In many war combatants returning from the battlefield, appetitive aggression has been found to provide resilience against the development of PTSD after being repeatedly exposed to high levels of violence. Dr MeyerParlapanis and Dr Augsburger have carried out research on a sample of war combatants in Burundi, examining the relationship between their exposure to or perpetration of violent acts and their appetitive aggression.

greater aggressive tendencies than males and females in civilian control groups. “Furthermore, the more violence perpetrated, often the higher the levels of appetitive aggression,” explains Dr Meyer-Parlapanis. Overall, participating combatants suffered more severely from PTSD symptoms than civilians and had a significantly more positive attitude towards aggression. A GROUND-BREAKING SEX COMPARISON Aggression is often considered to be a predominantly masculine trait. Perhaps as a result of this, most studies of appetitive aggression have been carried out on male samples. Dr MeyerParlapanis and Dr Augsburger, however, incorporated both male and female

Their studies did, however, reveal sex differences in combatants who were also victims of childhood maltreatment and traumatic events. In males, both of these factors were positively associated with appetitive aggression; in females, traumatic events had no association with appetitive aggression and childhood maltreatment was negatively associated, suggesting that appetitive aggression was less likely to develop in those individuals. Furthermore, perpetrated events were more strongly correlated with levels of appetitive

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aggression for females than males, and, unlike males, females’ acquired dispositions towards aggression did not appear to attenuate their mental health issues after repeated exposure to violence. One of the research papers by Drs Meyer-Parlapanis and Augsburger suggests that “in both sexes, appetitive aggression may have evolved as a biologically prepared response to cruel environments but might develop along different trajectories”. Dr MeyerParlapanis has further explored the theme of sex similarities and differences in appetitive aggression in her doctoral thesis as a means to deconstruct what is commonly understood as the ‘cycle of violence’. BREAKING THE CYCLE OF VIOLENCE The research carried out by Drs Meyer-Parlapanis and Augsburger highlights the need for further initiatives to expand appetitive aggression to actively include females. Appetitive aggression is a key factor in fuelling cycles of violence, often resulting in recurring maltreatment and conflict, frequently with ripple effects across generations. Ultimately, the work of Drs Meyer-Parlapanis and Augsburger suggests that while some sex differences have been observed in the way individuals react to repeated exposure to violence, ultimately both

The left side depicts reactive aggression as is typical when one is in a threatening situation. Emotional arousal increases, associated with negative emotions such as fear or disgust, as the body prepares for fight or flight. The right side depicts appetitive aggression as is typical when one is hunting or attacking. Emotional arousal similarly increases, associated, however, with positive emotions such as excitement or desire. POMC is the precursor protein involved in the activated stress axis modulating pain, whether it be triggering cortisol release in the hunted or endorphins in the hunter. (Figure adapted from one originally published in: Elbert, Moran & Schauer, 2017. Lust for violence: Appetitive aggression as a fundamental part of human nature. e-Neuroforum, 23(2), pp. 77-84.)

An enhanced appetitive aggression has been found to reinforce the cycle of violence sexes may be comparably vulnerable to experiencing appetitive aggression. As Dr Meyer-Parlapanis says, “Neither sex is immune to appetitive aggression and should not be underestimated as

such in the consideration of mental health interventions and reintegration programs.”

Behind the Bench

Dr Danie Meyer-Parlapanis

Dr Mareike Augsburger

E: daniejmeyer@gmail.com

E: m.augsburger@psychologie.uzh.ch

T: +49 7531 88 4065

T: +41 44 635 73 05

W: http://loop.frontiersin.org/

W: www.psychologie.uzh.ch/de/bereiche/hea/

people/257588/bio

psypath/Team/Augsburger-Mareike.html

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Research Objectives Drs Meyer-Parlapanis and Augsburger’s work looks at the psychobiology of proactive human aggression. In particular, they focus on the sex similarities and differences in the development of appetitive aggression. Funding ERC, DFG Collaborators • University of Konstanz: Prof Dr Thomas Elbert; Dr Maggie Schauer, Dr Anselm Crombach, Dr Corina Nandi

Q&A Is appetitive aggression part of human nature for both sexes and, if yes, what evidence is there to support this? Danie: Elbert, Moran and Schauer (2017) delineated that “…appetitive aggression…is… an intrinsic part of the human behavioural repertoire” (p77). However, scientific discourse continues to generalise appetitive aggression as a human experience while simultaneously limiting it as a primarily male experience. Our studies have provided evidence that we cannot have it both ways: females are capable of experiencing appetitive aggression and further studies investigating appetitive aggression in all members of a population are crucial if we want to continue making the claim that, sex aside, appetitive aggression is a part of our human condition. What main differences have you found in the appetitive aggression of male and female war combatants? Danie: Appetitive aggression in male combatants was associated with abuse or trauma experienced as children. For female combatants, on the other hand, life-threatening events experienced in childhood were not associated with appetitive aggression and there was even a negative

• Université Lumière de Bujumbura: Prof Manassé • Medical School Hamburg: Prof Dr Roland Weierstall • vivo international: www.vivo.org/en/ Bio Danie comes from Atlanta, Georgia, USA and studied under Prof Dr Thomas Elbert at the University of Konstanz, Konstanz, Germany. She submitted her doctoral dissertation entitled “Deconstructing the Cycles of Violence: A focus on female experiences of appetitive aggression”. She currently works in Cologne,

association for those who experienced child abuse. We also saw that the more violence female combatants had perpetrated, the greater the association with appetitive aggression compared to their male comrades, whose appetitive aggression was more associated with general combat experience. Mareike: Most likely, males and females develop appetitive aggression along different trajectories. Cumulated exposure to childhood violence contributes to the evolvement of aggressive behaviour in both sexes. However, regarding specifically the joy of acting violently (i.e. appetitive aggression), the impact of child maltreatment differs. Whilst it boosts the development of appetitive aggression in males, it has the opposite effect on females: the more childhood violence, the less appetitive aggression. In females, active participation in warrelated violence (also if forced to do so) seems to be a lot more relevant for becoming appetitively aggressive. How do these differences compare to those observed in the appetitive aggression of males and females among the general population? Mareike: This is a very interesting question. Up to now, most research has been done in populations affected by long-term war and crisis. As a consequence, empirical evidence for the concept of appetitive aggression in non-war affected general populations

Germany on trauma and aggression related to displacement and integration. Mareike is currently affiliated with the University of Zurich working on associations between experiences of sexual violence, risk behaviour (a “coactor” of aggression) and gender role perceptions. Contact Dr Danie Meyer-Parlapanis, M.S. University of Konstanz, 78457 Konstanz, Germany

is rather limited. When it comes to female appetitive aggression outside a warzone, research is almost nonexistent so far. Danie: Our first appetitive aggression venture into civilian populations investigated the sporting form, Appetitive Competition Motivation (ACM), in high-level, female football players. These civilian women reported experiencing forms of appetitive aggression, in this case manifested in unsanctioned fouls in a high contact sport. The higher the league level, the more accessible was ACM. In this study, we also considered the impacts of upbringing style and other socialisation factors. Less traditional households and increased access to toys and role models that were not considered traditionally feminine seemed to play a role later in these female athletes savouring some aspects of the aggression displayed on the pitch. What are your next steps in terms of research and investigation? Mareike: We are currently investigating the female cycle of violence by means of a meta-analytical approach. This will give us a great overview about the current state of research regarding female aggression, its predictors and consequences. Based on findings derived from the meta-analysis, we will develop further studies.

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Behavioural Sciences ︱ Dr Raul Acosta Garcia

Emerging forms of metropolitan governance in Latin America As Latin America’s middle classes have expanded considerably in the last few years, so have their aspirations for improved living standards, especially in metropolitan areas. Since 2007, Dr Raúl Acosta García of the University of Konstanz has been investigating the efforts of grassroots activists in Guadalajara, Mexico. During this time, he has witnessed a wave of activism through which people without any previous political experience have creatively challenged local government decisions. He has named their engagements ‘aspirational activism’ as they are not driven mainly by ideology, but by yearnings for a better quality of collective life.

Activists from the collective Ciudad para Todos (City for All) celebrate World Car-Free Day in Guadalajara, on September 22nd, 2013. © Raúl Acosta García

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ver the last few decades, Latin America has had a rollercoaster type of economic development, albeit with a somewhat upward trend. This has meant that an increased proportion of the region’s population has become middle class, although, this has often resulted in high levels of economic vulnerability. With an increase in affluence levels, education levels have risen and an increase in leisure travel has been observed as well. An aspect of this process that has not often been investigated, is its implications for the political sphere, especially regarding non-governmental forms of organisation and engagement. Dr Acosta García’s research project entitled “Aspirational Activism in Urban Latin America” seeks to examine a growing demand for better metropolitan governance models in the region in a context where stark socioeconomic inequalities remain.

have gone through various periods of dictatorship or rulership under semiauthoritarian regimes. These played a role in the Cold War by suppressing leftist movements that were considered a threat by the United States. (An example of this is how Mexico has been analysed as living a ‘soft dictatorship’ during most of the twentieth century.) This has meant that many dissatisfied populations in Latin America either rebelled in outright desperation and with violence (for example, in guerrilla fighting), or remained quiet and adopted a submissive attitude.

Dr Acosta García has witnessed this movement in Guadalajara, one of his field sites, which has become one of the leading metropolises in Latin America. Several of his research participants now work for various local government offices as experts in the activist issues they previously participated in. Others belong to networks that span the whole of Mexico, Latin America, and beyond, through which they can learn from others and share their experience with activists and government officials from other cities. For many smaller cities throughout the region, it is much easier to relate to a successful case in the region, than to try to imitate what happens in Europe or the United States. This is known as a southsouth connection, which is increasingly important as the most rapidly growing metropolises are situated in the global south.

In a previous project, Dr Acosta-Garcia explored the role of dialogue in activists’ aspirations for improved forms of democracy

INCREASED EXPECTATIONS Latin American cities have grown at a rapid pace. Four-fifths of these city populations now live in towns or urban centres and a large proportion of these urban dwellers live in shanty towns. There has been a somewhat steady, albeit slow, improvement in the quality of infrastructure and housing. However, corruption remains one of the most difficult challenges to overcome, as it wears down the quality of government services and supervision, which in theory should ensure a greater quality of life and help avoid problems. In this context, Dr Acosta García has chosen to focus on activists who work towards improved policies for mobility and public space. The individuals who engage in these issues strive for good metropolitan governance through specific proposals, knowledgeable contributions, and creative performances in the public sphere. Through a social anthropological focus, Dr Acosta García’s research scrutinises the cultural underpinnings of what he identifies as a cultural shift in perceptions and practices of power. Numerous Latin American countries

As the Cold War came to an end and there was a global resurgence of the ideals of organised civil society, the 1990s witnessed a surge in citizenship initiatives and expectations. These coincided with an economic upsurge in the region. CYCLING AS A SYMBOL Dr Acosta García focuses on the activists that have chosen the bicycle as a symbol of their aspirations. With little to no infrastructure to provide safety for its users, its promotion presented clear potential. On the one hand, the bicycle was already used by thousands of poor workers and self-employed retailers. On the other, it was becoming an increasingly trendy vehicle for middle- and upper-class individuals to explore the city and countryside. This combination allowed activists to address some the region’s structural inequalities by promoting safety for all cyclists. This has come hand-in-hand with efforts by international agencies to reduce greenhouse emissions, and with some cities’ goals of attracting innovative companies and creative individuals. Therefore, there has been a convergence of goals which in cases like Guadalajara, has seen the influence of activists shaping visible changes such as more cycleways, better public areas, and improved public transport.

METROPOLITAN GOVERNANCE Many challenges exist when it comes to managing large cities. This is especially the case when the population is not used to basic democratic practices that occur in Latin America. A key change that Dr Acosta García has identified is urban activists’ desire to do away with the usual model followed in the region of trusting that a single person (usually a caudillo, or big man) would carry out the necessary changes. Many of the activists involved are scholars or specialists in issues like urbanism, environmental law, or mobility. Therefore, they seek to put forth models of governance that are adapted to regional practices but avoid unhealthy concentrations of power. Through a savvy combination of technical data and moral judgments, activists have positioned their struggles as radical changes in political culture. Dr Acosta García’s research ultimately aims to find out if this is the case, or if the protagonists end up reproducing what they have so strongly criticised. As this project has progressed, Dr Acosta García has noticed how the legitimacy many activists have gained has positioned them as strong men.

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What they do with this power in the next couple of years, will determine if they fall into the cyclic regional co-optation through which numerous movements have become parts of the institutional landscape or, if they manage to form an alternative political culture with repercussions beyond metropolitan governance. EXPERIENCING CHANGE An interpretation that has been advanced by Dr Acosta García is that whatever activists do, their influence among wider populations can already be identified as a positive form of empowerment. As the activists focused primarily on presenting live performances in public spaces (i.e., public theatre on streets, parks, and sidewalks), this helped onlookers to develop a type of empathy for how others experience the city. Drivers who previously reacted aggressively towards cyclists, for example, reflected on how vulnerable they are on busy roads. In addition to this, cyclists and pedestrians themselves were also able to identify how vulnerable they were in their day to day cycling in a way they had not previously done so beforehand. This may provide a key insight into how to address long-standing socioeconomic inequalities and their effects. Changes are already visible in some cities, like Guadalajara, where the number of cyclist deaths has dramatically fallen as cycling infrastructure has greatly improved. Dr Acosta García’s project aims to examine not only the physical changes that governments have carried out, but also the cultural adjustments that activists have achieved. The future goals are to provide more tools for both government officials and activists from other cities and regions that may potentially develop good practices in metropolitan governance. These goals are aligned with funding bodies increasing interest in research to positively influence social development. • For more information, please visit http://gepris.dfg.de/gepris/ projekt/298748707

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On November 9th, 2013, activists painted signs along six kilometres of a busy avenue to mark a ‘shared lane’ in order to make it safer for cyclists. © Raúl Acosta García

For a long time, major infrastructure projects in Guadalajara were car-centric. Over the last couple of years, cycleways have become more common

Behind the Bench Dr Raúl Acosta García

E: raul.acosta@uni-konstanz.de T: +49 (0) 7531 885671 W: http://gepris.dfg.de/gepris/ projekt/298748707 W: www.soziologie.uni-konstanz.de/en/chair-of-social-and-cultural-anthropologyprof-dr-thomas-g-kirsch/team/staff/weitere-ethnologen-an-der-universitaet-konstanz/raul-acosta/ Ethnology and Political Anthropology Department of History and Sociology University of Konstanz D-78457 Konstanz, Germany Office: Y324

Funding DFG

Q&A

What drew you to study aspirational activism in Latin America (Guadalajara and Sao Paulo) in the first place? Social anthropology is the study of human society and cultures. Social anthropologists seek to understand how people live in societies and how they make their lives meaningful. My interest in the political sphere has been focused on non-governmental efforts to address issues that individuals felt were not adequately dealt with by government institutions. In studying forms of collaboration between non-governmental organizations (NGOs) and social movements in Guadalajara, I noticed a double trend of increasing interaction among similar groups across Latin America and more sophisticated expectations derived from the growing prosperity throughout the region. To study the resulting phenomenon, I developed the term ‘aspirational activism’. What were some of the main challenges with getting so involved with the subjects of your study? To go beyond what people say, anthropologists seek to socialise with the communities we investigate. In the study of activism, this also means taking part in the public interventions and meetings that activists carry out. The main difficulty this generates is distrust among the people one

Bio

Research Objectives

is most interested in, as nobody likes being observed as a ‘lab rat’. This is addressed by trying to give something back. Thus, I always clarify that with my analysis, I want to provide feedback for activists and government officials to improve public decision-making processes.

analytic tool to investigate them. With the purpose of both seeking to position the concept and exploring its relevance, in 2019, I will organise an international workshop among anthropologists investigating the emerging middle classes around the world, but especially in the global south. Geopolitical shifts in power models may also play a role in reducing the influence of certain development agencies, so homegrown initiatives can become even more relevant.

Raúl Acosta García holds a DPhil (PhD) in Social Anthropology from the University of Oxford. Before joining the University of Konstanz, he was an assistant professor in ITESO, Guadalajara, Mexico, and Research Fellow at the University of Deusto, Bilbao, Spain.

What do you expect some of the main conclusions to be? After a few decades of stifled processes of democratisation in the region, various Latin American countries have gone through interesting processes of more assertive citizens’ initiatives regarding metropolitan governance. I foresee that my conclusions will point towards a changing political culture that derives from more awareness of the value of pressuring government officials to account for whether they reach their various targets or not and, with an overall vision of the expected result. This may provide clues to more complex political developments that are also currently taking place, like the rise of independent candidates for various offices, or the increasing role of consultancy firms in drafting policies. Are you aware of similar strategies from other similar citizen activist groups outside of Latin America? What have been the outcomes of their efforts? The concept of ‘aspirational activism’ can be applied to similar phenomena around the world. My aim is to develop it to an extent that it becomes a useful

Dr Acosta García’s research project seeks to examine the way in which a new generation of activists demands changes in metropolitan governance to improve the quality of life for urban dwellers.

Once you’ve finished drawing your conclusions of this study, do you have any other areas of Social Anthropology that you would like to investigate? There is plenty more that interests me in the field of political anthropology, but I am also increasingly engrossed by issues relating to biosociality and ethics. Regarding the first area, interactions between humans and other species of animals, plants, or microorganisms. But here, I also find the implications for political decision-making fascinating, (for example, regarding animal rights). My interest in ethics is very much linked to the political sphere. I intend to explore complex negotiations that occur among people whose moral frameworks are in stark contrast to each other. This approach could also be carried out in terms of aesthetics, materiality, and embodiment.

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Biology ︱ Dr Meghann Jarchow

A sustainable approach to environmental management Ten faculty members from the University of South Dakota and eleven undergraduate students from across the United States including Puerto Rico, came together through the Sustainable RIVER (Remediating InVasives to Encourage Resilience) program to study how a complex suite of historical and contemporary factors affect the current functioning and management of the Upper Missouri River.

Map of the Missouri River Basin. The six mainstem dams managed by the US Army Corps of Engineers and their resulting reservoirs are shown in addition to the Native American reservations that had significant flooding from the damming of the Upper Missouri River.

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ost of society’s grand challenges involve complex and interdisciplinary systems, and new approaches are needed to effectively address these challenges and create opportunities for enhanced sustainability in the future. This includes teaching upcoming leaders in science and society how to delve into research and action on these unwieldy systems that are biophysically, culturally, and historically complex. For the Sustainable RIVER project, the Upper Missouri River (UMR) was used as the focal system. The Missouri River is the longest in the United States, and its watershed drains approximately 17% of the contiguous United States. The UMR contains the unchannelised, but dammed, portions of the river. The lands surrounding the UMR were

home to numerous Native American communities, including the Očéthi Šakówiŋ (the Great Sioux Nation) and the Arikara, Mandan, and Hidatsa tribes, and today, are dominated by agricultural land uses, primarily grazing lands and annual row crops. A COMPLEX SYSTEM Six mainstem dams were constructed by the US Army Corps of Engineers on the UMR from the 1930s through to the 1960s, largely for flood control, and the reservoirs created from those dams make up the largest reservoir system in the United States. The siting of the dams resulted in disproportionate flooding of Native American reservation land. Reservations comprise approximately 10% of the land area of the Upper Missouri River Basin, yet approximately 30% of the land

Rebecca Krasky presenting a poster summarising her research at the South Dakota EPSCoR Undergraduate Research Symposium in Pierre, SD.

that was flooded in the creation of the reservoirs, was reservation land. Although the Native Americans who have cared for the UMR for millennia do not believe in ownership of land or water, the UMR is now heavily managed, and that management has dramatic effects – both positive and negative – on functioning of the river itself and the associated uplands. The dams on the Missouri River produce approximately 9 GW (gigawatts) of hydroelectric power annually. The Missouri River provides water to millions of people and crop fields, and acts as cooling water for power plants. Recreational benefits from the UMR have been estimated at $68 million annually. The frequency of flooding on the UMR has changed from two annual flood pulses with periodic larger flooding to no annual flooding and two major floods on the UMR in the past 60 years, which has prevented most city and farmland flooding but disconnects the river from its floodplain. The dams have caused downcutting of the river below the dams and delta formation above the dams. The physical impediment of the dam, reductions in abundance of prey fishes and aquatic insects, reductions in spawning habitat, and oxygendepleted conditions at the head of the reservoirs have contributed to the pallid sturgeon being listed as an endangered species. The marked reduction in the number and area of open sandbars, due to the cessation of flooding, has caused the least tern to be

A systems-thinking approach considers a variety of environmental, social and economic factors to produce an outcome that explicitly considers trade-offs and opportunities for synergies endangered and the piping plover to be a threatened species. Yet the dams have prevented some invasive species from moving upstream. The dams also provide services to the millions of people who live downstream. The lands surrounding the Lower Missouri River and subsequent Mississippi River require the reservoir system of the UMR to prevent large-scale flooding while maintaining sufficient water for navigation. All the above, combined with differences in the uses and value placed on the river by different people and communities, call for an approach to management that considers the needs of the river’s ecosystem and environment, as well as those of the people who use it. SUSTAINABLE RIVER RESEARCH Selena Olvera, a member of the Sisseton-Wahpeton Oyate, analysed the use of the river by Native American tribes throughout history by interviewing members of two tribes

within the basin, and highlighted the impacts that European settlement has had on them. The building of the Garrison Dam in North Dakota in 1947 took swaths of land away from the Arikara, Manda, and Hidatsa tribes. This forced the members of these tribes upland of the floodplain, which are generally more infertile, making agriculture to support populations difficult. Olvera stated that “The river is the source of life that connects us all to the Mother Earth and together as relatives. The people of the Očéthi Šakówiŋ (Seven Council Fires) are the caretakers of the Mníšoše (Missouri River) which in turn takes care of its inhabitants.” Geoffrey Gray-Lobe and Sebastian Ruiz studied the effects of invasive tree and shrub species on breeding birds in riverine forests. They determined the success of nesting efforts by birds in forests with different levels of invasive species, and found that some bird species performed better in woodland with higher levels of invasive trees

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and shrubs. Other species, however, performed worse with increased presence of invasive trees and shrubs. “The current flow regulation patterns on the Missouri River are the ‘new normal’ for the river, so the flora and fauna along the floodplain will have to respond to these changes,” noted Dr David Swanson, “Whether or not they are capable of responding is a further question that will need to be addressed.” Bethany Vázquez Maestre studied how drought affected suspended sediment loads in three tributaries of the UMR. The tributaries studied are downstream of the last dam on the Missouri River, and sediment from

the suspended load is nutrient rich, it is critical that we learn more about tributary contributions to the Missouri River,” stated Dr Mark Sweeney. Tyler Seidel evaluated the extent to which aquatic organisms, especially fishes, affect the quantity of insects emerging into terrestrial ecosystems and therefore available in terrestrial food webs. When fishes were excluded, the abundance of emerging insects increased by up to 900%. This increase in food resources caused an increase to the number of spiders that build webs above the water to capture emerging insects. “Although aquatic and terrestrial ecosystems are often thought of as distinct,” stated Dr Jeff

STUDENT PERSPECTIVES This summer, I learned about the many complicated issues that arise when human values do not align with what is best for the natural habitat. I witnessed the effects of anthropogenic intervention during my own research when we did not find any false map turtles within the reservoir lake created by the Oahe Dam. This was disappointing since this stretch of the river used to be riddled with the false map turtle before the dam was built. Sustainability is about trying to find a balance between taking and conserving. I’m honoured to have had a small part in seeking that balance for the Missouri River basin.” -SHAYLYN AUSTIN

This ultimately aids in the creation of a generation of scientists who will help advance society in creating a more sustainable future those tributaries are an important contribution to the sediment-deprived waters due to the dam upstream. They found that although the Vermillion River had the lowest discharge of the tributaries studied, it had the highest suspended sediment load. This raises the question of whether the Vermillion River is contributing disproportionally to the sediment load in the Missouri River compared to other, larger tributaries. “Our previous results suggest that sediment contributions vary greatly among tributaries. Since

Wesner, “There is a strong connection between what the fishes are eating and the resources that are available to terrestrial animals. In other words, rivers feed forests, and vice versa.” DEVELOPING STUDENT SUSTAINABILITY LEADERS Sustainable RIVER aims to affect the students beyond their specific research projects by enabling them to utilise a systems-thinking approach to evaluating research and opportunities for creating change.

This program has taught me so much not just about the Missouri River but the whole world. I have learned how the geological, ecological, and sociological issues all work hand in hand. Each area affects the other issues and this program has taught me that you must look at the bigger picture to try to address all the issues. -ALEISA LABELLE • To find out more about this project visit www.SustainableRIVER.org.

Sustainable RIVER students participated in six field trips, including two interpretive paddles on the river, covering more than 1000 km of the UMR.

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Behind the Bench Dr Meghann Jarchow E: Meghann.jarchow@usd.edu T: +1 605 677 3115

Research Objectives The Sustainable RIVER project had two primary research objectives: one focused on education and one focused on research. The first was to train student scientists who will become leaders in interdisciplinary research and in creating a more sustainable society through their appreciation of using a multi-perspective, systems-thinking approach to understanding and addressing challenges. The second objective was to better understand how invasive elements in the Upper Missouri River affect the sustainability of the river and the humans who depend on it.

Research Team Expertise included: sustainability, ecology, geology, anthropology, and Native American studies.

Posthumus, David Swanson, Jacob Kerby, Jeff Wesner, Mark Dixon, Mark Sweeney, Matthew Sayre, Meghann Jarchow, and Silvana Rosenfeld.

Student Researchers: Ethan Jennings, Kriston Lynn, Selena Olvera and Tyler Seidel (University of South Dakota). Aleisa LaBelle and Shelley Kosola (Nebraska Indian Community College). Shaylyn Austin (University of Michigan), Geoffrey Gray-Lobe (Augustana University), Rebecca Krasky (Macalester College), Sebastian Ruiz (Florida International University), and Bethany Vázquez Maestre (University of Puerto Rico – Río Piedras).

Bio Dr Jarchow is the Director of the Sustainable RIVER program. She is also the Coordinator of the Sustainability Program at the University of South Dakota.

Funding National Science Foundation (NSF)

Faculty Mentors: (University of South Dakota): Drs Brennan Jordan, David

Q&A

What initially inspired you to coordinate this project? To be a successful researcher in sustainability, I believe that you must be able to do interdisciplinary research. This includes being able to understand systems from multiple disciplinary perspectives, to have a broad enough understanding of the system to ask insightful questions, and to develop technical skills to allow for deep exploration into questions of interest. There is a tendency in student research training to focus on building technical skills to answer specific research questions, but this fails to train the students on how to approach their research from a more holistic perspective. The goal of this project was to offer broader student research training. What have been some of the most interesting outcomes of the project so far? It has been rewarding to see the value

that the students got from working with one another. One student commented “Being able to see the varying perspectives of my fellow participants truly expanded my way of thinking and analysing problems.” This begins to show students that they can be experts and the creators of knowledge. What are some of the difficulties faced in addressing the sustainability challenges of the Upper Missouri River? A goal of this project was to evaluate how to “Cultivate a more resilient Missouri River that meets the needs of multiple stakeholders and sustains diverse, functioning ecosystems,” and our group identified many ways through which we could cultivate a more resilient Missouri River. Yet the obstacles to realising a more resilient Missouri River can seem intractable. In sustainability work, there is tension between the sadness that comes with deeply understanding the challenges we face and engaging with the fact that we all can have a positive role in creating a better, more sustainable future.

Contact Meghann Jarchow, PhD, Assistant Professor, Sustainability Program Coordinator, University of South Dakota, USA

How easy would it be to apply the approaches developed here to other fields? Although this project is focused on the Upper Missouri River, many of the foundational themes that exist in this system are present in other systems. The interdisciplinary, systems-based approach used in the Sustainable RIVER project can be applied to a broad range of other fields. How do you expect the project will advance in the upcoming years? We will continue to improve our methods for developing students who are able to work in interdisciplinary teams. For upcoming years, we will have more of the students work in teams of peers to promote peer-topeer learning and to better utilise the diversity of experiences and expertise of the students. We will also offer more opportunities for the students to work with stakeholders and other faculty mentors.

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Biology ︱ Dr Tracy Johnson

From beer to brains

How yeast molecular genetics prove the importance of introns Scientific discoveries often come from the most unlikely of places, and Dr Tracy Johnson’s work is no exception. Using a yeast system typically used to make beer or bread, Dr Johnson and her team at UCLA have uncovered important genetic findings that could highlight the importance of intron retention during gene expression. Her research looks at the science of gene expression, investigating the way in which cells synthesise, splice, and process RNA to generate the key proteins that regulate how we, as humans, continue to function.

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hen you think of the human body, you probably think of the bones, organs, or the skin. But what about the genes that make each of us unique – the biological fingerprints that denote our hair colour, eye colour, and how tall we become? The 46 chromosomes we receive from our parents at conception go on to shape our bodies later in life. The 20,000 genes they carry are responsible for producing the many proteins and enzymes that are vital for keeping all the cellular processes inside of our body functioning properly. Genes provide the biological information that dictate how every cell in our body functions – from producing key enzymes, to manufacturing proteins critical to cell growth and proliferation. To synthesise these important proteins though, the gene must first go through the key process of transcription.

TRANSCRIBING AND TRANSLATING GENES Transcription is the process by which DNA is copied into messenger RNA (mRNA), using an enzyme called RNA polymerase. This enzyme effectively “unzips” the DNA’s double-helix, breaking apart the hydrogen bonds between DNA nucleotide bases – adenosine (A), cytosine (C), guanine (G) and tyrosine (T). The RNA polymerase then matches complementary nucleotide bases (C–G; G–C; A–U; U–A) to the existing single DNA strand, to form an mRNA strand (uracil (U) replaces the tyrosine found in DNA). This mRNA strand is then exported so that it can be translated into a protein. Translation is the process by which the mRNA strand is used as a template to make a protein. During this process, the mRNA strand is decoded by a ribosome outside of the nucleus to produce a specific chain of amino acids. This

Figure 1. Mechanism of pre-mRNA splicing.

Excised Intron

Intron

Exon

5’

3’ Precursor RNA

chain later folds to become the active, functioning protein of the cell. SPLICING RESEARCH TOGETHER During the transcription phase of gene expression, the RNA undergoes “processing” before it can be exported and translated. A key reaction, RNA splicing edits the nascent pre-cursor messenger RNA (pre-mRNA) into the mature mRNA strand needed to form the protein (Figure 1). This process removes nucleotide sequences, known as introns, from the pre-mRNA. The molecular machine which carries out this process is called the spliceosome. This leaves the mature mRNA strand comprised only of exons, and it is these nucleotide sequences which encode the final protein.

5’

3’

Reaction Intermediate

of particular interest for Dr Johnson and her team. For her recent National Science Foundation (NSF) grant, she is studying the influence not only of intron removal, but also intron retention in protein synthesis. As she explains herself: “Most studies into gene function focus on RNA post-splicing – after the introns have been removed and the mature mRNA is exported. Since introns are generally degraded after removal, little attention is paid to what functions these introns could have. In some cases, however, it appears that intron removal is surprisingly inefficient, and therefore, intron retention is a reality that merits a

5’

3’

Ligated Exons

In fact, 75% of the genes in activelygrowing yeast are believed to rely on the protein GCR1 encodes. The cell’s ‘decision’ to produce this protein depends on the cellular environment and the availability of glucose. Dr Johnson and her team have now discovered that regulated splicing and intron retention appear critical for this – ensuring GCR1 gene expression, and ultimately glucose metabolism, can continue regardless of cellular conditions. In differing levels of glucose, Gcr1 protein (Gcr1p) expression varies in order to support the cell’s metabolic needs. To regulate this and ensure Gcr1p expression can suitably adapt to the changing environment, the cell relies on regulated splicing of the GCR1 RNA. Remarkably, both spliced RNA and unspliced RNA produce Gcr1p, with the intron containing the regulatory code needed to initiate translation from the unspliced RNA. The level of spliced vs. unspliced GCR1 is dependent on the cellular conditions, yet both are essential for ensuring effective glucose metabolism.

Genes provide the biological information that dictate how every cell in our body functions – from producing key enzymes, to manufacturing proteins critical to cell growth

It’s a little like having a bag of Skittles sorted by colour and aligned. RNA splicing removes the green, yellow and red Skittles (introns), leaving only the purple and orange Skittles (exons) behind. These purple and orange Skittles form the mature RNA that can go on to encode the final protein.

Dr Johnson’s research focuses on this area, looking at how cells synthesise, splice, and process RNA to regulate gene expression. Through her role as Professor of the Molecular, Cell and Developmental Biology in the Division of Life Sciences at the University of California, Los Angeles (UCLA), she and her team have recently investigated how introns contribute to gene expression. RNA SPLICING: AN INTRON-DUCTION RNA splicing has long been an area

deeper understanding.” To this end, Dr Johnson’s research has uncovered a remarkable example for how important intron retention could be. Using a single-celled yeast called Saccharomyces cerevisae as a model system, her work has pinpointed a gene that could harness several important observations within gene expression – called GCR1. This gene provides an effective example of the importance of splicing regulation in cells: in Saccharomyces cerevisae, GCR1’s RNA, both spliced and unspliced, allows the cell to adapt to certain cellular conditions. YEAST GENETICS The GCR1 gene encodes a protein responsible for the regulation of genes that support glucose metabolism – yeast’s preferred source of energy.

Now, here’s where it gets interesting. Dr Johnson and her colleagues have found that the proteins from the unspliced and spliced GCR1 RNAs associate with each other to form “dimers” – homodimers and heterodimers. So, instead of one Gcr1 protein, there are at least three different functional forms of the protein from three combinations of Gcr1 protein dimers (see Figure 2). In other words, one gene leads to three functional forms of the protein, and

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Figure 2. Model depicting how different Gcr1 proteins are produced and how they function.

DNA RNA synthesis and processing

RNA Unspliced

Spliced

RNA export and translation

Gcr1 proteins

Gcr1 proteins function in the nucleus to help regulate gene expression Gcr1 target genes involved in glucose metabolism

these can then regulate the expression of GCR1 target genes. In essence, both RNAs, with and without the intron, are necessary to produce the proteins that are crucial for the cell to fulfil its key metabolic function. This consequently highlights the importance of intron retention. INTRON RETENTION Dr Johnson’s work opens several avenues for further research, and creates a paradigm for exploration into the influence of intron retention. One such avenue could include investigating the ‘quality control’ mechanisms hypothesised to prevent the export of unspliced RNA, which appear to be evaded in the GCR1 example. Another avenue could look into the translational start site of protein synthesis. In typical circumstances, the protein synthesis machinery scans the RNA strand starting from the end until it finds the first triplet codon (a group of three nucleotide bases) to initiate the start of translation. In the GCR1 system,

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Dr Johnson’s research has established innovative new findings from a yeast system typically used to create beer or bread however, this appears not to be, as the protein synthesis machinery seems to be preferentially attracted to the intron, rather than the initial starting codon. Both of these avenues are currently being investigated by Dr Johnson and Dr Munshi Azad Hossain, a research scientist in Dr Johnson’s laboratory. BEER, BREAD AND BRAINS Dr Johnson’s further research will also look to apply her yeast-derived findings to mammalian cells – which she is confident will come to fruition. In fact, research has recently suggested the potential benefit on intron retention in the mammalian brain, which Dr Johnson cites as a source of excitement for her own work.

She said: “A recent report in mammalian neurons provides a remarkably similar example of how a retained intron can be crucial for RNA function in the mammalian brain.” This report highlights that Nxf1 protein RNA contains a retained intron in both hippocampal and neocortical neurons, with proteins produced from RNAs that also form important dimers (Li Y et al. Mol Biol Cell 2016). This mechanism proves vital in modulating cellular function. Dr Johnson’s research has established innovative new findings from a yeast system typically used to create beer or bread. Her research challenges existing beliefs that introns are simply a “genetic refuse” and demonstrates that there is a lot more to introns than meets the eye.

Dr Tracy Johnson

E: tljohnson@ucla.edu T: +1 310-206-2416 W: http://www.mcdb.ucla.edu/faculty/tljohnson W: http://bioscience.ucla.edu/faculty/tracy-johnson

Research Objectives Dr Johnson’s research focuses on investigating how cells synthesise, splice, and process RNA to regulate gene expression. Her recent NSFfunded research highlights importance of intron retention, using the GCR1 gene found in yeast as a model system. Funding National Science Foundation (NSF)

Q&A

How did you first become interested in gene expression? And what particularly peaked your interest in investigating RNA splicing? I’ve always been intrigued by the fact that, although the DNA in each cell of an individual’s body is the same, those cells must perform specific functions. So, clearly there must be important mechanisms that control which genes are expressed in different cells under different conditions. I find RNA splicing to be an absolutely fascinating process. The typical human gene is interrupted, on average, 10–12 times by introns. In human genes, most of the sequence of any given gene is intron – 98% vs. 2% exons. Nonetheless, there is still so much to learn about the functions of introns and the remarkable machinery that removes them (and in some cases, does NOT remove them), i.e., the spliceosome. As your research has largely used yeast as a model system so far, when

Collaborators • Munshi Azad Hossain • Julia Claggett

laboratory to UCLA in the department of Molecular, Cell and Developmental Biology.

Bio Professor Johnson earned her Bachelor’s degree from UCSD and her PhD from UC Berkeley. She was a Jane Coffin Childs postdoctoral research fellow at the California Institute of Technology and joined the faculty at UCSD in 2003. In 2013, she moved her

Contact Tracy L Johnson, PhD Professor UCLA, Department of Molecular, Cell and Developmental Biology Los Angeles, CA 90095 USA

do you hope to replicate your findings within mammalian-derived genes? Actually, we have already started using a particular type of immune cell called a macrophage to examine how splicing is regulated in response to specific signals. In this case, instead of asking how yeast cells regulate splicing to respond to glucose, we are asking how splicing regulation helps the immune cell respond to the presence of a pathogen. We think that many of the lessons that we learn about yeast gene regulation will inform our thinking about the same basic processes, like transcription and splicing in mammals.

understanding? Actually, a better way of phrasing this is that when we think of intron-containing genes, there is an assumption that the only important parts of the genes are the exons, the protein coding region. Perhaps since introns are removed and, usually, degraded we’ve underestimated their potential for coding functional RNAs or even, as is the case of GCR1, functional proteins. However, with the advent of increasingly sophisticated sequencing technologies, it is clear that there is likely to be more intron retention that we’ve previously appreciated.

What applications could your work have pharmaceutically, in terms of developing effective medicines or therapeutics? A first step toward developing effective drugs and therapies is understanding, in fine molecular detail, how basic gene expression processes work.

Where do you hope to see your research progressing to over the next five years? I would like to understand how sophisticated regulation of genes like GCR1 allow cells to respond to their environments. While S. cerevisiae has been a powerful tool for gaining detailed mechanistic insights, we would also like to see how the basic mechanisms apply to other more complex systems such as mammalian cells.

You mention that introns are a relatively ignored area of research. Why do you think this is, and what more needs to be done to improve

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Biology ︱ Dr Diego Bernal

Into the deep understanding swordfish eco-physiology Cold-blooded vertebrates, such as fish, are extremely susceptible to changes in the temperature of their surroundings. Yet one successful ocean predator, the swordfish, migrates from tropical to temperate seas, and dives daily from warm surface waters to cooler depths, with seeming ease. Drs Diego Bernal and Chugey Sepulveda of the University of Massachusetts Dartmouth and the Pfleger Institute of Environmental Research (PIER), are working together to explain the physiological mechanisms underpinning this ability, with implications for understanding vertebrate respiratory and muscle function, and for maintaining healthy populations of swordfish and other marine species.

s terrestrial animals, we are accustomed to an environment that undergoes dramatic temperature change that occurs over both long (i.e., from summer to winter) and short time frames (from day to night). As warm-blooded mammals, we have the capacity to regulate our body temperature to mitigate the physiological effects of these environmental changes. Other groups, like marine fish, aren’t so lucky, as drastic changes in temperature can have lethal repercussions. In the marine realm, the high heat capacity of water provides fish with a buffer against rapid changes in environmental temperature. For this reason, most marine species have evolved to inhabit relatively narrow and homogeneous thermal niches. Thus, even though most fish do not have physiological control over their body temperature, they still are able to maintain a relatively constant thermal environment in which metabolic processes are optimised. However, certain fish species do not follow this trend, with body temperatures and physiological processes subject to extreme thermal variation on both a daily and seasonal basis. These thermal fluctuations are primarily in response to daily and seasonal migrations in search of rich prey sources that aggregate in temperate and polar regions as well as the waters well beneath the thermocline. A LIFE OF EXTREMES One remarkable species has been shown to possess great tolerance to changing thermal environments. The swordfish (Xiphias gladius) – a large marine predator that roams all the world’s oceans – is among the few fish species known to traverse extreme thermal barriers on a daily basis, spending

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Swordfish caught using deep-set techniques developed by the PIER team.

prolonged periods hunting both at the surface at night and at great depth during the day. This diurnal activity pattern results in extreme thermal fluctuation, with physiological processes subject to temperature changes in excess of 15°C within a matter of minutes. Although many fish species also exhibit tolerance to short-lived changes in temperature, the swordfish has been shown to reside and hunt for prolonged periods in very disparate conditions, providing a daily pattern that subjects physiological processes to extreme and contrasting conditions. This daily pattern provides swordfish with a unique foraging opportunity that allows them to feed on rich prey resources both during the day and at night.

wide swordfish fisheries have been routinely implicated with high levels of bycatch of sensitive species like sea turtles and marine mammals. From a physiological perspective, understanding how swordfish tolerate extreme thermal conditions and how they transition rapidly between them, offers insights not just into this species, but also into how other organisms respond physiologically to changing environmental temperatures. It may even

that power swimming – particularly significant in such fast-moving predators – and secondly the low levels of oxygen experienced at the depth where swordfish hunt during the day. Every sprinter knows that muscles work better when they are warm. In their US National Science Foundation-funded project, Dr Bernal and Dr Sepulveda aim to quantify this effect in swordfish. Their work documents any changes in muscle temperature in free-swimming fish during dives and subsequently assesses invitro muscle performance at the same range of temperatures in a laboratory setting.

Understanding how swordfish tolerate extreme conditions and segregate from other species has led to the development of selective, low-impact fishing gears

Understanding how swordfish tolerate extreme conditions and segregate from other species has also led to the development of selective, lowimpact fishing gears. By documenting depth trends and dive characteristics, researchers have been able to identify times and locations that lead to increased selectivity in swordfish fisheries. This is critical given that world-

help managers of fisheries develop new, more sustainable fishing practices. Drs Bernal and Sepulveda are bringing their complementary expertise in physiology, ecology, and marine resource conservation together to answer these fascinating questions. MUSCLE MATTERS A diving swordfish faces two fundamental issues as it moves from warm to cool water and back again. Firstly, the effect that changing temperatures may have on the muscles

Swordfish have several anatomical adaptations that may help maintain their swimming muscles at temperatures that are warmer than their surroundings: the main swimming muscles are held close to the centre of the body and are supplied with blood via an elaborate network of vessels that act as a heat exchanger, effectively conserving body heat. This mechanism, known as ‘regional muscle endothermy’, clearly enables swordfish to maintain high swimming performance while at depth in cold water, but it does not fully account for their ability to

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blood, and to explore potentially unique ultrastructural adaptations in their gills and muscles that enhance their oxygen-transporting ability. They hope to shed light on the physiological basis of swordfish tolerance to extremes of temperature and oxygen deficits: as the researchers describe it, “adaptations for life on the edge.”

Onboard disections aimed at isolating live muscle preparations for in-vitro studies of muscle function.

survive such rapid dives and to spend such long periods at depth. In fact, other predatory fish including tuna and some sharks have a much greater capacity for regional muscle endothermy than swordfish, however, they cannot sustain such long dives. Drs Bernal and Sepulveda proposed an explanation for this discrepancy: from the data collected to date, the team has proposed that swordfish use physiological thermoregulation coupled with muscles that operate across a large range of environmental temperatures. When their empirical measurements of body and water temperature from freeswimming diving swordfish were put into computer-generated thermodynamic models, they found that swordfish can alter and control the rate at which their entire body exchanges heat with the surrounding water, effectively slowing down the rate at which their body cools during a dive and accelerating the rate of rewarming when they return to the surface. Their work has also shown that swordfish muscle can function at a range of temperatures, including very cold conditions that have been shown to be lethal to many other pelagic fish.

cooling by routing blood through vessels armed with heat-exchanging manifolds deep inside their bodies, keeping them warmer and defending against the cold. Conversely, when returning to warm surface waters, swordfish may accelerate heat exchange with their surroundings by routing blood through vessels that short-circuit the heat exchange systems. The net result is that swordfish operate at warmer temperatures than their surroundings for a longer proportion of the time than other fish. This may give them a competitive advantage relative to other predators and their prey. In addition, the ability to warm up rapidly decreases the amount of time swordfish spend ‘basking’ on the surface, freeing up more time to exploit the rich food resources of the ocean depths.

FINE-TUNING FISHERIES A final, fundamental aspect of Bernal and Sepulveda’s research lies in how the detailed physiological and ecological data garnered during the study relate to local fisheries. Sepulveda and his team at PIER have dedicated much of the past decade trying to develop alternative means to harvest swordfish, ones that are more selective than some of the more traditional fisheries used around the world. The key to this work is understanding where and when swordfish segregate from other species and developing alternative fishing gears that selectively target swordfish at depth. Increasing gear selectivity and minimising unwanted interactions with protected species like sea turtles and marine mammals is a win-win scenario for both managers and fishers. It is the teams hope that new knowledge on their physiological specialisations can be used to develop cleaner fisheries that offer new opportunities for dwindling fishing communities.

Bernal and Sepulveda postulate that the basis for physiological thermoregulation in swordfish lies in their complex, two-part circulatory system

PERFECT PREDATOR Bernal and Sepulveda postulate that the basis for physiological thermoregulation in swordfish lies in their complex, twopart circulatory system. When diving into cooler water, the fish may slow down

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The next question for the research team is how these prolonged dives influence the swordfish’s muscle function and its ability to uptake oxygen from the water. Certain layers of the deep oceans tend to be lacking in dissolved oxygen compared to the surface waters, and in most fish the ability of the blood to bind oxygen varies with temperature, producing a complex set of interactions for fish to tend with. Bernal and Sepulveda have teamed up with colleagues in the US and Canada to examine how temperature affects the oxygen-binding capacity of swordfish

The collaborator’s physiological data may also provide crucial insights into how swordfish movements and behaviours change with our changing climate. As our oceans change with time, factors including prey distribution and abundance, oxygen availability and sea temperature can influence the movements of this global resource. They hope their research may provide a set of biological insights that help explain how swordfish are capable of the feats they accomplish daily and how this information may help keep populations of swordfish and other marine species at sustainable levels in the future.

Behind the Bench Dr Bernal

Dr Sepulveda

E: dbernal@umassd.edu T: +1 508 415 1975 W: http://www.umassd.edu/cas/biology/facultystaff/diegobernal/ W: http://www.pier.org W: https://www.fishecophysiology.net/ Research Objectives This collaborative work is focused on documenting and better understanding the physiological specialisations that allow certain fish species to exploit some of the harshest conditions on the planet. The work specifically tests hypotheses related to the effect that temperature has on muscle and cardio-respiratory performance in pelagic fish species. Additionally, this work has coupled these physiological investigations with movement studies to aid in the development of new, low-impact fishing gears that increase selectivity and reduce bycatch in modern-day fisheries.

Q&A

The swordfish is clearly a unique species. How did you first discover its remarkable combination of behaviours? Despite the presence of global fisheries dedicated to the harvest of swordfish, very little biological information exists for this species. Since the 1960s, there have been numerous reports from the open-ocean fisheries showing that swordfish were captured at depth during the day and in shallower water at night. That work indicated their capacity to move extensively up and down the water column. Then, in the 1970s and 80s, there were a series of papers by Francis Carey and his group that began to uncover some of the swordfishes unique physiological and morphological adaptations that allows them to be active predators in the deep, dark, and cold layers of the ocean. For example, they can warm their eyes and brain to enhance sensory perception. Since then, we have continued that line of work but have focused on how swordfish can sustain swimming during their descents into cold water and to try understand if, and how they can maintain their active swimming ecology, even when other top predators apparently cannot. What are the implications of your findings for our understanding of muscle function in other species? Swordfish are not the only fish that dive deep and cold, but they are unique

Funding • National Science Foundation (NSF) •N ational Oceanic and Atmospheric Administration (NOAA)

Bio Dr Bernal is a member of the Biology Department at the University of Massachusetts Dartmouth.

Collaborators Drs Jeanine Sepulveda (MiraCosta College), Douglas Syme (University of Calgary), Colin Brauner (University of British Columbia), Mark Okihiro (California Department of Fish and Wildlife), Nick Wegner (NOAA Southwest Fisheries Science Center).

Dr Sepulveda is the director of research and education at the Pfleger Institute of Environmental Research (PIER) in Oceanside California.

in that they stay at depth for prolonged periods of time. How they can do that without markedly affecting their capacity to swim is what makes them unique. By learning how swordfish muscles can continue to function, even when facing rapid and large changes in temperature and potentially under low oxygen conditions, we will better understand how animals have adapted to inhabit environmental conditions that should be limiting.

We hope that our work will help provide fisheries with species-specific information that can lead to increased gear selectivity and reduced bycatch. Furthermore, we hope that this type of data can also be collected from other species and used to increase fishery selectivity based upon ecological and physiological differences. Expanding the scope of traditional fisheries and looking outside of the box for bycatch solutions continues to be a goal of both Sepulveda and Bernal’s laboratories.

How do swordfish cope with the longerterm changes of temperature they experience during migration between cooler and warmer latitudes? We do know that many migratory fishes appear to acclimate their bodies throughout their slow progression to cooler waters. However, some other species that migrate more rapidly (tunas and swordfish) and appear to spend more time in cooler waters have evolved a suite of unique adaptations to stay warm. This allows them to potentially swim longer and faster, and increase sensory perception and maybe enhance their rate of growth. Although we are just beginning to understand how these animals can cope with short-term (minutes) changes in environmental conditions, we still have more to learn about their longterm (months) strategies to deal with these changes, which takes on a new sense of importance in the face of the potential oceanographic shifts associated with global climate change.

Contact Diego Bernal, PhD Professor University of Massachusetts Dartmouth 285 Old Westport Road Dartmouth, MA 02747-2300, USA

What do you each bring to the project? And what can you achieve together that you could not achieve alone? The two laboratories have unique attributes and areas of expertise. Bernal has spent more than a decade working in the laboratory coupling his work with the field. In contrast, Sepulveda has diverged from his colleagues’ path and focused more heavily on field studies that have fishery relevance. The coupling of the Bernal and Sepulveda laboratories has resulted in some strong well-rounded studies that tie the field to the laboratory. This synergistic research has bridged the traditional gap that separates field and laboratory investigation and broadened our understanding that allows us to work on questions that others cannot.

How would you like to see fishing practices change as a result of your studies?

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Biology ︱ Drs Tim Griffin and Pratik Jagtap

Open-source bioinformatic solutions for ‘Big Data’ analysis Drs Tim Griffin and Pratik Jagtap along with the Galaxy-P team from the University of Minnesota are working to develop workflows on an open source platform for the analysis of multi-omic data. They are currently focusing on using a Galaxy-based framework to investigate the integration of genomic datasets with mass spectrometry-based ‘omics’ data. But in the long term, they aim to expand the platform to cope with many other ‘Big Data’ domains.

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urrently, a major limitation to what we can discover from complex datasets derived from nextgeneration technologies is our ability to analyse them. This is where the work of Dr Tim Griffin, Dr Pratik Jagtap and their research team will play an important role. THE ‘BIG DATA’ ERA Moore’s Law predicts that computing power will double approximately every two years, and with this, the cost of high-powered machines will also decrease. However, this cannot continue indefinitely and 2017 may be the crunch point at which physical limitations intervene, with the rate

of progress becoming ever more saturated. But what influence has this increase in computer power had on science? One of the major advances has been the ability to generate data using next generation, high throughput techniques, resulting in ‘Big Data’. Although ‘Big Data’ has been used to define many datasets, the term often corresponds to what are now commonly known as ‘omics datasets’ – genomics, metabolomics, proteomics, transcriptomics and epigenomics to name but a few. For example, in biomedical science, we see large scale,

Mass spectrometry data

Determine novel peptide sequence variants

Galaxy-P workﬂows

Sequence database search

Proteogenomics

Peptide spectral matches

Metaproteomics Functional & taxonomy analysis

Database generation

system-wide approaches being used more and more commonly. These include the 1000 Genomes Project, the emergence of personalised medicine – tailored to an individual’s needs – and systems biology, examining multiple, interacting pathways concurrently as one giant network. However, the analysis of these large and complex datasets requires an analytical platform which can cope with the intense informatics requirements, as well as the ability to access disparate software from different ‘omics’ domains. Many wetbench researchers will not have access to this level of compute-power or expertise locally, and therefore there is an increase in remote, or cloud, open-access platforms being used to access the necessary bioinformatic tools needed to cope with the complex results that researchers are obtaining.

a multi-disciplinary, collaborative project between Dr Griffin’s lab and the Minnesota Supercomputing Institute, which involves software developers, data scientists and wet-bench biological researchers. Specifically, the team are focusing on mass spectrometry (MS)-based ‘omics’ data (metabolomics and proteomics) and how they can harness an existing opensource framework, called Galaxy. Put simply, mass spectrometry represents a high throughput technique that sorts ions based on their mass to

GALACTIC PLATFORM Galaxy was originally developed over a decade ago to solve problems in genomic informatics. It can be hosted on a scalable compute infrastructure, helping to cope with the problem of large data volume, and can be accessed remotely by researchers across the globe. Supported by a team of experts and software developers, Galaxy integrates many individual ‘omics tools in a single environment, and also has many functionalities that promote workflow sharing and reproducibility. The latter is particularly important, as there may be multiple research projects that can utilise one particular dataset or workflow. Data sharing and transparency also encourages collaboration, and increases the number of expert approaches that can be combined to maximise novel findings.

One of the major advancements is the ability to generate data using next generation, high throughput techniques, resulting in ‘Big Data’

ONE SOLUTION FOR ALL At the University of Minnesota, Drs Tim Griffin, Pratik Jagtap and team are working on solutions to analyse these complicated datasets. This is

charge ratio. Once certain signatures have been recorded for individual ions, this information can, for example, be extrapolated to identify peptides, the building blocks of proteins. Tandem mass spectrometry (MS/MS) further expands on this by using at least two stages of mass analysis.

In particular, the Galaxy for proteomics (Galaxy-P) team investigates ways in which genomic and transcriptomic data can be integrated with MSbased proteomics data. From here, they aim to verify the expression of

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Members of the Galaxy-P team, (http://galaxyp. org/people/)

protein sequence variants that result from sequence variations at the DNA or RNA level. This approach, known as proteogenomics, commonly uses transcriptomic data translated in silico to produce a customised protein sequence database. This database is subsequently used to match proteins obtained through MS technologies. The major advantage of this approach is that no existing reference sequence is required, and so novel protein sequence variants, which may previously have gone undetected, can be identified. The analysis can also be extended to compare expression levels of genes and proteins. Similar to proteogenomics, metaproteomics is also based on integration of metagenomic data with MS-derived proteomics data. However, unlike the previous approach, this concentrates on integrating these with sequence data derived from bacterial communities (microbiomes). As before, metagenomic data are translated in silico to create a protein sequence database. MS/MS peak lists, derived from the raw data, are matched against the database. Once peptides of interest have been identified, they are assigned to taxonomies and verified. Additional

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analysis using tools for functional analysis such as MEGAN, provide information about the functional categories of microbial protein expression. Metaproteomics can provide us with functional data to complement the taxonomical findings of a metagenomic approach. The main draw of this approach is that it can potentially be used to analyse data from diverse sample types – ranging from clinical to environmental samples. An example of where Galaxy-P (galaxyp.org) provides ideal tools could be in helping cancer researchers identify which protein sequences may have a functional role in causing a specific cancer. Not only does Galaxy-P provide the necessary tools required for complex analyses, it can also potentially train non-expert, bench scientists through public Galaxy platforms (tiny. cc/galaxyp-proteogenomics; z.umn. edu/metaproteomicsgateway). This platform provides small-scale data for users to access and use with already published workflows. Existing studies have already used the Galaxy-P platform successfully to look at a range of topics, from proteogenomic analysis of hibernating mammals, to protein expression in the lungs of patients with acute respiratory distress syndrome.

TO INFINITY AND BEYOND Drs Griffin and Jagtap hope their work will provide a novel environment to integrate multiple ‘omics’ datasets, and that this approach will provide unique opportunities for future discovery. So far, the Galaxy-P team has advanced the abilities of Galaxy to cope with the many challenges of multi-omics informatics. An accessible, unified environment now exists to help nonexperts navigate the analysis of MSbased proteomics and metabolomics data, in addition to a platform with the potential to develop workflows for proteogenomic and metaproteomic analyses. The next steps will continue to involve the consultation of biological researchers to help the team translate their informatics findings into basic biological contexts, and to aid projects which address human diseases. The team will also continue to develop visualisation tools that can help with the interpretation of outputted data. There is also potential to add extra layers of omics to the analysis. So, for example, metabolomics could be included in the mix. Using this approach, the possibilities for new discoveries are endless.

Behind the Bench Professor Tim Griffin

Professor Pratik Jagtap

E: tgriffin@umn.edu E: pjagtap@umn.edu T: +1 612 624 5249 W: http://galaxyp.org/ Research Objectives Drs Griffin and Jagtap’s research focuses on the Galaxy-P project – developing, testing, optimising and applying multi-omics software tools to a variety of biological questions, including cancer and big data research.

Bio Professor Tim Griffin serves as the Principal Investigator on the Galaxy for proteomics (Galaxy-P) project, as well as the Faculty Director for the Center for Mass Spectrometry and Proteomics at the University of Minnesota.

Funding • National Science Foundation (NSF) • National Institutes of Health (NIH)

Research Assistant Professor Pratik Jagtap has been the co-leader of the Galaxy-P project since its inception in 2012, helping to develop and apply software and workflows in metaproteomics, proteogenomics and more recently dataindependent acquisition methods.

Collaborators • Minnesota Supercomputing Institute • Galaxy software platform developers • Jetstream research computing resource

Q&A

If your research were awarded a considerable amount of money and granted access to the world’s most powerful computer – which informatics tool would you develop? A tool that integrates outputs from all ‘omics’ platforms and provides a ‘Google earth’ like interactive visual data. Such a tool would be extremely useful to a biological researcher in both providing an overview of ‘data landscape’ for biological interpretation while providing opportunities to dive-in into regions of interest for validation and actionable intervention/follow-up. We continue to be amazed and fascinated by the depth of analyses that the Galaxy platform offers in challenging fields of research. Another avenue might be to use such a powerful compute platform to re-analyse existing publically available proteomic and transcriptomic datasets using newer multiomic tools, and develop tools to mine for new discoveries. What was the biggest challenge you had to overcome when developing Galaxy-P? The development of tools and workflows for multi-omic analysis of mass spectrometry data provided challenges at many levels. Be it at the conceptualisation stage, or at grant seeking stage, or at tool selection or workflow stage, we looked at all the challenges as opportunities. Deciding which of the many effective software tools to implement in Galaxy has been a challenge, as well as understanding the many different ‘omic

sub-fields and how different software tools work, as well as which are at the forefront in terms of functionalities. However, the biggest challenge and priority in efforts has been to maintain the relevance of workflows in a constantly emerging environment where the inputs are diverse and outputs offer deeper and newer interpretations. What is the most niche/unexpected dataset that you’ve been asked to analyse? The breadth of biological research and flexibility of the Galaxy-P workflows has exposed us to many interesting datasets. These range from human salivary datasets for metaproteomics and proteogenomics, to dental plaque metaproteomes in presence of sugar to the study of metaproteomes from the North Pacific Oceans. But the most unexpected dataset has been the study of cardiomuscular protein expression in hibernation of ground squirrels. Human hearts lose the ability to function at temperatures of 20°C and below. The study tried to shed light on how the heart of hibernating animals can withstand these low temperatures. We are certain that we will continue to see more of these interesting datasets as we continue our research work. In the future, do you see Galaxy-P becoming a desk-based tool that can easily and universally used by anyone, anywhere in the world? The research community has been using Galaxy platform for genomics studies for quite some time now and there is a stable ecosystem of developers and users, which makes this sustainable. We have

@usegalaxyp

Contact Dr Tim Griffin PhD Professor and Director, Center for Mass Spectrometry and Proteomics University of Minnesota Dept. of Biochemistry, Molecular Biology and Biophysics 6-155 Jackson Hall 321 Church Street SE Minneapolis, MN 55455 USA

seen a gradual increase in interest in using Galaxy-P amongst researchers as we have promoted it via research publications, workshops and presentations worldwide. Along with the Galaxy community of developers and researchers, we have been working on making the workflows available via downloadable tool containers or by making public instances available so that researchers can access pre-installed tools and workflows for the research areas of their interest. The vision for the future is that researchers will access these software tools remotely, where they are housed on powerful cloud based hardware. Leading on from this, do you think that younger students and early career researchers should be given compulsory bioinformatic training as part of their studies? Absolutely! Bioinformatics has become a necessary research skillset for experimental researchers. Programming skills enable young researchers to perform novel analyses of previously acquired data. For users, analytical and data interpretation skills expand their ability to seek newer avenues in their research fields. We strongly believe that bioinformatics training will help in introducing and honing skills in programming and data processing, and helps in continuing to expand the breadth and depth of questions that can be sought by the future generation of scientists. ‘Big Data’ will only continue to be generated in biological research, and having the ability to speak both languages in terms of biology and computational science will be a critical skill, and one that is very much in demand in years to come.

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COMMUNICATION

The changing perception of climate change In the 2016 nature documentary Before The Flood, Leonardo DiCaprio summarised the need to combat climate change by saying: “You [humans] are the last best hope of Earth. We ask you to protect it or we, and all living things we cherish, are history” – he has a point.

ack in 1896, a Swedish scientist named Svante Arrhenius found that doubling the amount of carbon dioxide in the atmosphere would increase the surface temperature of Earth between 5 and 6OC. However, his claims were widely disputed and largely ignored by the scientific community, with scientists believing that the instruments used at the time would not have been accurate enough to calculate such an association. They also believed that the Earth’s oceans would quickly absorb any excess atmospheric carbon dioxide. GLOBAL WARMING: REAL OR HOAX? This controversy of opinion surrounding climate change has not gone away over the years. It’s been over 120 years since Arrhenius’ research was first published and yet many still believe the concept of climate change and global warming to be a ‘hoax’, blown out of proportion by governments and the media. And yet, climate change is happening. Polar ice caps are melting. The planet is getting warmer. So, why do some still insist that it’s not as bad as people think? You’d be hard-pushed to find a polar bear with the same outlook. A GROWING CONTROVERSY Despite the abundance of scientific evidence showing that the planet has

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got warmer year on year, and the strong consensus that this is due to humaninduced greenhouse gas emissions, many remain unconvinced that global warming is actually occurring. Not only that, but there remains controversy around whether the effects of climate change will be as bad as the science makes out, and whether there is a need to act against its threat. As Donald Trump has recently proven through his withdrawal from the Paris Agreement for climate change, leaders are ignoring the science put in front of them. Instead, the public are manipulated into thinking that climate change isn’t as serious as it actually is, and yet its threat isn’t going away. A CHANGING WORLD More needs to be done to spread the message, and now more than ever. The debilitating effects are already being seen: hotter summers, longer allergy seasons, food shortages – research from the Medical Society Consortium on Climate and Health is even predicting that within the next 100 years, the US will look unrecognisable.

So, herein lies the million-dollar question: how do you shape public perception to help communicate the potentially dire consequences of global warming? Put simply: with a lot of persistence, time and effort. There needs to be a relationship between science and the media to ensure that scientific evidence is presented to the public in a way that is factually accurate, yet easy to comprehend. The risk of simply ignoring global warming is not even worth contemplating. With increased ignorance comes increased danger – only through a united world effort can climate change be managed effectively. Gandhi once famously said: “Be the change you want to see in the world” – maybe it’s time we listened.

Social Media for Scientists RSM was born out of multiple conversations with researchers who see a real benefit in connecting with a broad audience over an ongoing basis. Social Media can now be considered one of the most prominent and important engagement tools of the modern era. We help you get the ball rolling and can even provide long term Social Media Management support.

Start your Social Media journey now: www.researchsocialmedia.com

Partnership enquiries: simon@researchoutreach.org Careers and guest contributions: emma@researchoutreach.org www.researchoutreach.org