Research Features - Issue 103 by Research Publishing International Ltd

ISSN 2399-1542 ISSUE 103

A MARVELLOUS MIND

An exclusive feature with Dr Nicolas Bazan

WHO: MARIE-PAULE KIENY

ALZHEIMER’S RESEARCH UK

The Assistant Director-General of the World Health Organization explains their R&D Blueprint action plan, detailing the importance of research to prepare for the next big epidemic.

Dr David Reynolds, Chief Scientific Officer of Alzheimer’s Research UK tells us more about the research his organisation is conducting, emphasising why science cannot afford to forget about dementia.

EUROPEAN STROKE ORGANISATION Research Features speaks to Dr Valeria Caso, President of ESO, to find out about Features the Research 3 organisation’s work and the impact they are having in the field of stroke research.

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This Issue

TO ISSUE 103

rom basic to applied science; neuroscience to minority health to cancer; individuals to some of the world’s largest and most influential research bodies – this issue reflects the fascinating diversity of Health Science.

We were delighted to hear first-hand from Dr Marie-Paule Kieny, Assistant Director-General of the World Health Organization, the details of their R&D Blueprint – the research action plan to ensure the global community is as well-prepared as possible for the next epidemic. We also had the pleasure of speaking to noted neuroscientist, Dr Nicolas Bazan, about his research, his career and life beyond the laboratory. We heard from Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, one of the world’s largest dementia-focused research organisations. And Dr Valeria Caso, President of the European Stroke Organisation, explained how its members are helping improve patient outcomes for stroke. Cary Adams, CEO of the Union for International Cancer Control, spoke to us about the importance of a combined global effort to combat cancer and how we all have a role to play. The researchers that we spoke to this issue work across neuroscience, cancer and minority health. One thing, however, unites their work: by delving into the mysteries of Health Science, they are helping uncover the information that will prove valuable to us in the coming years. Whether by improving diagnostics, developing culturally sensitive healthcare or finetuning technology, every project in this issue is a great example of the value we place on research and its outcomes.

Published by: Research Publishing International Publisher: Simon Jones simon@researchfeatures.com Editorial Director: Emma Feloy emma@researchfeatures.com Editorial Assistant: Patrick Bawn patrick@researchfeatures.com Junior Editor: Luna Dewey luna@researchfeatures.com Designer: Christine Burrows design@researchfeatures.com Head of Marketing: Alastair Cook audience@researchfeatures.com Project Managers: Annie Venables annie@researchfeatures.com John French John@researchfeatures.com Julian Barrett Julian@researchfeatures.com Kate Rossiter Kate@researchfeatures.com Contributors: Barney Leeke, Ella Gilbert, Kate Feloy, Petra Kiviniemi

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CONTENTS

14 06 14 20 24 28

A marvellous mind: an exclusive feature with Dr Nicolas Bazan

Spotlight on WHO: How to stop the next Ebola Using fluorescent viruses to illuminate neuronal circuits

Exploiting fungal mechanisms to breach the blood–brain barrier

Spotlight on Alzheimer’s Research UK: Breaking the misperception around dementia

32 36

Innovative technologies expedite cognition drug development Bad Breaks: how stress and meth use combine to dramatically weaken the blood–brain barrier

Spotlight on ESO: The structural backbone of European stroke research

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70 44 48

How to tackle disparities in HIV healthcare

How Indigenous Traditional Medicine and modern science are working together to combat diabetes

Spotlight on UICC: Leading the Global Fight Against Cancer

Novel mouse models set to uncover hidden drivers of aggressive prostate cancer

52 58

The ‘intelligent’ human immune system can respond naturally to fight cancer

Promising new model for the molecular classification of endometrial cancers

Connections: the importance of mentoring and collaboration to research success Social Media: Blogging for scientists – a quick guide

High precision dose monitoring can enhance targeted tumour therapy

Dr Bazan with a molecular model of adiponectin receptor 1

A marvellous mind Dr Nicolas Bazan of Louisiana State University Health New Orleans, School of Medicine (LSU) has spent a lifetime uncovering fundamental neurobiological processes, identifying early instructive signals as disease modifiers for neurodegenerative diseases and transforming academic medicine, becoming a household name to thousands of neuroscientists. However, like the great thinkers of history it doesnâ&#x20AC;&#x2122;t stop there, he has also found the time and talent to write books, make a film, mentor the next generation, patronise the arts and lead communities forward with his fresh ideas.

Neuroscience

Those who witnessed him achieve selection to the faculty of the University of Toronto at the age of twenty-six must have known he was destined for great things. From here he moved back to his home country of Argentina where he became the founder of the Instituto de Investigaciones Bioquimicas. He also set up a graduate programme in biochemistry and assembled a large group of students and fellows to work in his newly established lab. With exceedingly limited equipment and resources, he struck on two budgetarily feasible ideas: using early amphibian (toad) development as a model of cellular membrane biogenesis and using the retina to study the brain – a decision that would prove enormously beneficial to his work. This productive period was, however, cut short in the early 80s by the political turbulence in the country. In fear of his safety, Dr Bazan was forced to leave his successful institute and flee with his family back to the United States. The move to LSU quickly followed, where a few years later he was asked to become the founding Director of the Neuroscience Center of Excellence. There he certainly found his scientific home, but it is as likely also that his long stay is due to the finding of a different satisfaction in the cultural melting pot of New Orleans. He credits his faith and family, along with the strong relationships he has built with many around him, as the grounding force that has helped him overcome the hurdle of sudden displacement and other setbacks, among them his triumphal bout against advanced inoperable cancer 14 years ago. Dr Bazan celebrates rather than laments the difficulties he has faced, saying ‘adversities bring strength and renewed perspective’. His awards, honours and collaborations make for a very long list, so long that no one seems to have the time or space to publish it in full. From membership of editorial boards across Europe and the American continent, to chairs,

• Traumatic Brain Injury • Stroke • Parkinson’s

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r Bazan has featured in so many magazine articles, from Forbes to his local New Orleans Living, that his background and upbringing is almost a matter of public knowledge. Born in Los Sarmientos, Tucuman province, Argentina, it was in Tucuman City that he studied medicine. Drawn to this subject after experiencing first-hand the chilling effects of neurological disease in his family, he completed his training at Harvard Medical School after a year’s stint in New York’s Columbia University College of Physicians and Surgeons.

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elected to Academic Societies and fellowships of distinguished faculties in the United States (US) and further afield; Dr Nicolas Bazan is a name synonymous with first-class neuroscience research. As Michael Moskowitz, Professor of Neurology at Harvard Medical School/Massachusetts General Hospital puts it, he ‘is passionate about everything he does in life, especially his science, and this passion has driven a lifetime of discoveries that have inspired both his students and colleagues’.

underlying pathology. Considering the difficulty of establishing treatments for such diseases, it is no wonder that Dr Bazan himself believes that, ‘the only way to conquer them is by getting a new understanding of the cellular and molecular mechanisms engaged in the onset and early progression of brain and retina disease’. This has been his focus during a lifetime of research, a labour which he says he has been, ‘lucky to have been able to contribute to’.

THE MAN OF SCIENCE Dr Bazan focuses his attention not on the lucrative or straightforward cases, but on those neurodegenerative diseases for which there is no known cure. It is perhaps even more telling therefore, that he has made such inroads into the understanding of the

Here again the list just goes on and on. There have been breakthroughs in the understanding of the response to the foremost causes of long-term disability in the US – cerebral ischemia (stroke) and seizures (as in epilepsy) – the mechanism of which is now known as the Bazan Effect (as

Dr Bazan focuses on those neurodegenerative diseases for which there is no known cure 7

Neuroscience

Bengt Samuelsson, a Swedish researcher and Nobel Laureate at the Karolinska Institutet in Stockholm, defines it, ‘the Bazan effect is the release of polyunsaturated fatty acids during seizures and ischemia’). There is the identification of targets for novel therapeutics, and the uncovering of the novel compounds themselves, to combat the onset and progression of epilepsy; a condition which 30% of US patients do not have adequate control over. Or you can point to the identification of a novel protective molecule to hopefully slow the onset of Alzheimer’s disease. Dr Bazan has also targeted chronic pain by developing a novel generation of nonaddictive, non-toxic analgesics (painkillers), which he is bringing to market via a new startup company he co-founded specifically for this purpose, using the findings from his work on injury and inflammation of the brain. His work has been recognised by distinguished colleagues around the world. Dr George Carman, Chief Scientific Officer at the New Jersey Institute for Food, Nutrition, & Health, Rutgers University, says Dr Bazan, ‘has dedicated his career to conducting the highest level of science to the underpinnings of brain function and diseases’. His work has also included a related and equally challenging area, blindness caused by retinal degeneration, and once again he is bringing

his experience and intellect to bear with stunning effect.

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Photoreceptor cell

A MAN CAN BE KNOWN BY HIS EYES The focus of Dr Bazan’s work from its discovery at the earliest stage in his career is the brain release of arachidonic acid and Healthy docosahexaenoic acid AdipoR1 (DHA) upon stimulation. Retinal (Long Loop) DHA is an omega-3 fatty pigment DHA acid, the precursor of which NPD1 DHA epithelial cell is only available from dietary Liver sources, and is retained in higher levels in the brain and retina than any other Omega-3 body tissue. DHA is a key Fatty acids (Diet) Ablation of the component of membranes receptor protein that captures DHA engaged in brain and retinal (Short function, acting at the Loop) junction between brain cells Elongation of DHA NPD1 known as the synapse, and 32:6n3 36:6n3 34:6n3 38:6n3 in retina photoreceptors. AdipoR1 This molecule has been the 22:6n3 Retinal subject of intense study by Degenerative Diseases Dr Bazan and his colleagues. Inner Segment

Long loop (liver to retina) and short loop (RPE to photoreceptors and back) for DHA conservation. NPD1 is made on demand, when uncompensated oxidative stress arises. DHA is elongated in the inner segments making the key components for photoreceptors’ function. AdipoR1 is necessary for vision: it captures DHA and establishes neuroprotection instruction cascades. Its genetic ablation or mutation leads to retinal degenerative diseases (e.g., autosomal dominant retinitis pigmentosa or some forms of AMD).

The systems employed by the team have been many and varied, but it was during their use of the retina (the light-sensing part of the eye directly linked to the brain) as a model for research on

neurones that DHA’s role, particularly that of bioactive derivatives, in retinal function and disease was established. Using this approach, they uncovered the mechanism by which DHA is accumulated in the differentiated neurones, the photoreceptor cells, having been absorbed from the diet. Dr Bazan postulated and then demonstrated both the ‘long loop’ of transport from the liver to the brain and retina, as well as a ‘short loop’ by which this fatty acid is recovered back to replenish the cells of the retina. This process assured the Bazan team of DHA’s status as a key molecule in normal neural function. They then went on to further elucidate the fate of this molecule as it is first cleaved and then modified by a range of enzymes to produce bioactive docosanoids, molecules which are now known to promote homeostasis and neurorestoration (maintenance and repair respectively). One such of these was named Neuroprotectin D1 (NPD1) because of its role in fostering homeostasis, inhibiting uncompensated inflammatory signals and preventing apoptosis (programmed cell death) as well as other forms of cell death. The discovery that the availability of this potent molecule is decreased, along with its precursor DHA and the enzyme that makes one from the other, in the brain memory areas from early stage Alzheimer’s Disease (AD) patients in particular, convinced Dr Bazan and his colleagues that its presence is likely essential in

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Harnessing the power of the arts Dr Bazan has, in addition to his successful scientific career, embraced the arts with equal success. His two published novels (and there are more waiting for publication) follow the life of a neuroscientist. One of these, Una Vida: A Fable of Music and the Mind has been made into a compelling and poignant movie Of Mind and Music – a process that Dr Bazan was involved in throughout. (Left) Dr Bazan has been married to Dr Haydee Bazan for over 50 years; she leads research on cornea nerve repair and regeneration. (Centre) Nicolas Bazan lab members, administrative support and technical personnel of the Neuroscience Center of Excellence. (Right) With artist Taryn Möller Nicoll.

preventing the onset of neurodegeneration. As the retina photoreceptors which provide the stimuli for sight are a type of differentiated neurone, it seems logical that a substance that prevents the death of neurones in AD could also be involved in age-related macular degeneration (AMD), the loss of sight associated with retinal cell death, as well as other inherited retina degenerations. Dr Bazan has led the way in describing the complex interplay of molecules involved in the management of homeostasis in retinal cells, particularly the retinal pigment epithelium (RPE) which is the layer of cells nourishing and sustaining the retinal visual cells. His work is so important it has been described by Prof Joan Miller, Professor and Chair of Ophthalmology at Harvard Medical School, as, ‘a lasting contribution to our understanding of the role of lipids in the retina, especially their function as modulators of neuroinflammation, which is the basis of so many ocular diseases’.

THE RENAISSANCE MAN Dr Bazan’s most recent research is just the latest in a lifetime of discovery. Bengt Samuelsson describes him as, ‘a leading neuroscientist and eye researcher’ and points to his work on the Bazan effect, showing that his influence is truly international. However, all his colleagues attest to knowing someone whose intellect is not constrained to a single subject, who has made as much of a mark in the other aspects of his varied life as he has in the scientific community. Prof Edmond Fischer, Nobel Laureate and Professor Emeritus of Biochemistry at the University of Washington says, ‘What impresses me most about Nicolas is his enduring enthusiasm and passion, not only for science, but for all of the wonderful things life has to offer. He is the epitome of the renaissance scholar.’

Dr Bazan demonstrated both the ‘long loop’ of transport from the liver to the brain and retina, as well as a ‘short loop’ by which DHA is returned to the retina www.researchfeatures.com

The film traces the encounter between a successful neuroscientist and a captivating street musician with Alzheimer’s disease. For Dr Bazan, the act of taking his deep knowledge of the world of neuroscience and translating that into a thought-provoking narrative has created a very powerful tool: ‘I wanted to contribute to removing the stigma of mental illness in society, because mental illness of any kind is just a disease. I wanted also to create awareness about Alzheimer’s disease, and in a way convey a message of hope that science may actually conquer this disease one day.’ ‘In art it’s the same’, says Dr Bazan, ‘because one can, in an oil painting, illustrate the beautiful, and yet sad, chaos that happens in the brain during Alzheimer’s disease.’ His dialogue with brilliant artist Taryn Möller Nicoll during her residency at LSU Neuroscience Center of Excellence has led her to create a visually arresting portrait of the degenerative processes that occur in the brain. With the tools of writing and art up his sleeve, Dr Bazan is lifting the unseen neurodegeneration that underlies so many conditions into the light.

What first piqued your interest in neuroscience? Well, it was a very early childhood experience that I had. I was six or seven years old and an aunt was taking me to a piano lesson. To make a long story short, she had an epileptic seizure on the street. It was a very traumatic experience to me – all the piano books flew into the air due to a grand mal seizure. My mother told me that my aunt, her sister, had epilepsy which was a brain disease, and that stuck in my mind. It was not something that I always thought about but very likely, on reflection, that motivated me to go to medical school and to become interested in the brain and neuroscience. Later on, my mother strongly encouraged me towards medicine. She really stimulated me to read and to think about medicine, and her message was that by doing something in the medical field I could help people with diseases that were very difficult to cure or to treat. And a lot of your work relates to neurodegenerative diseases. How did you become interested in them? Well, it started with epilepsy. During my time at Harvard Medical School I was a fellow at a laboratory, at the Massachusetts Mental Health Centre. This was a psychiatric hospital with a major research effort. I was very impressed by a therapy that was being used intensively at that time, we’re talking about

Acyl DHA

I moved to my first faculty appointment at the Department of Biochemistry, University of Toronto, and I was very lucky to be appointed assistant professor at a very early age and Assistant Director of the Neurochemistry Section of the Clarke Institute of Psychiatry. I was 26 years old and again I continued my interest in how experimentally produced seizures would change brain chemistry. So my very first connection was epilepsy and also at that time I began exploring how ischemia, the shortage of blood to the brain often as a result of stroke, also produces these changes.

Your work on experimental seizures and stroke led to the Bazan Effect being named after you. Could you briefly explain what the Bazan Effect is? I was trying to identify specific chemical changes in the brain due to seizures or to shortage of blood, of ischemia. And I found the release of two types of essential fatty acids, omega-6 and omega-3. The long names are arachidonic acid The role of and docosahexaenoic acid. DHA and its

Traumatic Brain Injury Stroke P

the mid-60s, which was electroconvulsive therapy or electroshock. That was, and still is, a treatment used for people who had forms of depression that were refractory to all other medical treatments. One of the things that electroconvulsive therapy does is triggers seizures in patients. And in my mind, I began putting together those early thoughts, or experiences, or connections with epilepsy, and how electroshock might modify or rectify brain chemistry.

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Neuronal Hyperexcitability Seizure Susceptibility

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Epileptogenesis Resolution & Clearance Homeostasis

Essential fatty acids are so-called because our body is unable to make them. We have to get them or their precursors from the diet. Arachidonic acid goes all over the body to all the tissues, but the other one, docosahexaenoic acid, goes mainly to the brain and to the retina, that is, to the nervous system. Both become part of the structure of the cells. And at that time we didn’t know that an acute event like a seizure or ischemia would trigger the release of these fatty acids in tiny amounts. Release means that the chemical connections that they have

in the membranes are broken and then they become free fatty acids. So, I developed methods to identify this and what was surprising was that the speed of release was very, very high. So the idea was, is this a post-mortem phenomenon? Is this something pathological? Or is this event related to function? And looking at the electroshock experiments that I did at that time, in fact what we found is that once the fatty acids were released, after the shock was over they came back into the membrane. So, it was a reversible phenomenon and that suggested that this was linked to function. Thereafter we found a connection between what happens during seizures, and what happens when the brain develops neurodegenerative diseases. Can you explain the role of these two fatty acids in a healthy nervous system? What do they do normally? Well the first one, arachidonic acid was shown to be the precursor of prostaglandins and many other important mediators that were discovered by Professor Bengt Samuelsson at the Karolinska Institutet. Because these mediators have 20 carbon atoms, they are called eicosanoids. When I moved to New Orleans in the very early 80s, in my laboratory we obtained evidence that perhaps DHA may also be converted into biologically active messengers or mediators, and because they have 22 carbon atoms we suggested calling them docosanoids. We began looking at them intensively in various conditions linked to the function and diseases of the eye and of the brain, and in 2003 and 2004 we participated in the discovery of Neuroprotectin D1, which is the first messenger or mediator of DHA. We characterised this molecule and found that sure enough it’s involved in experimental ischemic stroke, and it’s involved in functions, and these functions of the eye and of the brain included Alzheimer’s disease. As I understand it, DHA and

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Neuroscience

Micromanipulator to isolate single neurones, astrocytes and photoreceptor cells to decipher the transcriptome in early stages of diseases: (from left) William Gordon, PhD, and Jonathan Fuerst (4th-year LSU Health School of Medicine medical student) with Dr Bazan

docosanoids, its derivatives including Neuroprotectin D1, are there to help protect neurones. Is that correct? Can you tell me more about this? In our laboratory, we design ‘hypothesisdriven’ experiments. So, we have ideas and we test them. The science must be driven by rigour, and the rigour of science is how you design experiments and how you test a hypothesis. During this process, although we always have ideas, we have a lot of surprises, a lot of unexpected findings. And although we predicted that there were going to be docosanoids, our findings were more surprising and had other implications than those we had predicted. It must have been a very exciting time to be working in the laboratory. It still is, because this is an ongoing exploration. In fact, now we have a set of new molecules that we will be reporting in the near future, that we have recently discovered in my laboratory and that could actually be an additional game changer in understanding all of these responses. We wanted to decipher how the brain or the retina responds very early on to injury or to the onset of pathology. Just think for

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example about Alzheimer’s disease. If we go into a model of Alzheimer’s or into a donor patient’s brain with Alzheimer’s disease and try to see the changes happening when the disease is already fully on-board, it’s very difficult to identify the causality. What are the early events? Over many years, my laboratory has focused almost exclusively on very early events of several models of diseases. All these diseases that we are talking about have no cure, but we believe that if we can decipher what happens very early in them, we might be able to harness those events to create disease-modifying therapies. So how close do you think we are to a treatment for a condition like Alzheimer’s or Parkinson’s? That is a very important question. I believe we are much closer now than five or ten years ago. We have much more information. We have many more experimental approaches, and we have new clues about the early disease development through the work of many people throughout the world. We also successfully applied NPD1 and these concepts in cellular models that recapitulate aspects of Parkinson’s disease. I believe that, if we can slow down the onset or early disease progression in the next few years it will be a

tremendous triumph, because Alzheimer’s disease is very complex and it’s multifactorial, and it has many aspects that make it a major threat to humanity nowadays. Absolutely, and as our worldwide population ages, it’s becoming more and more prevalent, isn’t it? Yes, because age is the number one risk factor and one woman out of five over the age of 65, no matter what we do in the next few years, will get Alzheimer’s disease. Also one man out of eleven over 65 will get Alzheimer’s. We do not know why there’s this difference, that’s one of the clues that nature gave us, and we are actively exploring the gender difference. The magnitude of this disease is tremendous, for the care givers, for the families and for the health care system. This is something that will have a growing and tremendous impact on humanity in the near future. It’s very interesting also that the second cause, what I would call the number one environmental cause of Alzheimer’s disease is traumatic brain injury, and we are neglecting this. Trauma to the brain is an environmental risk factor for cognitive dysfunctions like Alzheimer’s disease.

That’s really interesting, isn’t it? It certainly suggests an area to look into. Well these things give us hints in order to go and design experiments where we can actually go into the intimacy of the molecular principles that are involved in the development of diseases like these. Many laboratories now are using a stem cells-like approach as well. In my laboratory, we are reprogramming adult cells into induced pluripotent stem cells (iPSCs) that become neurones, enabling us to get an insight into molecular principles of neuronal survival and neurorestoration. Then, having those cells in the laboratory, one can identify which are the molecular mechanisms that are actually changing, and also one can use those cells to test experimental compounds that could become drugs or treatments in the future. So the development of having neurones differentiated from patientspecific iPSCs can recapitulate molecular phenotypes of Alzheimer’s disease or other neurodegenerations. This human genomics approach will also facilitate implementation of precision medicine. To go back to your question, “When can we have a treatment?” the answer is, there are enough tools and information that make me very optimistic that we are going to see at least effective treatments to slow down onset and early disease progression in the not too distant future. Which is fantastic news, isn’t it? It’s amazing that things are progressing like that. As a global population we are getting a lot older. Do you feel that ageing and age-related diseases are getting enough priority and focus at the moment? I believe so. I want to take this opportunity to tell you that ageing is not a disease. Many people will age successfully. Successful ageing means, like many people that you and I know in their 80s or 90s, having cognition and sight preserved. We have many examples throughout history, Albert Einstein, for example. Ageing doesn’t mean disease, and I think that’s one of the challenges of neuroscience. We need to find what is it that could make us age successfully. We know certain things: we know, for example, about certain dietary recommendations. We know also about physical activity and intellectual activity, and there are genetic predispositions,

Some of the clinician–scientists who work closely with Dr Bazan: (from left) Rostyslav Semikov, MD, MSc; Hemant Menghani, MD; Ifeanyi Iwuchukwu, MD; Janet Rossi, MD

and epigenetic changes that we don’t understand very well. So, during ageing a multitude of factors converge that lead us to think about the brain and sustaining cognition, and about the retina and preserving sight, because these functions use very important cells. When you first started looking at the relationship between DHA and the retina you were using the eyes as a way to find out more about the brain, and then you started discovering a lot of really interesting things about the eye itself. Is that right? Absolutely. This was Argentina in the early 70s and we didn’t have many resources. We would go at three in the morning to the slaughterhouse, get cows’ eyes as they processed the meat, bring them to the laboratory and peel the retinas off. And that was a beautiful nature-made brain slice. We began by asking questions that we were interested in because of the neurological and ophthalmological implications. And suddenly it became very apparent that diseases of the retina, like age-related neurodegenerative diseases, for example Alzheimer’s, and other diseases of the brain have mechanisms in common. The retina

is an exceptional model to ask questions of the brain, but it’s also a very important organ that fails in ageing and many vision-related diseases, some inherited, some age-related. One aspect that fascinated me very early on about the retina, was the cell called the retinal pigment epithelial (RPE) cell which can eat the tip of the photoreceptors every day in our eyes. Thus necessity, due to lack of funding in the early 70s, made us design experiments using toads that became ideal to ask these retina questions. This is a fascinating process. Yes, it is very fascinating. It’s called phagocytosis and, every day, the tip of each photoreceptor is shed and is phagocytosed by this cell. The RPE cell then processes the remains of the photoreceptor and retrieves certain molecules back to the retina to rebuild part of the photoreceptor cell daily. This is called renewal of the photoreceptors and among those molecules that are retrieved is DHA. So we identified those processes, and named the loop that brings DHA back from the cell to the retina, the short loop (the one that brings DHA from the diet, truly from the liver, to the retina and brain, we named the long loop several years ago) and we’ve

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Neuroscience

Detail

increase the levels in your brain? The answer is yes. However, we found in my laboratory here in New Orleans in the 80s that DHA and its precursors need to go through the liver before going to the brain and to the retina. So even today we don’t understand how it is that the brain and the retina tell the liver, ‘Send me DHA’ when they need it to build or regenerate membranes. So, despite a good diet with good amounts of omega-3 fatty acids like DHA, it’s important to realise there might be impediments to the delivery by the liver. In fact, about six years ago it was reported that in inherited forms of Alzheimer’s patients there is a deficit in liver enzymes for DHA metabolism.

That is something that fascinated me from the very beginning, because phagocytes throughout the body are there for eliminating dead cells, eliminating debris, eliminating foreign bodies, but these RPE cells eat the tip of the photoreceptor by phagocytosis in order to renew that structure, that photoreceptor cell that is obviously essential for vision. Yes, and with the long loop DHA is sent from the liver up into the brain. Does that mean that your diet can affect the amount of DHA that’s in your brain? So, if you eat a diet rich in fatty acids that could help

How do you find the time for it all? Perhaps it’s that you have a motivation and a vocation of service. I feel that I’m in a quest to find, as I said earlier in this beautiful chaos, to find a molecular logic. How is it that biology has come up with the extraordinary cells that we have in our retina and in our brain? How can we put these things together in biology and then move into medicine, and eventually be able to help people with diseases when that logic fails? And so it’s easy. It’s just an easy task and that motivation is a driver in my mind in a way. It’s there seven days a week, 24 hours a day and it’s very spontaneous. It’s very inspiring to hear about everything that are achieving and have achieved. Are there any things that you’re particularly proud of? Well, we have five children and I’m very proud of them. Each of them has their own successes and their own activities, and so that’s something that I’m very proud of. And now they have given us 12 grandchildren and two additional step grandchildren. Of course, my wife, also a scientist, has been fundamental to everything that we have talked about today. And I’m very proud to have a lot of colleagues in different stages of their scientific life working with me. So, those are very important components of my life.

Dr Bazan celebrates rather than laments the difficulties he has faced, saying ‘adversities bring strength and renewed perspective’ www.researchfeatures.com

FUNDING NEI, NIGMS and NINDS, NIH; EENT Foundation; BrightFocus Foundation; Foundation Fighting Blindness; Edward G Schlieder Educational Foundation; The Lupin Foundation; Tucker Couvillion III Memorial Fund in Parkinson’s Disease; Research to Prevent Blindness COLLABORATORS Nicos Petasis (USC, CA); Julio Alvarez Builla Gomez (U. Alcala, Spain); Dennis Rice (Novartis, Cambridge, MA); Jennifer Lentz, Ludmila Belayev and Walter Lukiw (LSU, New Orleans); Ricardo Palacios Pelaez (Diater Lab, Spain); Andy Obenaus (LLU, CA); Marianne Schulzberg (KI, Sweden); Charles N Serhan (Harvard, MA)

All photography by Darryl Schmitt

been trying to understand how this process is regulated because the retinal pigment epithelial cell is the most active phagocyte in our body. We have many, many cells in the body that do phagocytosis and the function of them is different to the one in the eye.

RESEARCH OBJECTIVES Dr Bazan’s work focuses on uncovering the molecular processes that underpin neurodegenerative diseases such as Alzheimer’s and Parkinson’s, agerelated macular degeneration, traumatic brain injury, pain, epilepsy and stroke. Much of his current work centres on deciphering the molecular principles of mitochondria significance in cell survival, autophagy, neuroinflammation and single cell transcriptomics that underlie neuroprotective and neurorestorative activities of DHA and its derivatives, including novel approaches to neural stem cell generation and applications.

BIO Dr Bazan is the founding Director of the Neuroscience Center of Excellence at the Louisiana State University Health Sciences Center, School of Medicine, New Orleans. He has been appointed to the highest academic rank in the LSU System, a Boyd Professor (1994-present) and is also: the inaugural founder of The Ernest C. and Yvette C. Villere Chair for Research in Retinal Degeneration (1984-present); a Founding Senate Member of the German Center for Neurodegenerative Diseases (DZNE) 2009-2016; Foreign Adjunct Professor of Neuroscience in the Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Sweden (2016-); Chairman Emeritus of the Board of Governors of the Association for Research in Vision and Ophthalmology (ARVO) Foundation.

WHO: How to stop the next Ebola

Ebola and Zika epidemics have caused frenzies of panic and hysteria worldwide – so how do we stop the next one? Well, the World Health Organization’s R&D Blueprint action plan could provide the answer. Dr Marie-Paule Kieny, Assistant Director-General of WHO, recently spoke to Research Features about this, detailing the importance of platform technologies and relentless research preparation.

ollowing worldwide epidemics of Ebola in 2014 and Zika virus just last year, it has become clear that a contingency plan to combat outbreaks is badly needed.

This is where the experts come in – the World Health Organization and a global collaboration of research institutions around the world. Their solution is one of precise planning, detailed organisation and faultless preparation, to ensure that the one thing they have not had on their side during recent epidemics becomes less of a concern next time around… time. Saving time is one of the pinnacle components to WHO’s Research and Development (R&D) Blueprint action plan against future epidemics. Research Features recently spoke to Dr Marie-Paule Kieny, the Assistant Director-General of WHO and the

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Could you tell us a little more about WHO's R&D Blueprint action plan, outlining what it is you are hoping to achieve from it? The main purpose comes from the lessons learned following the Ebola crisis, to conduct research and development and evaluate new diagnostics, vaccines and medicines. We should not remain unprepared against other infectious diseases which could create similar epidemics. Research needs to be advanced, drugs need to be developed and vaccines need to be prepared during this so-called peace period – the time we have between epidemics. This is so that when an outbreak hits, these medical measures will have been tested and prepared in advance. Unfortunately, it is difficult to test their true efficacy without an actual outbreak. So for example, in the absence of Ebola, you cannot assess whether an Ebola vaccine is efficacious or not, although you are able to push the research and development until that stage. Once you have data on safety, you have data on immunogenicity, and you can work out the dose to use when an epidemic hits. By preparing beforehand, you can immediately start evaluating efficacy once an epidemic starts, and then, if everything goes well, have an effective tool ready quickly following the outbreak onset.

head of the R&D Blueprint team, to discuss how their plan could equip researchers with the tools they need to combat future epidemics. Hello Dr Kieny! Thank you speaking with us today. What does your role involve as the Assistant Director-General of WHO, and what kind of responsibilities do you have on the R&D Blueprint team? I am the Assistant Director-General in charge of health systems and innovation, so I don’t typically deal with emergencies. However, during the Ebola epidemic, I was appointed the lead for all of WHO’s research and development (R&D) work on Ebola, because of my background in R&D and vaccines. I am currently leading the R&D Blueprint team in collaboration with my colleagues responsible for emergencies, particularly in relation to epidemic threats.

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The other purpose for our R&D Blueprint is to create a framework – an enabling environment – especially in developing countries that are prone to these kinds of epidemic. This is about advancing clinical trials, discussing material transfer agreements and helping these affected countries establish a national committee to review research projects. At the time of an epidemic, you have investigators of all kinds coming from everywhere. Preparing a framework during this peacetime for how investigations should be conducted during an outbreak, helps to create an environment for organised research.

Why was the R&D Blueprint action plan set up in the first place? Did it develop primarily as a result of the Ebola outbreak? Yes. Following the Ebola outbreak we had an R&D Summit in May 2015 where we were challenged to develop a plan that would ensure these medical counter-measures could be advanced and available for any future epidemics. After this, all discussions and consultations for the R&D Blueprint action plan were undertaken with all kinds of stakeholders and countries, culminating in this collaborative plan. We then presented this at the World Health Assembly to ministers of all 194 countries from the member states of WHO, who welcomed it and requested we implement it as soon as possible. Which are the key areas that the R&D Blueprint action plan will focus on? In the action plan we have three main areas. One is about improving coordination and fostering an enabling environment. This is to try to respond to the problem that we had during Ebola, where there was a lot of goodwill, but very poor coordination. Global coordination is not about WHO telling everybody what they need to do. It is about us convening a forum where the different global stakeholders can come together and discuss what they propose to take on and what their proposed role will be during research. There is this mapping of stakeholders and a good understanding of who’s doing what, and also the potential to see organisational gaps that need to be filled – it’s about building a global coordination mechanism. In terms of our second approach, this is to accelerate research and development, assessing the epidemic threats that we have discussed already and drawing up a list of priority diseases. For each of these priority diseases, we will then look to develop what is called an R&D Roadmap. This will look at each of the diseases and establish what

The main purpose for our R&D Blueprint action plan is to conduct research and development, evaluating new diagnostics for effective vaccines. We should not remain unprepared against infectious diseases 15

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is in the pipeline, what are the gaps, what is known, what is unknown, what needs to been done, and where the gaps are in terms of funding. Of course the WHO secretariat cannot do that just on its own – the R&D Roadmaps are not about what we will do, it’s about what the international community together will do. We have already conducted one R&D Roadmap, showing us what the needs are for the MERS Corona Virus, what information is currently available and what further work needs to be done to standardise operational procedures. Our third aim for our R&D Blueprint plan is to harmonise regulatory pathways and obtain a general consensus between researchers for the work that needs to be done when outbreaks arise. This is so that, when there is a debate around obtaining clinical trial authorisation, there is a common understanding between cultures. How often will these roadmaps be produced for each of the priority diseases? We have ten priority diseases to develop roadmaps for, so I think they should all be produced in two years’ time. Of course, the ones that have been developed first will then be revised regularly to take their progress into consideration. With the Zika virus occurring last year, and the Ebola virus outbreak occurring the year before that, are you worried that there will be another outbreak next year, as these epidemics seem to be happening on a more annual basis? Yes, but the main difficulty is that you always prepare for the last war, yet the one coming is more of the same. For example, as you say, following on from Ebola we had Zika and Zika is a completely different virus. Not only is it happening in other countries that are more prepared for mounting a public health response, but there is also a big question with Zika, especially in terms of how much it’s spreading worldwide. As you may have seen, it’s no longer seen as a public health emergency of international concern, but it seems to still be spreading. For the time being we don’t know to what extent, so it’s difficult to know what we will need to combat Zika in the coming years. So what will be the next epidemic? That’s what is so difficult to know. Will it be one of the priority diseases that we have identified, or will it be something that comes from the

animal world that we don't yet know about? This is why creating an enabling research environment to conduct research against completely new and unexpected threats is so crucial. When Ebola struck, there were no vaccines or any medical teams available at the time, readily prepared for the outbreak. Yet, after WHO intervened, it sped up the process of intervention massively. Is that basically the point of the R&D Blueprint plan, to prevent the time-lag following epidemic onset? Yes. Of course when we say there were no vaccines or treatments, we simply mean that there were no commercial products available at the time – there had of course been a number of years of work into this disease. However, this research was not for the purpose of preparing a plan against an epidemic. Instead, the Ebola virus was seen by a number of countries as a disease that could be weaponised. Therefore, because of biosecurity concerns, there had been some prototypes which had been worked on in Canada, in the US, and in some other countries but none of them had gone to testing on humans. So when the Ebola outbreak hit, we were lucky that these prototypes existed as they could be immediately used to evaluate the disease further. We weren’t so lucky with Zika though, as nobody had ever thought Zika would do anything. When this virus hit, we had nothing prepared – no prototypes, no trials, nothing. We want to ensure that this doesn’t happen again. The aim for our R&D Blueprint plan is to make sure that all of these priority diseases have therapeutic treatments advanced through at least the early stages of evaluation in animals. That way, when an epidemic hits, we will be ready to advance testing in humans. For other diseases that we may not necessarily know about, the only thing we can do is make sure we have a structure in place. This will ensure the clinical design is appropriate in view of a particular disease’s characteristics, transmission and incidence.

A WHO researcher working in the Ebola lab at Donka Hospital, Guinea

Will the R&D Blueprint plan incorporate educating the public as well or is it more research-focused? It’s more research-focused but will also place high value on communication. One of the tools we are developing is aimed at guiding good community engagement practices, seeing how we engage with communities to help them understand what a disease is, what research is going on, and how they can be part of it. So you can apply your disease R&D Roadmaps to update them about what’s going on before and during an outbreak? Yes, exactly. With the reduction of time it takes to release treatments and vaccines once

What will be the next epidemic? That’s what is so difficult to know. This is why creating an enabling research environment to conduct research against completely new and unexpected threats is so crucial www.researchfeatures.com

an epidemic hits, is there a risk that the efficiency and success of these treatments will be reduced, because you’re releasing them under more rushed circumstances? Well this is why it needs to be worked on in advance during the global peacetime between epidemics. This will give us more time to look at the safety and the pharmacodynamics, so that we can at least have the basic knowledge in place before intervening in an affected country. For example, when the Ebola outbreak first hit, we worked primarily on finding a vaccine against it, but by September there had been no clinical trials. This is why there was a need to do parallel trials, in order to feel confident that when you go and start trials in Guinea or Sierra Leone or Liberia you are not hurting people. During the clinical development of vaccines, there is usually the first phase which involves a few dozen people. Following this, there is the second phase, involving a few hundred people, before the third and final phase, involving a few thousand people. Because of the time pressure on Ebola, we had to start multiple phase one trials at the same time – because single clinical trial centres

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Dr Marie-Paule Kieny (far left) alongside fellow researchers following an Ebola vaccine trial in Guinea

cannot do 100 people together in parallel but we needed a detailed evaluation as soon as possible. In fact, during the production of the Merck vaccine in Guinea, we had four clinical trial centres start efficacy evaluation at the same time.

make sure we pinpoint which diseases could cause an epidemic. Ideally, the phase one and phase two trials will have been done in advance anyway, so you would have these results ready for when the outbreak struck – it’s all about the preparation.

So in other words, phase two trials were effectively replaced by multiple phase one trials because of the need to save time.

If a researcher is reading this and wants to get involved, how should they go about doing this? Will there be any fund-raising activities to gather more support? We are doing a lot of advocacy work but we cannot just rely on investments from a single country – this is a global responsibility to ensure better preparation. We had a

Do you aim to implement that strategy for future epidemics as well? Potentially, although of course we would need to formalise it beforehand, and also

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consultation surrounding this in Oslo last year, and following that discussion some funders have come together to create CEPI – the Coalition for Epidemic Preparedness Innovations. This is an initiative designed to create and test vaccines for epidemic diseases in advance of outbreaks. CEPI adopt the priority list of the Blueprint and they are now seeking funding.

Vaccines aren’t the only area we are looking at developing though. Other investments into diagnostics will also be needed because, while having a vaccine is fantastic, you also need to have other things available to support it. We will look to continually finance research because our R&D Blueprint is not an R&D product initiative – instead, it is a tool to convene, to discuss, to agree on norms, and to then develop these norms into an effective solution. Looking towards the future, what kind of impact do you think we will see from your R&D Blueprint plan in say, ten years’ time? In an ideal world, the plan would be that, for all the diseases identified, there would be diagnostics ready to use, a number of laboratories in different places around the world able to diagnose said diseases, and vaccines at a point where their efficacy could be tested.

Contact World Health Organization Geneva, Switzerland E: bagozzid@who.int W: www.who.int @WHO @mpkieny /WHO

What are platform technologies? When an emergency strikes, it is important to have prior knowledge in place to come up with an effective solution. Imagine you were stuck up a tree – it would be better to know how to climb than not. Platform technologies replicate this concept within epidemic outbreaks. By providing a platform of background knowledge against a particular disease, these technologies can be used to develop vaccines and techniques that can diagnose viruses, in almost a ‘plug and play’ format. As Dr Kieny puts it: “If you need to develop something in an emergency, it’s always better that there is some prior knowledge about the type of technology you use. So for example, if you want to develop a diagnostic technique against a new disease, platform technologies effectively mean you can just plug and play – you have a basic machine, a basic knowledge of how to develop diagnostic products, and then you just adapt accordingly.

safety, efficacy and dosage, and you can start running tests immediately after an outbreak. One of the fundamental ideas for our R&D Blueprint plan is to identify platform technologies that could be used to rapidly generate effective products against unknown diseases, to combat the effect of epidemics." Developing these platform technologies is a vital component of WHO’s R&D Blueprint action plan. Working together with CEPI – the Coalition for Epidemic Preparedness Innovations – Dr Kieny hopes to ensure that techniques are prepared in advance of the next epidemic, especially in terms of determining technologies versatile enough to serve more than one disease.

"One of the technologies used by Johnson & Johnson against Ebola is based on an attenuated virus that has been used as an experimental vaccine for a whole number of other diseases, including malaria, HIV and tuberculosis. In effect, having these platform technologies in place potentially enables us to serve more than one disease.

Having these technologies in place ensures safety, efficacy and – perhaps most importantly of all – saves time. Dr Kieny says: “If you look at the vaccines which were developed for Ebola, there are numerous examples of how effective these platform technologies can be. There was, for example, the vaccine developed by GlaxoSmithKline which, similarly to the Johnson & Johnson vaccine, used an attenuated virus platform that had previously been used against malaria. We had far fewer questions to ask about this, because the technology had already been used before.”

"So in the middle of an outbreak if you say, ‘I have this technology and now I will put in an Ebola gene’, you can rapidly progress because you already have a lot of background knowledge about

In other words, if you have a knowledge of the platform beforehand, it is much quicker and safer to develop vaccines, so that the reaction of the international community can be sped up when an epidemic next strikes.

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All photographs ©Sean Hawkey

So who will be the funders? So far the Norwegian government is a funder, The Wellcome Trust, The Bill and Melinda Gates Foundation. A number of other governments could also join to make up this money, to help further research and development into vaccines.

Using fluorescent viruses to illuminate neuronal circuits In recent decades, researchers have begun unravelling the complex web of connections that underpin all perceptual and cognitive processes in the brain. To map these details, researchers require methods to trace the individual connections between specific neuronal cells. Dr David Lyon and his team have developed a novel technique for specifically targeting inhibitory and excitatory neurones, with the capacity to label individual cells and their connections. Their work opens the door to detailed analysis of neural connectivity with unprecedented specificity, providing tools for understanding the intricacies of neuronal excitation and inhibition in the brain.

Neuroscience

n the School of Medicine at the University of California, Irvine, Dr David C Lyon is an Associate Professor and ViceChair of the Department of Anatomy and Neurobiology. There he is leading research devising new methods for tracing neuronal circuits in the brain. The human brain contains hundreds of billions of neurones which form an intricate array of neuronal circuits that facilitate brain function. They are involved in every sense we perceive, thought we have, and emotion we feel. How the complex circuits underlying these processes function is increasingly being revealed by researchers. However, progress has been limited by the tools available. Employing cutting edge molecular biology techniques, Dr Lyon and his research group have been devising new methods to enable them to relate the structure of the mammalian visual cortex to its function. They are investigating the organisation of cortical areas of the brain, delving into the detail of the circuitry that underlies sensory capabilities at the level of individual neurones. COMPLEX CORTICAL CIRCUITS Neurones are specialised cells that are electrically excitable; they transmit sensory information through electrical and chemical signals throughout the brain. Series of interconnected neurones arranged in pathways form neuronal circuits, which can regulate their activity via feedback loops. Cortical inhibition and excitation work together through networks of inhibitory and excitatory neurones in these circuits to control and modulate complex cortical computations. Neuroscience is progressing in building our understanding of these networks. However, there is still a vast amount of detail that remains unknown. Furthering our knowledge of the connections involved and how they change in the event of dysfunction is imperative if we are to better understand disorders of the brain that occur in the event of injury and disease. In doing so we will increasingly discover new avenues for the development of targeted therapeutics, meaning fundamental neuroscience is of great importance for medical progress. DIFFERENTIATING DETAILS The details of how neuronal function is regulated by inhibitory and excitatory neurones have remained unclear, primarily due to technical limitations. As the two cell

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A. Targetting rabies virus infection with helper viruses Helper virus delivers: YFP, TVA & RabG

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The technique is capable of fluorescently labelling thousands of presynaptically connected neurones in the visual cortex of any mammal 21

Neuroscience

types are intermingled in the brain, study of each population in isolation has proved challenging, with existing neuronal tracers unable to easily differentiate between these cells. Therefore, despite several decades of research piecing together neuronal connections, it has been impossible to unveil the connectivity throughout the brain in cellspecific detail. Using an innovative combination of genetic engineering and molecular techniques, Dr Lyon and his team have developed a method of differentiating between inhibitory and excitatory neurones. They use different colours of intracellular fluorescent protein labelling, allowing precise identification of the individual cells. Furthermore, their new technique allows routes of input to these neurones to be traced back upstream, towards the cells and brain regions they originated from. HARNESSING THE POWER OF VIRUSES Taking advantage of viruses that have the capacity to infect brain tissue, Dr Lyon and his team have devised an ingenious way of uncovering the complexities of neuronal circuits that have thus far eluded researchers. Their first step in developing the technique involved creating a modified version of the rabies virus, which could specifically establish infection in inhibitory or excitatory neurones. The researchers genetically modified the virus so that it can only infect cells that present a specific protein on the cell surface. However, to differentiate between other cell types, they targeted the virus to a protein that is not usually present on cells in the mammalian brain. Therefore, they also needed to deliver this protein to the cells they wanted the rabies virus to infect. To facilitate this, Lyon and his team utilised two other modified ‘helper’ viruses, one designed with specificity for excitatory and another for inhibitory neurones. Each of these viruses was genetically constructed so that they would introduce the gene coding for this crucial protein to the cells, which when expressed would allow the modified rabies virus entry. DISTINCTIVE FLUORESCENT GLOW In addition to requiring specificity of infection to the neuronal cells of interest, the researchers needed a way of identifying the individual cells and of differentiating between infection with the helper virus and modified rabies. Therefore, Dr Lyon and his team also

Targeting EnvA-DG rabies virus infection to, and monosynaptic retrograde spread from, excitatory neurones in mouse V1 using the lenti-αCamKII-YTB helper virus Liu et al., 2013, Current Biology

Dr Lyon’s new technique allows routes of input to these neurones to be traced back upstream, towards the cells and brain regions they originated from engineered both viruses with genes encoding for fluorescent proteins that would be expressed once infection is established. They used a yellow fluorescent protein to identify helper virus infection and a red derivative, called mCherry, to highlight rabies-infected cells.

the helper viruses also delivered RabG to the starter cells. Therefore, these cells also contained this critical component for rabies to spread to connected presynaptic neurones, which once infected with the modified rabies were labelled red as the virus expressed the fluorescent mCherry protein.

To test their new system, they introduced each helper virus to the brain tissue of mice in the region of the visual cortex. The helper viruses infected the target inhibitory or excitatory neuronal cells, expressing both the protein that renders the cells susceptible to infection by modified rabies virus and the yellow fluorescent protein. Next they introduced the rabies virus, resulting in targeted rabies infection of these cells. As a result, the rabies-infected starter cells were distinctively labelled with the presence of both mCherry and yellow protein fluorescence.

REACHING HIGHER LEVELS OF COMPLEXITY Dr Lyon’s results showed that the technique is capable of fluorescently labelling thousands of presynaptically connected neurones in the visual cortex of any mammal. The data yielded wide-scale input patterns to each of the neurone types in this region, which allowed the researchers to conduct comparisons of these inputs that had never been possible before.

RETROGRADELY TRACING INPUTS The system works with high specificity for labelling upstream presynaptic neurones from the starter cell due to another clever modification. The rabies virus the team used is also a deletion-mutant that is missing an essential gene coding for a protein known as rabies glycoprotein (RabG). RabG is required for the viral infection to spread to neighbouring cells. Prior to rabies infection,

They further demonstrated the efficacy of the technique and its potential for research in the brains of different species by targeting inhibitory neurones in the cat brain visual cortex. This not only produced novel insights into the neuronal circuitry of a large and complex mammalian brain, but also proved that the method can be utilised in larger scale animal models. Therefore, this groundbreaking technique provides researchers with the first ever tool to explore the connections between specific cell types in the neocortex of higher-order mammals.

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Detail What sparked your interest in neuroscience and led you to working in the field? Seeing a psychologist as an adolescent initially piqued my interest in the great unknowns of the brain and drove me to be a Psychology major in college. At first I thought clinical psychology was my calling to better understand why people thought the way they did, then neuropsychology because it promised better insights into how different structures of the brain related to human behaviour. I finally settled on studying animal models because it offered more experimental control and because you could work more directly with the brain. Why did you choose to use rabies virus as the viral vector for your novel methodology? Rabies is amazing in that it has specifically evolved to spread across synaptic contacts between neurones in the brain, and saliva glands, so that animals become demented from eventual neurone death and then bite some other animal to pass the virus along. In some ways, rabies virus chose me – I happened to be at the right place at the right time in Ed Callaway’s lab as a new postdoc where work by him and Ian Wickersham had just begun on genetically modifying rabies to control its infection of particular brain circuits. But, by that time I already had a keen interest and a lot of experience in tracing circuits of the brain; rabies offered a unique opportunity so I have taken advantage of it ever since. Could this method be combined with other existing techniques to further enhance its potential for brain research? Absolutely. Like many other viruses, rabies

can be used to deliver genes that can express a wide range of proteins useful in manipulating and observing the anatomy and function of neural circuits: from fluorescent calcium indicators for measuring neural responses in vivo to opsins for optogenetic manipulation of neurone activity. What are your plans for future research following on from this work? Now we are building on our approach by incorporating opsins within the rabies virus to allow for optogenetic manipulation of cell-type specific circuits in the visual cortex. In addition, we are developing new helper viruses that allow us to target rabies virus infection of specific subtypes of inhibitory neurones. For example, at this year’s Society for Neuroscience meeting we showed that in the cat primary visual cortex we could specifically target and optogenetically manipulate the parvalbumin-positive inhibitory neurones which make up around 40% of cortical inhibitory neurones and found that this had a significant effect on tuning properties of excitatory neurones. What do you think is the greatest remaining challenge facing neuroscientists to constructing a complete map of the neuronal circuits in the brain? Reconstructing the complete circuit in the mouse brain will take a lot of work, but seems entirely possible: doing so for a more complex brain such as in a non-human primate seems a far greater challenge, especially when trying to relate the circuits to complex functions.

The data yielded wide-scale input patterns to each of the neurone types in [the visual cortex], which allowed the researchers to conduct comparisons of these inputs that had never been possible before www.researchfeatures.com

RESEARCH OBJECTIVES Dr Lyon’s research has led to the development of a novel method to track the presynaptic connections in neural pathways. Using genetically modified viruses, Dr Lyon and his team have traced pathways in the visual cortex of both the mouse and cat brain. FUNDING The Whitehall Foundation, the National Institute of Neurological Disorders and Stroke, the National Eye Institute COLLABORATORS • Ed Callaway, PhD, Professor, Salk Institute; key intellectual collaborator, helped with planning for cell type specific targeting using AAV and promoter fragments; Senior author on our 2007 Neuron paper showing EnvArabies targeted tracing technique • Markus Ehrengruber, PhD, Visiting Scientist at UC Irvine, Lecturer, University of Zurich, Switzerland • A li Cetin, PhD, Allen Institute for Brain Science, Senior Manager, Viral technology • Roberto Japelli, PhD, research scientist, Salk Institute BIO David Lyon is an Associate Professor and Vice-Chair of the Department of Anatomy and Neurobiology in the School of Medicine at the University of California, Irvine. He received his PhD from Vanderbilt University. He then received postdoctoral training at MIT followed by the Salk Institute for Biological Studies. CONTACT David C Lyon, PhD Associate Professor & Vice-Chair Dept. Anatomy & Neurobiology School of Medicine 317B/364 Med Surge II University of California Irvine CA 92697-1275 E: dclyon@uci.edu T: +1 949-824-0447 W: http://www.anatomy.uci.edu/lyon.html @dclyonneuro

Neuroscience

Exploiting fungal mechanisms to breach the blood–brain barrier

Dr Angela Gelli is a professor in the department of Pharmacology at the University of California, Davis, where she is the principal investigator at the Gelli Lab, as well as a founder and president of NanoCERE Technologies. Her research focuses on the pathogenesis of a fungus called Cryptococcus neoformans, which can cross the blood–brain barrier (BBB) and is the leading cause of fungal brain infections. Dr Gelli’s research has exciting implications for the delivery of drugs into the brain to treat a variety of neurological diseases.

r Gelli’s work focuses on Cryptococcus neoformans, a fungal infection capable of causing brain damage and death due to its ability to cross the blood–brain barrier. The brain protects itself from foreign and toxic bodies by having a tight wall between the brain and the blood surrounding it, called the brain endothelium, or blood–brain barrier (BBB). C. neoformans is important because it can cross this barrier, often causing devastating brain disease. The fungus causes meningoencephalitis, a form of fungal meningitis, which worldwide infects approximately one million people and causes around 600,000 deaths per year. It predominantly infects people with already impaired immunity, such as those who are HIV-positive. The disease is fatal in the absence of treatment but occasionally even after successful treatment neurological deficits can remain. This is thought to be because of the permanent change caused to the BBB following a breach. CROSSING THE WALL There are two main mechanisms by which foreign (fungal) bodies can cross the BBB:

firstly, the ‘Trojan Horse’ mechanism, whereby cells passively migrate across the barrier inside white blood cells; secondly, the transcellular mechanism, which allows the active internalisation of cells by triggering receptors in the endothelium. C. neoformans uses the second, transcellular mechanism by causing changes in protein expression. In order to gain access to the central nervous system (CNS), the fungus engages the endothelial cells that form the barrier to the brain, damaging vital parts of the cell structure and causing their irreversible decline. This compromises the integrity of the BBB as a whole, which partly explains why those who have recovered from infection can experience neurological sequelae and a more permeable BBB. THE SMUGGLER Gelli’s work has shown that C. neoformans crosses the BBB by means of a metalloprotease called Mpr1 that is secreted by the fungus. Metalloproteases are enzymes that degrade proteins, and Mpr1 is part of a family called fungalysins produced by some fungi.

Most chemotherapy drugs are severely limited by their inability to cross the blood–brain barrier but Gelli’s research may change this

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Ovoid C. neoformans transcellular migration Brain Side Attachment: cycto-skeleton remodeling, microvilli, membrane changes â&#x20AC;&#x201C; MPR1

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Mpr1 works by promoting attachment to the surface of endothelial cells by changing the physical characteristics of the C. neoformans–endothelium interface. In an active, receptor-mediated process, Mpr1 stimulates the formation of strand-like protrusions on the endothelium surface called microvilli, which act almost like Velcro to enhance the adhesion of C. neoformans on the endothelium. The precise mechanism by which C. neoformans migrates across the brain endothelium and into the brain is not yet clear but Gelli’s team is working on

resolving this, using proteomics and RNA sequencing techniques. What is abundantly clear, however, is the crucial role that Mpr1 plays in facilitating migration across the BBB. In vitro and in vivo studies by Gelli’s team showed that strains of C. neoformans that did not express the metalloprotease could not cross the BBB, demonstrating its importance in breaching the endothelium and gaining access to the CNS. Furthermore, the team also engineered a non-pathogenic form of yeast that could

Exploiting how C. neoformans crosses the blood–brain barrier may be key to developing a platform technology that will facilitate the delivery of drugs for the treatment of neurological diseases 26

cross the BBB purely by getting it to express Mpr1. STOPPING IT IN ITS TRACKS Revealing exactly how C. neoformans crosses the BBB is an extremely important step in developing methods to prevent infection. If the ability of the fungus to enter the brain can be limited, then the virulence of the meningoencephalitis can be reduced. Gelli’s research therefore has exciting implications for treatment – if we can block the function of Mpr1, the major tool that C. neoformans has to invade the brain, then it will not be able to breach the brain’s defences. Given that we are able to diagnose the presence of C. neoformans in blood serum before patients develop symptoms, this would be a very welcome development. The lateral flow assay, a test that takes ten minutes, can detect the fungus quickly. Being able to block metalloprotease activity and prevent brain penetration would dramatically improve our ability to treat meningoencephalitis.

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Detail What inspired you to start investigating the mechanisms behind C. neoformans’ ability to cross the brain endothelium? The notion that a soil-dwelling fungus could evolve to infect humans and ultimately breach the central nervous system has always fascinated me. I believe that exploring these mechanisms might lead the way to innovative approaches for delivering therapeutics into the brain. How many other vehicles like Mpr1 do you think might exist? At this point we don’t know but we are actively searching for other fungal geneproducts that might play a role in breaching the blood–brain barrier. How much would the ability to get drugs across the blood–brain barrier revolutionise the treatment of neurological diseases? Currently, only about 5% of all drugs penetrate the blood–brain barrier. This is a huge hindrance to treating the many devastating brain disorders that exist. If we can harness the strategies used by this

HOW C. NEOFORMANS CAN HELP CURE BRAIN CANCER Exploiting this new information about how C. neoformans crosses the BBB may also be key to developing novel platform technologies for the delivery of drugs that can treat other neurological diseases. Prime examples of such diseases are aggressive forms of brain cancer such as glioblastoma, the most common form of brain cancer in children, which currently has a mortality rate of around 80%. Most chemotherapy drugs are severely limited by their inability to cross the BBB but Gelli’s research may have found a way to change this. Gelli hypothesises that Mpr1 could be attached to non-toxic nanocarriers laden with anti-cancer drugs to ferry them across the endothelium and into the brain where they can treat aggressive tumours. They have been working with siliconebased nanoparticles, which are easily manipulated and biocompatible.

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pathogen to invade the brain, perhaps we could develop a drug-delivery vehicle that is specific for the brain and do this in a manner that is safe and non-invasive. How quickly do you think we could begin to develop a platform using the Mpr1-mediated pathway across the blood–brain barrier? We are still in the early stages of fully developing the technology and performing proof-of-concept studies. Are there other applications to this mechanism? We have shown that Mpr1 plays a major role in the pathogenesis of C. neoformans – this implies that blocking Mpr1 activity could prevent cryptococcal meningoencephalitis in patients infected with C. neoformans. We are currently performing high-throughput screens in order to identify small molecules that block Mpr1 activity and that could one day be used to treat individuals that are at high risk for developing cryptococcal infection.

They hope to test the ability of Mpr1 to facilitate the internalisation of neurological drugs into the brain using in vitro and in vivo techniques, following three research aims. They will first create a recombinant version of Mpr1 which can effectively penetrate the endothelium. They then aim to track nanocarriers in in vitro models of the human BBB and in vivo models of glioblastoma in mice, before examining the activity of these nanocarriers, this time laden with drugs to treat tumours, in a mouse model of glioblastoma. The dire need for a mechanism to get neurological drugs into the brain to treat life-threatening diseases makes Gelli’s work exceedingly important. The team hope that the Mpr1-mediated pathway is just one of many that they will unearth and can apply to a variety of neurological diseases. Hopefully they will be able to revolutionise chemotherapy and drastically improve clinical outcomes.

RESEARCH OBJECTIVES A large proportion of Dr Gelli’s research focuses on understanding the mechanisms used by fungal pathogens when crossing the blood–brain barrier. In particular, her team’s work looks at the actions of Cryptococcus neoformans, establishing areas of the fungus for drugs to be designed and produced against. These can then be used to combat diseases associated with the pathogen, such as meningoencephalitis. In addition, her work may contribute important data on how to deliver drugs directly to the CNS. FUNDING • National Institutes of Health (NIH) • National Science Foundation (NSF) • The Hartwell Foundation COLLABORATORS • Dr Susan Kauzlarich (Solid State Chemistry Professor, UC Davis) • Dr George Thompson III (Medical Microbiology and Immunology, Clinician, UC Davis) • Dr Eduardo Blumwald (Distinguished Professor Cell Biology, UC Davis) BIO Dr Gelli is a professor in the department of Pharmacology at the University of California, Davis. Professor Gelli has broad scientific and leadership experience conducting research in areas of molecular biology, calcium signalling, fungal pathogenesis and hostpathogen interactions. Dr Gelli is also founder and president of NanoCERE Technologies. CONTACT Angela Gelli, PhD (Professor, Hartwell Investigator) Dept. of Pharmacology, School of Medicine, University of California 3503 Genome and Biomedical Sciences Facility (GBSF) 451 Health Sciences Drive Davis CA 95616-5270 E: acgelli@ucdavis.edu T: 530-754-6446 (Office), 530-754-6179 (Lab), 530-752-7710 (Fax) W: http://acgelli.faculty.ucdavis.edu/

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Alzheimer’s Research UK: Breaking the misperception around dementia Dr David Reynolds is the Chief Scientific Officer for Alzheimer’s Research UK, and a long-serving peer of dementia research. He recently discussed his role with Research Features, emphasising why science cannot afford to forget about dementia.

ementia is a condition that has tormented science for countless years. But now, finally, fresh treatments and cures may be within reach.

That is according to Dr David Reynolds, the Chief Scientific Officer of Alzheimer’s Research UK – one of the largest dementiafocused research institutions worldwide. He recently sat down with us at Research Features to discuss the exciting scientific developments being made within dementia research, highlighting the importance of fundraising initiatives to raise support. Hello David – thank you for speaking with us! How would you describe your role as Chief Scientific Officer of Alzheimer’s Research UK (ARUK)? Alzheimer’s Research UK is the UK’s leading dementia research charity and one of the largest fundraising charities in the world focused on finding solutions to dementia through research. As such, the charity has ambitious research plans and fundraising targets to make those plans a reality. My role as Chief Scientific Officer is to direct the Research Strategy at ARUK, to ensure we fund the highest quality research through the most rigorous processes and that we have our finger on the pulse of the changing

research landscape. I want us to be in a position where we can move quickly to fill knowledge gaps and translate important new findings towards benefits for people with dementia and their families. What are Alzheimer’s Research UK’s core principles in terms of history, heritage and background? The charity was started in 1992 as ‘Alzheimer’s Research Trust’, by a small team of influential people shocked by the lack of investment in research. The first grant was awarded in 1998 to Professor Michel Goedert at the University of Cambridge, whose pioneering research has revealed key insights into the pathology underlying the diseases that cause dementia. Since that time, the charity has funded over 650 projects, investing over £66 million of funding into research. In 2010, our Dementia 2010 report threw into stark relief the huge impact of dementia on

society. Revealing a cost to the UK economy of £23 billion a year – more than the cost of cancer and heart disease combined – the report acted as a wake-up call for government over the urgent need for more research funding. A year later, in 2011, we changed our name to Alzheimer’s Research UK and our work has continued to grow from strength to strength. Over the years, we’ve built a reputation as the charity thinking differently about dementia, using creative campaigns and ambitious research initiatives to challenge misperceptions, shape the research landscape and drive people to get behind this important cause. In 2014, we launched our Drug Discovery Alliance with three institutes at UCL, Cambridge and Oxford – the first of its kind for dementia. Which areas of dementia are you currently researching? We’re a biomedical research charity, which means that much of the research we fund focuses on the biology of the diseases

The dialogue around dementia is changing. For years, research has been on the backfoot, which has not been helped by misperceptions that dementia is just ‘a bit of forgetfulness when people get older’ www.researchfeatures.com

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behind dementia – like Alzheimer’s disease, vascular dementia, dementia with Lewy bodies and frontotemporal dementia. Our knowledge of the pathological changes driving these diseases has grown hugely over the past few decades and is now informing clinical and lab-based research in our portfolio looking at preventions, treatments and diagnostics. Over the past few years, we’ve seen a significant shift in the focus of the research we fund. Whereas five years ago it was necessary to focus on supporting key discoveries in unravelling the causes of dementia, we’re now able to put greater emphasis on translating these breakthroughs towards tangible benefits for people with dementia and their families. Why is it so important to find treatments and cures for dementia-causing diseases? Dementia has now overtaken heart disease as the leading cause of death in the UK, but it’s not an issue just confined to this country. There are a staggering 47 million people across the world living with dementia and with life expectancy rising in many countries, this number is set to increase. There are, of course, strong economic arguments for investment in research for new treatments. A treatment that could delay the onset of dementia by five years would cut the number of people affected by the condition by one third – as well as the cost to the UK economy. But looking behind the statistics tells an equally powerful story. Each number represents a person with a story, a history and a family around them. Dementia puts immeasurable strain, not just on the person but on those around them who often have to put their lives on hold to keep everything together. It’s been almost 15 years since the last dementia drug was licensed and that’s just not good enough. We must continue to ensure that dementia remains at the top of global political agendas and that there is sustained funding for pioneering research that will deliver this progress for those who need it most. What impact do you think Alzheimer’s Research UK has had on dementia research since it was first founded in 1992? Which do you think have been your most significant breakthroughs or accomplishments? Our researchers have made real progress in unpicking the complex biology of diseases like Alzheimer’s. Our funding has revealed over 21 new risk genes for Alzheimer’s – discoveries that are now pointing researchers towards key processes

such as inflammation in the disease. We were also the first to open a dedicated Stem Cell Research Centre focusing solely on harnessing this emerging technology to model key processes in Alzheimer’s and screen potential new drugs. In terms of diagnostics, we’ve funded innovative studies looking at how to detect biomarkers in blood to predict those most likely to develop the disease, as well as supporting teams using sophisticated

algorithms to reveal subtle changes on brain scans that could increase the accuracy of diagnosis. We’ve supported followup studies on failed clinical trials of new Alzheimer’s drugs that are now shaping the ongoing search for new treatments to slow or stop the disease. I’m proud that our funding has supported people and projects that are building our core understanding of the diseases behind dementia and informing future clinical

It’s been almost 15 years since the last dementia drug was licensed and that’s just not good enough. We must ensure that dementia remains at the top of global political agendas www.researchfeatures.com

reality. Our Dementia Consortium and Drug Discovery Alliance partner academic researchers with dedicated drug discovery expertise, with the aim of fast-tracking promising targets towards clinical trials. By partnering with pharmaceutical and biotechnology companies, we can ensure that we’re not wasting time covering alreadytrodden ground and that the targets we are pursuing have the greatest potential to work in patients. Why are these collaborations so important within scientific research? Having worked in the pharmaceutical industry and in academic research myself, I can see the value that each sector brings to partnerships. While academic scientists often have the freedom and creativity to pursue really innovative ideas, the bioindustry sector has the know-how to turn those ideas into medicines and diagnostics that work in the clinic. Bringing these sectors together has proven effective in catalysing the search for new medicines in disease areas like cancer and I’m confident we will see the same benefits in dementia research too. Alzheimer Research UK show dementia in a different light during their #santaforgot advertising campaign

practice around how to best diagnose and treat those affected. Alzheimer’s Research UK is renowned for its collaborative work in the UK and worldwide. Could you tell us some more about the recent collaborations you have formed with The Drug Discovery Alliance and the Alzheimer’s Research UK Dementia Consortium? Dementia is such a huge issue that one organisation alone isn’t enough to crack it. We need charities, industry and government to bring their brains to bear on this problem and each brings important expertise to the table. We’re starting to see dementia science advance to the stage where longheld ideas can be tested in the clinic, but clinical trials are costly and we rely on industrial partners to turn these ideas into

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Have there been any exciting developments recently in terms of clinical trials for potential treatments? Although the number of clinical trials for diseases like Alzheimer’s is low compared to other common diseases, we are seeing some promising drugs coming through the pipeline. In 2013, leaders of the G8 countries set a global ambition to ‘find a diseasemodifying treatment for dementia by 2025’ – a target that has focused attention across the world on this issue. Many of the current Alzheimer’s treatments in clinical trials target the amyloid protein, which builds up in the brain early in the disease. Following on the heels of some high-profile failures of anti-amyloid drugs in clinical testing in recent years, efforts are still continuing with these drugs to see if they can show benefits. While we hope they do, we also need to be conscious of the fact that 99% of clinical trials in Alzheimer’s have failed over the past decade and we must have an effective back-up plan. That’s why ongoing drug discovery initiatives are so important.

clinical trials – giving us the best chance of success for people with dementia. Dementia diseases, such as Alzheimer’s, have recently been named the biggest cause of death in England and Wales. How do you see the landscape of Alzheimer’s research changing over the next ten years? Do you think a cure could be found? Personally, I feel that dementia is coming out of the shadows and rightly so. For years, research has been on the backfoot and this has not been helped by enduring misperceptions that dementia is just ‘a bit of forgetfulness that happens when people get older’. I believe that the dialogue around dementia is changing and thought-provoking initiatives like our #sharetheorange and #santaforgot campaigns are helping to change the conversation. I firmly believe that research can deliver effective treatments and preventions for people with dementia – we’re already on the right track. The next decade will see a new era for dementia research and I’m excited to be part of that. • If you would like to find out any more information and view Alzheimer’s Research UK’s fantastic Santa Forgot advertising campaign, please visit their website at www.alzheimersresearchuk.org.

Contact Alzheimer’s Research UK 3 Riverside, Granta Park Cambridge CB21 6AD T: 0300 111 5555 E: enquiries@alzheimersresearchuk.org W: www.alzheimersresearchuk.org @ARUKnews /alzheimersresearchuk

We need to make sure we have a diverse pipeline of drug targets progressing towards

Innovative technologies expedite cognition drug development Dr Richard Keefe, PhD, is co-founder and CEO of NeuroCog Trials, a company that specialises in creating innovative tools and strategies to facilitate drug development and enhance assessment of cognition and functioning.

Neuroscience

euroCog Trials, a company co-founded in 2004 by CEO Dr Richard Keefe and President Caren Gadigian, develops innovative methods to assess cognition and function in diseases such as schizophrenia, depression, Mild Cognitive Impairment, and Alzheimer’s disease. The overall philosophy of the company is to facilitate drug development with new tools and strategies to enhance signal detection in clinical trials. They do this by developing new approaches that utilise virtual reality and computerised tools to augment the delivery of clinical assessment. Much of this technology has been used in schizophrenia treatment. Schizophrenia is a severe mental illness that affects most patients for their entire life. It impacts a person’s ability to engage with the world, affecting employment opportunities, the formation and maintenance of interpersonal relationships, and the ability to live independently. Although current antipsychotic drugs can help control some features such as hallucinations, they have little effect on the cognitive abilities of patients, so there is a drive to develop treatments that can assist in this domain. As part of a consensus initiative, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project, recommendations were made to standardise the cognitive measures used in schizophrenia trials. As part of this, a set, or ‘battery’ of tests was developed that would accurately measure change in patients’ cognitive function, divided into seven cognitive domains: speed of processing, attention/vigilance, working memory (verbal and non-verbal), verbal learning, visual learning, reasoning and problem solving, and social cognition. A VIRTUAL REALITY ASSESSMENT The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a computerand web-based tool that assesses patients’

ability to perform tasks that are a common part of everyday life, such as travelling on public transport, paying for shopping etc. The battery aims to measure functional capacity, or “real-world functional improvements associated with cognitive change” [Keefe et al., 2016]. The VRFCAT differs from other assessment tools because it is computerised and performance-based. This means there is the potential for this test to be delivered remotely, and an outside observer or informant of a patient’s behaviour, such as a family member, is not required. Other tests, like the UCSD Performance-based skills assessment (UPSA), have previously relied on pen-and-paper tests, with a role-play component that requires patients to act out certain tasks. However, many of these tasks, such as writing cheques or calling a phone directory, are now somewhat out-dated. The VRFCAT has six alternative versions which allows the test to be administered repeatedly over time, without the patient’s scores improving simply because they have performed the test previously, the so-called ‘practice effect’. HOW WELL DOES IT WORK? The NeuroCog Trials team assessed patients and healthy controls with a variety of different metrics to compare how well the VRFCAT performed at measuring functional capacity against other tests. The VRFCAT compares well with other measures, such as the UPSA, which has previously been used in trials. Different versions of the VRFCAT were used to measure the differences between them. The high degree of correlation between the VRFCAT and UPSA suggests that the VRFCAT is a useful tool that accurately measures the functional capacity of users. There was clear differentiation between the scores of schizophrenia patients and healthy controls. Better test times were associated with lower degrees of cognitive impairment as measured on the Schizophrenia Cognitive

NeuroCog Trials develops innovative technologies that utilise virtual reality and computerised assessments to augment the measurement of cognitive and functional abilities in clinical trials 33

Neuroscience

Rating scale (SCoRS) and higher Specific Levels of Functioning (SLOF) scores. DIGITISING EXISTING TESTS Another of NeuroCog’s innovative projects is the Brief Assessment of Cognition (BAC) App, which is a tablet-/app-based version of the pen-and-paper Brief Assessment of Cognition in Schizophrenia (BACS) test battery. The test measures a user’s ability to perform six tasks to assess their reasoning/ problem solving, working memory, verbal memory, and processing speed. In a paper co-written by Alexandra Atkins and others, Keefe and team compared the results of the BACS and BAC App methods. They found that there were no discernible differences between the traditional version of the test and the app version, and that there was a robust difference between schizophrenia patients and healthy controls. This supports the notion that the BAC App is appropriate for use in clinical trials. Tablet-based methods are useful because they allow the incorporation of all the benefits of computerised methods, such as standardised algorithms and voicedover instructions, while maintaining the interaction with the patient, which is important in cognitively-impaired or behaviourally-challenging populations such as patients with schizophrenia or Alzheimer’s disease. LOOKING BEYOND SCHIZOPHRENIA The VRFCAT and BAC App have potential applications beyond schizophrenia – for instance they are being tailored specifically for studies of patients with Mild Cognitive Impairment associated with Alzheimer’s disease, and are currently being used in trials of patients with depression and those at-risk for bipolar disorder.

Above and right: screenshots from the VRFCAT. Below: examples of the BAC App in action.

Novel technologies such as virtual reality and simple apps are increasingly being recognised as effective methods to administer treatment and assist with diagnosis. NeuroCog Trials’ wealth of scientific expertise will enhance clinical outcomes associated with diseases like schizophrenia and Alzheimer’s that impair sufferers’ cognitive abilities.

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Detail How has your scientific training informed your work as part of NeuroCog Trials? Everything we do at NeuroCog Trials is grounded in scientific principles. As a clinical psychologist, I was trained to pay very close attention to detail, as small changes in any experiment can have a substantial effect. Getting at the truth in human assessment is a fascinating endeavour, but you need to be trained not to fool yourself that you have a clinically significant finding if it is due to a weakness in your design and interpretation. We help companies design studies and create new outcome measures that get at the real effect of their treatments. What are the similarities between schizophrenia and Alzheimer’s disease? They are both cognitive disorders caused by neurobiological abnormalities of unclear origin. While Alzheimer’s research is farther along in terms of understanding some of the specific brain processes that are affected, both disorders have cognitive impairment as their core symptom. We have leveraged some of the work that I have been doing for 30 years in schizophrenia to create new tools for assessment in Alzheimer’s, which has been warmly welcomed by researchers in both areas of work. These are two of the worst conditions in all of humanity, and treatments are desperately needed. Are there other diseases you think your tools are particularly applicable to? Yes. We have been working in several other areas. The first is risk syndromes, such as the identification of people who are at risk for Alzheimer’s, schizophrenia, or bipolar disorder, yet have not yet developed the full-blown version of the illness. We have built our tools to be sensitive to subtle changes that occur before the illness strikes. That is the best time for treatment to begin,

but you need to know who has the illness and who does not. We feel our tools can help with that important prediction. We are also working in major depression and areas outside psychiatry, such as brain cancer, Multiple Sclerosis, and Opioid Use Disorder. Have you been able to see the benefits of the technologies your company has developed in action? Yes. It has been tremendously rewarding to see the use of our technologies in large-scale clinical trials. Our video recording platform was instrumental in identifying thousands of errors in test administration and clinical assessment across over 300 international assessment sites. Improvements in data lead to greater sensitivity to treatment effect, which is our primary goal. Our new tablet- and computer-based cognitive and functional assessments are being used in large trials, and so we are excited to see the results from these studies. We want to be a part of the programmes that develop treatments that can reduce suffering in these patients. That is our primary goal. What is next for NeuroCog Trials? We are building on the success of our new technologies. We are designing our assessment tools so that clinicians and raters feel not like they are dealing with burdensome new devices, but rather like they have been given natural extensions of themselves, helping them connect with their patients and the symptoms that are causing them pain. And we are thinking not in terms of how can we compete to make better devices than our competitors, but rather how we can provide the scientific community with tools that will reshape clinical assessment and clinical trials for the future.

Tablet-based administration of tests is useful because it incorporates the benefits of standardisation while maintaining the importance of the patient interaction www.researchfeatures.com

RESEARCH OBJECTIVES Dr Keefe’s work applies innovative strategies in neuroscience to measure human cognition. He co-founded NeuroCog Trials with this aim in mind and the company now works to develop cognitive assessment tools for use in clinical trials. FUNDING The company is privately owned and receives Small Business Innovation Research grants from the National Institutes of Health in the United States COLLABORATORS NeuroCog Trials was founded from Dr Keefe’s lab at Duke University Medical Center and maintains strong ties with many Duke faculty and other leading scientists in academia, government and industry. BIO Dr Keefe graduated from Princeton University, received his PhD in clinical psychology from NYU and completed his clinical psychology internship at Yale University School of Medicine. He is currently Professor of Psychiatry, Psychology and Neurosciences at Duke University Medical Center and has published over 220 peerreviewed scientific papers on cognition, schizophrenia, dementia, depression and other CNS disorders. CONTACT Richard Keefe, PhD CEO and Co-founder NeuroCog Trials 3211 Shannon Road, Suite 300 Durham, NC 27707 USA E: richard.keefe@duke.edu T: +1 919 401 4642 W: http://www.neurocogtrials.com/ /richard-keefe-9b126418

Bad Breaks: how stress and meth use combine to dramatically weaken the bloodâ&#x20AC;&#x201C;brain barrier Professor Yamamoto at Indiana University, and his collaborators, are cooking up new explanations for why stress and meth use are a common toxic mix â&#x20AC;&#x201C; a mix which breaks down the barrier that protects the brain from potentially deadly toxins and bacteria.

Neurology

he blood–brain barrier (BBB) is a unique lining of tightly connected cells in all the blood vessels of the brain. This creates a barrier between the cerebrospinal fluid (the liquid which surrounds the brain and spinal cord) and the circulating blood; this barrier is impervious to large, hydrophilic (water-soluble) molecules and bacteria. It allows the passive passage of lipid-soluble molecules and gases, such as oxygen and carbon dioxide, and contains proteins which provide an active transport system for essential nutrients such as glucose. This protects the brain from the majority of large and potentially toxic molecules which might be dissolved in the blood, whilst providing all the substances necessary for normal brain function. It is a unique feature of the blood vessels of the brain, not found anywhere else in the body. This barrier has a distinctive purpose and its correct functioning is vital to human health. Methamphetamine, n-methylamphetamine known colloquially as ‘meth’, is a potent psychoactive stimulant used as a recreational drug. For this reason, its use and supply

are heavily restricted in most countries. It is well-known to be a highly addictive drug but the damaging effects that it can have on the brain extend beyond addiction and are less widely-known. This neurotoxicity (potential for damaging the brain) is well documented and is a significant factor in its removal from use as a therapeutic drug, and subsequent restriction in an attempt to prevent recreational use. Despite this, its misuse is prevalent across Asia and the United States of America, leading to the requirement to better understand the patterns of use and potential for causing disease. BREAKING DOWN THE BARRIER A number of factors are known to affect the tight junctions of epithelial cells in the BBB (special proteins that hold the cells close together to restrict diffusion between them). Ischemic stress associated with stroke is one such factor, and it is this which has provided the key to Prof Yamamoto’s work. Ischemic stress (a state of low oxygen that is deadly for cells) results in neuroinflammation, the release of signalling molecules in the brain in much the same way as when any other part of the body is damaged and becomes sore

No stress + Saline

Stress + Saline

No stress + Meth

Stress + Meth

The green fluorescence is restricted normally to the brain capillaries but diffuses out of the capillaries into the brain tissue when exposed to Meth. This effect of Meth is exacerbated when combined with chronic stress.

Neurology

A magnified image shows that the green dye highlights the capillaries in the brain but the capillaries become leaky and the dye diffuses out of the capillaries after exposure to Meth.

A. Intact BBB

What first attracted you to the research of drugs of abuse and addiction? My research background is in neurodegenerative disorders and the mechanisms underlying those disorders. The findings that drugs of abuse and addiction produce such pervasive changes in the brain and behaviour prompted me to examine if similar mechanisms underlying neurodegenerative disorders also underlie drugs of abuse. How will your research help those recovering from meth addiction? We have applied our thinking about neurodegenerative disorders to problems related to the consequences of meth addiction. We and others are beginning to understand how molecules that play a role in neuroinflammation and neurodegeneration may also be involved in changes that occur within the brain after exposure to meth and that these chemical changes during withdrawal from drug use could be involved in precipitating relapse to drug taking. Therefore, we may be able to curb relapse to drug taking by

B. Permeabilized BBB

mitigating the chemical changes that occur during withdrawal from drug exposure. What is unique about the way you are researching neurological damage from drug abuse? Past efforts have appropriately focused only on the drug per se, in order to understand how the drug works. However, now that we have a fairly good idea about the action of the drug alone, we can try and model the more realistic situation whereby drug abuse most often co-occurs with a variety of other conditions, such as stress. Thus, we are trying to unravel the complex interactions between stress and drugs of abuse that increase the liability to addiction and brain injury that may not be explainable by simply studying the drug in isolation. Moreover, the traditional line of thinking with regard to drug addiction is that the primary effect is due to the direct action of the drug on the brain. We now have evidence that the action of the drug outside of the brain on peripheral organs can initiate inflammatory processes that are responsible for the drugâ&#x20AC;&#x2122;s neurological effects. Damage to the bloodâ&#x20AC;&#x201C;

brain barrier increases the probability that peripheral factors can enter the brain and have neurological effects. After uncovering the mechanism of neurological damage, what is the next step in developing effective treatments? Once the mechanisms of the neurological damage are understood, those mechanisms can now serve as targets for possible therapeutics. It is important that there be a clear understanding of the precise mechanisms involved that in turn, could be selectively targeted to avoid untoward side effects of the treatment. Where do you think drug abuse research will be focused in the future? An important focus of drug abuse research in the future would be on effective treatment strategies that are based on solid scientific findings. Efforts on strategies that prevent drug addiction are admirable but more efforts directed toward understanding how we treat an established addiction and the relapse to drug abuse are needed.

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and swollen. One effect of this is to reduce the concentration of these tight junction proteins, possibly through post-translational modifications, resulting in an increase in permeability of the BBB. The same situation is observed in both stress and acute highdose meth use; the first through an increase in cyclooxygenase (COX, an inflammationpromoting enzyme), the second through an unknown mechanism which may well be similar to that responsible for meth’s neurotoxic properties. Neuroinflammation is also known to be involved in diseases induced by chronic psychological stress, and chronic stress is known to be associated with increased recreational drug use (known as co-morbidity). Prof Yamamoto’s hypothesis is that this chronic stress causes neuroinflammation which, in turn, exacerbates the damage to the BBB caused by meth use. His aim is to now uncover the mechanism by which meth use contributes to BBB damage, with the long-term goal of assessing how these co-morbidities impact on human health over time. Once these effects are understood, there will be an improved knowledge base on which to build effective treatment strategies. STUDYING STRESS Prof Yamamoto’s group are the first to successfully demonstrate increased neurotoxicity from combined stress and meth use. To date he has also shown that the scope of meth damage is larger than the traditional models of neurotoxicity allow for, with structural damage to the BBB a significant element. He has now begun to show that this structural damage, exacerbated by chronic stress, is persistent rather than transitory – a significant consideration in the treatment of recovering addicts. By using self-administration regimens of drug abuse in animal models, combined with proven methods of inducing a chronic stress response, Prof Yamamoto’s group are able to study this co-morbidity in a unique

manner. This method more accurately mimics the situation in human drug abuse situations where self-administration is the norm. It also follows the pattern of drug abuse related to chronic psychological stress, such as in those suffering from post-traumatic stress disorder, where half of long-term sufferers have turned to recreational drug use. By then measuring markers of BBB integrity, such as the concentration of tight junction proteins and the diffusion of fluorescently-labelled molecules of varying sizes, Prof Yamamoto’s group will be able to clearly establish the long term effects of this co-morbidity. REBUILDING THE DEFENCES Once these mechanisms are established, and the role of COX-mediated neuroinflammation investigated, the group aims to use treatments already shown to combat neuroinflammation to restore BBB integrity. This is important for the treatment of meth abuse, because it has the potential to reduce not only the neurotoxicity associated with the drug itself, but also the associated rise in other neurotoxins in damaged brains and the prevalence of bacterial and viral infections in addicts. A weakened BBB is particularly dangerous in this instance as it is in place specifically for the purpose of preventing the spread of infection to cerebral tissues. Prof Yamamoto has spent his career fighting against drug abuse in an unusual way, by investigating both its damaging effects and the way it interacts with associated psychological conditions. The fact that drug abuse does not exist in isolation, but rather is precipitated and exacerbated by these conditions, makes this research vital in addressing the health and social impacts of meth abuse in particular. Prof Yamamoto’s research is bringing to light previously unknown effects of meth abuse, which promises to have a significant impact on future treatment and therefore recovering addicts’ outcomes.

Detail RESEARCH OBJECTIVES Professor Yamamoto and his team focus their research on the mechanisms behind the toxicity of psychostimulant drugs. In particular, they focus on methamphetamine and MDMA – both widely abused drugs that cause neuronal damage of which little is known. FUNDING These projects are funded by the United States National Institutes of Health grants: DA007606 and DA035499 COLLABORATORS • Nicole A Northrop, PhD • Reka Natarajan, PhD BIO Bryan Yamamoto, PhD, is Professor and Chair of the Department of Pharmacology and Toxicology and the Robert B. Forney Professor of Toxicology at Indiana University School of Medicine. His research over the last 28 years has focused on how drugs of abuse affect the neurochemistry of the brain and cause brain injury. CONTACT Professor Bryan Yamamoto 635 Barnhill Drive Room A401 Indianapolis, IN 46202 USA E: brkyama@iu.edu T: +1 317-278-8590 W: http://pharmtox.iusm.iu.edu/faculty/ bryan_yamamoto/ bryan-yamamoto-ba95962a

Prof Yamamoto’s hypothesis is that chronic stress causes neuroinflammation which, in turn, exacerbates the damage to the blood–brain barrier caused by meth use www.researchfeatures.com

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ESO: The structural backbone of European stroke research Dr Valeria Caso is the current President of the European Stroke Organisation (ESO) – an institution who represent the voice of stroke disease within Europe. She recently spoke to us at Research Features to emphasise the current situation within stroke disease research, clarifying what further research needs to be done to ensure improved patient outcomes in the future.

ounded only 11 years ago, the European Stroke Organisation (ESO) has announced itself as the voice of stroke research across Europe. Working collaboratively with some huge corporate partners, including AstraZeneca and Boehringer Ingelheim, ESO are going above and beyond to ensure stroke research receives the funding and attention it requires. Not only that, but they are adding a stroke of organisational genius to the development of treatments and rehabilitation methods for stroke disease sufferers. We spoke with Dr Valeria Caso, the President of ESO, to ascertain the influence her organisation has had on improving stroke research in Europe since its inception back in 2007. Hello Valeria! Could you tell us a bit more about your role as the President of the European Stroke Organisation, outlining the kind of responsibilities and objectives you have there? My main goal is to ensure that stroke treatment is delivered in the same way all over Europe. We are currently updating our

guidelines to highlight the main objectives for stroke clinicians, physicians and researchers. We want to develop a research plan – a treatment plan – to outline what the objectives are that we must reach by 2025. I will leave my post as President in 2018, so this is now my key focus – to review the burden of non-communicable disease in Europe and outline the major goals we must reach by 2025. Could you tell us a bit about ESO’s background and the work into stroke research that you do there? Our aim is to be the voice of stroke in Europe, which I think we have now become. If you look at our conference’s main trials and the research presented during our recent conference, you can see how the leaders of stroke research are all now a part of our society. In fact, most of the research that is currently being funded within stroke treatment is carried out by our members. The society itself was founded in 2007, where we initially existed as a conference managed by one of our colleagues. We then decided as a big society to take over this responsibility and organise the conference

The ethical approach to future work is very important. It is vital to ensure that research is carried out ethically, effectively, within the right hands, and with the right level of care 41

Spotlight

ourselves as an organisation. Our vision for this was to make our conferences purely academic, not-for-profit events, which ensure that what we are doing is based on quality science, rather than a continual beg for support. ESO has several corporate members, including AstraZeneca, Amgen and Boehringer. How important is it to have these worldwide collaborations with other research institutions, especially in terms of enhancing stroke research and improving patient outcomes? For me, it’s fundamental. It’s important to collaborate with industry because it can provide an important analytic difference to the improvement of healthcare. For example, we’re working on a very important project now in Eastern Europe, called ESO-EAST, where we hope to improve stroke treatment and awareness in Eastern European countries. This project has been supported by Boehringer Ingelheim and EVER Pharma, two of our industry partners. It’s not about luck; it’s about how research can receive unrestricted grants to continue vital work. ESO recently ran a ‘Stroke Update’ conference in Stockholm. Could you tell us some more about this, and why these events are so important in progressing stroke research? We run a big conference annually called the ESOC – our European Stroke Organisation Conference – and then we also run an event every three years called The Karolinska Stroke Update. These are events where we discuss current guidelines and issues within stroke research with an audience, the president and other stroke-related professions who are present. We provide a method for the audience to participate and be involved because we believe this is vital to progressing stroke research. For example,

this year we discussed how to reach cognitive end points in neurological trials, so it’s important to provide a platform where all members can interact with the thinking process. These events are open to everyone, so anyone can be involved – including stroke sufferers themselves. We have another closed event as well called the European Stroke Science Workshop. This is a science workshop where we meet physicians and researchers from all over Europe to discuss the latest research developments. This event can be very positive for younger physicians especially, as it offers them an opportunity to present their latest findings. What kind of influence has ESO’s work had on stroke research? Do you have any examples of accomplishments you are particularly proud of? We have seen a huge influence as a result of our work. One notable example of this has come from my university where students came to study from Eastern Europe. When they left my institution, they were equipped with many tools and techniques that will help to progress stroke research back in their home countries. For example, they were taught how to write research papers and specific transcripts, and were given an opportunity to carry out research – collecting data themselves and writing it up. There’s a particular style you need for this, especially within science: when you know there is a problem, you must find a way to solve it. To do this within Eastern European countries, you must firstly understand where the problem is and learn how to collect data without using the computerised stroke registries that more developed countries are used to. In these countries, you can go through the registry and in just five minutes have the data you need sent straight back to you. This is something that doesn’t exist in Eastern Europe, so it’s important to teach stroke researchers, from less-developed countries especially, techniques that can

help them to obtain data wherever they are in the world. It’s fantastic to see how much colleagues without funding do for stroke patients, and it is especially satisfying to witness the determined intentions of our researchers. What we as a stroke organisation need to do is support them. Even if the standard of their research is different to ours, we can ensure that the work they are doing is worthwhile and helping the wider community. Aside from your role as President of ESO, you are also a stroke neurologist at the University of Perugia Stroke Unit in Italy. How does it feel to be such a recognised peer of stroke research? Is it ever difficult

My main goal is to ensure that stroke treatment is delivered in the same way all over Europe. We want to develop a research plan that outlines the major goals we must reach by 2025 42

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Dr Valeria Caso (middle right) alongside colleagues at ESO's recent Stroke Update Conference in Stockholm. From far left: Prof Natan Bornstein; Dr Nemanja Popovic; Dr Kateryna Antonenko; Prof Valeria Caso; Prof Dejana Jovanovic; Dr Ziyoda A Akbarkhodjaeva; Dr Tamar Saldadze; and Dr Robert Mikulik.

the rules surrounding the administration of stem cells need to change. They need to be administered in a controlled manner, to ensure their ethicality and safety during randomised trials. The ethical approach to future work, especially in terms of stem cells, is very important. It is vital to ensure that research is carried out ethically, effectively, within the right hands, and with the right level of care.

finding the time to balance both these positions? That’s such a good question because I don’t know! It’s a lot of work, I can tell you that for sure, but you already know that when you take on the responsibility of being President. I have worked in this job for two years now but have had a strong motivation to do it throughout. When I first started, I was in a great position because of the excellent preparation and groundwork my predecessors had left. My main objective throughout my presidency was to expand the political influence of ESO, which has been surprisingly easy. There is now a large amount of interest in our organisation because we are at a recognisable level to achieve the objectives that we set out. What are the ethical considerations you have to take into account when researching stroke disease? How do you conform to these at ESO? So, at ESO we follow the Declaration of Helsinki, and it is very important to reflect the ethics of this in the research we fund. This is something we absolutely need to do. We need to be compliant with all the rules

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that are set out for us, and we need to be the organisation that supervises researchers so that nothing happens outside the current ethical view of research. Where do you see stroke research going over the next ten years or so? Are there any areas you are particularly excited about? I think what we are particularly excited about looking into are the cognitive aspects of stroke disease – the decline of motor functions within the brain during strokes. During all of our trials, we need to understand that we are not only working on the vascular aspects of stroke health within the brain, but we also need to consider the affect of strokes on cognitive function. The second area we need to look at is rehabilitation. Patients are living longer and longer, and some will have a disability for twenty, thirty years. We need to give them the opportunity to work on their disability, by progressing research in areas such as virtual reality, robotic rehabilitation, and potentially even stem cells. We are not yet able to say whether stem cells will have any effect: further research has to answer this question. In order for this to happen though,

• Dr Valeria Caso is the current president of the European Stroke Organisation. Aside from her presidency, she has authored and co-authored more than 200 published research papers and acted as a peer reviewer for countless others. Her own research has been largely related to international projects looking at cervical artery dissections, intracerebral haemorrhages and acute stroke treatments. Dr Caso is also a stroke neurologist at the University of Perugia, where she has supervised several masters, residents and MD-theses. Currently, her personal research focuses on preventing stroke disease within women, looking at the underlying mechanisms behind stroke disease onset.

Contact European Stroke Organisation (ESO) PO Box, 4002 Basel/Switzerland E: esoinfo@eso-stroke.org T: +41 61 686 77 76 W: www.eso-stroke.org /ESOstroke

How to tackle disparities in HIV healthcare

The experiences and healthcare outcomes of people living with HIV can vary greatly depending on a multitude of factors, including level and type of care, drug use, race and gender. With a research background in health outcome disparities in minority groups, Associate Professor Amy R Knowlton from the Johns Hopkins Bloomberg School of Public Health, is conducting innovative longitudinal research to discover how we can improve the quality of life of people with HIV and their caregivers.

ue to recent advancements in medical knowledge and treatment methods, HIV-positive individuals are now living longer. However, as they age they often experience higher levels of chronic pain and disability, particularly among past and current drug-using persons. This has led to research that is focused on how best to provide care for

people living with HIV and how to ensure their needs are met as they approach end-of-life. Although almost half of the people living with HIV/AIDS in the US medical system are African American, and almost half have current or past drug use disorders, there are very few studies that focus on their specific care needs. Dr Knowltonâ&#x20AC;&#x2122;s research findings suggest that current illicit drug use impacts vulnerable

populations' HIV treatment success through its adverse effects on the quality and function of their supportive relationships. Results of a study of drug-using persons on HIV treatment indicated that among those with high social support, 61% of former drug users, compared with 30% of current drug users, had controlled levels of plasma HIV. Among those with low social support, there was no significant difference in viral control for current as compared to former drug users; 23% of current drug users were virally controlled as were 27% of former drug users. African Americans and drug users have higher morbidity and mortality rates than whites and non-drug users, and this is related to their challenges in engaging with healthcare providers, maintaining caregiving (unpaid, emotionally or instrumentally

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Minority Health

term effects of distressing symptoms and caregiving on both patients’ and caregivers’ quality of life. The findings will enhance understanding of the best approaches to sustain caregiving to African American drug users living with HIV. INFORMAL CARE: BLESSING OR BURDEN? One of the most striking points to come out of Dr Knowlton’s work is the importance to HIV-positive drug-using persons’ engagement in medical care and treatment adherence of their informal caregivers (defined as persons providing unpaid emotional support or instrumental assistance to someone with a chronic or disabling condition), and the challenges faced by these caregivers. Disadvantaged African Americans have been found to provide higher rates of caregiving compared to more advantaged and white US populations. Informal caregivers tend to be family or friends, and previous studies have found that most persons with HIV who use drugs report a main caregiver who is either their kin or main partner. Dr Knowlton’s prior studies have found that the receipt of informal care, and better communication between caregiver and patient, are associated with optimal adherence to HIV treatment and viral control.

supportive) relationships, and adhering to HIV medications. These populations also suffer significantly from chronic pain (which has been defined as pain that occurs on at least half the days for six months or longer) that is often underestimated and under-prescribed for by health professionals. SETTING NEW GOALS Working towards increasing the quality of life of people with HIV, Dr Amy Knowlton is currently working on the AFFIRM Care project. This project aims to investigate the complex themes of chronic pain, palliative care interests, and the role of caregivers. Dr Amy Knowlton's work focuses specifically on African American populations living with HIV/ AIDS, with an emphasis on enhancing their equitable care and support, and quality of life. The AFFIRM Care study examines the long-

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However, providing care often comes at a cost. Dr Knowlton's prior studies have found that a third of caregivers doubt their ability to continue and almost two-thirds feel they have no-one they can turn to to discuss the challenges they face in their care provision. Furthermore, many caregivers perceive a sense of HIV stigma by association, presenting an additional barrier to their ability to establish strong support networks. Lastly, Dr Knowlton has identified a gender imbalance in the benefits of receiving informal care. For men, having a main partner and reciprocating support from their partner were associated with better adherence to HIV treatment. In contrast, adherence to HIV treatment in women has been found to be greatest (92%) in those with no main partner and lowest (57%) in those with an HIV-positive partner. This is thought to arise from a difference in gender roles, with women’s ability to self-care compromised by the demands of caring for their partner. CHRONIC PAIN AND DRUG USE A high proportion (30–60%) of Americans in HIV medical care suffer from chronic pain, which has a significant negative impact on their wellbeing and quality of life. Dr Knowlton’s work has found that the negative

impact of chronic pain reaches far beyond the immediate effects on individuals. The presence of chronic pain in people living with HIV has been found to reduce their reciprocity of support to their caregivers and affect negative interactions (e.g., insensitive interactions, unwanted advice, neglect, or rejection) with their support network members. Chronic pain, independently of depression or current drug use, is also associated with poor communication with and lower trust of their healthcare providers, which in turn is associated with their non-adherence to HIV treatment. Chronic pain is also associated with depression and drug-use relapse, which often results in poor engagement with HIV healthcare and low success of HIV treatment. The links between pain and drug abuse are further complicated amongst opioid users by the possibility of opioid-induced hypersensitivity to pain and opioid tolerance. These two conditions are often difficult to distinguish, may co-occur, but require very different treatment. Furthermore, drug users are less likely to be prescribed effective pain medication due to fears from health professionals of abetting their addiction. However, a good rapport between patient and healthcare provider has been shown to have a positive effect on pain management. BREAKING THE BARRIERS To address these challenges, Dr Knowlton is currently focusing on palliative care, a medical speciality new to the US that aims to enhance the quality of life and reduce suffering of people living with a serious illness. The AFFIRM Care study will assess patients’ chronic pain, treatment aims and end-of-life healthcare preferences. It will inform how palliative care principles can be introduced into routine HIV clinical practice. It will also facilitate communication among patients, caregivers and medical providers to encourage collaborative treatment decision making. Additionally, the findings will inform how to involve caregivers in the advance care planning of patients with mental or drug use disorders to ensure their care is aligned with the patients’ care preferences if they become unable to make healthcare-related decisions. Dr Knowlton’s study also aims to address the issue of caregiver stress and burnout. The study will longitudinally examine caregivers’ resource and skills needs to promote their quality of life and inform ways to facilitate sustained care through end-of-life whilst minimising the possibility of care cessation.

Your research focuses on disadvantaged racial/ethnic minorities living with HIV/ AIDS and current or prior drug abuse. Why do you think this is an important population to study and understand? African Americans and those with a drug-use disorder make up a large proportion of the population of persons with HIV/AIDS in US medical care. These populations continue to have significant challenges engaging with healthcare providers and accessing and adhering to HIV medications, which affects their higher morbidity and mortality rates compared to whites and non-drug using persons with HIV/AIDS. African Americans living with HIV/AIDS and drug use disorders have major challenges with chronic pain and suffering, which is inadequately acknowledged or addressed in clinical care. In our studies, two-thirds of our samples report chronic pain that interferes with their function. We have found in our current study that chronic pain interference in function is associated with low adherence to HIV treatment; only 39% reported excellent adherence to HIV treatment, which is necessary for viral control. Why do you think caregiving is important to study in this population? Our research findings reveal that caregivers have major positive influences on the population’s engagement in HIV healthcare, treatment adherence, and viral suppression, over and above effects of depression and active drug use. Of the HIV patients on HIV treatment in our prior study, half reported current heroin or cocaine use, 44% unstable housing, 79% pain symptoms (32% often or always), 40% memory problems, and yet 70% had treatment success, as indicated by a controlled viral load. Our findings have revealed that this patient population’s receipt of informal care, better communication with, and reciprocity of support to their caregivers, were associated with their improved depressive symptoms and HIV treatment adherence and their viral control.

Our results underscore the degree to which caregiving is normative in disadvantaged African American communities, and that caregiving can be considered a critical aspect of their social capital, and a vital community resiliency. Your current study is examining the study population’s interests in palliative care. What is palliative care and how does it differ from the traditional model of medical care in the US? In the US, aggressive medical care is the default care approach through end-of-life, even when little to no benefit is expected for the patient’s health and wellbeing. Alternatively, palliative care is concerned with managing serious, often chronic or potentially life-limiting, conditions for which there is no cure. It aims to reduce patients’ pain and suffering, optimise their function, and to enhance the quality of life of patients and their caregivers through end-of-life. It recognises that caregiving relationships are the main structure of people’s care, and supports caregivers’ roles in patients’ health and well-being, in part by facilitating their engagement in patients’ healthcare. And it can be used at any stage of serious illness, and along with curative or aggressive therapies. Palliative care emphasises interpersonal communication to establish patient-caregiverdoctor collaborative decision making and mutual understanding of the goals of patients’ healthcare and their treatment preferences through end-of-life. Advance care directives are considered important for promoting patient autonomy and dignity at end-of-life. Yet only a fifth of US adults complete advance care directives, and much less so among disadvantaged and African American populations. Palliative care also encourages patients to designate a proxy healthcare decision maker. The study population has low marriage rates and caregivers of more diverse role relations than legal definitions of next-of-kin. So, it is especially important for them to choose and formally document their designated healthcare decision makers.

One female study participant tearfully described her experience of her commonlaw husband’s end-of-life with AIDS-related dementia. She reported that she and his mother waited helplessly by his hospital bedside for a week as he lay in a coma, waiting for his 21-year-old son to be located to give doctors legal permission to remove him from kidney dialysis and ventilation machines. She said that she and his mother were certain he would never have wanted all the aggressive treatment he was given, and regretted his suffering for it. Research to date suggests that palliative care in the US healthcare system can positively impact patient and caregiver depression and anxiety, quality of life, and patients’ healthcare costs, and even longevity of terminally ill persons. Palliative care is especially relevant to the study population as they often have chronic pain and other complex multi-morbidities, high utilisation of acute care services and intensive treatments, and little clinical attention has been given to their quality of life. Thus, for HIV, it has been recommended that palliative care programmes primarily address chronic pain, and that palliative care principles be incorporated into routine clinical practice for HIV patient care at any illness stage.

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Minority Health

Detail RESEARCH OBJECTIVES Dr Knowlton’s work focuses on the health experiences of minority groups. Her current project looks at the experiences of HIV-positive African Americans with a history of drug abuse. FUNDING • NIH: National Institute on Drug Abuse • NIH: National Institute of Nursing Research COLLABORATORS • Cynda Rushton, PhD • Thomas J. Smith, MD • Nancy Hutton, MD • Jessica Merlin, MD • Jennifer Wolfe, PhD • Lee Bone, RN • M ary Mitchell, PhD

In what way is your Affirm Care study of relevance to health policy on advance care planning? The AFFIRM Care study period coincides with implementation of landmark US (Maryland) state legislation to promote advance care planning through Maryland Medical Orders for Life-Sustaining Treatment (MOLST). The legislation requires that MOLST forms be filled out by/for all hospitalised patients with serious health conditions and that these be used by care providers as direct medical orders. In the absence of MOLST forms, the default is usually aggressive end-of-life care. In practice, the legislation has been slow to implement, in part because there has been little education of the public, patients or healthcare providers. The present study will examine this process, explore patients’ understanding of the forms, and educational or training needs to improve their advance care planning and healthcare decision maker designation. You have begun working with religious leaders as part of the study. Why is that important to promoting palliative care and advance care planning? A significant proportion of AFFIRM study participants report a reluctance to engage in palliative care or advance care planning as they perceive that it shows a lack of faith

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in God to determine their fate. We have found that local faith leaders are highly supportive of palliative care and advance care planning and confirm its consistency with their religious doctrine, and thus may play a potential role in educating the public about it. They report that in the absence of patients’ advance care planning and designation of healthcare decision makers, they are frequently called on to make such decisions or mediate family disagreements about end-of-life care, a role which they felt they are ill-equipped to do. As part of the AFFIRM Care study and at the request of a pastor on our community advisory board, we convened a workshop for local African American faith leaders to learn about ways to link their congregants and health ministries to medical and behavioural health services, to link with their caregivers, and resources for promoting their community members’ palliative care and hospice use. We are now in the process of developing and piloting an intervention that engages the patient population, their caregivers and healthcare providers, and local faith leaders in promoting chronic pain management and other forms of palliative care as well as advance care planning.

BIO Amy Knowlton is an expert on the role of support networks and caregiving relationships in healthcare and treatment adherence and its health impact among vulnerable populations with potentially stigmatising conditions. The research findings inform the development and testing of models of home- and communitybased HIV care through end-of-life. CONTACT Amy Knowlton, ScD Associate Professor Johns Hopkins Bloomberg School of Public Health 624 N. Broadway, Room 745 Baltimore, MD 21205 E: aknowlt1@jhu.edu T: +1 410 502 5368 W: http://www.jhsph.edu/faculty/ directory/profile/994/amy-r-knowlton MORE INFO: • Coalition to Transform Advanced Care: C-TAC www.thectac.org/ • End-of-Life Nursing Education Consortium - American Association of Colleges of Nursing www.aacn.nche.edu/elnec • Cambia Health Foundation www.cambiahealthfoundation.org/

How Indigenous Traditional Medicine and modern science are working together to combat diabetes With global diabetes rates on the rise, particularly in Indigenous communities, Professor Pierre S Haddad from the UniversitĂŠ de MontrĂŠal has been working with Canadian Indigenous populations to investigate how medicinal plants can be used for diabetes treatment. Their work aims to translate Indigenous Traditional Knowledge into scientific language and provides an exemplary template of how to conduct research on Traditional Medicine.

Minority Health

lobal cases of diabetes mellitus (DM) have increased dramatically over the last few decades and are predicted to continue, with the International Diabetes Federation (IDF) predicting one person in ten to be diabetic by 2035. Type 2 DM (T2DM) is characterised by the bodyâ&#x20AC;&#x2122;s deregulation of blood glucose, resulting in blood glucose levels remaining chronically elevated. Levels of T2DM are disproportionately high in Indigenous communities. This trend is evident in Canadian Indigenous communities, who suffer significantly higher rates of T2DM (17.2%) than the rest of the country (5%).

American Larch, Larix laricina

within the diabetes research community. This research requires a careful approach in many areas, notably protection of Indigenous intellectual property rights and protection from over-exploitation of plant resources.

CULTURALLY RELEVANT HEALTHCARE The discrepancy between diabetes in Indigenous and non-Indigenous communities has been linked to rapid changes in lifestyle and genetic predisposition. In addition, the issue is confounded by the fact that a conventional drug-based approach to diabetes treatment often has limited success within Indigenous communities as it fails to address the holistic approach of Traditional Medicine (TM). Many Indigenous healers take a holistic approach to medicine, addressing the patientâ&#x20AC;&#x2122;s physical, mental, emotional, and spiritual wellbeing, with medicinal plants often playing a key part. Therefore, there exists a need for a more culturally relevant approach to diabetes medicine. To this effect, the World Health Organization (WHO) published a resolution in 2009 promoting preservation, research and inclusion of TM in healthcare.

A NOVEL APPROACH: MODERN SCIENCE ALONGSIDE TRADITIONAL KNOWLEDGE The initial aim of Professor Haddad and his team was to provide a proof of concept that medicinal plants used in Cree TM hold antidiabetic properties. To achieve this, medicinal plants were firstly identified using a novel ethnobotanical approach based on a set of diabetes-related symptoms. Ethnobotany is the scientific study of how plants are used by humans, including their application to health and wellbeing. Plants which were found to have the highest antidiabetic potential were then screened for primary (glucose-lowering) and secondary (toxicity, drug interactions, complications) activity. This screening process used a comprehensive platform of in vitro cell-based and cell-free bioassays to better understand the target tissues and mechanisms of action (Table 1) of the plants. Bioassay-guided fractionation (repeated separation of components in an extract to isolate pure, biologically active compounds) was then used to identify the active principles of the most active species, with in vivo animal models of diabetes used to confirm the biological activity of key plant species. In parallel to this scientific approach, Cree Elders and healers prioritised medicinal plants for treating diabetes symptoms, according to their Traditional Knowledge.

To address specifically the dramatic rise of diabetes in Canadian Indigenous communities, the Canadian Institutes of Health Research established the Team in Aboriginal Antidiabetic Medicines (CIHRTAAM) in 2003. As lead of the CIHR-TAAM, Professor Haddad works together with academic colleagues and Indigenous communities to translate Cree Traditional Knowledge (TK) of medicinal plants into the scientific language that is better understood

THE POWER OF PLANTS A striking finding from this research is that the majority, four out of six, of the plants found to have the highest antidiabetic potential by the scientific study are the same as those prioritised by the Cree Elders and healers. This result confirms not only the great wisdom and knowledge of Indigenous healers but also the value of cross-cultural collaboration in health research. In addition, many plants were found to have multiple biological activities

A striking finding is that the majority, four out of six, of the plants found to have the highest antidiabetic potential by the scientific study are the same as those prioritised by the Cree Elders and healers 49

Minority Health

that are complementary to those of other species, raising an interesting possibility that plant combinations could be customised to treat different diabetic profiles. FACTORS OF SUCCESS Stemming from collaboration and cooperation (so-called participatory communitybased research), the success of this research depended heavily on the relationships between researchers and participating Indigenous communities. In order to acquire successful results, it was vital to gain the trust of communities involved. Anxieties from the Cree communities typically concerned ownership and misuse of TK alongside fears that the publication of results would lead to the over-exploitation of plant resources. To address these concerns, Haddad and TAAM firstly endeavoured to build trusting relationships by ensuring a strong personal presence, for example at regular meetings, and personal accountability, by giving their ‘word of honour’. Indeed, the culturally sensitive approach of TAAM to this project can be summarised by their declaration that 'we have underlined respect, patience, humility, and interconnectedness as fundamental guiding principles'. Another key element of this collaboration was a legally binding research agreement that ensured the protection of collected TK and the consent of Elders at all stages of the project. It also included a protocol for the pre-publication review of documents by Cree Elders. The hope is that these documents can serve as an adaptable template for future research. In addition, cultural brokers, with understanding of both community values and the academic world, were used to bridge the gap between science and TK. LOOKING TO THE FUTURE Whilst TAAM’s work has provided interesting results, Professor Haddad stresses the importance of further research. In particular, the period of use of medicinal plants needs to be increased in future studies and the impact of long-term use of medicinal plants needs to be investigated. In addition, future studies would benefit from the use of modern methods such as genechip technology to better understand the activity of medicinal plants used in TM. Professor Haddad’s work has illustrated the value of collaborating with Indigenous communities to fully understand their wealth of Traditional Knowledge. Professor Haddad and his team's approach provides an inspiring example of collaborative research that could be applied to many other projects in the scientific community.

Labrador Tea, Rhododendron groenlandicum

A key element of this collaboration was a legally binding research agreement that ensured the protection of collected Traditional Knowledge and the consent of Elders at all stages of the project Common Name

Principle mechanisms behind antidiabetic activity

Balsam Fir

Reduces hepatic glucose production Uses both insulin-dependent and insulin-independent mechanisms

Speckled Alder

Limits the expansion of adipose tissue in anti-obesity activities

American Larch

Enhances insulin sensitivity

White Spruce

Inhibits intestinal glucose transport and activity of liver glucose-6phosphatase Protects preneuronal cells from high glucose toxicity

Balsam Poplar

Antiobesity effects: • Suppression of adipogenesis • Improved insulin resistance • Favoured “energy wastage” mechanisms such as fat oxidation

Labrador Tea

Acts on muscle, liver, adipose tissue and intestine in vitro through insulin-dependent and insulin-independent activities Improves insulin sensitivity and reduces fatty liver in vivo

Northern Labrador Tea

Improves in vitro glucose transport and adipogenesis Protects preneural cells from glucose toxicity Prevents AGE (Advanced Glycation Endproduct) formation

Purple Pitcher Plant

Stimulates glucose transport in muscle cells Protects against diabetic neuropathy

Showy Mountain Ash

Increases glucose uptake by skeletal muscle cells Protects preneuronal cells against glucotoxicity Inhibits intestinal glucose transport

Lingonberry

Lowers blood sugar levels May enhance insulin sensitivity, reduce hepatic glucose production, and increase muscle glucose disposition

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Detail What are the challenges of using lifestyle changes to prevent and treat Type 2 diabetes within Indigenous communities? As with any community, lifestyle changes are hard to implement and interventions proposed need to be culturally relevant. In addition, the focus should shift away from stigmatisation, from managing perceived ‘weaknesses’ toward encouraging and celebrating resilience. Interventions should also be more holistic (physical, mental, emotional and spiritual) and rooted in community-based approaches rather than individual-based ones. What are the barriers to Indigenous communities accessing conventional drug-based diabetes medicines? One could cite the typical factors such as remoteness and low income that significantly limit access to conventional health professionnals and their drugbased therapies. However, there are also questions of mistrust toward modern drugs, notably because of their non-negligible side effects. Finally, drug-based therapies are not holistic nor culturally well-adapted. To what other branches of research could a legally binding research agreement between Indigenous communities and research scientists be applied? The answer is quite simple… All!!! There is no reason why any research with Indigenous communities should not be framed by high ethical standards. What is the most important next step to address the dramatic rise in Type 2 diabetes in Indigenous communities? Although culturally adapted treatment options are crucial to develop, prevention strategies that are holistic, culturally relevant, community-based and engage multiple stakeholders should be a high priority.

How could Traditional Medicine be commercially exploited whilst protecting Indigenous Traditional Knowledge? This is a loaded question… Elders, notably Traditional Medicine knowledge holders say that Traditional Medicine knowledge is gifted and learned/experienced from the land and from mentors. They also see themselves more as custodians rather than owners of this knowledge and associated intellectual property. We heard two important issues raised by Elders and knowledge holders. Firstly, Traditional Medicine should be easily accessible; yet, commercialisation did not raise enthusiasm among Elders and knowledge holders. Secondly, Traditional Medicine knowledge should be protected and passed on. We had numerous discussions on how best to protect Indigenous Traditional Knowledge. The current legal framework in Canada, and often elsewhere, does not provide ideal protection, be it through intellectual property, patent or copyright laws as well as other tools. This being said, using the legal tools of the predominant culture (e.g. patents) is a lesser evil than not protecting at all. One potential avenue could be for Indigenous communities to develop ‘ethical’ traditional remedies that respect cultural and quality standards. As raised by our Cree partners, income generated by any potential commercialisation of Traditional Medicine should be controlled by the community and serve to 1) ensure the transmission and safeguard of Traditional Knowledge, 2) facilitate access to traditional medicines for community members and 3) encourage further ethical, community-based, participatory research with trustworthy academic scientists.

There is no reason why any research with Indigenous communities should not be framed by high ethical standards www.researchfeatures.com

RESEARCH OBJECTIVES Professor Haddad’s research focuses on how the Traditional Knowledge of Indigenous peoples can be translated and included in healthcare. FUNDING • Canadian Institutes of Health Research Institute of Aboriginal Peoples’ Health • Public Health Agency of Canada • Natural Health Products Directorate of Canada COLLABORATORS • Minnie Awashish, Kathleen Wooton and Jane Blacksmith, Cree Nation of Mistissini • Jill Torrie, Cree Board of Health and Social Services of James Bay • John Thor Arnason, PhD, Steffany Bennett, PhD, Brian Foster, PhD and Cory Harris, PhD, University of Ottawa • Alain Cuerrier, PhD, Montreal Botanical Garden BIO Dr Haddad is a tenured professor in the Department of Pharmacology and Physiology at the Université de Montréal. He has authored over 130 peer-reviewed publications and is recognised internationally for his work on medicinal plants and functional foods in metabolic diseases such as obesity and diabetes, notably relating to Aboriginal health. His fields of expertise include natural health products, Traditional Medicine, metabolic diseases, diabetes and obesity. CONTACT Pierre S Haddad, PhD Professor, Département de pharmacologie et physiologie / Pharmacology and Physiology Université de Montréal C.P 6128 Succ. Centre-ville / P.O. Box 6128, Downtown Postal Station Montreal (Quebec) Canada H3C 3J7 E: pierre.haddad@umontreal.ca T: +1 514 343 6590 W: http://www.taam-emaad.umontreal.ca/ /pierre-haddad-54311a26/en

Spotlight

UICC Leading the Global Fight Against Cancer Cary Adams, CEO of the Union for International Cancer Control (UICC), speaks to Research Features about how the organisation is uniting the global cancer community and what we can all do to contribute. Delivering a personal message for young global leaders of the future, Cary explains how the effort to combat cancer is a global concern that is shared across the world.

How does collaboration with partners, such as the United Nations (UN) and the World Health Organization (WHO), help UICC achieve its goals? Well, I think it works both ways. We can help them because the World Health Organization (like any organisation) has limited resources. For example, it can't employ the world's experts on cancer. What UICC can offer is access to the expertise of its over 1,000 members around the world, to help WHO to do a better job than they could do on their own. And that's critical to the smooth running of international governance on health, and applies to all the other disease groups. But equally, the decisions that can be taken at the World Health Assembly, when all countries get together to discuss health issues, can make a significant difference for us and our members around the world, and we can help implement those decisions. So, by way of example, a high-point in the last few years was in May 2014, when UN Member States for the World Health Assembly all signed off on a resolution which essentially said that no-one around the world should die in avoidable pain. Palliative care and pain relief is a critical part of health care across the globe. However, access to morphine, and other effective drugs, is not always available. For example, 80% of the consumption of morphine is within only about 7 or 8 countries in the world. Unfortunately, if you were to die of cancer in a lower- or middle-income country, you're very unlikely to have access to any pain

relief whatsoever. So it’s a desperate time for the patient, and their family, during those last few weeks. To get the World Health Assembly to agree that no one should die in avoidable or unbearable pain around the world, wasn’t just a major step forward for our community but also for our generation. Now we're working with WHO to develop the guidelines to help countries implement the changes required, so that morphine and palliative care is more readily available, particularly in lowand middle-income countries. In countries like these, the treatment infrastructure is not there, so as a result more people die from cancer than are actually cured. Do you think that governments around the world are taking the economic cost of cancer seriously enough? I would say that we generally, the cancer community and governments, have not done enough to understand the economic benefits of investing in cancer treatment and care. So I wouldn't blame the governments specifically but I think as a community we've not articulated the economic cost of cancer as well as we should have done. However, there has been work happening in the last couple of years which has allowed us to at least start that discussion. We worked with The Lancet last year to produce a commission report on radiotherapy. That report, which was coauthored by 140 individuals, very wellarticulated that investing in radiotherapy,

Spotlight

To get the World Health Assembly to agree that no one should die in avoidable or unbearable pain around the world, wasn’t just a major step forward for our community, but also for our generation cancer treatment and care was of net economic benefit to countries. Although investing in radiotherapy at the start is quite expensive, the financial return is within 15 years. So I think that we have tried to work in that space, in a better way, than we have done before. But I'm also conscious that in order to make the case for any politician or government to start refocusing their efforts on cancer, as opposed to other diseases, we need to make the case to the head, the heart, and the pocket. We can make the case from an economic perspective, the pocket, and that's important – to look at the relative value of investing in cancer treatment, as opposed to other things that a government has to invest in. We also need to appeal to the heart because this is a situation where there are lots of people dying unnecessarily and we shouldn't be allowing that to happen. We have the tools, we have the equipment, and we have the drugs to not only address many cancers around the world but also prevent them. We have the means to do this by, for example, reducing tobacco use around the world. And then we have to appeal to the head. This means using scientific evidence to show that by pursuing certain interventions we will reduce both the number of cancer cases and the number of deaths through cancer. It’s important that we have sound evidence and advice to give to governments on what they should be doing because it can become confusing. So, for example, it’s important – absolutely essential – that every government addresses the issue of tobacco use because it's linked to six of the biggest killers in the world, including lung cancer. For a government, if they are looking at priorities about where they should spend their money in health, probably the biggest

return they would get is increasing the taxes on smoking and cigarettes in their countries from tomorrow. This is something they actually could do now that will have a longterm positive benefit on the economy and health of the country. Also, the tax revenues themselves can then be used to address things such as education, or to invest in other health programmes. So, there's lots that can be done - but I do believe that we are starting the process of speaking more eloquently about the economic case for action. You have previously made a plea for employers to ‘put the health of their workforces at the centre of their corporate social responsibility agendas’. Could you tell us a bit more about what you think this could involve? This is something that we have been working on for the last couple of years, with colleagues in the NCD (Non-Communicable Disease) Alliance, as well as some of our corporate partners, in order to raise the profile of the value and impact that employers can have in terms of delivering global health improvements. Something like 60% of the world's population is employed. And that's a very captive audience on a day-to-day basis, where people aren't exposed to adverts on poorquality food but are very much exposed to the opportunities that the leaders of that organisation can give them. Making improvements, for example, in any canteen food or simple things, such as putting bicycle parking outside the front door of the company to encourage people to cycle to work. Another one is having tobacco-free environments and offering advice and help to those who want to quit smoking. Employers can also provide their employees with health training, and invite NGOs to come in to do free screenings for women for breast cancer, as well as providing other positive opportunities.

So, there's a lot that companies can do to signal the importance of healthy living to their own employees and also beyond that to ease the path back into employment for those who do, unfortunately, have a non-communicable disease or suffer from ill-health. This includes making sure they are given every opportunity to return to the company, and to be as effective as they were before they left. Given the large numbers of companies, and the large numbers of employees, it's certainly a means through which we can impact people’s lives from a health perspective on a day-to-day basis.

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What are your most prominent current projects within UICC's strategy for the next 24 months? Well, we have a very busy next twenty-four months ahead of us at the moment. A major thing for UICC is the World Cancer Congress. We have just held this in Paris, where we also had the World Cancer Leadersâ&#x20AC;&#x2122; Summit. That's where we bring over 3,000 people from around the world, who are passionate about cancer control, to learn from each other. They are then inspired to make a difference for cancer control in their own cities, or in their own countries. We are starting to prepare for the 2018 World

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Cancer Congress, in Kuala Lumpur, and the ambitions there will be even higher; we are aiming to have more people attend and to have an even greater impact. So that's one aspect of our work at the moment, but in terms of the next couple of years, there are two or three areas we're working on which will be quite important. The first one is capacity building. This year, we've established a focus area for helping our members around the world to, 'do an even better job tomorrow than they already do today'.

What that means is that we identify, through UICC's network of incredible organisations, opportunities to share best practices across all of our members globally. Thinking, for example, what is Cancer Research UK doing in the UK that can be transferred and used by other organisations around the world? It can also include distributing funds to lowand middle-income countries, when funding for initiatives is not there. Or it could mean arranging fellowships, which is where we take an individual from one country to another country to be trained in a specialist area that is relevant to them and their organisation. And also running workshops as well, so a lot

of face-to-face and peer-to-peer training. Additionally, the development of online services, toolkits and guidelines, in multiple languages, would be a personal ambition for the next two years: moving away from predominately English capacity-building training and education and moving towards French, Spanish and other languages. I think it would benefit our members around the world tremendously because, despite the fact that we have the internet, it's actually sometimes very difficult to get great ideas shared. So the other area, which would be important to us, would be to make sure that cancer stays on the global health agenda. We're currently in discussion with some countries, as well as the WHO, on whether there's a possibility for the World Health Assembly to pass a resolution pulling together all the great work we've done in the last few years on cancer. This would involve making a declaration of intent, following through on the palliative care resolution and following through on the essential medicines and the essential technologies work we're doing with them at the moment. Every country would then make a public declaration that cancer is important to them and they are going to follow through on their promises from previous years. I don't know if we can achieve that in 2017, but given that the question was regarding the next 24 months, I'm more confident that by 2018 we may have something that we can celebrate. You mentioned briefly the World Cancer Congress. What makes this event so unique? Well it's probably, and I think I can say this with some conviction, the only cancer congress in the world which covers the full spectrum of cancer control, i.e., we have experts in the field talking about prevention, early detection, treatment and care. We supplement that with a whole series of different topics related to, for example, global advocacy - how to do advocacy, and how to use social media. We also cover event topics, like how to fundraise better, because (like most organisations) NGOs face the challenge of raising enough funds to be effective, and we can't do much without funding coming in to all our organisations. So, the event’s quite unique in terms

2016WCC Opening Ceremony, (from left to right: Princess Dina Mired from Jordan, President-elect of UICC; the French Minister of Health, Marisol Touraine; Princess Lalla Salma from Morocco; the President of France, François Hollande; Queen Letizia of Spain; and Tezer Kutluk, Immediate-past President of UICC)

of its composition and the programme, which is really built around implementation science. Indeed, there are many other cancer conferences, but they tend to be focused on very specific areas, like radiotherapy, chemotherapy, liver cancer or breast cancer. But what we're able to do, at the World Cancer Congress, is to address the full spectrum of cancer control issues. Now what this means for the delegates is that they come along to a mini-university. People like myself, CEOs, we're very busy people, so for a CEO who generally has to know a little about a lot, as opposed to a lot about a little, this is the perfect environment for them to come and find out what the current thinking is. Example topics might be alcohol and cancer or physical inactivity and cancer. Or they might want to find out about screening, what works on vaccinations, what's operating

around the world on palliative care, where we are on the global discussion on NCDs and what is working at an advocacy level. Even, how do I better develop my strategy going forward so I'll have great impact? And on top of all that, they have the most wonderful opportunities to meet their peer group from around the world, exchange business cards and develop their own network of collaboration or support. So it is quite a unique environment, and we're very happy with how it's developed in the last few iterations. When we were in Melbourne, in 2014, we received feedback from delegates that 98% of them would recommend it to a colleague, or a friend, which is an outstanding result, and 80% of them also rated it as 'outstanding' or 'excellent'.

In order to make the case for any politician or government to start refocusing their efforts on cancer, as opposed to other diseases, we need to make the case to the head, the heart, and the pocket www.researchfeatures.com

Spotlight

World Cancer Day, which takes place every 4 February, is also a key platform of UICC’s. What role can research/researchers play in the day? The World Cancer Day is a completely open day and environment for everyone who has a passion about cancer and wants to get involved. We design it specifically around a broad theme. It has the tag line "We can. I can." and therefore this question is quite relevant because everyone who is reading this, or is involved in cancer, can do something on World Cancer Day. We provide fact sheets and bullet-point information, for people to hopefully use to reach out to their communities. Or at least to reach out to newspapers, journals and the media more generally and through social media to get messages out which are consistent with the overall messaging that we try to co-ordinate from Geneva. Now the important thing is that what we provide is a framework, within which we give latitude for people to operate. So we're not going to be very specific, i.e., you must say something about a particular cancer, or something about vaccinations. We allow every individual to use that day as a framework through which they can project their own views, their own ideas on what they're doing on cancer. So, for example, any researcher who's involved in something to do with cancer can use this day to project what they're doing, and they can use it to reach out to local cancer organisations to collaborate. And there are also many that use it to raise funds and/or run events. People can even just use it to contact journalists. We know that (having worked so well over the last seven years) World Cancer Day is pretty much ear-marked in most journalists' or media outlets' diaries, and the week before that day they're looking for good stories. So this is a great opportunity, during a very packed year when there is a lot going on, to use 4 February to project your messages, to get across your interests and your ideas, to a media that's ready to take those ideas on. How should we all be encouraging the development of new technology and drugs to improve the detection, prevention and treatment of cancer? Well I think we should all be encouraging everyone who's involved in innovative research for new drugs and technology, in

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all aspects of cancer control. That could be encouraging the development of new vaccinations. If we are to use the human papillomavirus and it's link to cervical cancer as an example, then vaccinations play a pivotal role in the prevention of a huge number of cancer cases. So any breakthroughs on drugs which are vaccinations and/or treatment are very much appreciated. I understand that there may be a period of time when those drugs may be priced at a level that may not be accessible to many around the world. But hopefully over time, as they become generic, they'll then impact the health of our children and our children's children in the future. In regards to other technologies, it's well known that in order to treat cancer successfully, probably about 50% of cancers require radiotherapy. Therefore, we need companies to invest in making that technology more effective, and cheaper for low- to middle-income countries – because the current prices are really quite high for these countries to invest in. Of course we also need great diagnostics for pathology. Across that whole range of areas, we need innovation, we need companies to invest, we need governments to invest, and we need breakthroughs from small, enterprising individuals that will change the whole paradigm, and the way that we can prevent and treat cancer. Do you have a personal message for today’s young researchers, who as tomorrow’s cancer pioneers, hope to enact change and

drive progress in the fight against cancer? I do. First of all, they're doing a very important job. Cancer rates around the world are going up, and up, and up. We're looking towards a world where potentially double the number of people will be dying of cancer, due to our ageing population and the increasing number of people on this planet. Everyone involved in cancer research has a very important role to play. Probably the most inspirational people I've met in this community are the ones who have stepped up, away from where their work may have been, whether it be research, nursing or being an oncologist, to consider themselves to be a global citizen and to want to do more. So, my personal message would be to encourage any young researcher to firstly stay in role, do a great job, make the breakthroughs we absolutely need to control cancer in the future, but also to keep an eye on what else they can do on a global level to help drive progress for cancer in global health and development agendas. We work with people around the world who are incredible researchers, but they find time and energy, and make an effort to be part of that global work that we do. And they want to be involved in global advocacy, they want to be involved in international projects which touch the lives of people in more difficult situations in lower-/middle-income countries. Some of our board members are leaders in their fields, but they are also global citizens working on the global field, and those sorts of people are very special.

Detail BIO Born in London, Cary Adams has a BSc Honours degree in Economics, Computing and Statistics from the University of Bath, United Kingdom and a Masters degree (with Distinction) in Business Administration. He is a Harvard Business School Alumni having attended the School’s Executive General Management programme in 2003. In 2009, Cary made a career change, moving from the management of international businesses in the banking sector to become CEO of UICC based in Geneva, Switzerland.

RESOURCES www.uicc.org /uicc /uicc.org/

Detail How has your career in oncology led you to this current project? My PhD studies introduced me to the emerging field of epigenetic therapy in lymphoma. Seeing the clinical success of these therapies, I became deeply interested in epigenetic/genetic interplay underlying cancer initiation and progression. My postdoctoral training presented me with a two-fold challenge: Firstly, how do we distinguish indolent from aggressive prostate cancer? Secondly, could we find successful implementation for epigenetic therapy to successfully treat lethal prostate cancer? My current use of genetically engineered mouse models stems from my direct training, and now my lab's research focus is to use such novel models to understand the genetic/epigenetic basis of aggressive prostate cancer and implement these discoveries towards providing biomarkers and/or therapeutic strategies for clinical use. Might the sequencing results from your directed mutagenesis screen uncover other genes that result in prostate cancer cell phenotypes, in addition to the genetic switches involved in aggressive disease progression? This is possible, yes. Our primary goal is to discover genes that cooperate with c-MYC (a well-known oncogene that drives multiple cancers, including prostate cancer) towards a more aggressive phenotype; insertional mutagenesis allows for loss of or gain of function of genes, and in the context of MYC-driven prostate cancer, we may identify genes that work against c-MYC, in turn making the cancer less aggressive. Once you identify mutated genes specifically implicated in aggressive disease, how does this information

translate to diagnostics? Will patient DNA be sequenced to look for the mutation? This could occur in multiple ways. Initially, our discoveries could be validated using human prostatectomy or biopsy samples (DNA, RNA, protein). Ultimately, we would prefer to see this be utilised by testing blood or urine samples from patients. This is non-invasive and less stressful to the patient. These samples can have DNA and/or RNA extracted and tested for genes of interest. Is there potential for your methodology to be adapted for use in research investigating other forms of cancer? Very much so, and it already has been successfully utilised by multiple researchers throughout the world. How do you see your research unfolding over the course of the next 5 years or so? While our generation of novel mouse models will continue, we have successfully converted many of our current mouse models and human samples to 3D organoid cultures. 3D organoid cultures represent a much more rapid platform for genetic/epigenetic discoveries and preclinical therapy testing. In regards to clinical translation, we are currently generating patient 3D organoid avatars. Patient samples are sequenced through a commercial source, genetic drivers are identified, and treatment options are provided to the clinician. In tandem, we are generating the companion 3D organoid avatars to validate the genetic aberrations and conduct preclinical therapy testing. We believe this will add valuable data to the final clinical decision to achieve the most successful outcome for the patient.

RESEARCH OBJECTIVES Dr Leigh Ellis aims, through his work on the genetics of prostate cancer, to uncover the biomarkers that will allow practitioners to distinguish between indolent and aggressive tumours. FUNDING • Prostate Cancer Foundation • National Cancer Institute COLLABORATORS • Dr Massimo Loda (Dana Farber Cancer Institute) • Dr Christopher Sweeney (Dana Farber Cancer Institute) • Dr David Goodrich (Roswell Park Cancer Institute) BIO Dr Leigh Ellis was awarded his BSc and later his PhD at The Peter MacCallum Cancer Centre by the Australian National University. He moved to the Sidney Kimmel Cancer Center at Johns Hopkins and then to Roswell Park Cancer Institute as a postdoctoral fellow before becoming assistant professor of oncology at Roswell in 2012. Since then he has been awarded Prostate Cancer Foundation Young Investigator Award, National Cancer Institute R21 Award and National Cancer Institute R01 Award. CONTACT Leigh Ellis, PhD Member of Faculty Harvard Medical School Brigham and Woman’s Hospital Dana-Farber Cancer Institute 450 Brookline Avenue Boston, MA 02215 USA E: ellis.leigh@gmail.com W: http://www.dana-farber.org/ @drleighellis /leigh-ellis-776807b

[Our research] has already been successfully utilised by multiple researchers throughout the world www.researchfeatures.com

Cancer

High precision dose monitoring can enhance targeted tumour therapy Proton beam therapy offers the potential to treat cancerous tumours without damaging the surrounding tissue. Dr Steven Vigdor, Professor Emeritus of Physics at Indiana University, hopes that his new venture, Phenix Medical LLC, will bring this technology closer to the patients it can benefit. The company develops cutting-edge instrumentation to aid in the delivery of ion and proton beam radiotherapy.

roton beam therapy is a type of radiotherapy that targets tumours with beams of radiation to treat cancer. However, rather than using x-rays, which can damage surrounding tissue, proton therapy uses positively charged sub-atomic particles, protons, to destroy cancerous cells. 30% of patients receiving radiotherapy would benefit from proton or ion beam therapy instead of the conventional x-ray therapy they already receive. However, this type of therapy is not widely available. Cost has previously been the major limitation in delivering this treatment on a large scale â&#x20AC;&#x201C; the facilities required were in the past exceedingly expensive and consequently there are relatively few in operation. However, new technologies are bringing costs down and the number of radiotherapy clinics offering this type of ion beam and proton treatment is increasing by 16% per year globally. PENCIL BEAM SCANNING Recent improvements that have been made include the upgrade to intensitymodulated proton therapy via pencil beam scanning (PBS), and the use of compact superconducting pulsed beam accelerators

such as synchrocyclotrons. PBS is a method that delivers the required dose of radiation to the tumour extremely precisely. Protons for the treatment are produced with a particle accelerator, which can deliver particles in a continuous beam, or in pulses of controlled intensity and duration. Pulsed beam technologies can deliver an instantaneous beam current hundreds or thousands of times greater than continuous beam technologies. The use of synchrocyclotrons can reduce operating costs and makes full automation of this technology possible. HOW IT WORKS The advantage of PBS becomes clear when you look at a tumour in three dimensions. PBS can deliver radiation over a very narrow range at fixed beam energies. This means that tumours can be targeted precisely, and that damage to surrounding healthy organs and tissue can be limited. This is because the tumour is â&#x20AC;&#x2DC;paintedâ&#x20AC;&#x2122; in 3D by scanning the volume with a beam, tuned to find the exact depth and lateral position of the tumour. The intensity and energy of the beam are adjusted continuously during each scan to deliver a radiation dose

Dr Vigdor and colleagues have performed several tests to confirm that their prototype delivers at sufficiently high precision

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precisely tailored to the size and shape of the target tumour.

position and beam energy â&#x20AC;&#x201C; this process is called dosimetry.

that operate at much higher dose rates before they exhibit this behaviour.

The technique improves the clinical outcomes of therapy by reducing the toxicity, time and cost associated with individual treatments, and improves the range of tumours that can be targeted, including ones in close proximity to critical healthy organs.

To measure dosage, most technologies use air ionisation chambers. These measure direct ionisation in an air-filled chamber by applying an electrical field. However, these are not precise at high dosage rates because ions recombine in the chamber, creating non-linear effects (i.e., when the output signal no longer changes in strict proportion to the delivered dose) that are difficult to quantify to the precision of which pencil beam scanning is capable. It is highly desirable to minimise this non-linearity for as long as possible, by developing dosimeters

Scintillation is a process whereby particles are excited by incoming radiation and re-emit the absorbed energy in the form of light. Phenix Medical have developed a gas scintillation detector (GSD) that monitors radiation dosage in real time, with precision of 1% over large areas up to 30Â cm x 30 cm. They have shown that the GSD dose measurement has an extremely high resolution: up to a few hundred microns (a thousandth of a millimetre) in the spatial dimension and tens of microseconds in the temporal dimension.

THE GAS SCINTILLATION DETECTOR For pencil beam scanning technology to work effectively, it is important that the amount (dose) of energy being delivered is accurately measured as a function of beam

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Cancer

Above: illustration of pencil beam scanning in action. Right: a gas scintillation detector mounted at Chicago Proton Center. Below: comparison of the distribution of delivered dose as a function of depth in a patient for proton beams vs. X-rays. Target region

100

Dose, %

Photon beam

Skin surface

Multi-energetic proton beam Mono-energetic proton beam

Depth in tissue

This is possible because they measure the de-excitation of gas molecules on the nanosecond (one billionth of a second) scale, and because they use xenon, which gives off lots of scintillation light (meaning it is easier to measure) and re-absorbs very few of the photons it produces. TESTING THE WATERS Dr Vigdor and colleagues have performed several tests to confirm that their prototype delivers at sufficiently high precision. Because the technology is so cutting-edge, there were no clinical facilities yet available to test the prototype instrument that used PBS with pulsed beam accelerators, so they tested the GSD using continuous beam therapy PBS and, separately, pulsed-beam accelerators without beam scanning. They first tested the spatial resolution and dose accuracy of the beam scans. The effects of gas contamination and impurities were determined by slowly adding carefully calibrated amounts of dry air into pure xenon at atmospheric pressure. They found that the effects were negligible if the contamination was less than 0.5%, achieved by keeping the xenon chamber tightly sealed. Above this level, the accuracy and precision of the dosimeter was significantly reduced. After making small corrections for background noise and loss of charge during resets of the readout electronics, the team were able to verify that the GSD technology was able to produce the required spatial and temporal precision to

measure dosage. Indeed, GSD is able to meet the requirements of the US DOE, NIH and National Cancer Institute that: “A spot size less than 5 mm FWHM at isocenter should be achievable for all ion species at all energies … Position accuracy pulse-to-pulse should be within ±0.2 mm and should be monitored during beam delivery.” Perhaps most importantly, they also measured non-linear effects driven by light production in the scintillating gas, adjusting where necessary to minimise these. Whereas air ionisation chamber-based dosimetry is associated with ion–ion recombination, and therefore non-linear behaviour above a certain threshold (130 nA/cm2), these tests indicate that the GSD response remains linear at this level, and at much higher

intensities. With new pulsed beam accelerators, the beam intensities may be very high (>1μA/cm2), so this is an encouraging result. Further testing will be necessary to confirm this behaviour once more facilities come online. FURTHER DEVELOPMENTS The Phenix Medical team aims to improve the technology further by building software to detect and correct problems with the beam in real time and improve specific aspects of the instrumental design, such as the windows through which the beam enters and exits the instrument. Further testing is required but they hope that their GSD will be able to facilitate extremely high precision PBS proton therapy, with consequent benefits for patients.

[Pencil beam scanning reduces] the toxicity, time and cost associated with individual treatments, and improves the range of tumours that can be targeted www.researchfeatures.com

Detail How has your background as a nuclear physicist helped you develop GSD? The issues critical to the development of next-generation dosimetry – improving device precision, speed of response and spatial resolution – are also central to the development of state-of-the-art detectors for particle and nuclear physics. My long experience in the latter fields means I am aware of the latest technologies, and able to choose the one best suited to the clinical environment of a proton beam therapy centre. What motivated you to work on this particular type of technology? We chose gas scintillation because of its intrinsically fast response time and its lack of reliance on ionisation of gas molecules, thereby removing the non-linear behaviour caused by ion recombination effects. We were then able to achieve the desired high spatial resolution by collecting the scintillation light in a modest number of photo-detectors, keeping the cost of the dosimeter down to a level competitive with alternative technologies that deliver poorer performance. Where do you see this technology going in future? Because air ionisation chambers are the current industry standard, the gas scintillation approach will probably see its greatest application as secondary dosimeters generally required by regulatory agencies. It will provide much higher spatial resolution and better linearity than the primary dosimeters, and comparable dose measurement accuracy with different sensitivities to possible changes in beam characteristics or environmental conditions. Our tests with clinical beams to date have successfully demonstrated the expected performance levels of the technology. So, what remains are basically the engineering challenges of adapting the GSD design to fit within the dose delivery system constraints at specific clinics. Are your developments driven by improvements in PBS, or vice versa? Or is it more of a joint advance?

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The improvements to pencil beam scanning technology are already under way. The first patient treatment with this approach using a pulsed beam accelerator began in Nice, France in September 2016. Several additional new clinics combining PBS with pulsed beams and very high instantaneous dose rates will be launched within the coming two years. Our developments have been driven by anticipating the need to deliver real-time dosimetry whose precision matches the capabilities of these new therapy centres, where treatment delivery depends on the proper operation of a great deal of beam delivery hardware and software that can develop glitches or more serious problems. The clinical needs require combining fast detector response, high dose accuracy and linearity, and excellent spatial resolution in a cost-effective dosimeter package. How much of a difference do you think this technology will make to cancer therapy? As costs are coming down, the proton therapy field is growing rapidly. Pencil beam scanning will soon dominate the methods of beam delivery because it offers the greatest precision in sparing healthy tissue surrounding a tumour. Ongoing improvements in treatment planning, beam delivery, tumour imaging and allowance for organ motion during treatment all promise to increase the fraction of radiation patients treated with proton or ion beam therapy from the current 1% toward the 20–30% who might benefit from this more precise form of treatment. But these improvements must be matched by comparable improvements in dosimetry technology, in order to verify that the precisely tailored radiation dose is correctly delivered. This is where the GSD technology comes in: it can be an essential component of the overall improvements that bring proton therapy to a much wider range of patients over the coming decade.

RESEARCH OBJECTIVES Dr Vigdor’s work applies his background in physics to a medical setting, helping to develop technology that facilitates the treatment of cancer. FUNDING Small Business Innovation Research grant (#5R44CA162664-03) from the US National Institutes of Health COLLABORATORS The research was carried out in collaboration with Keith Solberg (who was Principal Investigator on the NIH grant) and Alexander Klyachko of Phenix Medical LLC, and with aid from Dr Mark Pankuch of the Northwestern Medicine Chicago Proton Center. BIO Dr Steven Vigdor is Professor Emeritus of Physics at Indiana University, where he taught and carried out fundamental research in experimental nuclear physics for 31 years. In 2007 he became the Associate Director for Nuclear and Particle Physics at Brookhaven National Laboratory on Long Island, New York. After retiring from Brookhaven, Vigdor returned to Bloomington, Indiana in 2013, where he joined his former colleague John M Cameron in launching a small business, Phenix Medical LLC, focused on developing stateof-the-art instrumentation to support new clinics delivering proton and ion beam radiotherapy. Vigdor is also working on a book to provide an experimentalist’s account of ongoing efforts to explore the physical fine-tuning that allows life to exist in our universe. CONTACT Steven Vigdor, PhD Senior Vice President Phenix Medical LLC 120 West 7th St. Suite 313 Bloomington, IN 47404 USA E: svigdor@phenixmedical.com T: +1 812 345 0267 W: http://www.phenixmedical.com/ /steven-vigdor-3688469

The ‘intelligent’ human immune system can respond naturally to fight cancer Dr Xuemei Zhong, PhD, is Assistant Professor of Medicine at the Boston University School of Medicine, in the Haematology and Oncology section of the department. Her research looks at how the ‘intelligent’ human immune system can be stimulated to fight diseases like cancer without reliance on high doses of drugs and short-lived therapies, with a particular focus on a process called immunosurveillance.

Cancer

he ongoing battle against cancer may finally have an end in sight. According to Dr Xuemei Zhong’s ongoing research, our best hope for containing and clearing cancer lies in our first line of defence – our commander and army of foot soldiers, and our body’s very own doctor – the human immune system. Dr Zhong and her team at Boston University are looking at ways of improving our understanding of this system as a tool to combat disease, to find new ways of reducing cancer rates without having to rely on the single-target-based treatments typically found in current therapies. Having identified a specific type of protective B cell (NIMPAB), her research has now established how vital these can be within the immunological process, due to their ability to mop up and kill cancer cells. INTELLIGENT TACTICAL APPROACH The part of the immune system that recognises and removes cancer cells naturally is called the ‘immunosurveillance’ system. This term describes the body’s ability to recognise and remove harmful cells. It differs from the conventional immune response in that it does not cause significant or systemic inflammation in order to remove threats to the body. Instead, it is an ongoing, self-renewal maintenance process that operates in the background. SURRENDERING THE VETERAN Cancer treatments that stimulate the immune system typically induce the conventional inflammatory response. However, the effects of such methods are usually short-lived and difficult to control because cancer cells adapt rapidly and develop drug resistance. Most cancer therapies focus on manipulating a single factor, such as a signal pathway or biomarker, without considering the 'ying and yang' sides of the same factor. For example, if you remove a causative factor, you may have removed the ‘attraction factors’ for healing. Dr Zhong says this slows down healing and explains the short-lived and ineffective nature of many current treatments. LEARNING FROM FAILURE When the body’s natural immunosurveillance system fails to remove cancer cells quickly enough, they accumulate and cause disease. By understanding what happens when this

L2pB1 cells are a major B cell population in the peritoneal cavity. (A) Peritoneal washout cells from BALB/c mice were stained with anti-B220 (clone RA3-6B2, eBioscience), anti-CD5 (clone 53-7.3, eBioscience) and anti-PD-L2 (clone TY25, eBioscience) and analysed by flow cytometry. PD-L2 expression on each cell population is shown. L2pB1 cells and L2nB1 cells are highlighted by arrows. Isotype matched control antibody staining is shown as blue in the histograms. (B) A smear of peritoneal washout cells from BXSB mice was stained with anti-CD20 (clone L26 BioCare), anti-PD-L2 (clone TY25, eBioscience) and DAPI, as indicated, and examined by fluorescence microscopy.

process goes wrong, Dr Zhong and her team aim to find methods of improving the system, and therefore of preventing cancer. Harmful foreign bodies stimulate an immune response, and this allows the system to learn, meaning that the likelihood of infection is reduced the next time the body is exposed to the same factors. However, the failure of cancer prevention is a little different. According to Dr Zhong’s hypothesis, one of the causes of modern day failure of cancer prevention is ‘deviation and exhaustion’ of the immunosurveillance system with multiple on-going battles. This hypothesis is supported by the mounting evidence reported that the risk of cancer is increased in obesity patients and other chronic lifestyle diseases.

In order to find ways of ‘restoring’ or ‘rebooting’ immunosurveillance, Dr Zhong has been focusing on specific and unique cells that are critical in the immunosurveillance system. BUILDING AN ARTILLERY Conventional B lymphocytes as we know from our biology text books are the B cells which produce antibodies against foreign bodies and inhibit their activity. Conventional B cells are also termed B-2 B cells to differentiate from the B cells that Dr Zhong's group has been studying in mice, which are termed B-1 B cells. Both B-1 and B-2 B cells can fight against foreign invaders. However, B-1 B cells are also designed for immunosurveillance with their unique natural IgM antibodies and

Restoring the body’s natural ability to defend itself against disease is the key to unlocking more sustainable and effective cancer prevention and treatment 67

Cancer

other features to recognise, inhibit, kill and remove cancerous cells. Dr. Zhong named these cancer-fighting B-1 B cells "Natural IgM-Producing Phagocytic B Lymphocytes" (NIMPAB). WAGING WAR NIMPAB cells have been identified as a vital player in strengthening immunosurveillance. More specifically, Dr Zhong's team has found that a type of NIMPAB cells in mice, called L2pB1 cells, actively accumulate inside tumours. Depletion of L2pB1 cells in mice results in larger tumours. These cells displayed growth-inhibition and deathinducing functions in 3D tumour spheroid culture. Dr Zhong's group also found L2pB1

cells have potent antigen presentation capacity and thus are likely to present tumour antigens to T cells. These T cells are another type of white blood cell that form part of the immune system, which scan and kill tumour cells. L2pB1 cells also secrete the highest amount of anti-inflammatory cytokine IL-10 among all B cells. This makes them the best B cell candidate to control inflammation in and around tumours. Regulating inflammation is critical for reducing angiogenesis and tissue damage to prevent tumour metastasis. NIMPAB cells generate antibodies that are unlike those used in cancer drugs on the

It is difficult to manipulate the immune system without affecting its own healing mechanism. The ultimate goal for cancer immunotherapy is to restore immunity and then let it work on itself

How crucial has your other work on diseases like lupus been in informing your research on cancer therapies? Great question. We started to study the same type of B cells in autoimmune diseases like lupus. That was based on a traditional concept that autoimmune diseases are caused by auto-antibodies that recognise self antigens and consequently bring selfdestruction to our body. Since the B cells we were interested in recognise mostly self-antigens, we thought they could be the cause of autoimmune diseases. Despite our finding that these B cells do generate antibodies that recognise self-antigens, our data showed something unique and contrary to what we hypothesised. The auto-antibodies from these B cells do not just react to a single epitope of an antigen as with traditional B cells. Instead, the same antibody reacts to various self-antigens simultaneously. All these antibodies are IgM isotype with

low affinity but high avidity and their DNA sequence is germline coded; they were the ‘original design’, not the result of external stimulation such as vaccination or infection. They exist in animals that have been born to totally pathogen-free, sterile environments. As reported by other groups, these IgM auto-antibodies are very different from those pathogenic auto-antibodies in autoimmune patients. Thus, this led us to hypothesise the function of these B cells in the opposite direction – their protective functions rather than pathogenic functions. This revelation led to our current research on the role of these B cells in the immunosurveillance of cancer because cancer cells are mostly ‘self’ and need to be recognised and removed. We believe the antibodies produced by NIMPAB cells recognise certain pattern of cancerous cells rather than a single marker. Moreoever, cancer cell elimination happens every day in healthy individuals without eliciting any autoimmunity. Our study led us to believe NIMPAB cells are the best candidate for such a job.

market. These antibodies occur naturally in both healthy individuals and cancer patients. The objective of Zhong’s work is to stimulate the migration of these cells in and around tumours, which will allow them to kill and remove cancer cells without causing metastasis (the spread of cancer caused by cells breaking away and forming new tumours elsewhere in the body). Metastasis can often occur if an over-zealous inflammatory response is elicited. NO ATTACK, NO DEFENCE It is difficult to manipulate the immune system without affecting its own healing mechanism. The ultimate goal for cancer immunotherapy is to restore immunity and then let it work on itself. To find a way of encouraging the production of NIMPAB cells around tumours, Zhong has been working with Dr Joyce Wong and Dr Tyrone Porter, who both specialise in nanomedicine, to develop novel nanotechnologies to mobilise NIMPAB cells in and around tumours. Modern cancer treatments are limited by the rapid evolution and adaptation of cancer cells

Are NIMPAB cells the only type of cells that stimulate the destruction of tumour cells? No – in our immune system, no single type of cells or status of cells can work alone. It is always teamwork. However, NIMPAB cells play a very unique role. To put it in a metaphorical way, in healthy status, NIMPAB cells are like a custodian who patrols our body to remove senescent cells, cancerous cells, metabolic trash and toxins etc. In chronic disease status, NIMPAB cells are like rising liaisons or even commanders on the battlefield. They identify the problem as they are equipped with unique tools that others don’t have, i.e., natural IgM antibodies and surface IgM and other receptors. They launch the first wave of solutions, secrete antibodies, regulatory cytokines to adjust inflammation level and phagocytose target cells and cell debris or vesicles. They relay the information to other cells by antigen presentation and cell–cell contact or by secreting chemokines to remotely recruit proper team members or soldiers to the battle ground. In summary,

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Detail RESEARCH OBJECTIVES Dr Xuemei Zhong's work focuses on how the immune system works in dealing with chronic health issues like diabetes and cancer. The main objective for her work is to create an effective and self-sustainable immunotherapy against cancerous cells. FUNDING • Nanotechnology Innovation Center (BUnano) • American Cancer Society (ACS) • National Institutes of Health (NIH): National Cancer Institute (NCI)

to new drugs and treatments. Zhong hopes that this more holistic approach to cancer treatment, which focuses on sustained, longterm improvements rather than single-focus, quick fix treatments, will improve patient outcomes and lead to better health. She believes that restoring the body’s natural

ability to defend itself against disease is the key to unlocking more sustainable and effective cancer prevention and treatment, and consequently better patient outcomes. It appears the foot soldiers on the frontline had the silver bullet all along.

NIMPAB cells are not the only type of cells but play a central role in coordination.

that given the essential finances, personnel, and time, we will absolutely translate these into clinical treatment.

Would an enhanced immunosurveillance response be more useful as a preventative or as a curative treatment for cancer? The answer is ‘both’. From a preventative point of view, the amount of NIMPAB cells and natural IgM in our body may indicate subclinical health status. Naturally boosting them may tip the scales and prevent the accumulation of small problems from mounting into chronic disease. In terms of treatment, supplementing NIMPAB cells and natural IgM will change the outcome of the on-going battle; like when your commander or troops are exhausted in a long battle and you suddenly airdrop fresh troops and a new commander to the front line. How well do your findings translate from the mouse model to humans? We have identified NIMPAB cells in both the mouse model and humans. We are confident

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Can these treatments be applied to other diseases? Absolutely. As we mentioned before, NIMPAB cells are the custodians of our body. Cancerous cells are one of the many things they take care of. All modernday chronic diseases are a result of an imbalanced internal environment and the resultant accumulation of certain forms of cells, molecules and toxins in our body. NIMPAB cells and their natural IgM can benefit all kinds of chronic issues. One clinical example is IVIG. Through currently unknown mechanisms, IVIG can treat many diseases beyond its original use as a mere Ig supplement to help immunodeficiency patients battle infection. As large-scale industrial production techniques advance, you will see massive production of natural IgM for the treatment of many diseases.

COLLABORATORS • Dr Tyrone Porter http://www.bu.edu/medal/groupmembers/tyrone-porter/ • Dr Joyce Wong http://people.bu.edu/wonglab/ BIO Dr Xuemei Zhong received her PhD degree in Immunology and Pathology from Boston University School of Medicine. She is currently Assistant Professor in Medicine at the same school. Her research interest is to study the intelligent design of our immune system and the effects of our lifestyle on our immunity and most importantly how to restore our immunity to resolve top health issues like cancer. Her research project to develop a novel cancer immunotherapy, which is featured here, is laying the groundwork for a revolutionary future cancer therapy. CONTACT Xuemei Zhong, PhD Assistant Professor of Medicine Rm. 437A, EBRC, Section of Hematology and Oncology, Department of Medicine Boston University School of Medicine 650 Albany St. Boston, MA 02118 USA E: xzhong@bu.edu T: +1 617 638 7028 W: http://www.bumc.bu.edu/hematology/ research/xuemei-zhong-phd-2/ /xuemei-zhong-09b55ba

Detail Why do you think endometrial cancers have previously been under-researched? I think that because historically most women do well and survive this disease, it gained less attention. However, from a raw numbers perspective it is an incredibly common disease that should raise the alarm (~10,000 new cases in the UK, ~60,000 new cases in the US last year). We have an urgent need to do better for the 20–25% of all ECs diagnosed that have bad outcomes, and to try and spare the women who have very favourable outcomes from unnecessary treatments and worrisome visits. What attracted you to this area of research? Seeing the challenges that pathologists face every day and that managing oncologists (for example, me, as a surgeon) subsequently face in determining which surgery or treatment(s) is best. I have worked in five different cancer centres and seen at least five different strategies in management. Even in our own centre there is often disagreement as to what is ‘best’. How has your previous work informed your current research? Working on ovarian cancers with a

THE BENEFITS OF PROMISE The clearest benefit of the ProMisE model is consistent categorisation of endometrial cancers so that ‘apples’ can be studied with ‘apples’ and the best treatment for a category of tumours can be determined. Therapy can be more tailored to the individual, meaning that there could be fewer negative side-effects associated with over-treatment and less missed opportunities of under-treatment. This will minimise the disruption to a person’s life as well as the potential complications from treatment. For those who are diagnosed before they reach menopause, this may offer a chance to preserve their fertility by avoiding or delaying complete surgical staging if it is unnecessary. Of course, this also implies an economic saving for healthcare services if fewer costly treatments are required.

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‘subtype-specific’ approach has certainly changed clinical management and research. The same rationale and desire for a paradigm shift was clearly needed in endometrial cancer. Do you think ProMisE could soon replace other methods of cancer diagnosis, such as ESMO? I don’t think any component currently used in risk stratification will be completely abandoned, although some factors may hold less importance. Specific parameters, like tumour grade, patient age, or ESMO risk group may be added to ProMisE and provide greater prognostic strength. In the coming months, working with 1000 cases tested thus far, we will be testing which factors are the most important to move forward with. As our German collaborator has said (and taken from a German proverb) we don’t want to throw the baby out with the bathwater! What do you think is the most significant benefit of your model? Consistent reproducible prognostic categorisation of endometrial cancers so that treatment effects can be studied and optimised within the same categories.

There are further specific benefits to McAlpine and Talhouks’ model, including identifying women who may have a hereditary cancer syndrome (Lynch Syndrome) that puts them at higher risk of developing other cancers. ProMisE can provide empowering information about the behaviour/biology of a tumour, informing women how likely it is that their cancer will come back or how likely they are to die from this disease. Targeted therapy, specific to ProMisE subgroup, can be applied, offering a step towards precision medicine. Overall, the model represents a cost-effective assay that can be implemented in a clinical setting to improve the categorisation and risk stratification of endometrial cancer. Drs Talhouk and McAlpine believe this represents a turning point to improving outcomes for the thousands of women who develop this disease every year.

RESEARCH OBJECTIVES Together, Drs McAlpine and Talhouk have developed this molecular classifier stemming from an international study, the Cancer Genome Atlas (TCGA). McAlpine and Talhouk made the molecular tests simpler and at lower cost so that testing could be performed in any cancer centre. FUNDING Canadian Institutes for Health Research; BC Cancer Foundation; Vancouver General Hospital & UBC Foundation; VCHRI COLLABORATORS C Blake Gilks, David G Huntsman, Melissa McConechy, and Samuel Leung have been critical to the success of this project. We are grateful for local and international collaborators including Dianne Miller; Janice Kwon; Stefan Kommoss; Frieder Kommoss; Lien Hoang; Anthony Karnezis; Cheng Han Lee; Niki Boyd; Rob Soslow; Martin Kobel and our fantastic lab team of Amy Lum, Winnie Yang, and Janine Senz. BIO Dr Aline Talhouk is a biostatistician working with BC’s Gynecological Cancer Research (OVCARE) team. She completed her PhD in Statistics at UBC in 2013 with a focus on computational statistics and machine learning, and was the recipient of an Alexander Graham Bell Graduate Scholarship. Dr Jessica McAlpine is from Vancouver but received her medical training in the US, returning in 2006 to join the OVCARE team. She is an Associate Professor at UBC and Director of the OVCARE Tumor Bank. She is the recipient of the 2012 CIHR New Investigator Award and the 2016 BC Cancer Foundation Clinical Investigator Award. CONTACT Dr Jessica N McAlpine, MD OvCaRe Research Program 675 West 10th Avenue Vancouver BC V5Z 1L3 CANADA E: info@ovcare.ca T: +1 604 675-8211 W: http://www.ovcare.ca

Dr Bazan with Larry Hollier, MD, FACS (Chancellor, LSUHSC at New Orleans, Professor of Surgery) with a molecular model of neuroprotection D1 (NPD1), the centre of their collaboration on concussion and traumatic brain injury

Connections: the importance of mentoring and collaboration to research success Dr Nicolas Bazan is well-known for his scientific rigour and the exciting developments he has made in the world of neuroscience. Those who havenâ&#x20AC;&#x2122;t met him, however, might not be aware of the warmth and care that the man behind the science brings to his professional relationships. We wanted to find out more about how Dr Bazan has built up an extensive network of collaborators and colleagues and the effect this has had on his work.

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Neuroscience

from Harvard Medical School in Boston, Prof Nicos Petasis at USC in Los Angeles and others: ‘Dr Petasis and Dr Alvarez-Builla are exceptionally talented medicinal chemists with whom we have developed these, and other, new molecules through collaboration’. Interdisciplinary cooperation was also a significant part of Dr Bazan’s work in the biotech company he set up 16 years ago to develop novel analgesics (pain medication). This was one of the first biotech companies in New Orleans and collaboration was key to its success, involving experts in medicinal chemistry (Prof Julio AlvarezBuilla Gomez at the University of Alcala in Spain), pharmacologists (Dr Dennis Paul, LSU and Anthony Vaccarino, UNO) and other physiologists and biochemists.

cientific research cannot stand alone; it builds on the work that has come before it and lays the foundation for future research. In a similar way, scientists themselves cannot afford to act as islands in the ocean of global research. Dr Bazan has recognised this from the beginning of his career and takes great care to ensure that the voices of his colleagues, collaborators and students are listened to and appreciated. COLLABORATION Dr Bazan has collaborated with many scientists throughout his career. His work on docosanoids was, he says, ‘enriched’ by the collaboration with Prof Charles N Serhan

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As Dr Bazan says, ‘Their expertise was critical; collaborators are the intellectual pieces of a puzzle’. Now Dr Bazan has set up another company with his son Hernan Bazan, MD, a clinician–scientist interested in postsurgical pain, to develop a new generation of non-addictive painkillers, similar to acetaminophen (paracetamol in the UK) that, unlike this drug, is non-toxic to the kidneys and liver. As proof of the collaborative success, the company will soon be patenting second generation analgesics. Dr Bazan has also patented a family of compounds developed with Prof AlvarezBuilla that might help treat epileptogenesis (the process by which a normal brain develops epilepsy). He explains how he feels lucky that inventions can stem from the

Dr Bazan with Hernan Bazan, MD (Vascular Surgeon at Ochsner Hospital, Clinician-Scientist, Co-Founder of South Rampart Pharma) showing model of novel generation of non-toxic, nonaddictive pain killers just identified

work in his laboratory: ‘All of a sudden, you have an invention and then that invention becomes a patent, a potential innovative idea.’ He describes himself as ‘only the little inventor’ – the university owns all the patents and outside companies then license them and try to apply them. Having successfully set up companies in the past, he sees no reason not to do it again. He is now starting another company with the aim of using collaboration to speed up the development of these molecules into potential therapies. INSPIRATION As well as those scientists that Dr Bazan has collaborated with on specific projects, he has also been influenced by multiple others. As a medical student, he worked in his spare time in the Institute of Biology (Tucuman) under Prof Else Brauckmann and Francisco

All of a sudden, you have an invention and then that invention becomes a patent, a potential innovative idea 75

Neuroscience

Barbieri on early amphibian development. In the summer he worked under Prof Hugo Pablo Chiodi at the institute of High Altitude Biology (Jujuy, Argentina) where he became interested in responses to hypoxia and brown adipose tissue. At the same time, he met several prominent Argentine scientists who he found inspirational: Bernardo Houssay, physiologist and Nobel Laureate; Luis Leloir, physician, biochemist and Chemistry Nobel Laureate; and noted neurobiologist Eduardo De Robertis. He also cites an early visit by Sir John Gurdon to his Argentine laboratory in 1973 and the conversations they had as a strong positive influence on his research programme. He credits another Nobel Laureate, Eddy Fischer, as having offered ‘friendship, generosity and insightfulness’ that has been important to him in the past two decades. Sir John Vane, renowned pharmacologist and joint recipient (with Bengt Samuelsson and Sune Bergström) of the Nobel Prize in Physiology or Medicine, was also a close friend to Dr Bazan for many decades. The two scientists often visited each other in London and New Orleans. ‘He was’, says Dr Bazan ‘exemplary to me in many ways’. Dr Bazan became the President in 1994 of the William Harvey Medical Research Foundation to support the research at The William Harvey Research Institute, St. Bartholomew’s Hospital Medical College in London, established by Sir John Vane. CROSSING BORDERS The international aspect of Bazan’s connections continues to grow. He has

been involved with a ‘superb’ programme in Germany called the DZNE from their very beginning and says he finds it ‘very rewarding to see that active discoveries are happening and being actively translated into patients’. He has also built bridges between science and the arts, embracing two disciplines that are often seen as polar opposites. His writing has led to two of his novels being published and it is clear that he places a high value on helping creativity and science work together: ‘I believe that when you’re thinking about brain function and retina function, all of a sudden you’re involved in big concepts, trying to figure out how nature helped put cells together that yield sight and cognition

Microfluidic technology for next-generation sequencing: Marie-Audrey Kautzmann, PhD (Fellow); Jessica Heap (Research Associate)

as an output. I believe writing about what I’m interested in, in a more general way, is an outlet to express interpretations of what might be going on in biology and medicine. So, the connection with writing and with art is an outlet.’ He also emphasises the importance of collaboration in this arena, pointing to his ‘great collaborators’ Richie Adams and Brent Caballero who he worked with to adapt one of his books for the big screen. Adams helped with the screenplay and was a ‘superb director’ and Dr Bazan collaborated with both of them, plus ‘the splendid cast and dedicated crew … to make the film happen’. MENTORING However, despite these connections within the research sphere and beyond, Dr Bazan has lacked a clear sustained mentor in his career. He likens himself to a professional ‘orphan’ without one defined person to turn to for advice and support. Perhaps, he suggests, that is why now, as an experienced scientist, he places such value on mentoring.

Confocal Microscopy to identify regulation of neuronal cell survival at cell level: with postdoctoral fellows Surjyadipta Bhattacharjee, PhD; Aram Asatryan, MD, PhD

Dr Bazan was confronted with the responsibilities of mentoring at an earlier age (28) than most. Having recently returned to Argentina and founded a new school, he was responsible for a department and institute of young scientists. He is often asked why he left his successful post in Toronto to return to Argentina. Dr Bazan gives his reasons simply: ‘The single most important reason was my desire to contribute to the development of scientists and to contribute to advancing

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Liquid ChromatographyMass Spectrometer to unravel lipidomics in cell signalling: Bok Kyoo Jun, PhD (Instructor); Uday Patel (Research Associate)

academic excellence in the country where I was born, as I had been doing in Canada.’ LEADING THE WAY Here, he made the decision to lead by example, something he has continued throughout his career: ‘Rather than preaching about dedication, focus, study, effort, etc. I have done it, spontaneously. I strongly believe that by leading by example in mentoring and other ways of life, we reach farther and more profoundly into others.’ In 2000 he conceptualised, wrote and directed the grant entitled ‘Mentoring Neuroscientists in Louisiana’, funded by NIH. This was the first of its kind in the state of Louisiana. Now in its 15th year, the grant can be considered to have been a great success and has served as a model for several others. It puts into

practice several of Dr Bazan’s ideas around the importance of mentoring promising young faculty members and supporting young scientists through their early careers. He feels strongly that there are huge benefits for the mentor as well as the mentee saying, ‘It is a great reward to see independently successful scientists that trained under you.’ However, he is humble about the effects he has had on those he has tutored in this way: ‘Their successes are their own … I was just a facilitator to develop their early talent as a mentor.’ And that is the most important element of Dr Bazan’s approach to collaboration – his emphasis is on how he can support those around him rather than what they can do for him. George M Carman, Chief Scientific

‘It is a great reward to see independently successful scientists that trained under you. Their successes are their own … I was just a facilitator to develop their early talent as a mentor www.researchfeatures.com

Officer at the New Jersey Institute for Food, Nutrition, & Health, Rutgers University, sums it up perfectly: ‘His scientific accomplishments notwithstanding, his greatest contribution is his dedication to the people that work under his tutelage, his associates, and scientific colleagues at large. Dr Bazan is an unassuming person who makes others feel valued, and facilitates the advancement of others.’

Contact Nicolas G Bazan, MD, PhD Neuroscience Center of Excellence School of Medicine Louisiana State University Health 2020 Gravier Street, Suite D New Orleans, LA 70112 USA E: nbazan@lsuhsc.edu T: +1 504 599 0831/32 W: https://www.medschool.lsuhsc. edu/neuroscience/faculty_detail. aspx?name=bazan_nicolas /nicolas-bazan-ba930716

RESEARCH SOCIAL MEDIA NEWS

Blogging for scientists: A quick guide Research Features’ social media guru, Alastair Cook, shares his tips for any scientists interested in starting a blog. Why a blog? Running a blog is a great way to get started on social media. It’s a place that you can create and curate entirely in your own image, hosting content you’ve developed or shared based on your own thoughts or opinions. Blogs are quick, free and can provide you with an important foundation for building an online profile and establishing yourself as a voice or leader within your discipline and beyond. One of the key strengths of a blog is its ability to fit within social media. You’re able to write long descriptive posts which you’re unable to on Twitter or which will get ignored on Facebook, but you’ll still have the ability to share them via these platforms. That doesn’t mean you have to, though – short posts, videos, images and other people's articles can also be shared too: whatever best reflects the style of blog you’re going for. Writing a blog post allows you to disembark from the rigidity of a scientific journal, but allows you to provide a greater depth of information than would be available in a news story. Let’s begin To get started I recommend using WordPress. The platform is incredibly customisable with a vast amount of themes you can choose to give your blog its desired look. Furthermore, there are various other ‘plug-ins’ which can be installed to boost your blog's integration across other platforms (e.g. Facebook,

Twitter, YouTube). The possibilities are almost endless. WordPress also provides you with a visual editor meaning that you don’t have to be proficient in HTML to help design and edit your website, making it a great choice for those who are less tech savvy and a quicker solution if you’re short on time. Finally, there are a wealth of tutorials available for Wordpress: if you have a problem there is likely to be a solution on YouTube or in another blog post on the internet. Discover your niche It’s important to identify what outlets a blog can provide for you. This will help you develop a style and maintain your blog. Having regular content updates is something that will allow you to generate subscribers and will improve your ranking in search engines. Potential uses for your blog: • Share journal articles • Advertise thoughts and scientific opinions • Review or comment on conferences and meetings • Circulate information about professional opportunities and events • Discuss your own research and publications • Critique research papers in your own and related fields of research • Share and comment on trending science stories • Explain your research field to both peers and a lay audience

which outlets you’d like to concentrate on is important for creating your blog’s own unique identity, creating this niche gives people a reason to follow you, as they will be accessing content that is unique to you. Share your work By now most of the hard work has been done, or so you thought! Trying to get your work noticed can be one of the hardest parts and is often why many people don’t persevere with their writing. A good way to get started is to share your work with aggregator blogs – these group together many other blogger’s work, usually by category, allowing people to discover you based on what they’re looking to read. Scienceblogs and ResearchBlogging are good places to start with this. Also share your posts through your own social media accounts and if you don’t have any then what are you waiting for..?

As you can see there is quite a large scope of information for you to be able to create regular content on. These are also topics that will not only encourage engagement and discourse but also appeal to both the scientific community and the lay audience. Isolating

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