ISSN 2399-1542 ISSUE 106
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PARKINSON’S UK Dr Arthur Roach, Director of Research and Development, discussed his role spearheading the charity’s search for a cure and the reasons he is hopeful that we are close to finding effective treatments.
GERONTOLOGICAL SOCIETY OF AMERICA Executive Director and CEO James Appleby explains why the society takes a cross-disciplinary approach to the study of ageing and the benefits this brings.
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CANCER RESEARCH UK We heard from Dr Iain Foulkes on how new breakthroughs in research are beginning to have an impact across cancer treatment and 3 Research Features what the UK-based charity is doing to ensure scientific breakthroughs continue.
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Whether it's investigating vital chemical processes, improving cardiology or shining a light on dentistry, ageing, cancer or autoimmune diseases, the work done by the researchers in this month's issue is, by its nature, relevant to us all. This issue, we also speak to some of health science's leading figures. Dr Jack Lewin, recent President and CEO of the Cardiovascular Research Foundation (CRF), looks back on his time at CRF, giving insight into their valuable work, and shares his plans for the future. We discuss the importance of a cross-disciplinary approach to ageing research with James Appleby, Executive Director and CEO of The Gerontological Society of America. He explains the importance of looking at the issue from all angles as our global population continues to age. Ageing is a considerable factor in the increasing number of Parkinson's cases. With 25 years' experience, Dr Arthur Roach, Director of Research and Development at Parkinson’s UK, is helming the charity's efforts to develop effective treatments he spoke to us about why he is confident this is within reach. Equally positive, Dr Iain Foulkes of Cancer Research UK discusses the charity's commitment to the fight against cancer and highlights the progress made so far. With research budgets being tightened across much of the world, it is important to recognise that the work carried out every day by researchers globally is contributing to such promising progress across so many areas.
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 Editorial Assistant: Miranda Airey miranda@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: Alex Davey, Barney Leeke, Christiane Wirrig, Karina New, Kate Porter, Kathrin Lauss, Patrick Bawn, Petra Kiviniemi, Rebecca Ingle /researchfeatures /ResearchFeature
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CROWDFUNDING FOR GIRLS’ & WOMEN’S EMPOWERMENT
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CONTENTS
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Making the grade: selective synthesis of alkene isomers
Parkinson’s UK: fast-tracking change
Diagnosing Parkinson’s disease before the onset of motor symptoms
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Breaking the vicious cycle: new potential therapy for Alzheimer's disease
22
Cell transplantation for neural repair: improving outcomes following spinal cord injury
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At the intersection of the nervous system and innate immunity
30 34 38
The unifying theory of collaborative research Cancer Research UK: Fighting the feared disease
Novel kinase inhibitors offer fresh treatment hope for prostate and pancreatic cancer
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Battling blood cancer: virus targets multiple myeloma
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46 50 54 58 62 66
Elucidating the mechanisms of disease-causing bacteria
Taking a bite out of Latino oral health disparities Heart to heart with cardiology leader Jack Lewin
Bringing cellular processes to light Is there a ‘fat gene’ responsible for cardiovascular disease?
82 86 90
A programme of improvement for long-term dementia care Nanotechnology hits the spot in arthritis treatment Hydroxychloroquine – offering lupus patients something to SMILE about
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The importance of… explaining science simply
Testing the cardiotoxic effect of cancer therapies with microhearts
70 74 78
Repairing a broken heart GSA: Age is in the eye of the beholder
Reducing age-related vascular dysfunction
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Chemistry
Making the grade: selective synthesis of alkene isomers The production of specific isomers of commercially significant alkenes is fundamental to exploit their properties. Professor Schrock at the Massachusetts Institute of Technology (MIT) and Professor Hoveyda at Boston College are developing new methods of synthesising alkenes with previously unobtainable selectivity, which is destined to have a lasting impact on drug discovery and development.
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lkenes are a type of hydrocarbon, which contain at least one carbon– carbon double bond, and therefore have at least two fewer hydrogen atoms than their alkane equivalents. While alkenes are still relatively stable, they are more reactive than their single-bonded counterparts. Also known as olefins, they are found in many chemicals in the chemical and pharmaceutical industries and biology. DOUBLING UP Manipulation of carbon–carbon bonds is best managed through the use of transition metal catalysts. Olefin metathesis (OM) is the name given to the process in which two olefins react together to form two new olefins through the scission and reorganisation of the carbon–carbon double bond. Prof Schrock jointly won the 2005 Nobel Prize in Chemistry for his work on elucidating these mechanisms; in fact, molybdenum- and tungsten-based catalysts are known as Schrock Catalysts. Not content to rest on his laurels however, Prof Schrock
is turning his attention to the next major challenge in olefin metathesis. HANDEDNESS IS NOT SO HANDY Due to the fact that alkenes are found in two different conformations (cis or trans, also called Z or E), the formation of one isomer is an important goal in any organic chemical synthesis. Z and E isomers are different geometrical arrangements of the same molecular bond structure. Usually only a single isomer (E or Z) is found in biological systems, and enzymes, in particular, will typically only interact with one type of isomer.
Commercially available Schrock catalysts
Until a few years ago it was not possible to generate solely Z or E isomers in chemical synthesis, as they are energetically approximately the same and therefore produced as mixtures that are difficult and expensive to separate. Prof Schrock is investigating how this can be resolved by utilising novel catalysts that are themselves highly specific for forming a given Z or E isomer.
Olefins are important chemicals in the industrial and pharmaceutical industries due to their ability to polymerise, if cyclic, or to add new chemical groups at the site of their double bond www.researchfeatures.com
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Chemistry
Only SP metallacycles have been observed
Even a (reactive) methylidene oxo (a bisHMTO complex) can be isolated!
A PRODUCTIVE PARTNERSHIP Dr Schrock and Dr Amir Hoveyda have been collaborating for more than twenty years. Although the fundamental mechanism of olefin metathesis was identified some years ago, controlling the formation of Z and E isomers has seen rapid development in the last decade. It is an exciting time for organic chemistry generally and olefin metathesis and it is now possible to prepare alkenes in a commercially viable manner with a selectivity that was previously thought unobtainable.
As both the substrate and product of the reaction are alkenes, they can regenerate the starting material or any unwanted by-products. The purpose of designing selective catalysts for these reactions is to ensure only one of the thermodynamically possible reactions can occur, giving selective product formation. What the catalyst does is increase the rate of one possible reaction so it occurs faster than all the others, essentially winning the race to product formation. The breakthrough came with the development of molybdenum catalysts which were particularly effective for generating molecules containing a single Z configuration. The team achieved >99:1
selectivity for the desired Z isomer using their catalysts, but found that even fairly similar substrates needed subtly different complexes to achieve the same result. CRACKING THE ‘Z PROBLEM’ Selective production of the high-energy Z alkene isomer is plagued by problems. Some of these problems are resolved by the choice of ligand, which favours a particular orientation of the substrate during formation of the product. The problem is directing a catalyst to form only a single product in high yield. The team was able to adapt their techniques to a range of OM reactions (olefin fusion, ring creation, ring scission and combinations of these). Some responded
Profs Schrock and Hoveyda are well placed to continue the momentum that this exciting era in inorganic and organic chemistry has initiated 8
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Detail Why are olefins such significant molecules in organic chemistry? The carbon–carbon double bond is found in some of the most basic molecules in the chemical industry, starting with ethylene, and in biologically relevant molecules. What has been the highlight of your years of research in this area? The highlight has been the design and isolation of catalysts for producing one olefin product specifically in the OM reaction. Why is it such an exciting time to be involved in olefin research? Olefins will continue to be the starting point
in the chemical industry for many important chemicals and will continue to be found in a wide variety of biologically important molecules. How would you describe this complex chemistry in layman’s terms? Imagine that you and your dance partner form a ring with another couple and exchange partners that way. What impact do you expect from your current research? There is agreement that the OM reaction will continue to evolve and continue to change the way in which certain organic molecules are made.
There is agreement that the OM reaction will continue to evolve and continue to change the way in which certain organic molecules are made much more promisingly to the treatments, and a range of distinct, effective reactions was established. These advances have pushed this already powerful chemical tool to new heights. Progress in the understanding of the metal centre of the catalyst, and particularly how it is responsible for the stereoselectivity of the reaction, has been vital to move the field forward. The advent of these socalled ‘stereochemical-at-metal’ catalysts has ushered in an era of unprecedented selectivity of OM.
Many possible OM reactions still do not have suitably selective catalysts to drive them. There are also some reactions that require such high energy, and produce such a range of difficult-to-distil products, that they are not viable for production. Profs Schrock and Hoveyda, with years of experience in the field and a real passion for solving these problems, are wellplaced to continue the momentum that this exciting era in inorganic and organic chemistry has initiated.
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RESEARCH OBJECTIVES Dr Schrock has an extensive scientific background in inorganic chemistry, and one of his main research interests is studying catalytic reactions and the mechanisms of reactions involving alkylidene complexes. His latest research looks at improving access to olefins through a process called olefin metathesis. By having access to these alkenes, and enhancing their formation, Dr Schrock believes this exciting area of inorganic and organic chemistry could offer great benefits to medicine and the drug industry. FUNDING National Institutes of Health (NIH) and the National Science Foundation (NSF) COLLABORATORS This work has been accomplished through a collaboration with Professor Amir Hoveyda, who lends his expertise in organic chemistry to the project. BIO Richard Schrock won a Nobel Prize in Chemistry for his work on olefin metathesis. After studying for his PhD at Harvard University in 1971, he joined MIT in 1975 and became a full professor there five years later. Since then, he has become a member of the American Academy of Arts and Sciences, the National Academy of Sciences, a foreign member of the Royal Society of London and the co-founder of a Swiss-based company devoted to commercialisation of metathesis chemistry. CONTACT Richard R. Schrock, PhD Department of Chemistry, Massachusetts Institute of Technology (MIT), 6-331 77 Massachusetts Ave. Cambridge, MA 02139, USA E: rrs@mit.edu T: +1 617-253-1596 Amir Hoveyda, PhD Boston College, Department of Chemistry, Merkert Chemistry Center Chestnut Hill, Massachusetts 02467, USA E: amir.hoveyda@bc.edu T: +1 617-552-3618
9
Neuroscience
Diagnosing Parkinson’s disease before the onset of motor symptoms Therapeutic intervention that can halt or cure Parkinson’s disease before motor impairments occur is a major unmet medical necessity. Although new treatments show promise for treating the condition, there is currently no procedure available that can diagnose Parkinson’s prior to the onset of debilitating motor symptoms, at which stage most dopamine neurons have died or become damaged. Dr Good and Dr Robertson capitalised on two pre-clinical non-motor features of Parkinson’s. If tested for in combination, these two attributes may hold the key to early stage diagnosis and therapeutic intervention of the world’s most common debilitating movement disorder.
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r Kimberley Good is an Associate Professor working in both the Department of Psychiatry and the Department of Psychology and Neuroscience at Dalhousie University, Nova Scotia, Canada. There she works with Dr Harold Robertson, Professor Emeritus in the Departments of Pharmacology and Psychiatry to investigate indicators of Parkinson’s disease, with the aim of developing a method capable of detecting the neurological condition at an early stage. It is estimated that in the UK and Canada about one person in every 500 is affected by Parkinson’s disease, making it the most common movement disorder and the second most common neurodegenerative disorder. The majority of those diagnosed are over the age of 50, but the disease also affects many individuals at a younger age. Due to the steady global increase in life expectancy, the number of cases of Parkinson’s disease will continue to rise. A COMPLEX COMBINATION OF SYMPTOMS Although the symptoms of the condition vary between each individual, the primary motor symptoms characteristic of the
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disease are ubiquitous in their presentation. Due to the loss of muscle control, patients experience rigidity, slowness of movement, loss of fine motor skills, impaired balance, and tremors. The disease is progressive and symptoms appear gradually, becoming increasingly severe over time, and lead to difficulties in completing simple tasks, walking, and talking. Many people die from complications resulting from the disease, although Parkinson’s itself does not directly result in death. In addition to impairing movement, the disease is associated with a wide range of other non-motor symptoms. These include problems with the sense of smell, sleep difficulties, fatigue, depression, anxiety, and bladder and bowel problems. THE DEATH OF DOPAMINE NEURONS The classical symptoms of Parkinson’s disease are caused by the progressive death of dopamine-producing cells in the part of the brain known as the substantia nigra. One of dopamine’s key functions in the brain is to act as a neurotransmitter for the transmission of signals that co-ordinate movement and smooth muscle control. A dopamine deficit leads to a progressive decrease in the amount of effective signalling, and increasingly severe motor symptoms.
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Changes in sleep and olfaction (the sense of smell) occur in the majority of patients in the earliest stages of Parkinson’s, with subtle changes occurring up to a decade prior to clinical diagnosis
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Neuroscience
Study objectives
Key region of interest: Olfactory bulb/tract
1. Is olfaction altered in asymptomatic at-risk population?
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Olfactory Bulbs and Tracts
Asymptomatic at-risk populations: • First degree relatives of PD patients • Patients with REM-BD (Rapid eye movement behavioural disorder)
Although it is well established that the death of the dopamine-producing cells is the cause of the motor symptoms of Parkinson’s disease, why this deterioration occurs in some individuals in the first place remains a mystery. It is suspected that people develop Parkinson’s due to a combination of genetic and environmental factors, and it has been shown that the disease involves the build-up of abnormal aggregates of proteins called Lewy bodies in the brain. Despite this knowledge, no specific causative factor has been isolated as the trigger for this devastating neurological disorder. THE IMPORTANCE OF OLFACTION Over 100 scientific papers have described the loss of the sense of smell in patients with PD. Changes in olfaction occur in 80–90% of patients in the earliest stages of Parkinson’s, with subtle changes occurring up to a decade prior to clinical diagnosis. However, olfactory
Odorants
dysfunction is not specific to Parkinson’s but is also noted in other neurodegenerative disorders (e.g., Alzheimer’s disease). So although olfactory testing may identify those who are at risk, this process may also identify those who are at risk for other disorders. As there are currently no testing procedures available to diagnose PD before a patient exhibits motor symptoms, Dr Good and Dr Robertson have embarked on a project to develop a method that will enable earlier identification. They have employed a combination of smell testing and a sensitive MRI technique known as diffusion tensor imaging (DTI), to investigate non-motor
Dr Good and Dr Robertson have discovered that the testing methods they are using may be able to accurately detect the condition years before it can be diagnosed clinically 16
Olfactory Sensory Neurons
features that appear in the very early stages of the disease. The association between Parkinson’s disease and olfactory deficits is so strong that olfaction has been included in the most recent criteria for PD by the International Parkinson's and Movement Disorder Society. Although in isolation these changes are not sufficient to identify that a person is developing the disease, Dr Good and Dr Robertson have discovered that the testing methods they are using may be able to accurately detect the condition years before it can be diagnosed clinically. SMELL TESTING AND BRAIN IMAGING Initially, they confirmed that a group of patients exhibited a distinctly impaired sense of smell. Using a well validated test of the sense of smell along with imaging of the olfactory bulb region using DTI, differences were observed between Parkinson’s patients and control subjects. Brain imaging techniques can provide insights into the physiological changes that have occurred and may be associated with the olfactory deficits.
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Detail What led to you researching whether this particular combination of testing methods might be a viable approach for diagnosing Parkinson’s disease at such an early stage? Olfactory deficits have been reported in Parkinson’s for many decades. However, the lack of specificity hampers our prognostic ability. Others have used expensive and invasive imaging techniques to do similar studies. We wished to provide a simple (smell testing) and available (DTI MRI) method to be able to identify those who may be at risk of developing Parkinson’s. What are the next steps you plan to take in your research towards establishing the technique as a method for diagnosing early stage Parkinson’s disease? We need to test this paradigm on patients with other neurodegenerative disorders (e.g., Alzheimer’s) to determine the specificity of our findings. What have been the most challenging aspects of undertaking this study? Recruitment of first-degree relatives. Our projected number of first-degree relatives is ambitious and our numbers are low compared to what we had anticipated.
The DTI technique they are using for this research – a specialised type of MRI scan designed to measure the fluid diffusion characteristics within brain regions – has revealed that in the olfactory bulb of Parkinson’s disease patients there is a change in the amount of water diffusion in the area, suggesting structural abnormalities in this brain region. They have also found microstructural changes in the substantia nigra of these patients. These differences in diffusion imaging parameters likely reflect pathological changes that have occurred in the brain as a result of early stage Parkinson’s disease. PAVING THE WAY FOR PRE-CLINICAL PARKINSON’S DISEASE DIAGNOSIS The next phase of the project has an ambitious goal: to demonstrate the utility of using these methods for detecting
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Olfactory deficits have been reported in Parkinson’s for many decades How do you think early treatment will be approached in patients who are highly likely to develop the disease but it is in the pre-clinical stages? At-risk individuals are in a difficult bind: they may or may not develop the disorder. So, taking a medication that might prevent a disorder but that has side effects, might not help those who are not going to be affected. In fact, unnecessary medication may be detrimental instead of helpful. So, we need to find true ‘biomarkers’ that identify with great certainty those who are on the path towards developing Parkinson’s. Are there any other related studies you are working on or are planning to undertake in future? We will be including Alzheimer’s disease and Mild Cognitive Impairment patients in our protocol.
Parkinson’s disease at a far earlier stage than has ever been possible before. To do this, they are administering the smell identification test to a large sample of over 1000 neurologically healthy test subjects, who are first-degree relatives of Parkinson’s disease patients. They identify those participants whose smell test scores fall into the highest and lowest 10%. These subjects are scanned using DTI and the data is compared with Parkinson’s patients and healthy control subjects. If the protocol developed by Dr Good and Dr Robertson is successful in identifying at-risk individuals, this novel approach will provide an unprecedented window of time for therapeutic intervention. If the disease can be diagnosed and its progression halted before permanent damage occurs, we will finally have found a way of effectively curing Parkinson’s disease.
RESEARCH OBJECTIVES Drs Robertson and Good’s research focuses on the neurobiology of neurodegenerative disorders such as Parkinson’s disease. They are particularly interested in the olfactory system as a predictor of outcome in these disorders and in finding ways to assist in early diagnosis. FUNDING Dalhousie University Department of Psychiatry Research Fund; Canadian Institutes of Health Research; the Parkinson Society Canada COLLABORATORS Dr John Fisk, Dr Roger McKelvey, Dr Kerrie Schoffer, Dr Heather Rigby, Dr Tyler Rolheiser, Dr Namrata Joshi, Dr Ben Rusak, Dr Ronald Leslie, Dr M Naeem Khan BIO
Dr Kimberley Good completed her MSc and PhD in Neuroscience at the University of British Columbia. She is currently an Associate Professor in the Department of Psychiatry at Dalhousie University and is cross-appointed in the Department of Psychology and Neuroscience. Dr Good is a scientific member of the Nova Scotia Early Psychosis Program and the co-director of the Nova Scotia Psychosis Research Unit. She is also a faculty member associated with the Brain Repair Centre in Halifax NS, Canada. Dr Harold Robertson is a Professor Emeritus of Pharmacology at Dalhousie University and is a Fellow of Royal Society of Canada. Dr Robertson is the former Scientific Director of the Brain Repair Centre in Halifax, NS, Canada. CONTACT Dr Kimberley P Good, PhD Departments of Psychiatry and Psychology & Neurosciences Dalhousie University Halifax NS, Canada E: kim.good@dal.ca T: 902-473-4250
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These results by Dr Decourt suggest that lenalidomide has the potential to lower Alzheimer's disease brain pathology and to do so over a long period of time
Neuroscience
Breaking the vicious cycle: new potential therapy for Alzheimer's disease Dr Boris Decourt of Arizona State University is looking to the anti-cancer drug lenalidomide as a possible treatment for Alzheimer’s disease. This FDA-approved compound alters the actions of the inflammatory molecule, tumour necrosis factor alpha (TNF-α), tackling many physiological aspects and vicious pathological cycles of the devastating neurodegenerative disorder when given at an early stage of the disease.
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he World Health Organization estimates that a new case of dementia is diagnosed every four seconds. Alzheimer's disease (AD) is the most prevalent form of dementia, affecting approximately 47 million individuals worldwide, and imposing an estimated cost of $605 billion annually. These numbers are expected to triple by 2050 as the global population lives longer than ever before. Furthermore, it is thought that only 25% of people suffering AD actually receive a diagnosis. These figures emphasise the urgent need to discover a cure for AD, and the importance of scientific research for age-related neurodegenerative disorders.
NEUROPATHOLOGICAL HALLMARKS OF ALZHEIMER’S DISEASE AD is characterised by two major pathological features in the brain (used during autopsy to confirm the diagnosis of AD after death): firstly, the aggregation of small proteins named amyloid beta (Aβ) into senile (or amyloid) plaques outside of the cells; and secondly, the accumulation of an abnormal form of the tau protein into fibrillary tangles inside neurons. Aβ fragments are formed when the amyloid precursor protein (APP) is broken down by two enzymes called β-secretase and γ-secretase. The latter process is exaggerated in AD, which results in an excess of Aβ, which then aggregates into plaques (Figure 1). Both plaques and tangles impede cellular functions such as neuronal signalling and connectivity, which, over several years, leads to the death of neurons in brain areas associated with learning and memory.
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INFLAMMATION IN ALZHEIMER’S Dr Decourt and his team are studying the role of inflammation in AD, and are testing different methods to modulate brain inflammation. This is because many age-related disorders, including neurodegenerative diseases, are associated with chronic inflammation. Inflammation is a natural reaction of the body to defend itself against foreign entities (e.g., microbes), abnormal cells (e.g., cancer cells), and protein aggregates. In the case of AD, it has been shown that Aβ and amyloid plaques damage the structure and function of cells. This stimulates the immune cells located in the brain to develop an inflammatory reaction in an attempt to eliminate the cause of cell injury (Aβ and amyloid plaques) and the wounded cells and tissues. Moreover, the immune and other support cells are activated in the process and release an array of inflammatory molecules (called cytokines and chemokines), which may contribute to further cell dysfunction and neuronal death.
While inflammatory events were initially thought to be secondary to neurodegeneration, more recent studies have revealed that inflammatory mediators may be released at early stages of AD and exacerbate Aβ production – for example by increasing the levels of β- and γ-secretases (Figure 2). The vicious cycle created by these factors is pivotal to the progression of AD, and highlights the multifaceted and unrelenting nature of AD, as well as the challenges associated with the search for potential therapeutics. TARGETING TUMOUR NECROSIS FACTOR ALPHA FOR ALZHEIMER’S DISEASE The processes regulating inflammation are complex in nature, involving a combination of cells (e.g., white blood cells such as neutrophils and macrophages) and a plethora of molecules. A key factor in this inflammation is the cytokine tumour necrosis factor-α (TNF-α). Cytokines are molecules produced and released by immune cells to communicate with each other and other cells. TNF-α is one of the first molecules released during inflammation, thus its levels and the location and duration of its release often dictate for how long the immune reaction will last. Importantly for AD, the levels of both TNF-α and its cellular receptor TNFR1 were found to be elevated in the brains of AD patients, as well as in ageing individuals and sufferers of mild cognitive impairment (MCI), an early form of AD. Furthermore, in in vitro experiments, the addition of Aβ to cells results in the robust release of TNF-α. Additional investigations have shown that TNF-α stimulates the expression of APP, β- and γ-secretases, thus aggravating the release of Aβ. These results strengthen the connection between the presence of
Figure 1 Non-amyloidogenic pathway (most cells in the body)
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Inflammatory cytokines & chemokines • Neurodegeneration • Neuron loss
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Neuroscience
Aβ and TNF-α abnormalities. In relation to tangle formation, much less is known about TNF-α involvement, though recent data has suggested a connection. Consequently, some scientists have proposed to modulate TNF-α as a therapeutic intervention to slow down the progression of AD. Further evidence of TNF-α involvement in AD comes from studies on transgenic (Tg) mice – mice genetically engineered to develop AD-like symptoms and brain pathology (i.e., plaques and tangles). More than 30 Tg AD-like mouse strains have been created to date, and most express elevated levels of TNF-α in their brain compared to healthy animals. Different methods have been tested to reduce TNF-α activity in Tg mice, which include inactivating the TNF-α and TNFR1 genes, and using a large number of drugs of higher or lower TNF-α-inhibiting strength (e.g., aspirin). Most of these methods alleviated Aβ, inflammation and tau pathologies within the brains of Tg mice, and also led to improved working memory and cognition. However, to date none of the drugs has proven efficient at improving AD symptoms and pathology when tested in humans. ANTI-CANCER DRUGS Given the lack of efficacy of common antiinflammatory drugs to treat AD, Dr Decourt and his team have decided to test some of the strongest TNF-α inhibitors commercially available, called immunomodulators. The first compound they investigated was thalidomide. Preclinical data showed that thalidomide reduces Aβ loads and ADlike symptoms in Tg mouse models of AD. These data seeded the development of an NIH-supported clinical trial that tested thalidomide in AD patients. However, the high rate of adverse events recorded during the trial indicated that thalidomide is not a suitable treatment for AD given the frailty of these patients. Because of the toxicity recorded with thalidomide, Dr Decourt is now examining the therapeutic potential of the thalidomide
analogue lenalidomide. This compound is also FDA-approved for blood cancer treatment and is better tolerated by cancer patients than thalidomide. In a Tg mouse model of AD that develops Aβ plaques, just four weeks of lenalidomide treatment robustly reduced TNF-α and β-secretase gene expression to levels comparable to nontransgenic mice, and lowered the brain Aβ loads. Similar results were observed following a 12-week treatment period. Interestingly, the reduction of the β-secretase protein levels was not observed until the 12-week treatment period. These results from Dr Decourt suggest that lenalidomide has the potential
In a Tg mouse model of AD that develops Aβ plaques, just four weeks of lenalidomide treatment robustly reduced TNF-α and β-secretase gene expression … and lowered the brain Aβ loads 20
to lower AD brain pathology over a long period of time, by normalising the activity of enzymes responsible for the production of Aβ to non-pathological levels. FUTURE PROMISE These very encouraging results helped Dr Decourt and his group secure an NIH grant to take the investigations into lenalidomide further. First, the team are asking whether lenalidomide directly reduces β-secretase levels witnessed in the experiments outlined above, or whether this is mediated via a modulation of TNF-α activity in immune cells. Second, the effects of the drug are being assessed on tau pathology: there is assumed to be a link between TNF-α and tau abnormalities because tangles form in chronic inflammatory environments, but no study has assessed the potential of lenalidomide on tau tangles yet. Researchers will look at tau pathology alongside and independently of Aβ plaques in order to fully comprehend the mechanisms at play, using a combination of cell culture experiments and AD-like mice.
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Detail Looking at facts and statistics, the need for research into AD and treatment possibilities is clear. What was it that led you to study inflammation in AD in particular? During the first year I was working in Arizona for Banner Health, I read a lot of scientific papers about Alzheimer’s disease and noticed that inflammation was present at all stages of the disease. Why, in your opinion, do we not yet have a comprehensive treatment for AD? That’s a very difficult question for which the brightest minds on the planet have no answer yet. I believe it’s a combination of very complex mechanisms at play that are difficult to decipher, plus some lack of understanding of the natural function of some proteins involved in AD (e.g., Aβ is present in the blood and body of everybody, but we do not know what it does naturally), and a lack of good disease study models (Tg mice are created by genetic engineering using human mutations information, but only 5% of the AD cases in humans are due to genetic mutations; and, compared to cancer for example, no dog or monkey study is available at this time – we know for a fact that human and mouse metabolisms are different, particularly when it comes to drug treatment). Do your lenalidomide studies show promise for the use of other compounds targeting the inflammatory processes of AD? Several anti-inflammatory drugs have been tested in AD-like mice. While most work in mice, they don’t work in humans to treat AD yet. This is why we are using the strongest anti-inflammatory class of molecules for our studies. We first want to test whether they
Arguably most importantly, however, the team hope to find the optimal regimen of lenalidomide to reduce AD-associated symptoms and brain pathologies. This will entail varying the ages of animals receiving treatment, treatment course duration and dosages to determine the efficacy of lenalidomide as AD treatment. Biological markers such as TNF-α and other
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work in several AD-like mice. If they do, we’ll test the drugs in humans, and if they are efficient in humans we will investigate the molecular processes targeted by the drugs to find less toxic alternatives (even though it is lower than thalidomide, lenalidomide shows some toxicity in humans). Use of lenalidomide as AD treatment is particularly appealing due to its FDA-approved status. Could studies into multiple uses of FDA-approved compounds prove an effective approach to rapid treatment discovery for AD and other diseases? Given the success of the tri-therapy for AIDS, this approach of using multiple therapies is currently under investigation by other scientists. However, at this point it is difficult to decide which therapies are the most promising as none of them have proven effective individually in clinical trials. If your hypotheses are proven in the current study, what are the next steps leading to prescription of lenalidomide to treat AD and their timescale? Our current project is expected to provide the answers we need for a human trial in 2019. Thus, the first tests in humans will likely not start before 2019 or 2020 and last for two to five years. Then, we need to make sure the drug works for AD by measuring AD-specific biomarkers. Thus, in the best case scenario the drug will likely not be prescribed on a large scale before 2025. Another issue is the price of the drug. Currently in the USA, the pharmaceutical company Celgene sells a 10mg pill for $500. Conducting a thorough clinical trial with this price would require $2–5M, which very few sponsors are willing to invest at this point.
inflammatory markers, Aβ levels, amyloid plaques, and tau tangles, will be interrogated alongside assessments of cognitive measures such as working and spatial memories. This is particularly significant as, dependent on data collected from these studies, lenalidomide may continue into clinical testing as a very hopeful therapeutic to treat the enigma that is Alzheimer's disease.
RESEARCH OBJECTIVES Dr Decourt’s current work focuses on understanding the underlying pathology of Alzheimer’s disease and exploring possible new therapies. FUNDING We would like to thank the following agencies and institution for supporting our research project: NIA grants #P30 AG 019610 and K01AG047279; Alzheimer’s Association grants #AARF-16-443509 and #NIRG-12-237512; and the Arizona State University Biodesign Institute. COLLABORATORS • Gary D’Souza, PhD, Arizona State University-Banner Health Neurodegenerative Diseases Research Center • Marwan N Sabbagh, MD, Director of the Alzheimer’s and Memory Disorders Division at the Barrow Neurological Institute BIO Dr Boris Decourt is a neuroscientist focusing his translational research efforts on discovering neurological disorders’ biological mechanisms and possible therapeutic interventions via the regulation of inflammatory processes. His current research targets Alzheimer’s disease and associated brain pathologies. His ultimate goal is to translate his discoveries from bench to bedside. CONTACT Boris Decourt, PhD Assistant Research Professor, Arizona State University Arizona State UniversityBanner Neurodegenerative Disease Research Center at the Biodesign Institute School of Life Sciences E-Wing, Room 529 427 E Tyler Mall Tempe, AZ 85281 USA T: +1-480-965-8089 E: bDecourt@asu.edu W: https://biodesign.asu.edu/borisDecourt
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Neuroscience
Cell transplantation for neural repair: improving outcomes following spinal cord injury Dr Paul J Reier of the University of Florida began working in spinal cord repair research over 30 years ago. He and his former postdoctoral fellow, Dr Michael Lane of Drexel University, Philadelphia, are pursuing ways to improve outcomes for those suffering from spinal cord injury. They are currently exploring a promising experimental cell therapy approach, which has proven clinical safety and feasibility in both academic and biotechnology sectors.
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njuries to the spinal cord affect over 180,000 people worldwide each year. Their impact can be devastating, as the connections made by the nervous system between the brain and the rest of the body are disrupted. A LIFE-CHANGING DIAGNOSIS The majority of spinal injuries occur in the neck (~60% in the USA), mostly at the fourth and fifth spinal level. Troublingly, recent years have seen an increase in injuries at the higher, first to third, spinal level. These ‘cervical’ injuries can have particularly serious consequences, including pain, impaired use of and sensation in the limbs, effects on bladder and bowel function and even life-threatening impact on breathing. In addition to these disabilities are the tremendous lifetime costs of treatment and support, which can run into millions of dollars. The changes that result from a spinal injury are highly variable in nature, extent, and degree of reversibility, making this a complex condition to treat. While the initial trauma results in cell death at and around the injury site, this is followed by a chain of physiological reactions which, in turn, leads to further cell loss. This includes the two main types of spinal tissue: grey and white matter (Figure 1 overleaf). Grey matter forms the centre of the spinal cord and is composed mostly of cells called neurons, which are part of networks that relay sensory information from the body to the brain, and motor signals from the brain to the muscles. Other neurons in grey matter relay signals between neuronal networks at different levels of the spinal cord. On the other hand,
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white matter, running along the outside of the spinal cord, is composed of nerve fibres or ‘axons’ that are responsible for transmission of sensory signals to the brain and, conversely, motor commands from the brain to various levels of the spinal cord. Damage to those fibres accounts for paralysis and other functional deficits below the region of spinal cord injury. Once believed to be an incurable condition, a wealth of laboratory and clinical information has demonstrated the potential for restoring useful functions after spinal cord injury without requiring the regrowth of injured axons. Researchers agree, however, that no single treatment will be sufficiently effective; instead a combination of complementary approaches will be needed. These will include physical rehabilitation, drugs to help prevent progressive tissue damage or promote repair, electrical stimulation, and robotics. The research being pursued by Drs Reier and Lane, however, focuses on perfecting transplantation techniques for immature nerve cells – commonly referred to as neural progenitors or stem cells. HARNESSING NATURAL HEALING After a spinal cord injury, many patients undergo some degree of spontaneous recovery and behavioural adaptation, resulting in partial restoration of function. This is
attributed to ‘neuroplasticity’ – functional and/ or physical changes in nerve cells and their connections as a response to environmental stimuli such as injury. However, the extent of rehabilitation that can be achieved by natural neuroplasticity is both variable and limited. One aim of Dr Reier’s and Dr Lane’s collaboration is to develop therapies that harness and enhance the body’s natural neuroplastic potential. The current limit to plasticity in spinal cord injury is which tissues and connections have been spared by the trauma. If some repair of the spinal cord could be achieved, then there would be the potential for greater plasticity. Drs Reier and Lane are therefore investigating how communication between the brain and spinal cord might be restored by introducing new connections at sites of tissue damage. Through the use of ‘neural precursor cells’ (immature cells similar to stem cells), the team hope to provide a meaningful degree of recovery. Unlike embryonic stem cells, which may develop into any cell type in the body, neural precursor cells can become only neurons or glia. They therefore provide targeted building blocks for generating new spinal cord tissue. In a damaged spinal cord, neural precursor cells are envisioned to have potential for restoring communication across injury sites. By introducing neurons that can serve as functional bridges or relays (Figure 2 overleaf), they can effectively bypass any white matter pathways which do not regenerate. A LONG HISTORY OF SUCCESS Dr Reier and colleagues first started working in spinal cord repair in the 1980s, and his laboratory studies tested the possibility of repairing damaged spinal cords with transplanted fetal spinal cord tissue. At the time, despite rapidly growing interest in the use of fetal tissue for treating Parkinson’s disease, their proposition of utilising this material for treating spinal cord injury was met with scepticism. Nevertheless, those early studies demonstrated the primary requirements of this cell therapy: that embryonic cells could survive in, and integrate with, a damaged spinal cord. Moreover, they showed that even a relatively small number of
One aim of the collaboration is to develop therapies that harness and enhance the body’s natural neuroplastic potential 23
Neuroscience
“white” matter (axons and glia)
“grey” matter (neurons and glia)
Brain & brain stem
Graft relay
Figure 1
Figure 2
cells could grow, multiply and differentiate to replace damaged grey matter.
results. Modern scientific methods, including genetic modification, now permit tracking the distribution of neural precursor cells after transplantation and provide optimised conditions for selecting the most desired cell types for transplantation. There is also evidence that electrical stimulation of circuits silenced by spinal cord injury can promote neural activity, which may attract nerve fibre growth in a predetermined and functionally-relevant direction. Drs Reier and Lane are currently exploring new ways to incorporate advances in neurobiology and neuroengineering to optimise cell-based approaches for functional repair of the spinal cord. One way to incorporate recent technologies is to use optogenetic methods to stimulate transplanted cells. This very powerful method allows scientists to make donor neurons more active simply by shining light on them. Physiologically-patterned electrical activation of host and graft tissue may also enable more functionally relevant patterns of connectivity to be formed.
By the mid-1990s, Dr Reier’s research had progressed to demonstrating the safety and feasibility of transplanting embryonic nerve tissue in a small number of people with spinal cord injuries. This was the first clinical translation of its kind in the United States, and only second worldwide to a single patient study conducted in Russia. This technique has now been reproduced by several others in both academic and biotechnological settings, using a variety of proprietary cell lines. The experimental and clinical replication of this treatment demonstrates the promising nature of the approach. Recently, other laboratories have also reported independent evidence of the potential to establish novel, functional relays by transplantation of neural precursor cells. However, significant technical and biological challenges remain. NEW CHALLENGES, NEW SOLUTIONS One major issue is how to encourage the formation of new neural connections in useful directions, as the current random growth of nerve fibres between the host and implanted tissues gives variable functional
The restoration of sensory and motor abilities are what matters most to injured people, so promoting repair and neuroplasticity both aim to address this common goal. Putting
Cell therapy techniques are both logistically feasible and procedurally safe, but there is still a great deal that scientists do not understand 24
How does a typical spinal injury progress from the initial trauma to the chronic phase? There is a cascade of molecular and cellular events that follow a traumatic spinal cord injury, which promote inflammation, attract other cells to the site of injury, and initiate a ‘wound-healing’ like response. This removes cellular debris from the injury site, but may also contribute to further tissue loss and limit the potential for plasticity and repair. What exactly is meant by ‘neuroplasticity’ and why is it important in this field? There are many ways to define this word. To address this we default to a definition that we proposed in a recent research paper of ours by Hormigo et al (2017): “Neuroplasticity can be defined as the ability of the nervous system to make anatomical and functional changes that lead to persistent alterations in sensorymotor function. These changes can be mediated by a range of factors, such as prior synaptic activity (e.g., activity-dependent learning), persistent physical activity (e.g., rehabilitative training), or injury (e.g., SCI). Furthermore, this plasticity can also occur
an injured spinal cord together again to obtain useful, though not necessarily perfect, functions is clearly not a straightforward endeavour. Nevertheless, spinal cord injury research has made tremendous advances over the last three decades – the potential clearly exists for improving patients’ quality of life and reducing the spiralling costs of spinal cord injury. SPACE TO BREATHE Dr Reier’s and Dr Lane’s current research focuses on using cell therapy to treat one of the most devastating consequences of cervical injury to the spinal cord (at the level of the neck) – its impact on breathing. Restoring respiratory function is clearly very clinically relevant, but is also an important proof-ofconcept because the spinal circuitry involved with breathing is anatomically simple when compared with other networks involved in motor function. In addition, relatively short distances of repair would likely be necessary
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Detail ‘spontaneously’ (without external interference) following traumatic SCI. An important goal for SCI treatments is that they either: i) do not impair spontaneously occurring, beneficial plasticity, ii) limit any detrimental aspects of plasticity (e.g., spontaneously occurring pain), or even more preferably, iii) act synergistically to enhance intrinsic neuroplasticity and optimize the extent of lasting functional improvement.” How do neural precursor cells help stimulate the spinal cord to repair itself? As developing cells of neural lineage – which are therefore destined to become cells of the nervous system – they serve as building blocks for repair. They can replace cells that are lost, they are capable of releasing molecules that promote growth and limit inflammation, and they provide a substrate for growth of host axons (where there might otherwise be a scar or a cavity). What improvements can cell therapy bring to the life of a spinal injury patient? The extent of improvement that can be achieved will depend on where and when the cells are transplanted, which cells are used, which survive transplantation, whether the
to restore communication between respiratory centres in the brain and the spinal circuit controlling the diaphragm (the primary muscle for breathing). THE LONG ROAD AHEAD Drs Reier and Lane emphasise that the work is still at an experimental stage. Cell therapy techniques are both logistically feasible and procedurally safe, but there is still a great deal that scientists do not understand about how to maximise the use of cells for therapy. Several cell types have shown promise and some are now undergoing clinical trials, but continued research effort is required to ensure that the correct cells are being used, at the right time, in the right dose, and for the right purpose. As Dr Reier puts it: “Encouraging findings have been obtained, but there remains a great need to better understand the biology of this approach.” Challenges include practical and ethical
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host neurons connect with them, and how donor neurons become integrated with host cells. The molecules they release may limit cell loss if transplantation occurs early on, which may also limit the extent of functional loss a patient may encounter. If the appropriate neurons survive and connect with the correct neuronal pathways within the injured spinal cord, they can enhance motor or sensory functional outcomes. It is likely, however, that no cellular therapy alone will provide profound recovery from spinal cord injury though, so it is important to understand what cells are used and how other treatments may optimise therapeutic potential. What is the biggest challenge to putting cell therapy into practice for treating spinal cord injuries? There are many technical and biological issues; not just one. Optimising the formation of useful, new connections is clearly one challenge we are now keenly interested in resolving. Beyond that, there is always the issue of developing transplantation strategies without risking adverse outcomes such as pain.
considerations surrounding the source of neural precursor cells; the ability to culture sufficient numbers of cells for transplant; optimising the timing and delivery of the transplant procedure; and ensuring that the possibility of adverse outcomes is minimal. The main goal of the research at present is simply to bridge the gap between discovery phase and clinical application by enhancing promising research strategies and developing effective protocols for treatment. Both Dr Reier and Dr Lane are convinced that cell therapy will, in the long term, become an essential part of the toolkit for treating spinal cord injury, alongside drug treatments, engineering strategies and physical therapy. The remarkable potential of transplanted neural precursor cells to build upon neuroplasticity and aid functional recovery from spinal cord injuries will help to improve recuperation times and, ultimately, quality of life.
RESEARCH OBJECTIVES Drs Reier and Lane are especially interested in optimising regenerative strategies, such as neurotransplantation, to effectively promote spinal cord repair. FUNDING National Institutes of Health, Department of Defense, Paralyzed Veterans of America, Craig H. Neilsen Foundation, Bryon Riesch Paralysis Foundation, State of Florida Brain and Spinal Cord Trust Fund COLLABORATORS Drs David Fuller (Univ. Florida), Itzhak Fisher (Drexel Univ.), Giles Plant (Stanford), Shelly Sakiyama-Elbert (Univ. Texas at Austin) and the Center for Respiratory Research and Rehabilitation (http://crrr.phhp.ufl.edu/) BIO Dr Paul J Reier obtained his PhD in Anatomy from the CaseWestern Reserve University in 1972. He is currently a Professor and Eminent Scholar at the University of Florida, where Dr Michael Lane joined his laboratory as a postdoctoral fellow in 2006. Dr Lane subsequently advanced to Research Assistant Professor there three years later, and then in 2013 moved to become an Assistant Professor at Drexel University, Philadelphia. CONTACT Paul J Reier, PhD Anne and Oscar Lackner Professor of Neuroscience Department of Neuroscience University of Florida College of Medicine and McKnight Brain Institute, USA T: 352-627-9324 E: reier@ufl.edu Michael A. Lane, PhD Assistant Professor Drexel University College of Medicine Department of Neurobiology Spinal Cord Repair Center 2900 W Queen Lane, Room 245 Philadelphia, PA, 19129, USA T: (215) 991-8892 E: michael.lane@drexelmed.edu W: http://www.spinalrepair.org/
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Microbiology
At the intersection of the nervous system and innate immunity Innate immunity is an important part of the host defence against infections in many organisms along the evolutionary tree. Whilst there is ample evidence that the innate immune system and the nervous system interact, the exact mechanisms linking these two complex networks remain to be revealed. Dr Alejandro Aballay’s research focuses on this intersection. He has gained significant insights into the neural control of immunity by developing an experimental model system that minimises physiological complexity.
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hroughout recent years, it has been well documented that household antibiotics are not the reliable cure-all they were once thought to be. Numerous bacteria have mutated to gain resistance against antibiotics, leaving scientists with the question of how to combat this resistance and prevent immune infections. Dr Alejandro Aballay is one such scientist aiming to tackle this problem. His recent research utilising the Caenorhabditis elegans roundworm model is providing a promising insight into the role that the nervous system has in controlling the immune response to bacterial infections.
C. ELEGANS AS A MODEL SYSTEM Nervous systems in most model organisms are extremely complex and, thus, generally incompletely described. In contrast, each of the 302 neurons within the C. elegans nervous system are well characterised, as are many of their signalling molecules (secreted factors that can act on other cells at a distance). This relative simplicity and wealth of knowledge make the roundworm a prime model to study neural-immune communications using sophisticated laboratory techniques. CONTROLLING IMMUNE REACTIONS An innate immune reaction to infection involves a rapid and definitive antimicrobial
The relative simplicity and the wealth of neuronal knowledge about C. elegans make the roundworm a prime model to study neural-immune communications 27
Above: Fluorescence image of animals that exhibit high expression of a gene that is a marker of immune activation in the gut when dopamine signalling is inhibited in the nervous system Left: Image that highlights in orange dopaminergic neurons that are involved in the control of immune activation in the gut
response. This provides protection for the organism, so long as the reaction occurs with the appropriate intensity. Any aberration, i.e., deficient or excessive inflammation, can lead to diseases in humans such as cancer, Crohn’s disease, rheumatoid arthritis or Alzheimer’s disease. Along with the immune system’s self-regulatory mechanisms, the nervous system can act as a perfect ally in fine-tuning the immune response, due to its responsiveness to many types of stimuli. AT THE CROSSROADS Humans are protected by two main strands of the immune system – the innate and the highly specific adaptive immune system. C. elegans lacks the latter. Nevertheless, the roundworm possesses mechanisms
to recognise and respond to different pathogens through its inducible innate immune system. In addition, the nervous system of C. elegans uses a variety of signalling pathways in response to infections that do not only impact on immune functions, but also regular housekeeping mechanisms in cells. Dr Aballay’s group has, for example, determined a key role for certain proteins in nerve cells that are part of the family of G protein-coupled receptors (GPCRs) in controlling a signalling pathway that is as important in humans as it is in C. elegans’ immune system. This pathway elicits a microbicidal response via a conserved p38/ PMK-1 mitogen-activated protein kinase
Using a simple yet relevant model system, Dr Aballay has provided remarkable insights into host-microbial interactions and, in particular, control mechanisms of the immune system 28
(MAPK) that is critical for host resistance against bacterial infection. Dr Aballay’s research suggests that dopamine, a signalling molecule in the nervous system, inhibits the p38/PMK-1 MAPK pathway. Furthermore, sentinel neurons can control the unfolded protein response (UPR). UPR is crucial for the health of a cell and the survival of an infected worm. It ensures that host cells cope with the increased demand for new proteins during the course of an infection. The fact that C. elegans' neurons can restrain its innate immune response in various ways may give us a glimpse into the causes of poor immunity in stressed humans. OLD DRUGS, NEW TRICKS In a major undertaking, Dr Aballay’s group has screened an array of marketed drugs capable of activating the p38/PMK-1 MAPK pathway, determining whether these substances can confer protection against bacterial infections. A benefit of working with marketed drugs is that their bioavailability and safety profiles in humans are known and any new insights are therefore very relevant. One of those drugs, the last resort antibiotic colistin, protected the infected C. elegans independently of its antibacterial mechanism of action. What is even more remarkable is that this beneficial effect was associated with increased tolerance to the bacterial
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Microbiology
Detail How well do your research findings translate into humans? As long as we study conserved signalling pathways, I believe our research has great potential to be translatable. Despite the long evolutionary gulf between nematodes and humans, a number of seminal discoveries made in worms have been translated to humans. How relevant is C. elegans as a screening tool for drug discovery? C. elegans is a fantastic tool for drug discovery. Its genetic tractability makes it perfect for target validation. In addition, the entire animal is transparent, making it possible to study the effects of drugs that target single cells in the context of an entire live animal. What are the chances of finding new applications for old drugs through an improved understanding of the
interplay between the nervous and immune systems? It is too early to be able to tell. Will your discoveries help overcome the increasing threat of bacterial resistance to antibiotics? Any potential new approach and discovery in terms of mechanisms involved in the control of immune response against infections has the potential to aid and accelerate the discovery of new drugs that should alleviate the problem of bacterial resistance to antibiotics. What are your future research goals? We expect to identify targets and drugs capable of regulating signalling pathways that can be used to alleviate infections and conditions that involve a malfunctioning immune system.
Any potential new approach and discovery [...] has the potential to aid and accelerate the discovery of new drugs burden rather than the intensified killing of the pathogens. In other words, C. elegans was able to withstand the bacterial threat without having to kill it off. It is tempting to speculate that other antibiotics with the ability to modulate the immune response in such a way may improve health conditions of patients with chronic infectious diseases. What is more, Dr Aballay’s observation that the experimental inhibition of dopamine signalling in the nervous system enhances the immune response, opens up yet another group of drugs that may be tested for their ability to improve aberrant immune functions in humans. OTHER RESEARCH INTERESTS Dr Aballay has taken an interest in mechanisms involved in the recovery from
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infection. He found factors that lead to the reduction of innate immunity markers and the increase in genes involved in detoxification and other cellular regulation. He also researches how microbial infections can lead to neurodegenerative diseases.
RESEARCH OBJECTIVES Dr Alejandro Aballay’s early academic research into endocytosis and the intracellular transport of bacteria set him on his research career path. His recent research has focused on the organismal mechanisms of control of immune responses against bacterial pathogens, and the mechanisms involved in the control of recovery after infections. FUNDING • Dana Foundation (Neuroimmunology of Brain Infections and Cancers) • NIH: NIGMS (GM070977) • NIH: NIAID (AI117911) BIO Dr Alejandro Aballay is a Professor of Molecular Genetics and Microbiology, also serving as the Director of the Duke Center for HostMicrobial Interactions. He has made numerous contributions to the field of host-microbial interactions, focusing historically on bacterial virulence factors and their targets in host cells. CONTACT Alejandro Aballay, Ph.D. Professor, Department of Molecular Genetics and Microbiology Duke University Medical Center 207 Research Drive 264-265 Jones Building, Box 3054 DUMC Durham, NC 27710 USA T: +1 919 668-1783 F: +1 919 684-2790 E: a.aballay@duke.edu
Using a simple yet relevant model system, Dr Aballay has provided remarkable insights into host-microbial interactions and, in particular, control mechanisms of the immune system. Research into its interplay with the nervous system is much needed in a time when our lives are becoming more stressful. This puts our immune defence at risk and renders former household antibiotics useless against antibioticresistant pathogenic bacteria.
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The unifying theory of collaborative research
Immunology
Dr Karsten Hazlett of the Albany Medical Centre is a living example of how research collaboration can produce results impossible for individual researchers. Drawing together diverse investigators to tackle the problems involved in understanding the physiology and pathogenesis of bacterial pathogens, Dr Hazlett shows how this approach brings benefits for all involved.
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he conceptual underpinnings for much of Dr Hazlett’s work were forged during his postdoctoral training with Dr Justin Radolf at the University of Connecticut where he gained an understanding of bacterial physiology that has driven his subsequent research. The first of these tenets is that zoonotic bacteria (those which are passed from animals to infect humans) change composition in response to their immediate environment and these changes can impact efforts to understand microbial pathogenesis, immunology & vaccinedevelopment. The second foundational point is that a correct understanding of bacterial proteins (structure, function, localisation and regulation) is a prerequisite to understanding bacterial physiology, as well as to developing vaccines. COMING TO AN UNDERSTANDING Dr Hazlett says his lab is driven by a singular guiding principle – “that understanding a bacterial disease, from the bacterium’s perspective, will reveal translatable therapeutic opportunities”. This has been their goal throughout their recent research, which has consequently drawn in other groups with a similar aim to combat bacterial pathogens and better understand the underlying mechanisms of their activity. BACTERIAL AGENT AT LARGE In 2009, the group started work on a project to assess the dynamic composition of Francisella tularensis (Ft), the causative agent of tularemia. This bacterium is an intracellular pathogen which has been found in many different wild animals. Infection
of humans occurs through contact with these animals or via vectors (such as ticks and lice) – no human-to-human infection has ever been recorded. The pulmonary form of the disease (affecting the lungs) is often fatal and the bacterium has a low infectious dose, high virulence, and is readily spread by aerosol. For these reasons, the bacterium is a Tier 1 Select Agent meaning the US government believes it to have, "the potential to pose a severe threat to public health and safety". Because of this potential for use as a biological weapon, the group set about investigating how to discriminate between naturally-occurring Ft and those which had been cultured with the specific intention of infecting the public (i.e., bioterrorism). Simulating these differing conditions in the lab, the team used mass spectrometry to analyse the lipids and proteins of
Dr Hazlett’s lab is driven by a singular guiding principle – ‘understanding a bacterial disease, from the bacterium’s perspective, will reveal translatable therapeutic opportunities’ 31
Immunology
fractionated bacteria. Collaboration was once again a key feature of this research, with Drs Bob Ernst and Steve Kron, from the universities of Maryland and Chicago respectively, bringing their expertise to bear on the lipid and protein fractions respectively. THE ADVANTAGES OF TEAMWORK Convinced it is possible to develop a vaccine against this disease, Dr Hazlett and a second group focussed on three specific methods for improving vaccine efficacy. Firstly, maximising antigenic similarity, and ensuring that the vaccine composition is sufficiently similar to that of the bacterium during an infection. Secondly, optimising the capacity of this vaccine to stimulate an immune response in the individual. And thirdly, maximising the ability of the body’s cells to present the vaccine to the immune system for effective targeting. All of these approaches are also relevant to vaccine production more generally, so finding the answers for Ft would reap benefits for a host of other situations and organisms. Dr Hazlett, with his experience in the study and genetic manipulation of microbes, was well placed to get started, but once again it was bringing in the expertise of others which accelerated progress. Dr Tim Sellati, an Immunologist and expert in the study of immune stimulation and microbial pathogenesis, and Dr Ed Gosselin, a Vaccinologist skilled in the development and testing of immunogens which provoke protective immune responses, made it possible to apply a unique multidisciplinary approach to vaccine research, unifying and streamlining the development of inactivated bacterial vaccines. EXPANDING THE MODEL Their current research programme draws these strands together to further develop vaccine candidates, through testing in outbred animal models. The standard practice of using inbred strains in biomedical research has advantages in ease of use, but also has its limitations when considering its relevance to human disease. By assessing the efficacy of vaccines in both outbred models and immunologically manipulated inbred models, it is possible to identify so-called ‘correlates of protection’ – elements of both the physical vaccine and the host immune response which are crucial for effective protective responses to vaccination.
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The Hazlett Lab – Anthony (student), Prachi (post-doc), Kristen (student), Karsten, and Sarah (lab manager)
Once again Dr Hazlett has brought together a group of collaborating investigators who are able to progress the research using their diverse skills and experience. Alongside Dr Hazlett’s microbiological expertise, Dr Eileen Barry, a Vaccinologist, and the Immunologist/Aerobiologist Dr Doug Reed (who re-established the outbred rabbit model of tularemia used in current aerosol infection scenarios), will uncover protection mechanisms for aerosolised, virulent Ft in an outbred animal model that will be applicable to prevention of the human disease. A STAUNCH PROPONENT OF COLLABORATION Dr Hazlett believes it is this ability to collaborate on scientific investigations which is the key to unlocking the complex
mechanisms of action involved in vaccination research specifically, and biomedical research generally. To underline this concept he recently stated that, “My most enjoyable (and most successful) professional scientific experiences have been those in which a small group of like-minded investigators with differing backgrounds have come together for a focused, unified goal”. It is this unity of purpose which Dr Hazlett believes makes the small collaborative model such a productive and exciting way to work. His career to date has certainly shown how it can benefit not only the individual researchers, but also the wider scientific community, as the fundamental principles underlying observed phenomena are characterised and disseminated.
Dr Hazlett believes the ability to collaborate on scientific investigations is key to unlocking the complex mechanisms of action involved in vaccination research specifically, and biomedical research generally www.researchfeatures.com
Detail What excites you about researching bacterial pathogens? Since the bacteria keep evolving, we have to keep learning. On top of this, folks keep finding out more about how the immune system functions and how the pathogens and hosts interact. With each new piece of knowledge, opportunities for novel insights or practical interventions avail themselves. Chasing these developments/ ideas can be fun; ultimately, catching them is very intellectually satisfying. How has working collaboratively benefitted your research? Collaboration allows one to cast a broader net than most individuals (including me) can do by themselves. For me, collaboration has meant being able to think beyond isolated bacteria and individual bacterial proteins, and explore how bacteria operate in the context of a host and the multiple niches within the host environment. Moreover, as funding agencies have recently been encouraging well-constructed multidisciplinary grants, the “small team of experts” approach has become a valuable tool for academic medical researchers. For example, in 2006 the US National Institutes of Health implemented the Multiple Principal Investigator (MPI) funding mechanism specifically to “encourage collaboration among equals” and “maximize the potential of team science efforts in order to be responsive to the challenges and opportunities of the 21st century”. What advice would you give someone attempting to forge collaborative partnerships? I have had the best experiences with small groups of people (~3) with distinct scientific backgrounds and flexible personalities. Larger groups seem to be prone to becoming unbalanced and suffering from domineering personalities and splintered sub-groups – to the
detriment of the project. A group of three folks willing to interact as co-equals naturally fosters an “us” and tempers the elaboration of unnecessary “alpha-ness”. If you find yourself in a putative collaboration with someone who always needs to be the boss (even in your area of expertise), walk away and find or generate another group. There are good folks out there to work with and you did not get to this point in life to become someone’s beta. What is the next step in developing a vaccine for Francisella tularensis? Currently the two most effective candidates (developed by Eileen Barry and Wayne Conlan respectively) are live attenuated forms of otherwise virulent F. tularensis. These candidates are each more effective than the current gold-standard, (Ft LVS), and are both in various stages of advanced, pre-clinical development in outbred animal models. The efficacy of inactivated and/or sub-unit vaccine candidates has lagged behind largely because the correlates of protection for tularemia are currently ill-defined. As a result, tularemia vaccinologists are operating in an incomplete immunological landscape. By using live vaccines in both effective and sub-effective formulations, we are probing outbred, protective immune responses to identify the correlates of protection. Identification of these correlates will accelerate development of sub-unit vaccines, predictive immune assays, and novel vaccination/therapeutic platforms. What has been the most enjoyable aspect of your collaborations? Chatting with folks who look at a problem from different perspectives, coming up with novel interdisciplinary solutions, and testing the idea(s) with a “soup-to-nuts” approach.
With each new piece of knowledge, opportunities for novel insights or practical interventions avail themselves
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RESEARCH OBJECTIVES Dr Hazlett’s research focuses on bacterial pathogenesis, gene regulation, and vaccine development. His laboratory’s principle is: understanding a bacterial disease, from the bacterium’s perspective, will reveal translatable therapeutic opportunities. FUNDING • National Institutes of Health (NIH) • National Institute of Allergy and Infectious Diseases (NIAID) COLLABORATORS • Eileen Barry, PhD (University of Maryland-Baltimore) • Douglas Reed, PhD (University of Pittsburgh) • Edmund Gosselin, PhD (Albany Medical College) • Timothy Sellati, PhD (Southern Research) • Robert Ernst, PhD (University of Maryland-Baltimore) • Stephen Kron, MD/PhD (University of Chicago) BIO Dr Hazlett was born in Honolulu and received his BS degree in Biology/Chemistry at Frostburg State University in 1993. He later obtained a PhD at Albany Medical College and a postdoctoral fellowship at the University of Connecticut Health Center. He returned to AMC in 2005 and is currently an Associate Professor. CONTACT Karsten R.O. Hazlett, PhD Associate Professor Albany Medical Center 43 New Scotland Avenue Albany, NY 12208 USA T: +1 518 262 2338 E: Hazlett@mail.amc.edu W: http://www.amc.edu/Profiles/Hazlett. cfm
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Thought Leadership
Cancer Research UK: Fighting the feared disease Whether it be a family member, a friend or you yourself, everyone knows someone who has been affected by cancer. The disease has earned itself a fearful reputation, giving rise to the slogan 'cancer changes everything'. But Dr Iain Foulkes of Cancer Research UK believes that new breakthroughs in research are beginning to have an impact across cancer treatment. He spoke with us at Research Features to discuss these exciting developments in more detail.
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ancer. It’s a word that everyone dreads. And because people are living longer, we are now reaching a stage where one in two people will be affected. This capricious disease is hard to avoid. But thanks to ground-breaking research, survival rates are today double what they were 40 years ago – and it is Cancer Research UK’s aim to keep that survival rate rising Cancer Research UK (CRUK) is the world's largest independent cancer research charity. From grappling with rare forms of the disease, to testing new treatments, the charity is focused on turning scientific breakthroughs into better patient care as swiftly as possible – bringing forward the day when all cancers can be cured. Another key part of its mission is to inform. As such, it runs campaigns, such as Dryathlon and Race for Life, and a recent joint campaign with Channel 4, Stand Up To Cancer UK, aimed at raising awareness of the disease and influencing public policy. Dr Iain Foulkes has a busy role in the organisation as both the Executive Director of Research and Innovation and CEO of Cancer Research Technology. He recently spoke to Research Features about these roles in more detail, outlining the successes and setbacks of cancer research throughout his time at the organisation.
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Hello Ian! Could you tell us what your roles involve as the Executive Director of Research & Innovation and CEO of Cancer Research Technology (CRT) at Cancer Research UK (CRUK)? I oversee our research funding across population research, discovery science, drug discovery and development through to our clinical trial portfolio. As CEO of CRT, I am also responsible for ensuring research insights are developed and patient-benefit realised – often in the form of new drugs or diagnostics. We have the scope and capability as an organisation to go from the first funding of a research idea all the way through to a fully developed or commercialised innovation. We are also able to partner with organisations that can help at the earliest stages and ensure those ideas progress as rapidly as possible. What are CRUK’s core principles in terms of history, heritage and background, and which areas of cancer research are you currently looking into? We believe that it is only through a thorough understanding of cancer – at a deep biological level – that we can develop new approaches to beat the disease. We work closely with those we fund – researchers funded via our grants and our core funded institutes and centres. We want a dialogue with the research community that enables them to follow their ideas and discoveries, but also addresses our mission as a funding organisation – to beat cancer sooner. Traditionally we have funded and continue to
fund only the very best research, but we also try to facilitate teams to come together in new collaborations. Cancer research today requires lots of different capabilities and the UK has a wealth of them, but we need to find new models to support this capability as a network. We set out a strategy a couple of years ago that highlighted a number of areas where we wanted to see more research. These included a focus on specific tumour types where
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we have seen little shift in survival – brain, oesophageal, pancreatic and lung cancer. In addition, we set out to drive a big shift into the field of early disease biology and the early detection of cancer. How big an influence has CRUK had on research since it was first established? I think the organisation has had a huge influence on the landscape and focus of cancer research in the UK. In the past years
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We want a dialogue with the research community that enables them to follow their ideas but also addresses our mission as a funding organisation – to beat cancer sooner 35
we have established three new institutes (in Oxford, Cambridge and most recently London), we have developed a national network of cancer centres that rival many in the US, and our track record in partnering with industry to establish new therapeutics is second to none – we now see drugs based on Cancer Research UK’s research regularly used in clinical practice. Moreover, our ability to influence public policy based on research evidence has grown immeasurably over the past ten years and we’ve seen great success on issues such as tobacco control, radiation oncology and molecular diagnostics. From a personal perspective, are there any achievements you are particularly proud of? I’m fortunate to work in an organisation that attracts some brilliant people, and my job is to help turn their ideas into reality. Most recently we’ve been focused on establishing a more prominent global position with initiatives such as our Grand Challenge – a £20m award to bring the best scientists together from around the world to tackle the biggest problems on cancer. I think this is
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incredibly exciting and will hugely benefit the UK research ecosystem. Do you think cancer research receives as much funding and attention as it should? Cancer is a huge cause of premature death in the UK and even more so globally – survival is improving but as a combined figure 50% of patients don’t survive their disease – there is still much to do. Not only that, but cancer research is behind many of the advances in biological insight and technology development which benefit research across disease areas. What we should be doing as a research sector is building the argument for continued investment in the UK science base – it is one of the UK’s real strengths and an opportunity to attract the world’s best talent and organisations that help us defeat this and other diseases. How important have initiatives like the Stand Up To Cancer campaign been in highlighting the importance of cancer research? Hugely important. One of the strengths of Cancer Research UK is that we have to
We now see drugs based on Cancer Research UK’s research regularly used in clinical practice fundraise – all of our research is funded out of the generosity of the public. That means we have to engage a huge number of people in our work, in science, cancer awareness and celebrate the amazing achievements that UK science is delivering every day. Although your name (Cancer Research UK) has UK in its title, do you extend your research outreach to collaborate with other countries internationally as well? Much of our work is funded in the UK, although we have always fostered
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Thought Leadership
Dr Iain Foulkes
collaboration with international colleagues. More recently, we’ve started to play a more prominent role internationally with initiatives such as the International Cancer Benchmarking Partnership and Grand Challenges. There is a growing need for us to facilitate research across borders and bring the very best people together. The response we had to our first Grand Challenge call was extraordinary, so there is a real demand for funders to support the research community in this way. The CRUK website states that over the past 40 years, survival rates for cancer sufferers have doubled. Do you think it will be possible to improve this survival rate even further over the next 20 years? It is our ambition to accelerate progress and reach a position in 20 years where three in four people survive their disease for five years or more. The pace of discovery is fuelling this ambition and with genuine breakthroughs in fields like immuno-oncology we think it will be possible.
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Which direction would you like to see cancer research going in the future and how will CRUK’s research leadership strategy play into this? Firstly, progress in cancer research comes from the brightest minds following their ideas, with funders like Cancer Research UK providing the support for them to do so, and the resources to turn those ideas into new benefits for patients. I would hope our strategy continues to attract the very best people from all over the world to the UK and that the UK research community gets stronger as a result of our investments. Secondly, I think we need to continue to push for the boundaries around scientific and clinical disciplines to become more permeable. Ground-breaking discoveries are often made at the interface of research disciplines – for example, chemical biology and the development of next generation sequencing and physics and the refinement in radiotherapy dose delivery. I hope all funders can work together to facilitate multidisciplinary approaches. And thirdly, I hope we can continue to foster collaboration and team science, which is essential if you want to go from a discovery to a new therapy that helps patients. We have to balance the benefits of open competition to fund the best, with the need to bring researchers together in a non-competitive way to progress ideas through to the clinic.
How can our readers get involved with these activities and contribute their time to CRUK? Cancer Research UK is a big organisation, but every year we start from £0. The vast bulk of donations we receive are less than £50, so every amount helps. Log on to our website and see what you could do to help. There are so many ways to get involved and most have good side benefits, like Dryathlon and Race for Life. • If you would like to get involved with any of Cancer Research UK’s fundraising initiatives, or simply make a donation to their groundbreaking work, please visit their website at www.cruk.org.
Contact Cancer Research UK Angel Building 407 St John Street London, UK EC1V 4AD W: www.cancerresearchuk.org /cancerresearchuk/ @CR_UK
CRUK are renowned for their fundraising events and activities throughout the year.
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Novel kinase inhibitors offer fresh treatment hope for prostate and pancreatic cancer
Cancer
Mutations to kinase genes are associated with a range of diseases, including many cancers. Increased IKKα kinase levels have been identified as a key factor in both advanced prostate and pancreatic cancer progression, for which there are a lack of effective treatments available and an often devastating prognosis for patients. Professor Simon Mackay from the University of Strathclyde has developed two novel, first-in-class IKKα kinase inhibitors, which specifically target the aberrant cancer-promoting signalling protein. These new compounds have the potential to not only treat several other cancers, but also a range of inflammatory diseases, including arthritis.
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rostate cancer accounts for 36,000 new cases each year and around 10,000 deaths annually. This high mortality rate is not helped by the limited efficacy of current treatments. In fact, 80% of patients with an advanced form of the disease, who are treated with the standard androgen ablation therapy, go on to develop castrate-resistant prostate cancer (CRPC) – an incurable form of prostate cancer. Although newer, second-line therapies such as enzalutamide and abiraterone, and chemotherapies such as taxanes have extended CRPC patient survival, mortality rates are still high. TARGETING SMALL MOLECULES TO SPECIFIC PATHWAYS Encoded within the human genome are about 500 kinase proteins, which act as enzymes critical to cell function. It is when these proteins go awry that diseases, including many cancers, can occur. Prof Mackay is working towards developing a series of inhibitors aimed at a member of the kinase family known as IKKα. Intracellular signalling and activation of the pathway that IKKα is involved in has been identified as a key factor in the progression of prostate cancer from a hormonedependent to castrate-resistant pathology. Until now, no attempts have been made to directly intervene therapeutically in the IKKα-associated mechanisms of cancer
development. This provides a promising opportunity for the design of novel compounds, as the targeted inhibition of IKKα could turn off key signalling pathways that promote cancer cell survival, growth and proliferation. Currently, treating prostate cancer usually involves androgen ablation therapies – a treatment approach that often leads to resistance and relapse. This failure has been related to IKKα activity – IKKα regulates the inflammatory processes that occur when primary prostate cancer cells die, which is associated with the failure of androgen ablation therapy and the progression of the cancer to the castrate-resistant form. Other new drug treatments that have been approved in recent years have been primarily focused on decreasing circulating androgen levels and androgen receptor inhibition, and although these have been relatively successful, they on average still only extend survival by approximately eighteen months. By targeting the underlying processes associated with the development of CRPC, Prof Mackay’s novel class of IKKα inhibitors offer a new therapeutic intervention strategy for patients if it can be successfully introduced into the clinic. JOINT PANCREATIC CANCER FOCUS In addition to prostate cancer, their efforts to develop this novel class of drugs are
Intervening in IKKα-associated mechanisms provides a promising opportunity for the design of novel compounds, as the targeted inhibition could turn off some of the signals that promote cancer cell survival 39
Cancer
also aimed at tackling pancreatic cancer. As with CRPC, the IKKα regulated pathway has been found to be similarly amplified in pancreatic cancer, therefore providing an ideal target for intervention with an inhibitor. At present, the mortality rate within five years of diagnosis of advanced pancreatic cancer is shockingly high at 94–96%. There are an estimated 9,000 new cases every year in the UK and, due to inadequate screening and a lack of early clinical symptoms, most patients present with an advanced stage of the cancer, rendering it untreatable due to a lack of existing options. DISCOVERING NEW FIRST-IN-CLASS SELECTIVE INHIBITORS After identifying promising compounds, Prof Mackay and his team set to work on improving the properties of these molecules, enhancing their inhibitory activity and suitability for use as drugs, without compromising on potency or specificity. Unspecific kinase activity is a high risk due to the critical roles kinases play in healthy cellular pathways. In fact, off-target kinase inhibition can result in highly toxic effects, which is the reason why many similar drugs never make it through clinical trials. Despite these challenges, Prof Mackay and his research team have succeeded in producing two lead compounds, and are close to satisfying the criteria for further drug development. The first of the optimised compounds exhibits greatly improved potency for inhibiting IKKα. This comes after the researchers demonstrated that the compound could reduce and inhibit proliferation of cell lines derived from advanced prostate cancers. However, its water solubility needs to be improved as the researchers hope to develop a drug that can be taken orally. Therefore, they are continuing development to see if they can optimise the structure and formulation to produce a more water-soluble form. The second lead compound exhibits increased potency and water solubility, and is also incredibly specific: it only significantly inhibited one other kinase from the hundred they tested. Tests for growth inhibition on cancer cells were also successful. The only property that requires further development prior to the next stage of trials is to reduce the compound’s clearance from the body. The current compound has a higher rate of clearance than is preferred, meaning that it may be metabolised by the liver
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and expelled from the body. Ideally, Prof Mackay would like the drug to be able to be taken orally by patients only once a day, and therefore an optimised version of the compound that would last longer would be preferable. BROADENING REACH OF POTENTIAL EFFICACY As IKKα has been implicated in resistance to existing therapies, Prof Mackay and his team also carried out in vitro tests using the novel compounds in combination with other existing treatments to see if they would work in synergy with existing drugs. Excitingly, they found that the inhibitors have a “supra-additive” effect, with the cancer cells becoming more sensitised to the current standard treatments for both CRPC and pancreatic cancer. Prof Mackay and his team, working in collaboration with other research groups, have also begun investigating the effectiveness of their novel compounds on other conditions known to be associated
with abnormalities in IKKα function. So far, the compounds have been found to inhibit the growth of patient-derived multiple myeloma and chronic lymphocytic leukaemia in vitro. Not only that, but, as IKKα has been shown to be important in the development of colorectal cancer and some breast cancers, these drugs may prove to have a wider range of use in other cancers. As well as this, Prof Mackay and his team are also investigating whether the compounds could treat chronic inflammatory diseases such as rheumatoid and osteoarthritis. Although still in its early days of testing, effects look promising against key IKKα-driven processes and inflammatory markers in cells derived from patient osteoarthritic synovial tissue. Prof Mackay’s research on prostate cancer treatment has now progressed beyond the confines of cell-based studies to in vivo studies. Their preliminary experiments using mice with metastatic prostate cancer xenografts have yielded encouraging results, with significant tumour regression occurring.
Prof Mackay has succeeded in producing two superior kinase inhibitor compounds, and his research on prostate cancer treatment has now progressed beyond the confines of petri dishes to in vivo studies www.researchfeatures.com
Detail What first interested you in medicinal chemistry and what inspired you to pursue a career in research? As an undergraduate studying Pharmacy at the University of Bath, I thoroughly enjoyed the medicinal chemistry element of the programme, and had a great set of enthusiastic lecturers who clearly loved the subject. I decided to pursue a PhD in medicinal chemistry and was lucky enough to work for Roger Waigh at the University of Manchester. Roger was a member of the academic team (with John Stenlake and George Dewar – coincidentally, all based at Strathclyde at the time) that discovered atracurium, one of a very small number of drugs developed in UK academia to make it through to clinic. Roger was an inspirational (if somewhat demanding!) supervisor, who convinced me I had what it took to pursue a career in academic drug discovery research. What would you say are the most challenging aspects of getting from identifying a potential target to developing a compound that is viable for testing as a new drug? I’d say that the most challenging aspect has been coming to terms with the incredible complexity of biology. Cancer is continually evolving to counter everything we throw at it and so, in the spirit of maintaining an optimistic outlook, we need to believe that even if our next experiment doesn’t take us a step forward in developing a new treatment, it will at least give us a better understanding of what is evolving. So there’s progress even when things seem to fail! It is also crucial to have drug-discoverydedicated biologists and clinicians in your team in order to succeed. Convincing funding bodies that you have a viable target and the expertise to develop
compounds is also a challenge. Most of my time is spent trying to raise the necessary funding. What steps are needed to get the new compounds through to testing in human clinical trials? We need to demonstrate that our compounds cause tumour regression in animal models that is through engagement with the target IKKα. In parallel, we need to show there is no target-related or compound-related toxicity at concentrations that are therapeutically relevant in appropriate animal models. We also need to show that the frequency of oral dosing is reasonable, which is related to clearance. If a patient has to take a tablet too often in a day, there will be issues of compliance which will impact clinical efficacy. Ideally, we’re looking for a once- or twice-daily dose regimen. If you cannot increase the water solubility of the first lead compound and reduce the clearance of the second, is it possible to employ different methods of drug delivery and dosing schedules to use them in their current structure? All small molecule kinase inhibitors that are currently used clinically have faced these problems during development, so I’m confident we will ultimately address them – it is just a matter of time and resources. What are your hopes for the progress of this research over the following five years? Ideally, by partnering with a pharmaceutical company, to get an optimised drug candidate into clinical trials in patients with cancers likely to respond to IKKα inhibition
Even if our next experiment doesn’t take us a step forward in developing a new treatment, it will give us a better understanding of what is evolving
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RESEARCH OBJECTIVES Professor Mackay’s research looks to develop a unique series of IKKα inhibitors into compounds that offer the therapeutic potential for use in castrate-resistant prostate cancer and potentially pancreatic cancer as well. For the past 25 years, he has been applying medicinal chemistry to drug discovery, with his primary focus being drug development in cancer. FUNDING Currently funded by Medical Research Council (MRC) Originally funded by Cancer Research UK Prostate Cancer UK KEY TEAM MEMBERS Dr Andrew Paul; Prof Robin Plevin; Prof Gavin Halbert; Dr Marie Boyd; Dr Joanne Edwards; Prof Colin Suckling COLLABORATORS Professor Neil Perkins and Dr Elaine Willmore, University of Newcastle; Professor Chris Pepper, University of Cardiff; Dr Danny Huang, Beatson Institute for Cancer Research; Dr Martin Swarbrick, Cancer Research Technology Ltd; Dr Tim Hammonds, Cancer Research Technology Ltd; Dr Aymen Idriss, University of Sheffield; Professor Michael Karin, UCSD; Dr Peter Storz, Mayo Clinic BIO Prof Simon Mackay is Professor of Medicinal Chemistry in the Strathclyde Institute of Pharmacy and Biomedical Sciences, at the University of Strathclyde, Scotland. He is currently the Principal Investigator of a project to develop small molecules to treat prostate cancer, with the potential to treat numerous others. CONTACT Professor Simon P Mackay Chair of Medicinal Chemistry Strathclyde Institute of Pharmacy and Biomedical Sciences University of Strathclyde Glasgow, UK G4 0NR T: +44 (0)141 548 2866 E: simon.Mackay@strath.ac.uk W: http://www.strath.ac.uk
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Stem transplants have vastly improved remission rates compared to chemotherapy alone, but sadly the majority of patients will ultimately relapse
Microbiology
Battling blood cancer: virus targets multiple myeloma A successful treatment for the bone marrow cancer, multiple myeloma, has so far remained elusive. Pioneering research led by Dr Eric Bartee, of the Medical University of South Carolina, suggests a two-pronged approach to improving myeloma recovery rates, using a virus that is only harmful to rabbits.
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ultiple myeloma (or simply ‘myeloma’) is one of the most common blood cancers – making up 10–15% of cases and affecting some 24,000 new patients each year. Multiple myeloma affects the white blood cells known as plasma cells, which are produced in the bone marrow, and is typically found at multiple sites such as the spine, skull, pelvis and ribs. Symptoms can include bone pain and fractures as well as anaemia and, ultimately, it can result in death. A LIFE SENTENCE The progression of multiple myeloma under current treatment practices tends to follow a pattern of remissions and relapses, with only one-third of patients surviving more than ten years after diagnosis. Standard treatment for the disease involves repeated cycles of chemotherapy, to destroy myeloma cells in the body, followed by transplantation of replacement stem cells to enable the body to make healthy plasma cells. The transplant usually comprises of cells taken from the patient’s own blood stream prior to the chemotherapy – and hence is known as an ‘autologous’ stem cell transplant. Autologous stem cell transplants have vastly improved remission rates and survival times compared to chemotherapy alone, but sadly the majority of patients will ultimately
relapse. The prognosis for these relapsed patients, says Dr Bartee, is ‘grim’. HIDDEN AWAY There are two possible reasons for the return of cancer symptoms in multiple myeloma patients treated with autologous stem cell transplants. The most likely explanation is that small numbers of myeloma cells survive chemotherapy in inaccessible parts of the bone marrow, and can then re-emerge, multiply and spread. However, a second cause may also contribute: accidental contamination of the stem cell transplant with small numbers of myeloma cells circulating in the blood stream. These again can multiply and spread once transplanted into the body. Dr Bartee’s work focuses on eliminating both these sources of myeloma cells, in the hope of developing a treatment that will prevent relapse and improve survival rates for patients with multiple myeloma. AN UNLIKELY CHAMPION The unusual tool that Dr Bartee and colleagues are using in their research is a pathogenic virus related to smallpox and known as ‘myxoma’. This virus is the cause of the notorious ‘myxomatosis’ disease that has been used in many countries as a biological control agent against rabbits. Myxoma was recently discovered to belong to a group of
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Microbiology
A rabbit with myxomatosis – the virus does not cause disease in any other organism © Fletch 2002 at English Wikipedia
viruses known to target and kill cancer cells – the so-called ‘oncolytic’ viruses. Dr Bartee believes that the myxoma virus can be used to seek out and destroy myeloma cells – both within the body and in the stem cell transplants – before they are reintroduced to the patient. This offers two complementary avenues to improving clinical outcomes for myeloma patients. Unlike other viruses that have been tested as oncolytics, the myxoma virus should be completely safe, since it does not cause disease in any organism other than rabbits. It therefore poses no risk to the patient or the wider human population. It also avoids the problem – found with many oncolytic viruses such as measles – that the patient’s own immune system recognises and eliminates the virus due to previous vaccination or infection. FRONTLINE THERAPY Using laboratory mice as a model, Dr Bartee’s team has shown that the myxoma virus can distinguish between normal and cancerous cells, eliminating up to 90% of myeloma cells within 24 hours after treatment. The myxoma virus does this via two mechanisms. Firstly, in all mice tested, some myeloma cells were killed by direct contact with the myxoma virus particles. This rapidly induced a process of programmed cell death known as ‘apoptosis’. Although this translated into minimal increases in survival for the mice, Dr Bartee believes that it might have significant
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The myxoma virus has the potential to become a versatile tool in the battle against multiple myeloma clinical potential when combined with other treatments such as chemotherapy. Remarkably, however, in a quarter of the mice, complete eradication of the myeloma cells was achieved. This occurred through a second mechanism, in which the virus induced the mouse’s own immune system to attack the cancer cells. PROGRESS WITH ‘PURGING’ Dr Bartee’s lab is currently exploring whether the myxoma virus can be harnessed for use directly in multiple myeloma patients before, after, or in combination with existing chemotherapy drugs. However, the prospect of using myxoma in this way remains a long way off. For a start, unlike many other viruses, myxoma has not previously been used in humans, so a lot of work needs to be done to develop safe, clean and consistent stocks of the virus before clinical trials can begin. The second approach to using myxoma is
How was the myxoma virus’ ability to destroy cancer cells discovered? The initial discovery was actually made by my post-doctoral mentor Dr Grant McFadden. He had been studying the myxoma virus for many years with the goal of understanding the basic biology of viral infection. As part of this work, he was interested in understanding why the virus could infect rabbits but not humans or mice. The ability of any virus to infect a host is determined by a complex tug of war between the host’s anti-viral defences (in this case a pathway known as the interferon system) and the virus’s counter measures to these defences. Grant eventually found that myxoma induced a robust interferon response in all species. Myxoma’s countermeasures to interferon, however, only worked in rabbits. Therefore in all other species, the virus lost the tug of war. It has long been known, however, that the interferon system frequently doesn’t work correctly in human cancers. Therefore, Grant hypothesised that if myxoma virus was placed directly into a tumour, the host’s interferon system would be incapable of stopping the virus as long as it stayed in the tumour. Turns out he was right. What hurdles need to be overcome before the myxoma virus can be used directly to treat myeloma patients? While there are likely some additional experiments which should be done, the primary hurdle is to generate a virus of sufficient purity to use in humans. For traditional drugs, this is a relatively straight
further advanced towards clinical application. This method involves using the virus to decontaminate autologous stem cell samples prior to transplant into patients. The technique, termed ‘purging’, prevents reintroduction of any myeloma cells along with the vital blood-cell-producing stem cells. Using laboratory populations of human myeloma cells, Dr Bartee and colleagues have successfully shown – for the first time – that treatment with myxoma virus particles results in the rapid and complete death of myeloma cells, while completely sparing healthy blood-
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Detail forward process. However, for viruses it is much more complex since the virus must be grown in living cells: after the virus is made, it must be purified away from the cells used to grow it before it can be used in patients. This is a very difficult and expensive process. How does an autologous stem cell transplant work? Stem cell transplants are used in combination with a procedure known as myelo-ablative chemotherapy. Myelo-ablative chemo is basically treatment with really high doses of normal chemo drugs. This is more effective at killing tumour cells since you are using more of the drug. However, it comes at the cost of significantly increased toxicities. In the context of myelo-ablative therapy, the toxicity which is most concerning is the elimination of a patient’s hematopoietic stem cells (the cells which constantly produce new blood for the patient). Since you always need new blood to survive, myelo-ablative therapy by itself is actually lethal. To survive the procedure, it must therefore be combined with some method to replace the hematopoietic stem cells which were killed. Autologous transplant does this by removing a patient’s own hematopoietic stem cells before the myeloablative therapy is given and then giving these same cells back to the patient after the myelo-ablative therapy is finished. This has the advantage of being safe and easy; however, since the hematopoietic stem cells must be removed prior to treatment, the patient still has cancer when they are taken out. This unfortunately means that the blood or bone marrow where the hematopoietic stem cells
producing stem cells. When samples treated with myxoma were transplanted into mice, the mice remained healthy and no myeloma cells were detected in their bodies. This suggests that the myxoma virus fully and effectively purged the samples of cancerous cells. Treatment of autologous stem cell transplants with myxoma virus is a quick and easy process, making it an attractive strategy for improving outcomes of myeloma treatment. Unusually, myxoma is a virus that does not need to complete its life cycle and replicate itself to cause the death of host cells. Therefore, it
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reside often contains trace amounts of cancerous cells which are then given back to the patient during the transplant. Are the two methods of treatment using myxoma mutually exclusive, or might benefits be obtained from using both? We have not examined this specifically; however, they should absolutely be able to be combined. The treatment of myeloma which already exists within the patient (residual disease) is done by simply injecting large amounts of the virus into the blood stream. One of the beauties of the purging strategy is that the virus used to treat the autologous transplant sample never has to be washed away. You simply have to add it to the transplant sample, wait a few minutes for the virus to find and bind to the myeloma cells (10–15 mins is typically enough time in our studies) and then proceed with the transplant as normal. This means that any virus which does not bind to a myeloma cell ends up being injected directly into the blood stream, effectively mimicking the treatment that we demonstrated was effective against residual disease. We actually have some anecdotal evidence that using the virus as a purging agent during autologous transplant might make the treatment of residual disease better since the virus can bind to cells found in the transplant sample and use those cells as carriers to take it to the sites of residual myeloma. Understanding this effect and how these two treatments might be combined is actually one of the major issues we are interested in moving forward.
RESEARCH OBJECTIVES Dr Bartee’s work focuses on the treatment of multiple myeloma using the myxoma virus – an oncolytic virus. FUNDING NIH-NIAID; NIH-NCI; the American Cancer Society; the Medical University of South Carolina; the Hollings Cancer Center; the South Carolina Clinical and Translational Research Institute. COLLABORATORS Mee Y Bartee, Bjarne Bogen, Xue-Zhong Yu and Katherine M Dunlap. BIO Dr Bartee is an Assistant Professor of Microbiology and Immunology at the Medical University of South Carolina. He is currently working on an NIH funded project into the treatment of multiple myeloma. CONTACT Eric Bartee, PhD Medical University of South Carolina 96 Jonathan Lucas Street Charleston, SC 29425 USA T: +1 843 876 2775 E: bartee@musc.edu W: www.musc.edu
should be possible to create an attenuated virus that would have the same efficacy, without raising any concerns about infection. Having completed their preclinical trials in mice, Dr Bartee’s team are now keen to move towards clinical trials of this novel and promising weapon against myeloma. In combination with the existing approaches of chemotherapy and autologous stem cell transplant, as well as the exciting possibility of direct treatment of patients, the myxoma virus has the potential to become a versatile tool in the battle against multiple myeloma.
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Molecular Biology
Elucidating the mechanisms of disease-causing bacteria
Dr Justin Merritt, from the Oregon Health & Science University, studies disease-causing bacteria at mucosal sites in humans, especially in the mouth. His latest research on bacteria that cause tooth decay offers interesting and very novel insights into the processes that can trigger disease.
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he human mouth harbours more than 700 unique microorganisms that live on the teeth and oral mucosa. This so-called oral microbiome performs diverse functions for its host, for instance in food digestion, detoxification of environmental chemicals or immune responses. An imbalanced microbiome (termed dysbiosis) can have strong effects on health, with one example of this being dental caries (tooth decay). This is a major health problem worldwide, affecting 60–90% of schoolchildren and more than 95% of adults. In cases of advanced dental caries, few alternative options exist other than removing the tooth completely. BACTERIA CAUSE TOOTH DECAY Tooth decay is caused by dental plaque, which mainly consists of bacterial biofilm, forming on and around the teeth. A biofilm is an aggregate of microorganisms and other (secreted) substances that can adhere to surfaces. One major contributor to this biofilm forming on teeth is a bacterium
called Streptococcus mutans (S. mutans). S. mutans has specialised receptors that allow it to stick more readily to the tooth surface and it can grow on a wide variety of carbohydrates. However, in the presence of sucrose (table sugar), it starts converting this sugar-type into long, sticky polymers called glucans, which adhere to teeth. On its surface, S. mutans has proteins that bind glucan (glucan-binding proteins or Gbp) thereby greatly facilitating its biofilm formation and the resulting dental plaque. Sucrose is the only sugar that can be metabolised to form these sticky molecules. However, S. mutans can also catabolise sucrose and many other sugars for energy, producing lactic acid as a by-product. This creates an acidic environment in the mouth, leading to the dissolution of the calcium-rich tooth enamel. Simultaneously, S. mutans thrives in this acidic environment, outcompeting numerous other microorganisms that are not so tolerant of the acidity. In the long run, this allows S. mutans to dominate within the
What is it that makes Streptococcus mutans so successful at colonising the mouth, compared to all other bacterial species sharing its habitat? 47
Molecular Biology
oral microbiome, leading to tooth decay. Consuming sugar therefore aids S. mutans in creating the perfect conditions for its survival and success.
S mutans
However, what is it that makes S. mutans so successful at triggering tooth decay, compared to all other bacterial species sharing its habitat? How exactly does it regulate biofilm formation and could that be prevented? These are the key questions that Dr Merritt and his team have asked in their bid to improve oral health. HOW BACTERIA BECOME HARMFUL Bacteria can adjust to their environment through regulatory networks, which allow them to regulate the activity of their genes. In this way, they can quickly respond to changes in the environment such as stress or particular nutrient availability. This is one of the reasons why bacteria can live in so many different niches on earth and how initially harmless bacteria can cause diseases. Dr Merritt and his team at the Oregon Health & Science University study regulatory pathways within bacteria that cause oral diseases, such as tooth decay. In one branch of their research, the Merritt team shed light on a peculiar regulatory system that can control many disease-associated processes in S. mutans. FINDING UNEXPECTED ANSWERS The Merritt lab discovered a key gene in the disease-causing process for S. mutans called irvA. In S. mutans, the irvA gene is not active under normal environmental conditions, meaning it produces no mRNA. The reason for this is that a repressor protein called IrvR is bound to the irvA gene, preventing mRNA production. The Merritt lab discovered that upon stress, the IrvR protein cleaves part of itself – resulting in the irvA gene switching from an inactive to active state and starting mRNA production. This irvA mRNA then stabilises the mRNA encoding glucan-binding protein C (GbpC) – a biofilmenhancing surface protein – by preventing
Deferred antagonism assay using different clinical isolates of S. mutans. Growth inhibition halos surrounding the colonies are indicative of antibiotic production preventing the growth of the following species. Left: Streptococcus pyogenes Right: Enterococcus faecium
IrvR/A Regulatory System The IrvR/A regulatory system is found only in the Mutans group streptococci
the usual RNA degradation machinery of the cell from taking action. This machinery consists of RNases, which are enzymes that control RNA abundance by degrading unused, degenerate, or harmful (i.e., viral) RNAs out of cells. Without gbpC mRNA being stabilised by irvA mRNA, the former is rapidly broken down immediately after synthesis by a defined cellular RNase. However, by inhibiting RNase degradation of gbpC mRNA, the irvA mRNA causes greatly enhanced production of the GbpC surface protein, thus contributing to biofilm formation. Despite its peculiar regulatory function, the irvA mRNA is still a template for protein production, making it a molecule with two vastly different functions. These findings are exciting in the sense that mRNAs were thought to serve primarily as templates for protein production, rather than directly affecting cellular processes. The mechanism typically involved in protein
Studying disease-related processes in harmful bacteria will not only advance our understanding of those microorganisms, but could ultimately deliver novel therapeutic targets to tackle illnesses 48
creation does not apply to all produced RNAs of a cell: particular RNAs do not encode protein information, but instead perform certain functions in fine-tuning gene expression in their form as an RNA molecule. Until now, mRNAs have not been credited with similar regulatory capabilities, so these findings add an additional layer to known gene regulatory concepts. Future research efforts need to reveal whether this is an exceptional case or whether it occurs more frequently in (pathogenic) bacteria or even higher organisms. BROADENING THE VIEW Bacteria have a vast variety of gene regulatory strategies even among similar species. The Merritt lab is dedicated to exploring completely unknown regulatory mechanisms in harmful bacteria. One example of this is a new mechanism they have discovered in S. mutans, termed the LytTR regulatory systems (LRS). This system appears to be involved in both the initiation of S. mutans cell death as well as its secretion of toxic substances that prevent growth of competing bacteria. Studying disease-related processes in harmful bacteria will not only advance our understanding of those microorganisms, but could ultimately deliver novel therapeutic targets to tackle illnesses. As illustrated by the irvA work of the Merritt team, it can also reveal previously undiscovered mechanisms of gene regulation – which may have broader implications for research.
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Detail What led you to study gene regulatory mechanisms in pathogenic bacteria? I have always been fascinated by pathogenesis, but never imagined myself devoting so much effort to the study of gene regulation. However, this changed dramatically during my graduate studies of S. mutans. Here was an organism that exists as part of the normal flora in virtually all adults and yet it possesses a conditional ability to trigger disease. This seemed so counterintuitive and ultimately piqued my curiosity to understand how members of the flora like S. mutans regulate processes that can result in pathology to the host. What makes Streptococcus mutans an interesting model system for studying diseases at mucosal sites in general and gene-regulatory pathways in particular? There are a couple of qualities of S. mutans that I think make it a wonderful model organism. Firstly, it is an obligate member of the human microbiome. The human oral cavity is its only known natural habitat and therefore it is a relevant model organism for studies of human dysbiotic disease. Secondly, S. mutans has a relatively small genome and has an amazingly robust genetic system. It literally takes only several days from start to finish to create all types of mutant strains. Consequently, we are always willing to test unconventional ideas. Are there any drawbacks in the methods available to you for studying pathogenic bacteria? A major challenge for the study of dysbiotic diseases is that pathogenesis largely occurs in a polymicrobial context (i.e., as a pathogenic consortium of species). Much of our research requires studies of mixed communities of bacteria, which multiplies the complexity. This poses an even greater challenge when attempting polymicrobial infection studies of animal models of human dysbiotic diseases. Members of the
human microbiome generally exhibit poor survivability in other animals. How could your findings into cellular regulatory pathways be used to create therapeutics? Many of the classic bacterial diseases of antiquity are caused by foreign bacteria and can be treated using antibiotics, which is basically a scorched earth treatment strategy (at least at the microscopic level). Antibiotics kill a large segment of the bacteria in your body including the bad bugs. However, this approach has limited utility when particular species of one’s own flora are the problem, since it is very detrimental to one’s health to remove the flora, especially for extended periods of time. We are interested in finding the Achilles’ heel of particular species for targeted therapeutics. For example, we have found that LytTR Regulatory Systems seem to control a suicide-like pathway in S. mutans. Can we hijack LytTR Regulatory System gene regulation to trick S. mutans into killing itself, while sparing the beneficial species within the mixed community of flora? What are the next steps in your research? For our gene regulation studies, we are extremely interested to understand the role of uncharacterised RNA binding proteins as mediators of RNA–RNA interactions. For all cellular life forms, a large percentage of the gene regulatory interactions between RNA molecules involve imperfect complementarity (e.g. irvA-GbpC mRNAs). Because of the numerous mismatched bases between many interacting RNA molecules, hybridisation is often extremely inefficient without the aid of another protein to catalyse their interaction. Some of these RNA-binding proteins found in S. mutans even have analogous proteins in higher organisms.
RESEARCH OBJECTIVES Dr Merritt’s research focuses on the mechanisms used by signal transduction systems to control various virulence properties of several bacterial pathogens associated with oral disease. Within this, he has discovered the role of irvA – a key virulence gene. FUNDING National Institute of Dental and Craniofacial Research (NIDCR) National Institutes of Health (NIH) COLLABORATORS Dr Jens Kreth, Dr Rahul Raghavan BIO Dr Merritt studied a BS in Microbiology and Immunology prior to his PhD in Microbiology. Following this, he worked as a postdoctoral fellow at the University of California before working at the University of Oklahoma Health Sciences Center. He currently works as an Associate Professor at Oregon Health & Science University. CONTACT Justin Merritt, PhD Associate Professor, Department of Restorative Dentistry Affiliate Associate Professor, Department of Molecular Microbiology and Immunology Oregon Health & Science University MRB424 3181 SW Sam Jackson Park Rd. Portland, OR 97239 USA E: merrittj@ohsu.edu T: +1 503 418 2664 W: https://www.ohsu.edu/xd/education/ schools/school-of-dentistry/about/ academic-departments/restorativedentistry/
We are interested in finding the Achilles’ heel of particular species for targeted therapeutics www.researchfeatures.com
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Dentistry
Taking a bite out of Latino oral health disparities Ethnic minorities in the US show substantial oral health disparities (OHD), experiencing higher rates of dental caries, gingivitis, and/or chronic periodontitis. They also face barriers to accessing oral health services and are disproportionately less likely to seek regular and preventive dental care. Dr Gerardo Maupomé from Indiana University has launched the VidaSana initiative to identify social network factors that may contribute to these phenomena.
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r Maupomé has a career that has spanned continents. He first received dental training at the Universidad Nacional in México City, before being awarded first an MSc in Oral Pathology then a PhD in Public Health from the University of London. Returning to North America he carried out research in both Vancouver, Canada and Oregon, USA, before settling at Indiana University in 2005. Here he has combined his expertise and interest in both epidemiology, social and behavioural sciences, and dentistry to address the disparities facing underprivileged communities in the US. The existence of oral health disparities (OHD) among the Latino community is long established and has previously been attributed to lifestyle, biological susceptibility or structural barriers posed by healthcare systems. The role of personal interactions within social networks has largely been ignored, despite widespread
recognition that these networks contribute to healthcare decision making and to sharing norms and values that affect health status. TAKING A CLOSER LOOK A framework for evaluating such personal interactions, called the Network-Episode Model, has been developed for use in epidemiology in an attempt to better understand individual responses to illness. According to this model, episodes of illness should be viewed as affected by formal (professional) and informal networks. Individuals rely on these relationships to understand and address their health problems. Other members of their network can offer support, recommend or provide services, influence health behaviours such as substance use, and either encourage or discourage the following of treatment regimes. In a pioneer study targeting MexicanAmericans (MA), Dr Maupomé identified
The Latino population in the US is the fastest growing ethnic group in the country, yet it has particular and significant barriers to dental service provision and access, contributing to large oral health disparities www.researchfeatures.com
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Dentistry
The Tala Community social network. Green nodes represent all individuals in the community; a larger node indicates that one individual had more health discussion partners, connoted by the number of links converging on the node. The colour of the links represents the two topics of discussion addressed in the research. First, a commonly used namegenerator in network methods is depicted in blue: ‘Who do you talk with when you discuss important matters in your life?’ In red, ‘Who do you talk with when you talk about dental care and oral health?’ The links in purple between nodes indicate interactions when both important matters and oral health matters were discussed.
experiences of food, oral health behaviours, and dental care in the context of the networks the subjects lived in. This showed that the utilisation of dental services by MAs is moderated by their peers. For example, parents and co-workers were found to encourage the use of urgent dental care, whereas involving members of the extended family (such as grandparents) often contributed to a fatalistic view that oral diseases are inevitable. THE INFLUENCE AND LIMITS OF NETWORKS The study found that MAs were more likely to talk to family about oral health issues than discuss them outside the family network.
If these members were perceived to have greater dental knowledge then it was more likely that the subject would come up; this was particularly true if the MAs were less integrated culturally. This means that early in the acculturation process, family and peers have a major influence on how MAs access dental services. Dr Maupomé acknowledges some limitations in the study, which focused on a particular nationality of origin in one ethnic group. The design of the study also precluded any establishment of a causal link. To address the latter issue, and to further investigate the role of social networks in OHD, an expanded team is going back to the field.
The effect of this research is to provide the opportunity of tailoring programmes to disadvantaged communities, using their existing natural strengths and resources to improve the oral health of the population as a whole 52
A COMPREHENSIVE APPROACH Using a longitudinal study design (where subjects are observed repeatedly over a longer time period), Dr Maupomé hopes to begin developing a strong causal model of OHD in MAs. Looking at how networks, oral health culture and dental care attitudes influence one another over time, he hopes to gain an insight into the complex and dynamic mechanisms underlying OHD. The first aim of the study is one of characterisation. Looking at the customs, attitudes and behaviours around dental care and oral health among MAs, Dr Maupomé hopes to identify these more clearly so that they can be effectively monitored by the team. In this way, they can build up a clearer picture of the associations between these factors and other features of personal networks. The second aim is to use this information to determine the relationships between the diverse strands of interpersonal networks and behaviours. These include behaviours such as cultural integration, whereby individuals begin to take on the customs of the host country; the dynamics of personal and community networks, as MAs expand and develop their peer groups; and the distribution of customs and resources as these peer groups influence and support each other. These relationships result in the evolution of oral health behaviours, attitudes and outcomes, when all these various factors
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Detail How does your own background influence the focus of your research? Having had the privilege of living in a few countries and having travelled extensively, it soon became apparent that the root causes of poor health in general, and poor oral health, are rather ubiquitous. And the more appropriate tools to address those challenges go well beyond expensive clinical care repeated over and over again. Why do disadvantaged communities suffer from such health disparities? Underprivileged communities such as immigrants are in an extremely precarious situation – challenged by what is often low income, limited access to care, lack of knowledge to navigate health care systems, and the confluence of (new and old) cultural influences that often work against their health status. Considering that our time will be defined by the multiple, evolving, and complex trends underlying immigration movements throughout the world, it is clear that a methodical and multifaceted approach is essential to characterising immigrant health issues. What did your initial study discover about Mexican American communities?
come to bear on the physical health of the study subjects. GREAT CHALLENGES BRING GREAT REWARDS This is as daunting a task as any in complex science methods, but there are good reasons to pursue it with the passion that Dr Maupomé has for the subject. Firstly, to improve both the quality and the quantity of knowledge about the complex and everchanging mechanisms underlying OHD. Although effective public policy needs to be built on the foundations of accurate understanding of the factors involved, to date this empirical approach has been largely limited to individualistic models of patient motives and circumstances. Clinical guidelines would also benefit from such enhanced perspectives of where, how, and with whom people live, in order to provide
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That the cultural features of population groups moderate the web of influencing factors leading to oral health outcomes. And it is remarkable how many of these influences there are when you think about the vast array of issues present in the health landscape. What do you hope the VidaSana project will achieve? To further refine the methods available to understand the evolution of networks in the context of health issues, and to identify culturally specific resources to leverage solutions in an underprivileged population. How might the results of this research impact public policy and clinical practice? Simply throwing money at health care problems is expensive and ineffective – even if the fiscal realities of the world would allow for generous funding of health systems. We can harness existing strengths in the communities to create simpler, less expensive solutions if we understand the problems and the clients in the context of the landscape in which they live.
culturally sensitive clinical and preventive care strategies. The same is true of research efforts to provide practical solutions to OHD. Building upon these envisioned assets resulting from network science research, the ultimate goal is to provide the opportunity of tailoring programmes to MA communities, using their existing natural strengths and resources to improve the oral health of the population as a whole.
RESEARCH OBJECTIVES Dr Maupomé’s research focuses on oral health in Latino populations, in particular the influence of social networks on communicating oral health information and sharing social norms about dental care and oral health. FUNDING NIH: NIDCR Indiana Clinical and Translational Sciences Institute COLLABORATORS W R McConnell; B L Perry; B Pescosolido; E L Pullen; E R Wright; Ann McCranie BIO Dr Maupomé trained in dentistry at the Universidad Nacional in México City, before being awarded first an MSc in Oral Pathology then a PhD in Public Health from the University of London. Returning to North America he carried out research in both Vancouver, Canada and Oregon, USA, before settling at Indiana University in 2005. CONTACT Gerardo Maupomé, BDS, MSc, DDPH RCS(E), PhD Indiana University Health Sciences Building 1050 Wishard Blvd., suite R2200 Indianapolis IN 46202 USA T: +1 317 274 5529 E: gmaupome@iu.edu W: https://indiana.pure.elsevier.com/en/ persons/gerardo-maupome
The Latino population in the US is the fastest growing ethnic group in the country, yet it has particular and significant barriers to dental service provision and access, resulting in large oral health disparities. Using these techniques to map the factors and characterising the effects of relationships over time, Dr Maupomé and his collaborators have the potential to impact positively on this area of public policy and clinical care.
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Thought Leadership
Heart to heart with cardiology leader Dr Jack Lewin Whether it be founding the first Navajo Nation Department of Health, providing health care for all in Hawaii, or taking the helm of the largest interventional cardiology research organisation in the world – Dr Jack Lewin has seen health and health care from almost every possible vantage point. After leading the Cardiovascular Research Foundation for three years, Jack is now moving on. He recently met with us at Research Features to talk about his time at the organisation and discuss the vital work carried out there.
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r Jack Lewin was the energetic and dynamic President and CEO of the Cardiovascular Research Foundation (CRF) from 2013 to 2016. New Year 2017 saw a fresh start for the New York-based MD, who decided to move on to pastures new and is now focusing on his own health science innovation and policy consulting group, Lewin and Associates. He also continues to serve as Chairman of the Washington DC-based National Coalition on Health Care (NCHC).
Research Features caught up with Dr Lewin on the eve of his departure. Here he looks back on his time at the CRF and provides an insight into the organisation’s excellent work. He also discusses his earlier career and shares his hopes for the future. Hi Jack! Can you tell us more about the work of the CRF? The CRF is approximately a $57 million a year non-profit institution. It is the largest education and research organisation of its kind in the world, with respect to interventional cardiology. CRF puts on roughly 50 educational meetings a year, the largest of which is TCT, or Transcatheter Cardiovascular Therapeutics, which attracts about 11,000 scientists and clinicians each year in the United States. But it also has TCT meetings in many parts of the world, including Russia, China, India, South America and the Middle East.
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There are three major divisions of the Cardiovascular Research Foundation. First, there is the educational division, which produces TCT branded meetings around the world. It also runs an online education resource called TCTMD, which reaches about 70,000 people globally. Then there is a clinical trial centre which runs 30 to 40 clinical trials annually. These are multimillion dollar, major trials, funded mostly by industry. The CRF designs and organises them, analyses all the data, does all the statistics work and then publishes the results, and this is a very big part of the organisation’s operating purpose. The CRF’s third division is a separate facility in Orangeburg, New York called the Skirball Centre for Innovation. This is a preclinical research facility and the CRF often gives birth to new ideas and new devices, and does the initial work there, leading eventually to firstin-human trials which can be held anywhere in the world. As CEO and President, I managed the staff and ran these programmes, and also interacted with the outside world. Innovation is one of the CRF’s main goals. Could you tell us about some of the innovations that the organisation has been involved with? The organisation, founded by the iconic Dr Marty Leon, has been around for 25 years and
is always looking at the cutting edge of what is going to happen next. At the beginning of its life, the CRF team was envisioning the idea of percutaneous catheter-based interventions for coronary artery disease and heart attacks, and actually helped lead the way towards what is now common place in terms of angiography, and stents, and the whole idea of percutaneous intervention for heart disease. Similarly, the organisation has led other kinds of innovation movements, the latest one being catheter-based heart valve replacements. It has been a leader in percutaneous valve replacements as well. The organisation also works closely with the FDA (the consumer watchdog in the USA’s healthcare system) and other regulatory
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agencies, in terms of all those needs. It is capable of taking an idea from scratch and turning it into a new device or a new therapy, testing it out on a preclinical area, taking it to first-in-human trials and then actually doing the phase one, two, and three studies leading to FDA or CE (EU safety, health and environmental requirements) approval. It can thus take it the whole way, from an idea to a product that is in the marketplace, providing therapeutic assistance to people. How does the CRF keep abreast of all the latest ideas in cardiovascular research? CRF is not a membership type of organisation like a medical society, but there are 70,000 people who use the TCTMD site where there is a lot of scientific information, including
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If you go back to the 1980s, the idea of treating a heart attack without cracking open the chest, with stents and angioplasty rather than surgery, seemed like science fiction the tracking of clinical trials. All the slides and content of every presentation the CRF have ever produced are there. The CRF has a network of interventional cardiologists and scientists and industry leaders around the world and they often brainstorm ideas at the big meetings. They are constantly discussing what the next step is, what the next phase is, what kind of research needs to happen. So there’s a very open and creative exchange of ideas? Yes, the CRF team is really open about wanting to brainstorm what is next, even if it
seems unrealistic or impractical. In fact, if you go back into the 1980s, the idea of treating a heart attack without cracking open the chest with stents and angioplasty rather than surgery, seemed like science fiction, and even five years ago it seemed like science fiction to replace a heart valve with a catheter-based therapy, but it is now common place. The next phase will be bioresorbable scaffolds, so that you are not putting a foreign body in your artery, or in the heart, or endovascular space. Instead, you use a scaffold-stent that actually gets reabsorbed and no longer poses a risk of clot or thrombus formation. The CRF
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CRF's annual scientific symposium, Transcatheter Cardiovascular Therapeutics (TCT) is the premier educational meeting specialising in interventional cardiology. TCT brings together over 12,000 physicians and healthcare professionals from all over the world to present and discuss the latest research, techniques and innovations to improve patient care
are looking at personalised medicine, and genetics, and immunologic markers as they affect heart disease, and new ways to treat heart failure as well. So there is a lot going on in cardiovascular medicine. It is quite an exciting time. How do you see the landscape of interventional cardiology changing over the next ten years? I think the shift is going to be towards structural heart disease over the next decade. The CRF will be doing more and more on replacing heart valves in congenital heart disease and other structural kinds of therapeutics. That is going to be a major focus within cardiology, but I think that personalised approaches to using genetics and other risk factors will also become part of the prevention strategy in cardiovascular disease over the next decade. In America, 500,000 people die of a heart attack every year and that is unacceptable, and in fact more women than men. This provides a major challenge in terms of educating clinicians and women about the risks of heart disease, which often present differently than they do with men. But women are dying more frequently
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than men today of heart disease and this is a global problem. Why do you think that is? I think it is because women do not think of themselves as having as much risk as men, and their doctors do not think of them as having as much risk. In addition to that, the symptoms women experience, in terms of angina and coronary artery disease in general, often vary. They are very different from men in many cases. Often women do not realise that they are having a heart attack when they are and they do not seek help in time, and that results in a higher rate of preventable death than for men. You mentioned personalised approaches – how affordable do you think personalised approaches will be? Clearly we need to think about the health economics aspect of personalised medicine. But, when you think about how our risk factors in terms of our genetics vary significantly, and in terms of our lifestyle obviously very significantly, we need to tailor therapeutics to the prevention of heart disease in ways that incorporate all of that individuality, and tailor both our prevention and our treatment approaches. In addition to statins, which have dominated the therapeutics of atherosclerosis over the past couple of decades, we now have PCSK9 drugs. They are expensive, but are also promising for people who cannot tolerate
statins or who cannot lower their LDLcholesterol enough. It will be important to understand when that expense is warranted. The CRF is also going to be looking at heart failure, which has so many different aetiologies and so many different variables that you cannot look at it as a single disease. It is the most common and expensive cause of hospitalisation in the US and much of the developed world. But heart failure is going to be an area of great and promising research and experimentation in terms of new therapeutics, and I think there will be a lot more success in effectively preventing it from developing in people at risk, but also in treating it when it does exist, to provide better quality of life. Prior to your role at the CRF, as a commissioned officer in the US Public Health Service you founded and directed the Navajo Nation Department of Health, serving the needs of America’s largest American Indian tribe. How did this experience shape your understanding of delivering health care to minority groups? My seven-year experience as a commissioned officer physician in the USPHS on the Navajo Nation early in my career taught me a lot about the importance of cultural competence in engaging patients effectively in treatment adherence and improving health outcomes. The Navajo language is very difficult and their social customs are also unique. But gradually learning to speak some conversational
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Thought Leadership
The spectre of health policy and health care is certain to go through unparalleled and possibly chaotic change in the immediate years ahead. I want to be part of helping to make that turn out positively
Dr Jack Lewin
Navajo and adapting to traditional customs and gestures, I was able to be a better physician and was accepted as a member of a very different community. Gradually, as trust developed, I was invited to traditional healing ceremonies and cultural events, which greatly enriched my experience there. I also learned from this experience about the importance of public health in improving health outcomes, and began to focus on developing better water systems and quality and better nutrition, rather than wishing for a more modern intensive care unit in the face of limited resources. What career achievement are you most proud of? In terms of career achievement, being Hawaii's Director of Health during the late 80s and early 90s allowed me a major role in implementing the Hawaii Prepaid Health Care Act – the first state-wide universal access law to be passed in the United States. It gave all workers and their families, even employees in the smallest businesses, guaranteed access to comprehensive health care as a shared cost of the employer and the employee, creating near universal access to primary care in Hawaii. This significantly improved health
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outcomes and population-based preventable morbidity and mortality. What does the future hold for you? What's your vision for where you might take Lewin and Associates LLC? The future for me is beyond exciting: I have seen health and health care from almost every possible vantage point. I have had the privilege of practising medicine in a variety of settings including the USPHS American Indian Health Service; I have run a hospital system; I have started or managed three health insurance programmes; I have been a state public health director with 6000 employees and a billion-dollar budget; I served as CEO of both the California Medical Association and the American College of Cardiology, as well as being President and CEO of the Cardiovascular Research Foundation, thus experiencing the clinical research world as well. Along the way, I also chaired the Patient Safety Institute and started several entrepreneurial ventures.
organisations, representing 150 million Americans. I have got to know the Congress and several Presidents. So, what next? Well first, I learned at CRF about the creative pleasure of helping health start-up companies go from an idea to a new clinical innovation and then on to success in the marketplace, and I now am engaged in doing more of that. But, in addition, the spectre of health policy and health care is certain to go through unparalleled and possibly chaotic change in the immediate years ahead. I want to be part of helping to make that turn out positively. Health care remains the biggest, most complicated and, one could argue, most important sector of the US economy. Being freed up to fully participate in shaping the future of health care – a financially sustainable future with access for all, better care with consistently better outcomes, and improved national health status – that really excites me.
Contact Cardiovascular Research Foundation 1700 Broadway, 9th Floor New York, NY 10019 USA E: info@crf.org W: www.crf.org @crfheart www.facebook.com/CRFheart
I am currently Chairman of the National Coalition in Health Care in Washington DC, the oldest and largest health policy coalition in the US with 110 national member
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Optimisation of Cerulean A site-directed mutagenesis strategy was employed to optimise Cerulean fluorescence. (A) Residues on β-strand 7 (S147, D148; red), β-strand 8 (L166, I167, R168, H169; green) in the Cerulean X-ray structure (2wso.pdb [27]) were targeted for optimisation by site-directed mutagenesis. The chromophore is coloured blue. (B) T203 (orange) was targeted for optimisation due to its proximity to the chromophore. T65 (green) was also mutated. Markwardt ML, Kremers G-J, Kraft CA, Ray K, Cranfill PJC, Wilson KA, et al. (2011) An Improved Cerulean Fluorescent Protein with Enhanced Brightness and Reduced Reversible Photoswitching. PLoS ONE 6(3): e17896. doi:10.1371/journal.pone.0017896
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Physiology
Bringing cellular processes to light The key to understanding how diseases develop or how drugs work is to uncover what goes on inside our cells. However, experimental intervention may perturb normal cell signalling and produce unreliable results. Dr Mark Rizzo from the University of Maryland School of Medicine aims to overcome this substantial challenge by applying optimised fluorescent protein tags which interfere minimally with regular cell functions.
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o understand cell functions, we often analyse some form of output like a secreted substance, or we destroy cells to detect molecular changes caused by different treatments. Such experiments generate valuable insights, but barely explain how the proteins responsible for the observed effects actually work. Where are they in the cell? Do they change location or shape to perform their functions? Do they
interact with other cell components? It is extremely difficult to study proteins in action without disturbing a cell’s state. Dr Mark Rizzo is currently Associate Professor at the University of Maryland School of Medicine in Baltimore. He has set out to develop fluorescent markers that make proteins visible inside the living cell – so-called optical biosensors. FLUORESCENT PROTEINS Fluorophores are molecules with the ability to absorb light at a characteristic wavelength and emit it at a longer wavelength. For example, cyan fluorescent proteins (FP) can absorb light from a violet laser with 405nm wavelength and emit blue light at around 480nm. Using genetic manipulation, FP can be connected to other proteins in the cell. Essentially, this creates fluorescent tags that allow us to observe otherwise invisible proteins, using fluorescence microscopy or other suitable means. Many fluorophores bleach easily during light exposure, which makes long-term
experiments impractical. Some are also relatively dim, requiring highly sensitive detection equipment with strong amplification. Dr Rizzo’s team has recently modified the molecular structure of the cyan FP ‘Cerulean’ to improve its fluorescent properties. The result is a variant of this protein, mCerulean3, that is bright and has a lower level of bleaching. ENERGY TRANSFER Because the emitted wavelength of cyan FP is still relatively low in the spectrum of visible light, they can be employed as donor fluorophores in Förster resonance energy transfer (FRET) applications. The FRET method is based on the transfer of light energy from one fluorescent molecule to another over very short distances. This effect can be exploited to measure the interaction between fluorophore-coupled proteins or even changes in the shape of single molecules. Monitoring multiple fluorescent markers at the same time is still a challenge. Depending on the fluorophore combination, FRET technology can produce false positive results. In a quest for reliable multi-colour imaging tools, Dr Rizzo has delved deeply into the physical detail of FP light emission. The insights gained have informed the invention, in collaboration with Dr Jin Zhang at UCSD, of fluorescence anisotropy reporters (FLAREs). As such, Dr Zhang, Dr Rizzo and their teams have already now designed FLAREs in several colours that allow for the imaging of up to three markers at once. NICHE ENVIRONMENTS The challenges in designing effective FP go beyond their mere physical properties. A cell contains a variety of micro-environments with distinct biochemical characteristics, such as a low pH or strong oxidising processes. Some FP are not compatible with those extreme conditions and lose their function, or perturb cell processes. In addition, FP may be subjected to regular
It is extremely difficult to study proteins in action without disturbing a cell’s state. Dr Rizzo has set out to develop fluorescent markers that make proteins visible inside the living cell www.researchfeatures.com
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cellular measures of protein formation, transport and quality control. This can interfere with their structure and location in the cell. Altogether, these challenges can lead to unreliable results and artefacts in imaging experiments, restricting the use of many popular FP. Dr Rizzo and others have been working on the creation of resistant FP which function in diverse cellular micro-environments. Their work has not only expanded the repertoire of available tools, but also yielded significant detailed insights into the molecular changes needed to reduce the susceptibility of existing FP. CALCIUM SENSORS Calcium is a vital agent in various cell signalling processes. Dr Rizzo and collaborators have used the FRET method to study the role of calcium in blood vessels of conscious mice using non-invasive fluorescence microscopy. Importantly, while this set-up requires the mice to be sufficiently motionless during imaging, it does not involve pain – hence, anaesthesia is not required. This is a major advantage over studies in the past because it avoids unwanted interference with normal blood pressure regulation by anaesthetics. The team used transgenic optical biosensor mice which have a genetically encoded FRET-based calcium indicator molecule in their blood vessels. When this molecule is inactive, light energy is transferred from a cyan FP to a yellow FP. This results in detection of the yellow emission. When the sensor molecule is activated by calcium, it undergoes a structural change that creates enough distance between the two FP to
Normalised absorbance of fluorescence
Physiology
Wavelength (nm) Spectral properties of new CFPs Absorption (dashed lines) and emission spectra (solid lines) are shown for Cerulean (black), mCerulean2 (green), mCerulean2.N (red), and mCerulean3 (blue). Spectra were normalised to the peak absorption or emission values.
Dr Rizzo’s achievements have delivered improved versions of several fluorescent proteins, in terms of both their physical properties and usability across various cellular micro-environments Fluorescence properties of CFPs
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Detail Why did you decide to focus on optimising fluorescent proteins (FP) as a research tool? These reagents are very valuable to us because they can provide unique insights into the behaviours of living cells and organisms. Even so, FPs are imperfect, which at times limits the measurements that we can make using a microscope. The need to overcome these limitations is our motivation. Are your improved FP variants commercially available to other researchers? They are indeed available from the addgene.org plasmid repository, but not presently from commercial sources. Can FRET-based signals be detected with common types of fluorescence microscopes or is specialist equipment required? Most fluorescence microscopes can be easily set up to measure FRET by insertion of the right optical filters for illumination and detection. Ironically, this is often more difficult on fancier microscopes, such as confocals, that may not have had the right components built into them in the first place. These kinds of instruments generally need to be configured for FRET experiments at the time of purchase.
break the FRET effect. This leads to the detection of the cyan emission, because the yellow FP no longer receives any stimulating energy. The team found that calcium concentrations in blood vessels were indeed much more representative of the normal state, as compared to anaesthesia, and the set-up did not appear to cause stress in mice. In conclusion, using these biosensor mice in an experimental set-up with minimal discomfort provides a basis for more complex studies of the cardiovascular system in the future. Dr Rizzo’s other research interests include the regulation of blood sugar, a key factor in diabetes. His team used a further improved variant of the above-mentioned
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Can fluorescence imaging replace more traditional molecular techniques (such as Western blot)? Undoubtedly, fluorescence imaging is a powerful method that is very well suited for certain kinds of experiments like measuring calcium levels in living cells. That said, there will always be a need for complementary methods like Western blots because there are many things that fluorescence imaging isn’t good at. Assessing which protein variants are present in a particular tissue, for example, can be much more clearly determined by Western blots. What plans do you have for your future research? We are very interested in understanding the connection between diabetes and cardiovascular disease. It is our hope that these two areas of investigation will merge as the technology allows. We are also very interested in understanding how the nervous system regulates islet function and blood flow. On the technical side, there is also continued interest in fluorescent protein development and improving our microscopy approach for quantitative in vivo imaging.
cyan FP mCerulean3 to study the role of calcium in the signalling within pancreatic beta cells (the cells responsible for blood sugar regulation). Their work has revealed previously unknown details about calciumdependent processes in these specialised cells.
RESEARCH OBJECTIVES Dr Rizzo’s research utilises fluorescent proteins to analyse biological interactions and mechanisms. His biosensor technology, based on FRET-based probes, can be applied to numerous biological problems, and his research has included studies into adipocytes, skeletal muscle and smooth muscle. FUNDING National Institutes of Health (NIH) COLLABORATORS • J in Zhang, University of California, San Diego •W . Gil Wier, University of Arizona •E rik Snapp, Howard Hughes Medical Institute BIO Dr Rizzo received a bachelor’s degree in Biochemistry before completing a PhD in Molecular Pharmacology. He received post-doctoral training in Molecular Physiology and Biophysics at Vanderbilt University until 2005, when he joined the Department of Physiology at the University of Maryland School of Medicine. CONTACT Mark A. Rizzo, PhD Associate Professor Department of Physiology University of Maryland School of Medicine 655 W Baltimore S Baltimore, MD 21201 USA T: +1 410-706-2421 E: mrizzo@som.umaryland.edu W: https://sites.google.com/site/ rizzolabmaryland/
The achievements of Dr Rizzo and his collaborators have delivered improved versions of several FP in terms of both their physical properties and usability across various cellular micro-environments. These refined biological markers have tremendous potential to give researchers unprecedented insights into the intricacies of cell signalling in any tissue.
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Cardiovascular
Is there a ‘fat gene’ responsible for cardiovascular disease? The attribution of T-cell death-associated gene 51 (TDAG51) in the regulation of energy metabolism, has given Dr Richard Austin of McMaster University and St Joseph’s Healthcare Hamilton in Ontario a new target in the fight against cardiovascular disease (CVD) and related disorders. The regulation of this gene could potentially hold the key to preventing programmed cell death – a critical component in the clinical progression of CVD.
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n a distinguished career that includes holding the Amgen Canada Chair in Nephrology, Dr Richard Austin has focused on understanding cardiorenal syndrome, the coincidence of chronic kidney disease with effects on the cardiovascular system. Chronic kidney disease is directly associated with hypertension (high blood pressure) and vascular calcification (vessel hardening, where calcium deposits are found in the muscular middle layer of the walls of arteries). Dr Austin’s research programme seeks to better understand the cellular stress pathways which result in these effects. A VERY COMPLEX PROBLEM Diabetes and obesity are known to accelerate kidney disease, so Dr Austin and his team are also interested in identifying the genetic and cellular factors which promote these disorders. In this process, they have been successful in discovering several novel cellular factors that influence the development of vascular calcification – the underlying cause of cardiovascular disease in patients with end stage kidney disease. One such development was demonstrating
a causal role of TDAG51 in lesion development, plaque rupture and vascular calcification – major contributors to cardiovascular disease. Dr Austin has related these effects to stressing of the endoplasmic reticulum (ER, cellular tubules associated with protein and lipid synthesis), showing that reducing this effect supresses many of the pathways involved in cardiorenal syndrome. LET’S START AT THE VERY BEGINNING Much of this started with the implication of TDAG51 in the onset of obesity and diabetes in mouse models lacking the gene. Showing that these mice were more likely to have increased body mass linked to excessive fat production, particularly in the liver, the team also noted that the mice displayed insulin resistance similar to late-onset diabetes. Coupled with more data showing the gene’s expression was inversely related to hepatic steatosis (fat in the liver), their findings suggested that TDAG51 was involved in metabolism regulation related to lipogenesis (fat generation). It was clear this ‘fat gene’ was up to more than people had originally thought, so Dr Austin and his research team, in
Dr Austin’s research focuses on understanding cardiorenal syndrome – the coincidence of chronic kidney disease with effects on the cardiovascular system www.researchfeatures.com
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Cardiovascular
collaboration with a colleague, Dr Joan Krepinsky at McMaster University and St. Joseph’s Healthcare Hamilton, started to follow the trail of this troublesome factor. HOT ON THE TRAIL Following investigations into lesion formation associated with atherosclerosis (the build-up of fatty plaques in arteries which can cause hypertension, strokes and heart attacks), they found that macrophages (a type of immune system cell) form a major component of the cellular mass of these lesions. Their study looked at how proliferation of this cell type changed during the stages of lesion formation, determining that it was more active in the early and middle stages of growth. These findings led them to conclude that these cells, which work together with T-cells in adaptive immunity and tumour suppression, are important for the progression and stability of developing lesions in blood vessels. Clearly the control of macrophage proliferation is vital to how this process develops, and it is here that TDAG51 once again rears its head. A NEW DIRECTION Responsible, at least in part, for controlling the process of apoptosis (programmed cell death) in these cell types, the products of this gene play a vital role in the management of cell populations in developing lesions. This realisation has led Dr Austin to launch a new programme of research which will investigate the role of TDAG51 in apoptotic cell death associated with cardiovascular disease. The importance of this work is not to be underestimated. Cardiovascular disease is one of the foremost causes of death in the developed world, accounting for about a quarter of all deaths in both the UK and USA. Understanding the underlying factors and co-morbidities which give rise to these varying but related disorders, is fundamental to the development of effective therapies. Dr Austin, by drawing on his understanding of related pathologies, has been able to identify novel therapeutic targets, such as TDAG51, which may be effective in reducing the risk of developing later-stage symptoms of CVD.
Above: atherosclerotic plaque blocking a blood vessel Below: stages of apoptotic cell death
Nucleus
Cell Apoptosis stages EXPERT SCIENTIFIC SLEUTHS Dr Austin and his research team are utilising state-of-the-art biochemical and molecular approaches to investigate the role TDAG51 has to play in CVD. As well as this, he is using established mouse models of cardiorenal disease, and those with disabled TDAG51, to examine the in vivo effects of the gene, its products and potential therapeutic compounds. The human homologue of TDAG51 is called PHLDA1 (pleckstrin homology-like domain family A member1). Dr Austin and his collaborators have already demonstrated using SNP analysis that variants in the PHLDA1 gene in humans correlates with an increased risk of CVD. A number of the findings from Dr Austin’s laboratory have already been published in high impact scientific journals. Importantly, many of these discoveries have become the cornerstone for the development of novel therapies and detection methods aimed at
Dr Austin and his research team are utilising state-of-the-art biochemical and molecular approaches to investigate the role TDAG51 has to play in CVD 64
Nucleus breaks apart
Cell breaks into apoptotic bodies
reducing the risk of cardiorenal syndrome associated with chronic kidney disease. EYES ON THE PRIZE Clearly TDAG51 has a broad role to play in both metabolism and lipogenesis, making it an important target for obesity and diabetes treatments, but its implication in the progression of CVD means the research will not stop there. Reducing the incidence of atherosclerotic plaques in blood vessels is a key goal, as it is here that deadly thrombi (clots) can form, which can block the artery or break off and cause blockages elsewhere. This can, in turn, lead to ischemic events such as stroke or heart attack. The ability to tie all these strands together, to form a coherent picture of how these diseases interrelate, and how this informs their treatment, is where Dr Austin steps in. From obesity to diabetes, through chronic kidney disease to cardiorenal syndrome and cardiovascular effects, his research team has experience of investigating them all and a proven track record for advancing knowledge in these areas. With that level of expertise being brought to bear, novel therapeutics for this new target in CVD treatment are just around the corner.
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Detail How does chronic kidney disease result in CVD symptoms? This is an interesting and relatively unknown connection between CKD and CVD. However, the majority of information suggests that in CKD, particularly in the presence of diabetes/ obesity, there is a dramatic increase in the calcification of the medial layer in blood vessels. The process involves the smooth muscle cells changing into bone-producing cells called osteoblasts. This dramatically increases vascular calcification which affects the structure and flexibility of the vessel wall leading to changes in blood pressure and altering blood flow. These changes also increase the risk of blood clots and vascular damage, all of which contribute to CVD. What led you to look at TDAG51 as a potential therapeutic target in this area? We had demonstrated in our TDAG51 knockout mice that they show markedly reduced intimal calcification which is a hallmark feature of atherosclerosis and CVD. Given this novel finding, we felt that loss of TDAG51 in the blood vessel may protect against medial calcification which is a hallmark feature of CVD in patients with CKD. Our unpublished data does indeed show that loss of TDAG51 within the medial smooth muscle cell layer does protect against medial calcification. That is why we followed this potential therapeutic path. Why is TDAG51 implicated in such diverse effects as obesity, diabetes and CVD? This is the million dollar question!!! We do not have all the answers but TDAG51 seems to regulate a number of relevant pathways that connect obesity, diabetes and CVD. These include its effect on programmed cell death, response to cellular stresses such as ER stress, inflammation and oxidative stress. However, one very important aspect of TDAG51 is its ability to mediate cell differentiation. For example, loss of TDAG51 in smooth muscle cells blocks their ability to become osteoblasts.
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However, loss of TDAG51 can increase the differentiation of liver cells and pre-adipocytes into fat cells. The mechanism is unknown, as are the cellular factors that interact with TDAG51. This is where we are actively investigating how TDAG51 acts to regulate cell differentiation. I believe this is the key to better understanding how TDAG51 is involved in multiple diseases and the path to novel therapeutics aimed at either reducing or increasing TDAG51 expression or activity. How might this gene be targeted therapeutically? Good question. We are pursuing small molecules/biologics that can bind directly to TDAG51 and block its activity or reduce its stability in cells. We know that TDAG51 can be post-translationally modified via phosphorylation, acetylation or S-nitrosylation. It is possible that these modifications could affect expression/ activity of TDAG51. These can be explored as therapeutic targets. Finally, we know that TDAG51 is downstream of specific cell pathways that regulate its expression. These upstream pathways may be targeted as a means of regulating TDAG51 expression. However, this may not be as selective as direct TDAG51 agonists or antagonists. There’s still lots to do! What do you hope to achieve in your current research programme? We hope to better understand the underlying pathways and mechanisms by which TDAG51 mediates cell differentiation. I believe this is the key to better understanding how this factor has direct and variable effects on so many tissues and diseases. This information will be the cornerstone for the development of innovative approaches aimed at reducing CKD and CVD by targeting TDAG51 expression and/or activity
RESEARCH OBJECTIVES Dr Austin’s research aims to understand energy metabolism and, in particular, the role a specific gene – TDAG51 – has on influencing cell death in diseases associated with cardiovascular disease, such as obesity and diabetes. FUNDING Canadian Institutes of Health Research (CIHR) The Research Institute of St. Joe's Hamilton COLLABORATORS Dr Joan Krepinsky at McMaster University and St. Joseph’s Healthcare Hamilton BIO Dr Austin obtained his PhD in Medical Sciences at McMaster University before training as a Postdoctoral Fellow in the Department of Human Genetics, Hospital for Sick Children in Toronto. He currently works as a Professor of Medicine in the Division of Nephrology at both McMaster University and St Joseph's Healthcare Hamilton. CONTACT Richard C. Austin, Ph.D. Amgen Canada Research Chair in Nephrology McMaster University and St. Joseph’s Healthcare Hamilton 50 Charlton Street East Hamilton Ontario CANADA L8N 4A6 T: +1 905 522 1155 Ext: 35175 E: Rick.Austin@taari.ca W: https://fhs.mcmaster.ca/medicine/ nephrology/faculty_member_austin.htm
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Cardiovascular Stem cells
Testing the cardiotoxic effect of cancer therapies with micro-hearts Cardiovascular dysfunction following cancer treatment greatly impacts the quality of life of cancer survivors. Dr Tetsuro Wakatsuki and his colleagues from InvivoSciences Inc. aim to develop therapeutic solutions to this problem, by exploring the cardiotoxic effects of novel anticancer drugs using pioneering technology, such as 3D-engineered micro heart tissue.
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very 30 seconds in the United States a person is diagnosed with cancer. However, despite this depressing statistic, more people than ever are surviving the disease. Today, two out of every three patients are expected to live at least five years following their diagnosis, which corresponds to approximately 14.5 million cancer survivors in the US alone. For example, in the 1980s, the chance of surviving from breast cancer was 50:50, but now nearly 80% of patients survive. This is due to extensive research which has improved early detection, therapy and medication development. However, length of survival is variable and depends on several factors, including tumour severity, the patient's general fitness and the impact of treatment-related chronic diseases: chronic diseases, such as cardiomyopathy which affects the heart muscle, that arise as a result of treatment. CANCER TREATMENT-RELATED CARDIAC DYSFUNCTION Intensive cancer treatments can unfortunately have an adverse cardiovascular impact. For example, chemotherapy greatly weakens the heart muscle, and radiation results in cardiotoxic effects such as heart
inflammation, atherosclerosis and rhythm disorders. Anticancer medication such as tyrosine kinase inhibitors (which suppress cancer cell growth), can also induce cardiomyocyte apoptosis, hypertension and congestive heart failure. Angiogenesis inhibitors (which suppress blood vessel formation, thus isolating cancerous cells and inhibiting their spread) can also cause hypertension, increasing the risk of blood clots and heart failure. In fact, cancer-treatment-related cardiotoxicity is the third leading cause of therapy-associated mortality in cancer patients. Clearly, this severely impacts quality of life both physically and mentally – after all, it must be devastating for the cancer survivor to discover that they have another life-debilitating disease. CARDIO-ONCOLOGY Growing concern regarding cancer/ cardiotoxicity comorbidity has led to the development of a novel clinical discipline – cardio-oncology. The aim of this emerging field is to investigate the physiological mechanisms that cause cardiovascular disorders in patients undergoing cancer treatment, to improve detection and prevention of these heart defects and
Cardio-oncologists face many challenges. There is a shortage of hospital funding; a lack of training opportunities; limited awareness; and inadequate research relating to the relationship between cancer, therapies and the heart 67
Cardiovascular Stem cells
develop effective treatments. It is also essential that a balance is established between cancer elimination and cardiovascular protection. However, cardio-oncologists face many challenges, mainly due to the novelty of the field. For example, there is a shortage of hospital funding to develop cardio-oncology units; a lack of opportunities for education and training; limited awareness regarding cardio-oncology; and inadequate research relating to the relationship between cancer, therapies and the heart. Most importantly there is no simple diagnostic tool to monitor the severity of cardiovascular damage caused by cancer treatment. INVIVOSCIENCES InvivoSciences (IVS), established in 2001, aims to tackle these problems. The groundbreaking research of Dr Wakatsuki and his colleagues explores potential solutions to cardiovascular issues, using innovative cardiac safety assessments. The team at IVS use their award-winning technology – laboratory-made human micro heart tissue called NuHeartTM – to test the effects of potential new anticancer drugs on cardiac safety. According to the U.S. Food and Drug Administration (FDA), effective drugs which have minimum impact on heart health should be used as a first-line treatment option to newly diagnosed cancer patients. Induced pluripotent stem cells (iPSC) are the foundation of all the technological services that IVS offers. Patient-specific adult cells in blood, or even urine, samples can be reprogrammed into a pluripotent state. This means that the cell has the potential to differentiate into many different cell types in the body, including cardiomyocytes in the heart. In collaboration with the FDA National Center for Toxicological Research (NCTR) in Jefferson, Arkansas, a cost-effective and rapid assay was performed: this involved cardiotoxicity analysis of all 31 anticancer
Reconsituted 3D human heart tissues, NuHeart™, in 96-well plate undergoing a mechanical testing with Palpator ™ device Cutout: a close-up of the tissue itself
drugs belonging to a class called kinase inhibitors using human iSPC cardiomyocytes cultivated in micro-well plates. The preliminary data highlighted that different levels and types of cardiotoxicity generated by the kinase inhibitors can be seen in vitro and correlate well with some clinical observations, suggesting thorough studies with 3D engineered micro heart tissue should further confirm the observations.
micro wells, ultimately, the 3D micro tissue technology will bridge the gap between cell-based assays and clinical studies. Furthermore, this novel technology promotes personalised medicine: patient-specific cells obtained from blood samples can be used to generate heart cells, which are then used to grow micro-hearts, NuHeartTM. Therefore, patient-unique responses to new drug candidates can be explored.
3D ENGINEERED HEART TISSUE DEVELOPMENT The Research Team at IVS then took this research further to grow engineered micro heart tissue. Amazingly, these micro-hearts (see above image) can beat for weeks, even months. Micro human heart tissues are a significantly more predictive preclinical tool, compared to immature cardiomyocytes cultured on plates. Cells mature in a 3D tissue environment and mimic functions of healthy or diseased heart tissues, allowing the researchers to explore the physiological and pathological mechanisms underpinning both states. Because patient-derived organs and tissues can be reconstituted in
The primary focus of the IVS team is to study dose-dependent effects of new anticancer compounds on a range of cardiovascularspecific physiological mechanisms. These include oxidative stress, mitochondria dysfunction, excitation-contraction coupling, contraction duration, ion channel interference (regulators of heart rhythm) and damage of contractile structures. Drugs that display no, or little, cardio-safety risk move forwards in the testing process and are one step further toward commercialisation. Alternatively, compounds that do threaten heart health are further analysed and can sometimes be modified to improve their cardiotoxicity profile. Furthermore, the tool is being used to identify smart diagnostic tools for cardio-oncologists to monitor a patients’ heart condition that has been affected by anti-cancer drugs.
By identifying novel anticancer drugs that could compromise cardiac safety, the team at InvivoSciences are taking science one step further to detecting cardiovascular dysfunction earlier 68
CLINICAL ADVANCES Overall, the field of cardio-oncology has raised awareness of the cardiovascular risks of cancer therapy. Recently, the American Society of Clinical Oncology (ASCO) have proposed a set of guidelines for clinicians
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Detail Why do different cancer treatments result in cardiovascular dysfunction? There are two different reasons; one is on-target and the other is off-target effect. Any drugs are potentially toxic, especially the anti-cancer drugs designed to kill rapidly growing cells. Recent smarter drugs only target abnormally active and growing cells, i.e., cancer cells. Therefore, those targeted therapies are much less toxic and effective at killing only cancer cells. However, some of the proteins need to be active to the physiology of the cardiovascular system, including the heart. The cardiovascular system carries those drugs and it can therefore become damaged. The heart is one of the most sensitive organs to drug toxicity. How can 3D-engineered micro heart tissue be used to further our knowledge about cardiotoxicity? Immature cardiomyocytes are more sensitive to proarrhythmic drugs. If the toxicity test is too sensitive, potentially useful drug candidates may not move forward to the drug discovery pathway. The micro 3D heart tissue is one of the ways to attain many mature cardiomyocytes costeffectively for testing drugs. Can your technology be applied to clinical issues other than cardiovascular myopathies? This technology can reconstitute 3D tissues
to follow to reduce the risk of cancer patients suffering from cardiovascular myopathy during/following treatment, by identifying risk factors in patients vulnerable to cardiovascular injury. These include obesity, smoking, diabetes, hypertension and high-dose radiotherapy where the heart is in the treatment field. ASCO also emphasise the importance of performing regular echocardiograms/cardio MRIs during each stage of clinical care, to monitor cardiovascular activity. Interestingly, biomarkers, such as troponin, can also be used to identify early stages of cardiovascular dysfunction, before symptoms appear. Troponin, composed
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for different organs and tissues. Our 3D cell culture technology is designed to grow “Tissue Strip”. A tissue strip spans between solid structures like skeletal muscle attaching to bones, or skin covering bones or blood vessels, or stomach or heart enclosing biofluid and withstanding its pressure. We have applied this technology to fabricate skin, blood vessels, and skeletal muscles. There are so many orphan diseases (rare diseases affecting low numbers of people) with known and unknown mechanisms affecting those types of organs and tissues. What are your future research goals? For the cardio-oncology project, we need to continue the analysis of 31 kinase inhibitors and other target cancer therapies using cells and micro-heart tissues. The data need to be correlated systematically to the data obtained clinically to determine off- or on- target effects for further understanding of the toxicity mechanisms. The clinical data need to be organised more systematically, based on parameters that can categorise cardiotoxicity quantitatively. These data from pre-clinical testing and clinic trials can improve our understanding of the mechanism of anticancer-drug-induced cardiotoxicity. So, we can develop new approaches to reduce cardiotoxicity while maximising the efficacy of cancer treatment for the cure and healthy survival of cancer patients.
of three regulatory proteins, is essential for cardiac muscle contraction. Following cardiomyocyte damage, troponin is released and consequently is regarded as a highly efficient indicator of cardiotoxicity.
RESEARCH OBJECTIVES Dr Wakatsuki’s research focuses on 3D engineered micro heart tissues and their applications to issues seen during and after cancer treatments. He is the co-founder of InvivoSciences – a company whose research provides solutions to cardiac issues. FUNDING The IVS research projects have been supported in part by the following Institutes of NIH: NIGMS, NHLBI, NIA, NCATS COLLABORATORS FDA National Center for Toxicological Research (NCTR) in Jefferson, Arkansas BIO Dr Wakatsuki studied for his PhD in BioPhysics and MS in Mechanical Engineering both at Washington University. He later went on to work as Assistant Professor at the Physiology, Biotechnology and Bioengineering Center at the Medical College of Wisconsin before starting full-time at InvivoSciences, where he currently works as the CoFounder and Chief Scientific Officer. CONTACT Tetsuro Wakatsuki, PhD Chief Scientific Officer InvivoSciences, Inc. 510 Charmany Drive Suite 256 Madison WI 53719 USA T: +1 608-713-0149 E: tetsuro@invivisciences.com W: http://invivosciences.com/
Early detection of cardiovascular dysfunction ultimately means early treatment. Research has shown that some heart diseases triggered by anticancer drugs can be treated using common heart medications. However, the overall goal is to prevent cardiovascular damage in the first place. By identifying novel anticancer drugs that could compromise cardiac safety, Dr Wakatsuki and the team at IVS are taking science one step further to achieving this goal.
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Repairing a H broken heart
eart failure – the inability of the heart to pump blood effectively around the body – is one of the leading causes of disease and death in the Western world, affecting an estimated 5.7 million people in the US alone.
Dr Li Qian, Assistant Professor at the University of North Carolina School of Medicine has been fascinated by the heart since her undergraduate days. Now, her innovative technique for reprogramming resident cardiac fibroblasts in the damaged heart into functional cardiomyocytes could lead to a new treatment for heart disease, one of the Western world’s biggest killers.
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Heart failure occurs when healthy heart muscle cells, known as ‘cardiomyocytes', die – for instance, during a heart attack – and are replaced by scar tissue comprising a different type of cell, cardiac ‘fibroblasts’. Normal fibroblasts are an important structural component of a healthy heart, but following an injury, they are produced in too great a quantity in the wrong parts of the heart –what Dr Qian terms as ‘bad’ fibroblasts. The body cannot naturally regenerate lost cardiomyocytes so this change is generally considered to be irreversible. If only there
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Biomedicine
were a way to convert fibroblasts back into cardiomyocytes – the award-winning Dr Qian and her coworkers are exploring a way to do just that. REPAIR THROUGH REPROGRAMMING In 2012, Dr Qian published ground-breaking research showing that cardiac fibroblasts in living mice could be reprogrammed to become functional, contracting cardiomyocytes, when treated with the right ‘cocktail’ of proteins. The three proteins – ‘Gata4,’ ‘Mef2c,’ and ‘Tbx5’ – are all types of ‘transcription factors’, molecules that can switch genes on and off, thus controlling a cell’s function. Unlike previous cell regeneration studies, Dr Qian found that, using her cocktail, cardiac fibroblasts did not need to first be converted to stem cells in order to be reprogrammed into cardiomyocytes. In mice with induced heart attacks,
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treatment with the cocktail caused heart function to improve after eight weeks, and continue recovering for over three months. Dr Qian’s team showed that this was due to the conversion of cardiac fibroblasts into cardiomyocytes, which successfully integrated with the healthy heart tissue, while reducing scar size. Essentially, the once ‘irreversible’ damage caused by heart attacks could be reversed and healthy heart tissue regenerated – a potential game changer for the millions of people who suffer heart attacks each year. These findings – which were ranked second in the American Heart Association’s ‘Top
10 Advances in Heart Disease and Stroke Research’ in 2012 – together with her own laboratory’s recent work identifying molecular barriers of reprogramming, gained Dr Qian many awards, including the prestigious 2016 BoyaLife, Science and Science Translational Medicine Award in Stem Cell and Regenerative Medicine. Born and educated in China, Dr Qian moved to the US as a PhD student, to pursue her dream of carrying out basic science with real-world applications. She hopes that her discovery will eventually lead to a novel treatment for human heart disease patients, which she believes could be in
The once irreversible damage caused by a heart attack can be reversed and healthy heart tissue regenerated 71
Biomedicine
clinical use within a decade. However, the slow rate of cell reprogramming and limited understanding of the mechanisms underlying it has hampered the transition to pre-clinical trials. UNRAVELLING THE MECHANISMS To resolve this stumbling-block, Dr Qian’s latest project – ‘Molecular Mechanisms of Direct Cardiac Reprogramming’ – aims to work out exactly how fibroblasts are reprogrammed into cardiomyocytes. Normally, once a cell’s role is determined it cannot be reprogrammed. Dr Qian hypothesises that the application of her transcription factor ‘cocktail’ – with each protein present in the right proportions and at the right time – somehow overcomes the barriers that usually prevent cells from switching type. But to find the perfect cocktail – first for mice, then for pigs, and eventually for humans – she needs to understand the conditions under which heart cells are generated, both during reprogramming and from first principles – in foetal heart tissue. As Dr Qian points out, understanding the basic biology of the heart at the cellular level will provide the tools to fix it when it breaks. The project aims, not only to determine the optimal conditions for reprogramming cardiac cells in human patients, but to provide insights into how cells’ fates are determined in general, with implications for regenerative medicine of many types. Dr Qian says she was surprised that cells reprogrammed in a living heart more closely resembled endogenous adult cardiomyocytes, than cells reprogrammed in vitro. She thinks it likely that the microenvironment of the heart may enhance the success of reprogramming by providing growth factors, signalling molecules, and mechanical cues to cells undergoing reprogramming – all subjects that need further research. In 2016, Dr Qian made further progress towards increasing the rate of conversion from fibroblast cells to cardiomyocytes. Her team discovered – for the first time – that a protein called Bmi1 was interfering with the production of the protein cocktail in heart tissue. By blocking the gene producing Bmi1, they were able to dramatically increase the rate of reprogramming, giving a ten-fold greater rate of conversion to ‘beating’ heart cells.
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A magnified view of a cluster of newly derived in vivo iCMs in a reprogrammed injured (myocardial infarction) heart. Green, cardiac marker alpha-Actinin; red, fibroblast lineage marker demonstrating the fibroblast origin; blue, DAPI labelling nuclei.
Two overviews of reprogrammed iCMs from fibroblasts in a dish. Green, cardiac reporter αMHC-GFP; red, cardiac TroponinT (cTnT); blue, DAPI labelling nuclei.
A highly magnified view of two isolated cardiomyocytes from a reprogrammed heart, on the left side is an endogenous cardiomyocyte while on the right side is an induced cardiomyocyte. Green, cardiac marker alpha-Actinin; red, fibroblast lineage marker demonstrating the fibroblast origin; blue, DAPI labelling nuclei.
Understanding the basic biology of the heart at the cellular level will provide the tools to fix it when it breaks www.researchfeatures.com
Detail How did you first get into science? And how did you end up where you are now? The “onion cell” experiment in middle school was when I got so interested in science. I was immensely excited when I first saw a cell from a prep I made by myself. I want to use “POP” to describe how I ended up where I am now: Passion, Optimism, and Perseverance. I am also very fortunate to have had strong support from my mentors throughout my career especially my PhD mentor Dr Rolf Bodmer and postdoc mentor Dr Deepak Srivastava, without which I would not be where I am now. What is so novel and exciting about this method of reprogramming cells? It takes advantage of the endogenous existing “bad” cells (fibroblasts becoming the scar) to turn them into healthy heart muscles. What do you hope to achieve during the current project, looking at the molecular mechanisms underlying cell reprogramming? The successful completion of the current project will define the molecular components and determine the optimal condition for iCM reprogramming,
A PERSONAL APPROACH Dr Qian calls her technique ‘induced cardiomyocyte reprogramming (iCM)’. Because the body’s own fibroblasts are used, there is no risk of a reaction against them as might occur with transplanted cells. And, because it does not use stem cells, there is minimal risk of uncontrolled cell growth and possible tumour formation. Ultimately, the research could extend to other organs of the body such as the liver, pancreas or nervous system. Dr Qian also believes this is an opportunity to develop a form of ‘personalised medicine.’ Fibroblast cells are found not only in the heart but also in connective tissues throughout the body, such as the skin. If skin fibroblasts could also be reprogrammed into cardiomyocytes – or, potentially, any other
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and thus is expected to provide the scientific basis to translate a promising laboratory finding into a workable, efficient treatment for patients suffering from heart disease. What do you see as the challenges to converting your findings into clinical outcomes? One is the low efficiency, which can only be solved through understanding the molecular mechanisms of this process to further remove the barriers for improved purity, efficiency and speed. The other challenge would be the delivery method: how to efficiently and precisely deliver the reprogramming factors to the cardiac fibroblasts that need to be converted? Collaboration with bio-engineers will be essential to identify the optimal way. The third challenge is the safety issue: how to minimise the side effects of this approach? Large animal experiments would be key to address this challenge. How do you think we will be treating heart disease in twenty years’ time? Personalised treatment without open heart surgery and/or heart transplantation.
kind of cell – under the right conditions, Dr Qian believes she could use these in the lab to screen the cells of individual patients and find the most effective drugs for them, without any risk of dangerous side effects. Whilst moving forward towards human applications, Dr Qian believes it is important to continue studying animal models – as in the current project – to understand the underlying mechanisms she is harnessing. This will give a basic science foundation to overcome any unforeseen obstacles she may come across during the crucial move to pre-clinical trials, and beyond. Can science help repair a broken heart? With Dr Qian’s help, it can.
RESEARCH OBJECTIVES Dr Li Qian’s research focuses on furthering development of a therapeutic option for heart disease. Her work is specifically aimed at reprogramming adult cells found in connective tissue, known as fibroblasts, into cardiomyocytes. FUNDING Dr Li Qian is supported by AHA Scientist Development Grant 13SDG17060010, the Ellison Medical Foundation (EMF) New Scholar Grant AG-NS-1064-13, NIH/ NHLBI R01HL128331, and generous gifts from Dr Hugh “Chip” McAllister and Cecil Sewell. COLLABORATORS Dr Qian’s long term collaborator Dr Jiandong Liu BIO Dr Li Qian studied her undergraduate degree at Fudan University in Shanghai before undertaking a PhD at the University of Michigan. Following this, she became a Postdoctoral Fellow at the Gladstone Institute for Cardiovascular Disease before, in 2012, becoming an Assistant Professor at the University of North Carolina. CONTACT Dr Li Qian, PhD Assistant Professor The University of North Carolina at Chapel Hill Department of Pathology and Laboratory Medicine Campus Box #7525, Brinkhous-Bullitt Building Chapel Hill NC 27599-7525 USA T: +1 919-962-0340 E: li_qian@med.unc.edu W: http://uncliqian.web.unc.edu/
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GSA: Age is in the eye of the beholder Ageing is a process you simply cannot escape from – it is something all humans go through from birth. But what effect does this process have, in terms of the physiological, financial or anthropological impact, as well as the biomedical? James Appleby and his team at The Gerontological Society of America aim to provide the answers to this, offering a clear insight into every aspect of the ageing process. He spoke with us at Research Features about his role as Executive Director and CEO, outlining his views on the importance of reframing ageing.
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t is a pre-requisite of human life to grow and get older – you are born, you live, you die. Simple.
Currently, a lot of scientific research studies the biological effects of ageing, but what about everything else that goes with it, including the psychological, sociological and anthropological impacts of getting older? This is where The Gerontological Society of America (GSA) comes in. James Appleby, GSA’s Executive Director and CEO, is keen to stress that ageing does not solely involve the aged population – it is a process that begins at birth and lasts a lifetime. He also notes that the ageing process is not immutable and that making positive lifestyle adjustments at an early stage can have a significant impact on the latter stages of life. He recently discussed this in more detail with us at Research Features, clarifying the importance of GSA’s past and present research in light of the continually ageing global population. Hello James! Could you tell us about The Gerontological Society of America (GSA)?
There are three main things to know about the society. The first is that we are a professional membership organisation that includes all disciplines. That means that we have physicians and biologists who study ageing, but we also have psychologists, social workers, demographers, economists, occupational therapists, anthropologists and zoologists. Any discipline you can conjure up is really a part of the GSA membership. The second thing to know about the society is that our members study every facet of ageing. While people typically think of ageing as being about biomedical topics, our members also study the psychological impact of ageing, housing issues in ageing, product design issues, how social security should be structured, and so on. Then thirdly, perhaps to the surprise of many, GSA does not study exclusively the aged, we study ageing. We study ageing across the life course, because ageing begins at birth, and actually some research suggests ageing starts in utero in terms of the impact on one’s ageing process. That
GSA studies ageing across the life course, because ageing begins at birth. Changes you make in your lifestyle early on, whether physical, financial, or emotional, can change your later life trajectory 74
The conventional perspective on ageing among the American public is that it is all about decline, disability, and death, and yet the research shows that that is simply not the case
James Appleby, Executive Director and CEO of The Gerontological Society of America.
is particularly relevant because changes you make in your lifestyle early on, whether that be physical, financial, or emotional, can change your later life trajectory quite significantly. How difficult is it to coordinate a multidisciplinary organisation? It certainly makes it interesting when you sit down at a board meeting, because around the table you will have probably eight different disciplines represented, if you have an eleven-member board. Individuals come at process and decision-making very differently, depending how they were trained. But by and large it is absolutely enriching to have so many different disciplines at the table, especially when you are trying to solve a complex problem, like how to care for older adults with dementia or how to improve individuals’ utilisation of immunisations to protect them as they
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age. One discipline cannot solve these problems. If you can have a physician, a nurse, a social worker, a sociologist and an anthropologist around the table, you can come up with better informed solutions to complex issues. Since it was founded in 1945 the society has been a major force in the advancement of gerontology, both in the US and internationally. What have been GSA’s key achievements in that period? We certainly have been very active as a society, especially in terms of major publishing to help advance the field, but perhaps the most important thing that stands out in my mind is the role that the society played in establishing the National Institute on Aging, as part of the National Institutes of Health. Our key leaders were actively involved in drafting and refining the legislation. We advocated fiercely
among key players within the Washington environment to get support, and even after it was vetoed the first time around, our members kept up the fight to secure approval by the House and Senate, and ultimately to get a signature by President Nixon to establish the NIA. GSA has a strong publishing presence. Why is this aspect of communication particularly important to GSA? The way a scientific field communicates with itself and has a dialogue and debate with itself is through journal publishing and the publication of papers that have gone through a rigorous peer review process. Our journals, in many ways, are the life blood of what enables the field of ageing to progress because new insights are provided that allow other scholars to build upon those insights. As things are published, it allows individuals who have
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Thought Leadership
lot to learn from scholars who are working on similar issues in other countries. That really does bring forward this sort of crosscultural look at ageing, because different cultures look at ageing and the aged in different ways. GSA provides a global platform for scholars around the world to have that dialogue through our journals, through our Annual Scientific Meeting, and through the work of our interest groups.
other evidence to bring it forward that may challenge what has been published, which enables the field to advance. The society’s members come from more than 50 countries worldwide. How important is cross-cultural analysis in the work of GSA? The fact that our members come from so many parts of the world is very important to the society. In some ways, we have even reflected on the fact that our name, The Gerontological Society of America, is increasingly not aligned with the fact that 18% of our members come from outside the US. The ageing demographic is a shift that is happening in the vast majority of countries around the world. Japan is way ahead of us, Western Europe is ahead of us, but the US is quickly catching up in terms of the change in our ageing structure and scholars based here in the US have a
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This summer GSA is hosting the International Association of Gerontology and Geriatrics (IAGG) 2017 World Congress in San Francisco. You are the chief staff member leading the development of this event, which is the largest international conference on ageing. Can you tell us about the conference and about the approach you are taking to its development? We are very excited about this. This World Congress happens every four years and it rotates around the world, a bit like the World Cup of soccer does. Because of that rotation and because it only happens every four years, it actually only comes to US shores every 32 years. For me, and for most of our staff here, it will be a once in a lifetime event and opportunity. What is really great for us is that it really enables us to showcase our ability to be a collaborator, a convener and a communicator in the field of ageing, and do it in a way that is not just focused on the US, but truly in an international and global fashion. The theme of the conference is global ageing and health, bridging science, policy and practice. We are expecting 6,000 or more attendees, with well over half coming from outside the US, which will make it the largest IAGG World Congress ever. We are looking forward to making this a true happening in the field of ageing. By 2030 there will be more people aged over 60 than children under 10. What will be the impact of this demographic transformation, and what role will GSA have in the creation of strategies to deal with this? It is quite a statistic to think about. One thing to note is that current research indicates the shift is going to be a permanent one. It is not just going to happen and then return to the current age structures. It is going to be a very real change and what we are trying to do is begin to educate society and decisionmakers in government about how positive this change can be. For example, we are
now looking at research which indicates that age-friendly policies support economic growth. We are also embarking on a collaborative project to help change the narrative around ageing, to have it conform with what the science shows to be true. By that I mean the conventional perspective on ageing among the American public is that it is all about decline, disability, and death, and yet the research shows that that is simply not the case. While yes, ageing includes all of those things, the vast majority of older adults do not go down purely a path of misery and die. They age more slowly, they decline slowly, but if they take proactive steps they can maintain their health well into old age. We have launched a new project called Reframing Aging and it seeks to change this narrative, because we know that how people talk about issues affects how they think about issues, and how they think about issues changes their attitudes towards the decisions that they will make. We also co-produced a report entitled Gauging Aging, which includes a report on how the media looks at ageing, and the inherent bias they bring to it. For example, the media typically takes one of two tacks. There is the idea of the vulnerable older adults who cannot do anything for themselves and are very needy. And there is the narrative of the independent vital older adult who, even at age 80, is able to run marathons. While both of these narratives have some truth to them, the vast majority of older adults are somewhere in between and do not resemble either of those narratives, and neither of those narratives help to advance any real, meaningful dialogue around ageing.
Contact The Gerontological Society of America, 1220 L Street NW, Suite 901, Washington, DC 20005, USA. W: www.geron.org twitter.com/geronsociety www.facebook.com/geronsociety
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Reducing age-related vascular dysfunction Cardiovascular diseases (CVD) remain the leading cause of death, with ageing being the primary risk factor due in part to age-related changes within arteries that contribute to vascular dysfunction. Dr Amy L Sindler, Assistant Professor of Health and Human Physiology at the University of Iowa, is investigating how ageing and other age-related disorders worsen vascular function. In addition, her laboratory is interested in how pharmacological interventions and/or exercise training may be useful in combatting CVD risk in older individuals.
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geing is the primary risk factor of cardiovascular diseases (CVD) with nearly 90% of all CVD occurring in individuals over the age of 40. Complicating this burden is the fact that the global population of older individuals (aged 65 years and over) is expected to double by 2050. Ageing causes multiple changes to arteries that increase the risk of CVD, and two key contributors are stiffening of the large elastic arteries (aorta and carotids) and the development of vascular endothelial dysfunction due to loss of the vascular protective molecule nitric oxide (NO). To make matters even worse, other common age-associated disorders such as obesity, type II diabetes and chronic kidney disease (CKD) affect millions of people worldwide. As well as being debilitating in their own right, these disorders also contribute to the progression of vascular dysfunction and increase the
risk of dying of CVD. For example, between just one and two percent of individuals with kidney disease actually die of renal failure – instead, they die of CVD. Arterial stiffness and endothelial dysfunction are thought to be primarily to blame. Dr Sindler’s group investigates the underlying mechanisms which contribute to vascular dysfunction, as well as testing natural compounds for their capacity to reduce or reverse the CVD risk. Using preclinical models of ageing, kidney disease, and obesity, the group are able to probe how these factors affect vascular dysfunction using both in vivo (whole animal) and in vitro (isolated tissue) techniques. Dr Sindler’s work has the potential to change clinical practice by identifying the therapeutic potential of natural compounds to treat vascular dysfunction in individuals who have multiple co-morbidities (multiple conditions
Common age-related disorders such as kidney disease, type II diabetes and obesity affect millions of people worldwide. These diseases are debilitating in their own right. However, most people with other agerelated pathologies will die of CVD www.researchfeatures.com
at the same time) such as ageing, CKD, obesity and type II diabetes. MAKING THE MOLECULES AVAILABLE Recent work by the group has identified how improving the bioavailability of important signalling molecules such as the vascular protective molecule nitric oxide (NO) can improve vascular function. NO is a powerful vasodilator (blood vessel dilator), with a short half-life of only a few seconds in the blood, that is produced by the vascular endothelium (monolayer of endothelial cells lining the blood vessels). If NO is in short supply, the blood vessels are not able to respond appropriately, an effect which is known to contribute to vascular dysfunction. Dr Sindler's group, including colleagues at the University of Colorado Boulder, have shown that by providing precursors such as sodium nitrite in the form of dietary supplements, they can restore physiological responses to control levels and improve vascular (blood vessel) health in mouse models of ageing and diabetes. Importantly, the other metabolic markers were unaffected, demonstrating that the effects on the vasculature were independent of metabolic aspects of the disease and tying the results to increased availability of NO in the blood vessels. Taking this one step further, they showed that this effect is also seen in older adult humans. Sodium nitrite supplementation was well tolerated and increased available NO without altering blood pressure, an important consideration in the treatment of CVD. The mechanisms responsible for these beneficial effects are still not well understood, but are actively being studied by many scientists and may relate to multiple metabolic or cellular pathways. The group have therefore been identifying other disorders where nitrite
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Determining novel pathways by which age and age-related diseases contribute to vascular dysfunction is key to developing natural therapeutic strategies that can lower the risk of CVD and have the potential to improve the quality of life in older individuals
supplementation may be effective in treating vascular dysfunction and reducing overall CVD risk, as well as continuing their work investigating the underlying molecular pathways involved using preclinical models of ageing and disease. DAMAGE HERE, DAMAGE THERE One example of this is the close link between kidney disease and vascular dysfunction. Acute kidney damage can result in the initiation and progression of the decline in kidney and vascular function. These changes contribute to the increased risk of CVD, though the association is poorly understood. Similarly, even when managed appropriately, other risk factors such as obesity and type II diabetes can cause artery and kidney damage, which are also associated with increased risk of CVD. The stiffening of the aorta plays a key role in disease progression and is a predictor of future CVD events and death. Dr Sindler believes this is due to oxidative stress which reduces NO and also modifies structural
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proteins in arteries making them stiffer and less compliant. One new and exciting area currently being studied by Dr Sindler’s lab is whether increased oxidative stress may be caused by impaired nicotinamide adenine dinucleotide (NAD) and sirtuin function, which are NAD dependent enzymes that have anti-ageing properties. Dr Sindler’s lab is very interested in understanding the role of SIRT3 (one of the sirtuin proteins that are found in mitochondria and regulate metabolism and mitochondrial-derived oxidative stress). Normal biological processes create reactive oxygen species (ROS, highly reactive molecules), which have the potential to damage cells in a number of ways. For this reason, cells contain a range of protective measures which either attempt to ‘mop up’ the ROS or repair the damage they produce. This is one protective function of NAD and SIRT3; if these are not functioning correctly, the cells will sustain significant damage, leading to detrimental changes in arteries.
SENDING IN THE SUPPLIES Dr Sindler aims to counteract the deficits in NAD by providing supplements of a B3 vitamin precursor called nicotinamide riboside (NR). This was identified as a bacterial growth promoter as early as 1944, but only identified as a precursor of NAD in 2004, in her collaborator Dr Charles Brenner’s lab, and as a sirtuin activating compound in 2007. It is hoped that NR will increase the bioavailability of NAD and consequently improve SIRT3 activity, thus reducing ROS, oxidative stress and improving the bioavailability of NO. The net effect has the potential to reduce the subsequent vascular and renal complications contributing to the overall CVD risk. In order to achieve this her group must first elucidate the mechanisms by which ageing and other age-related disorders contribute to physiological dysfunction. This will then help to determine how reduced NAD availability mediates vascular and renal dysfunction. Once
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Detail Why is age-related cardiovascular disease (CVD) of such concern at the moment? CVD is the leading cause of death. Ageing is the primary risk factor contributing to increased CVD and nearly 90% of all CVD occurs in middle-aged and older adults. By 2050 the number of older individuals (65 years and older) is expected to double, further contributing to this massive biomedical and economical burden. How do other diseases contribute to the progression of CVD? In additional to the traditional risk factors that are associated with CVD, such as advancing age, male sex, high blood pressure, smoking, sedentary lifestyle, and dyslipidaemia (high cholesterol, triglycerides), individuals with other disease pathologies have additional risk factors to consider. These include, but are not limited to, oxidative stress, inflammation, endothelial dysfunction, vascular calcification, insulin resistance, anaemia, adipokine imbalance, and epigenetic modification. Very few treatment options exist to lower CVD risk in individuals with multiple co-morbidities. What successes have you had so far in addressing these issues? Previous work mostly focused on the healthy ageing process and attempting to slow down the arterial ageing by increasing physical activity, replenishing the vascular
this is better understood, the therapeutic potential of NR in this field will be determined more fully. A RICH HISTORY, A BRIGHT FUTURE A similar study with colleagues at the University of Colorado Boulder and Washington University School of Medicine in St Louis tested a related compound that increases NAD levels which was able to reverse age-related arterial dysfunction by decreasing oxidative stress. Dr Sindler’s current studies will continue to examine the implications of improving NO and NAD bioavailability on vascular
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protective molecule NO with inorganic nitrate/nitrite supplementation or other novel strategies that reduce oxidative stress and chronic low-grade inflammation. We know that exercise is one of the best ways to reduce and/or prevent age-related impairments in vascular function and reduce overall CVD risk. What is the next stage in your investigations of age and diseaserelated CVD? Investigating novel pathways that become altered and contribute to arterial ageing which can be slowed down and/ or prevented with naturally occurring therapeutic compounds. Our overall goal is to translate our findings into clinical trials determining the efficacy on improving CV health and quality of life of people at the highest risk. What, if anything, can individuals do to reduce their risk of developing CVD? Exercise; eat more healthy, whole food; maintain a healthy weight; minimise processed foods, salt, a sedentary lifestyle and excess stress.
Ageing is the primary risk factor contributing to increased CVD
and renal function in individuals who are at the highest risk. Understanding the pathways by which ageing and age-related co-morbidities contribute to increased risk of CVD and death, particularly in older individuals, is a vital step in developing therapeutic strategies which have the potential to save lives and improve overall human health. With such past success in testing novel mechanisms to treating these disorders with natural interventions, such as supplements and/or exercise, and understanding the body’s own processes and systems to reverse the damage, Dr Sindler is ideally placed to complete this work.
RESEARCH OBJECTIVES Dr Sindler investigates how ageing and other age-related disorders such as kidney disease, diabetes, and obesity worsen cardiovascular (endothelial function and arterial stiffness) and renal function. FUNDING NIH: NIA; NIH: AG; NIH: NHLBI; University of Iowa; University of Colorado; ChromaDex® support COLLABORATORS Drs Diana Zepeda-Orozco, Darren Casey, Marie Migaud, Charles Brenner, and Melissa Bates BIO Dr Amy Sindler completed a BS and MS in Exercise Physiology and PhD in Cellular and Integrative Physiology with Dr Judy Muller-Delp at West Virginia University. She completed post-doctoral training at the University of Colorado Boulder with Dr Douglas Seals. She is currently an Assistant Professor in the Department of Health and Human Physiology at the University of Iowa. Dr Sindler’s laboratory aims to provide new insight into novel pathways involved in vascular dysfunction, including the role of impaired nitric oxide (NO) and/or nicotinamide adenine dinucleotide (NAD) bioavailability with ageing, kidney disease, and obesity. CONTACT Amy L. Sindler, PhD Assistant Professor University of Iowa Department of Health and Human Physiology USA E: amy-sindler@uiowa.edu T: +1 319-335-7907 (office) W: https://clas.uiowa.edu/hhp/people/ amy-sindler
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A programme of improvement for long-term dementia care Dr Veronique Boscart is not only the CIHR/Schlegel Industrial Research Chair for Colleges in Seniors Care at Conestoga College, Ontario, she is also a practising nurse who takes a decidedly hands-on approach to research. She works in a long-term care home for older people living with dementia, and the aim of her research and everyday practice is to improve quality of life for residents and their families.
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communication, and well-being of those being cared for. Team development supports personcentred care to promote residents' feeling of wellbeing, satisfaction and involvement with care, and creates a home-like environment where care decisions are shared, the person’s choices and priorities are considered, and there is a respectful and sympathetic team presence.
ore than half a million Canadians live with dementia, and around a quarter of a million spend their later years in a residential care facility. In the UK, the number of people with dementia is around 850,000, with the number expected to rise to two million by 2050. This highlights the increasing importance of research into improving quality of care for people living with dementia in long-term care homes.
applies a collaborative care model referred to as ‘Neighbourhood Team Development’. This framework builds on academic and practice evidence that has shown that true person-centered care can happen when caregivers and residents with their families come together as teams to promote the best possible care and life for those living with dementia. The idea of person-centredness conceptualises the caring relationship between the team and the residents and creates opportunities for improving care,
PLACING PEOPLE AT THE CENTRE Dr Veronique Boscart received a Canadian Research Chair to focus on improving the care provided for people living with dementia in long-term care homes. In collaboration with Schlegel Villages (a group of long-term care and retirement homes), the Schlegel-UW Research Institute for Aging (RIA), and Conestoga College, Dr Boscart
Neighbourhood Team Development leads to better coordinated care, and Dr Boscart’s study contributed to the evaluation of this new model within a long-term care organisation
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NEIGHBOURHOOD TEAM DEVELOPMENT Neighbourhood Team Development aims to support and engage organisations and teams to implement person-centred care for those living with dementia in long-term care homes by focusing on the residents’ and team members’ qualities, the care-giving environment (or context), the personcentred processes or activities, and the
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expected outcomes of these processes. In short, it is an outcomes-orientated framework, which promotes staff working as a team to improve residents’ quality of care and life. Neighbourhood Team Development emphasises the role of the team of caregivers in the care and services provided to residents, and supports the organisation and teams to engage, build, and develop person-centred processes in the long-term care home. Previous work has highlighted that care for people with dementia can be task-focused, primarily because of the way that organisations are traditionally structured, and because individual staff jobs and skills are aimed at tasks in response to resident’s needs, not resident’s quality of care and life. This can result in care that is improperly planned or carried out (e.g., morning routines do not suit every resident, but do suit the organisation), and staff do not get a chance to focus on what truly matters to the resident. It also means that it is increasingly difficult to recruit and retain good staff members in these settings. A change in the culture of ageing in long-term care homes requires innovative approaches to teamwork, care and service planning and
respectful and caring relationships amongst teams, residents and their significant others. TESTING FOR SUCCESS Dr Boscart’s current research aims to investigate four key objectives to measure the effectiveness of the initiative. To do this, she has received financial support from the Canadian Institutes of Health Research and the Canadian Natural Sciences and Engineering Research Council. Firstly, she wants to know how Neighbourhood Team Development can be delivered in the way it was designed. Secondly, she wants to determine the contextual factors that contribute to the implementation of person-centred care. This might include, for instance, how team members relate to residents during care, or how well they know each other. Thirdly, she hopes to answer the question: how does Neighbourhood Team Development affect the care experience of residents, family and staff, and how does this affect the organisation? Lastly, Dr Boscart’s research aims to determine the mechanisms by which Neighbourhood Team Development has an effect, which will allow her to fine-tune it and make it more successful.
Overall, Dr Boscart has found that Neighbourhood Team Development can improve residents’ quality of care, by coordinating care and services, increasing residents’ choice and dignity, emphasising quality of life, and promoting best practices
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Dr Boscart has conducted hundreds of observations and structured interviews and collected data from thousands of residents, families, and team members to achieve these research objectives and to answer her research questions. Overall, she has found that Neighbourhood Team Development has the ability to improve residents’ quality of care, by coordinating care and services, increasing residents’ choice and dignity, emphasising quality of life, and promoting best practices. MEASURING INDICATORS To test these objectives, Dr Boscart evaluated the way that team members interacted with residents, families, and each other, how person-centred the care was, and the resident and family satisfaction with care. In addition, she measured resident quality of care indicators (number of falls, medications, emergency transfers, etc.), team members’ staffing levels and organisational outcomes (recruitment and retention). Lastly, she calculated the resources that were required to implement Neighbourhood Team Development. A ROBUST PROGRAMME FOR RESIDENTIAL DEMENTIA CARE What she learned is that Neighbourhood Team Development contributes to advancing the quality of care and life for long-term care home residents living with dementia. Neighbourhood Team Development engages team members to strengthen relationships within the team and with the residents, and builds an accountability structure for care and services delivered, thereby supporting the organisation’s structures and financial framework.
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Detail How does ‘person-centred’ care differ from traditional care? Traditional organisational design in health care is a hierarchical and structural system of care that limits resident-centredness, and places residents in categories labelled by medical conditions, disabilities, and the level of care that they need. This categorisation limits staff’s recognition of the uniqueness of each resident, resulting in few opportunities for residents to make meaningful decisions about how they live their lives in long-term care. Person-centred care models describe a home as an environment that directs and supports close relationships, residents’ choices and empowerment and promotes collaborative decision making, all with the goal of improving quality of care and life. What role do organisations like Schlegel Villages play in dementia care? Schlegel Villages has developed and implemented leading care practices for those living with dementia. For example, our Memory Care Neighbourhoods are designed for those residents with memory loss, and offers care and recreational programmes specifically designed for those with dementia. LIVING In My Today is a new dementia-care philosophy and corresponding education programme. It took more than two years to research and develop, and was created by an advisory group that included residents, family members, volunteers, and community partners. The education programme consists of an overview workshop and six in-depth modules based on the acronym LIVING (i.e., Learning, Improving, Validating, Interpreting, Nurturing, Greeting). LIVING in My Today takes on a crossfunctional approach to training which involved peer-to-peer facilitation and is open to residents, volunteers, families and team members. How do you see NTD working in practice? NTD is a comprehensive training and organisational change model to empower cross-functional neighbourhood teams to
grow and support resident-centredness in long-term care. NTD is based on the organisation’s mission and values, including organisational supports and team development processes. Core beliefs of NTD include consistent team assignments to a dedicated neighbourhood, respect of residents' choice and autonomy, and self-directed work teams on each neighbourhood. What do team members say to you about Neighbourhood Team Development? Linda, Sarah and Sylvester have all worked at Schlegel Villages for between four and eight years and they agree that positive efforts continue to move the villages farther away from the institutional style of care that used to be the long-term care norm. Education, they say, has much to do with this transition and now, they feel they are a key component of that process. Linda is a personal support worker in one of the neighbourhoods who values the more personalised introduction to village life and comfort to team members starting a new job: “When you walk into a new place,” Linda explains, “you kind of feel intimidated and if you can make a connection with one of the team members, it feels great. You know, you’ve got a friendly face – someone you can go to. It makes a big difference in starting a new job.” What are the key areas that still need to be worked on to further improve neighbourhood team development? A key area requiring improvement for the betterment of NTD is the overall recognition that a large organisational change, such as the one required for NTD implementation, requires significant organisational commitment and leadership, and takes time. "To my exquisite grandmother, who instilled in me a healthy respect for seniors and taught me that a person’s wisdom, interest, and enthusiasm leads to changes that matter.” – Dr Boscart
RESEARCH OBJECTIVES Dr Veronique Boscart’s research focuses on the quality of life and care for people living with dementia in long-term care homes through an initiative called Neighbourhood Team Development. Evidence indicates that the care of those living with dementia in these settings was below par – Dr Boscart’s initiative is seeking to improve this. FUNDING Natural Sciences and Engineering Research Council of Canada; Schlegel Villages; Schlegel-UW Research Institute for Aging; Canadian Institutes of Health Research; Canadian Frailty Network; Heart and Stroke Foundation; Ontario Ministry of Health and Long Term Care; Council of Ontario Universities; Ontario Ministry of Training Colleges and Universities (MTCU); Alzheimer’s Society of Canada. COLLABORATORS Dr Veronqiue Boscart works with the Schlegel Research Chairs at the Schlegel -UW-Research Institute for Aging and other researchers, educators and policy makers across Canada and internationally. BIO Dr Boscart began her nursing education and practice career in Belgium before moving to Canada. She currently works at Conestoga College, Schlegel Villages, and the Schlegel-UWResearch Institute for Aging, following her Post-Doctoral Fellowship at the University of Toronto. CONTACT Dr Veronique Boscart, RN, PhD CIHR/Schlegel Industrial Research Chair for Colleges in Seniors Care Conestoga College Institute of Technology and Advanced Learning 299 Doon Valley Drive Kitchener, ON, N2G 4M4 Canada E: Vboscart@conestogac.on.ca T: 519-748-5220 EXT 2964 @VBoscart
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Nanotechnology hits the spot in arthritis treatment
Dr Christine Pham, a rheumatologist at the Washington University School of Medicine, is designing strategies to safely deliver nanomedicine in the treatment of inflammatory diseases, such as arthritis. Her strategies promise to target pathways associated with inflammation, while leaving other vital immune responses unaffected.
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heumatoid arthritis (RA) is a chronic, incapacitating disease of the joints, characterised by painful swelling and progressive damage to the connective tissues affected. This is a major cause of disability and morbidity (the condition of being diseased), particularly in ageing populations. Although the underlying causes remain the subject of debate among researchers and clinicians, the symptoms are clear and welldocumented. CRIPPLING PAIN An influx of immune cells from the bloodstream leads to swelling and inflammation of the synovial lining of the
Inflamed synovium Pannus Synovial membrane Cartilage
Bone
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joints (the membrane that defines the joint space and retains the lubricating synovial fluid). This promotes the release of inflammatory molecules and degradative enzymes, resulting in damage to the connective tissue and the underlying bone of the joint in a vicious cycle that is painful and debilitating to the sufferer. Although there are several treatment options for RA sufferers, the therapy is often associated with severe adverse effects and is ineffective in a large segment of the patient population. Dr Pham leads her team in investigating alternative treatment options, targeting the inflammation that underlies the pathogenesis of rheumatoid arthritis and other inflammatory conditions. INTERFERING WITH RNA RNA interference (RNAi) is a relatively new technique for preventing the DNA that encodes specific genes from being transcribed and translated into proteins. In the normal process, DNA is first transcribed into messenger RNA (mRNA), which can be translated into proteins by the cellular machinery. In mammalian cells, this is a carefully orchestrated process that controls a multitude of cellular activities and protects against hijacking of the cellular machinery by viruses. RNAi techniques exploit intrinsic cell mechanisms to ‘silence’ a gene by delivering small interfering RNA (siRNA) that binds to complementary strands of mRNA,
Dr Pham’s research focuses on delivering siRNA that interrupts the expression of genes involved in inflammatory pathways commonly implicated in arthritis and other inflammatory processes
Ageing
Above: Dr Samuel Wickline Right: Dr Christine Pham (left) and Dr Linda Sandell
promoting their degradation and blocking protein production. LIMITING COLLATERAL DAMAGE Although RNAi is a promising technique, there are significant difficulties that prevent the effective delivery of siRNA. These include targeting only specific cells of interest, rather than the entire organism, to avoid “off-target” effects, and overcoming the rapid degradation and clearance of free siRNA in the bloodstream. Working with a technology spearheaded by Dr Wickline, Dr Pham’s research team has successfully overcome many of the problems associated with delivering siRNA to inflamed tissues in a whole organism. To do this, she has utilised a modified version of a natural peptide called melittin that forms a self-assembled nanocomplex with the siRNA. The goal is to target and “silence” specific pathways in diseased tissues, without affecting the global immune system.
The Pham/Wickline team was able to show that intravenously injected peptide-siRNA nanocomplexes localised to the immune cells in the inflamed joints of an RA mouse model, while free siRNA, which has a half-life of minutes, was unable to do so. The peptide-siRNA complexes were not sequestered in “off-target” organs such as the liver or spleen, suggesting focused delivery of siRNA to the region of interest, the inflamed joint. THAT HITS THE SPOT Having shown they could target the right location, the team progressed to inserting the siRNA specific for the protein p65 – a component of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. The p65 protein is normally held in reserve in cells by the presence of inhibitors until activated during an immune response. When activated, it promotes the production of a wide range of pro-inflammatory molecules called
Rheumatoid arthritis and osteoarthritis are chronic, incapacitating diseases of the joints. Dr Pham is investigating novel treatment approaches to these conditions, as well as other pathologies of immune system dysfunction 88
cytokines – essential for the correct immune response to infection, but also extensively implicated in RA pathogenesis. Following initiation of inflammatory arthritis in a mouse model, a three-day dosing regime of the peptide-p65 siRNA complexes “rapidly stabilised ankle swelling and significantly supressed arthritis score”. Along with the significantly attenuated disease score there was a marked reduction in the recruitment of leukocytes (white blood cells, the primary players in an immune response), suppression of inflammatory cytokine production as well as a reduction in bone erosion and cartilage damage. These effects were not seen with intravenous administration of free siRNA, which the researchers posit is due to the inability of un-complexed material to enter the cell and block the target mRNA. While the complex was effective at targeting only the area of interest it has no secondary effects elsewhere. This is particularly evident in the immune response, which was sufficiently robust despite the treatment regime, showing that this treatment has the potential to target just the elements of inflammation that have gone awry in this model of arthritis while sparing the immune system to respond to infection as needed. EXPANDING THE TREATMENT HORIZON While the researchers have taken advantage of the enhanced vascular permeability in RA (whereby certain molecules naturally accumulate more in inflamed than normal tissues through “leaky” blood vessels)
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Detail How has your involvement with rheumatoid arthritis as a physician affected your studies as a researcher? As a physician my research is diseaseoriented, focusing on elucidating pathways that may be targeted for treatment. What are the main challenges of working with siRNAs? siRNAs are short lived and taken up poorly by cells without a delivery system. A peptide-based nanoparticle delivery system protects the siRNAs from degradation during circulation in the blood stream and promotes their uptake inside the cell. Does the RA mouse model have limits? Although the cause of arthritis in this mouse model is different than actual RA, the pathways contributing to inflammation and articular damage are still relevant.
What is the next step for this research to move towards the bedside? A new company (Trasir Therapeutics, Inc., St Louis, MO) has been formed to develop the nanoparticle delivery system for clinical testing in a number of diseases that feature inflammation at their core including arthritis, cancer, atherosclerosis, and kidney disease. What is the potential impact for patients and what other disorders might be affected? Up to a third of patients with RA fail to respond to conventional treatment. On the other hand, there is currently no effective treatment for osteoarthritis. Translation of this technology to the clinic will impact a large segment of the population, potentially affecting many inflammatory processes beyond arthritis.
Translation of this technology to the clinic will impact a large segment of the population, potentially affecting many inflammatory processes beyond arthritis to deliver siRNA intravenously, they also recognise the possibility of utilising the system to explore local delivery of the peptide-siRNA complex to avascular tissues that are otherwise inaccessible through systemic delivery. Further processing of this basic concept could open the way for other disease processes to be targeted using the same technology, providing novel treatments for osteoarthritis, another extremely common form of arthritis with limited disease treatment options. Early work conducted in collaboration with Dr Sandell has shown that peptide-siRNA nanocomplexes targeting p65 may be effective in reducing cartilage cell death and damage – characteristics
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of osteoarthritis. The avascular cartilage is normally inaccessible even to locally delivered drugs due to the dense matrix that prevents their penetration, posing a challenge to osteoarthritis treatment. The peptide-siRNA complex can freely and deeply enter the cartilage matrix due to its size, thus overcoming a major drug delivery obstacle. As such, it presents a real option for osteoarthritis treatment. Dr Pham and her collaborators are confident that the site-specific gene-silencing activity of this platform, coupled with the minimal collateral damage to other parts of the immune system may have, “real translational potential for the treatment of many inflammatory processes beyond arthritis".
RESEARCH OBJECTIVES Dr Christine Pham is a rheumatologist whose research focuses on designing strategies to safely deliver nanomedicine to treat inflammatory diseases, such as arthritis (both rheumatoid and osteoarthritis). She has been especially interested in the role of siRNA for this purpose, as its delivery has been found to be effective in inhibiting the NF-κB signalling pathway common in inflammatory diseases. FUNDING National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Heart, Lung, and Blood Institute COLLABORATORS Samuel Wickline, MD (TGH Endowed Chair of Cardiovascular Medicine and Director of University of South Florida Health Heart Institute) Linda Sandell, PhD (Mildred B. Simon Professor and Director of the Musculoskeletal Research Center at Washington University School of Medicine) BIO Christine Pham, MD, is a Professor of Medicine and Pathology and Immunology at Washington University School of Medicine. She is a practising rheumatologist and physician scientist whose interests include the design of strategies to safely deliver nanomedicine for the treatment of inflammatory diseases, with a focus on arthritis. CONTACT Dr Christine Pham Washington University School of Medicine Department of Medicine Division of Rheumatology 660 S. Euclid Ave Campus Box 8045 St. Louis, MO 63110 USA T: +1 314-362-9043 E: cpham@wustl.edu
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Rheumatology
Hydroxychloroquine – offering lupus patients something to SMILE about Systemic lupus erythematosus (SLE) is a deadly autoimmune disease, characterised by long-term morbidity and a premature mortality rate. Dr Nancy Olsen, of Penn State Health, is leading a multicentre clinical trial to determine a preventative treatment capable of treating SLE at a much earlier stage.
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arly diagnosis is vital for all diseases, but none more so than systemic lupus erythematosus (SLE). This disease, more colloquially known as ‘lupus’, is an example of an autoimmune disease – a condition which arises due to the immune system mistakenly attacking healthy tissue across many parts of the body. Its symptoms can vary in severity, but often include swollen and painful joints, rashes, and chest pain at a milder level. However, in more severe cases, SLE can cause hair loss, mouth ulcers, swollen lymph nodes, and abnormal blood counts,. More worryingly though, SLE can also cause extensive damage to major organs, especially the kidney, and shorten lifespan. THE IMPORTANCE OF EARLY DIAGNOSIS Even though significant improvements have already been seen in terms of five-year survival rates, the damage done to major organs during the disease’s early stages is often irreversible and, as such, SLE patients can suffer with long-term morbidity and a
premature mortality rate. These outcomes are especially worrisome since relatively young adults and even children can be affected with lupus. Finding preventative treatments and diagnosing SLE at an earlier stage is therefore critical – not only for preventing its onset in the first place, but also for improving the outcomes of current sufferers. Fortunately, this is where the excellent work of Dr Nancy Olsen from Penn State Health comes in. MULTICENTRE APPROACH In collaboration with Dr David Karp of the University of Texas Southwestern Medical Center, as well as three additional medical centres, Dr Olsen aims to analyse the effect of an anti-malarial treatment called hydroxychloroquine in delaying or preventing the onset of SLE disease expression in high-risk patients. The clinical trial – entitled the Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE Project) – will take place across five enrolment sites throughout America: Penn
Dr Olsen’s SMILE project aims to analyse the effect of hydroxychloroquine in delaying or preventing the onset of systemic lupus erythematosus disease expression in high-risk patients www.researchfeatures.com
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State Hershey Medical Center, University of Texas Southwestern Medical Center, Oklahoma Medical Research Foundation, Cedars-Sinai Medical Center and the Medical University of South Carolina. During the trial, individuals at a high risk of developing SLE, and aged between 15 and 45 years old, will serve as the target population. These individuals can be identified in early or preclinical stages and, despite presenting with some elements of lupus, are referred to as having incomplete lupus erythematosus (ILE) – due to not fully satisfying the SLE classification criteria. These criteria will form the crux for defining patient inclusion within the trial, as it will only include patients at high risk of developing SLE, rather than patients diagnosed with the disease already. One required criterion for patient inclusion is the presence of antinuclear antibodies (ANAs). These are autoantibodies that are produced and recognise human cellular components (autoantigens). Detecting the level of these within patient blood serum is an effective method of screening for a range of autoimmune diseases, including SLE. Those individuals who possess a significantly positive level of ANAs, as well as exhibiting one or two other features used to classify SLE, will be eligible for inclusion in the trial. HYDROXYCHLOROQUINE VS. PLACEBO Patients involved in the trial will be treated with either a placebo or a medication called hydroxychloroquine. This drug is typically used to treat malaria and other inflammatory disorders, although it has also been approved for use in SLE for decades. Its mechanism of action is incompletely understood, but likely involves blockade of important toll-like receptors (TLRs) of dendritic cells. These TLRs typically stimulate the production of interferon (signalling proteins released by host cells in response to pathogens), causing dendritic cells to mature and present antigens to T cells in the immune system – stimulating an inflammatory response. By reducing this TLR signalling, hydroxychloroquine reduces dendritic cell stimulation, and therefore prevents the debilitating effects caused by the inflammatory process. AIMS AND OBJECTIVES The primary objective for Dr Olsen’s SMILE trial is to establish hydroxychloroquine as a viable treatment option for preventing SLE onset in high-risk patients. Secondary
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Dr Olsen is shown with her study coordinator, Jamie Carter, in the research laboratory (above). Research assistants are Mr Carl McAloose and Ms Danielle Feger (below).
The SMILE trial’s multicentre approach will provide a collaboration of ideas, a shared expertise and an accumulation of vital data that, fundamentally, will aid systemic lupus erythematosus research in trials beyond this one www.researchfeatures.com
Detail When did you first become interested in studying autoimmune diseases, such as SLE? I have been studying SLE and other autoimmune disorders such as rheumatoid arthritis since my fellowship training about three decades ago. What impact do you hope to see from the SMILE trial? We hope to establish that we can intervene in the early stages of lupus and prevent accumulation of disease effects; this will be a first step in designing a comprehensive prevention strategy. How important is having a ‘multicentre trial’ approach to the trial’s success? The trial will require a relatively large number of patients, and in addition each of the centres have different demographic patient characteristics,
so that we will have a diverse and representative enrolment. Should the trial prove successful, how soon do you hope to see hydroxychloroquine available as a preventative therapy for high-risk SLE patients? Since this is an approved medication, it will be available, but the trial should demonstrate how useful and safe it will be in relatively early or mild patients. How do you see the landscape of SLE research changing over the next ten years or so? Many new insights into the immunologic basis of SLE should lead to improved diagnostics and more targeted, effective and safe therapies.
Many new insights into the immunologic basis of SLE should lead to improved diagnostics and more targeted, effective and safe therapies
objectives will delve deeper into this, and will be broken into four key questions: firstly, does hydroxychloroquine reduce lupus disease activity and improve patient-reported outcomes? Secondly, does hydroxychloroquine prevent the accumulation of immunologic abnormalities, such as autoantibodies and cytokines? Thirdly, what is the immunologic profile like for hydroxychloroquine use in ILE patients? And fourth, how acceptable is the resulting toxicity profile from using hydroxychloroquine? Answering these questions will test Dr Olsen and her collaborators’ hypothesis that hydroxychloroquine is capable of slowing SLE onset. This, in turn, will ultimately determine whether the anti-malarial treatment should be given to ILE patients at high risk of developing SLE. Not only that, but the multicentre approach used within
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the trial will provide a collaboration of ideas, a shared expertise and an accumulation of vital data that, fundamentally, will aid SLE research in trials beyond this one. NEXT STEPS The Phase 2 clinical trial is estimated to be completed by 2022, with a projected enrolment of 240 patients across the five affiliated medical centres. Both the hydroxychloroquine and matching placebo treatments will be administered daily over a period of 96 weeks, with data accumulation ongoing throughout. All individuals will have standardised ophthalmology exams before and after the treatment period.
RESEARCH OBJECTIVES Dr Olsen’s research focuses on autoimmune diseases, including lupus, rheumatoid arthritis and inflammatory muscle disease. Her current research is part of a multicentre trial looking into the effect of hydroxychloroquine on individuals at risk for development of systemic lupus erythematosus. FUNDING • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) • National Institutes of Health (NIH) CO-INVESTIGATORS • Dr David Karp, MD, PhD (University of Texas Southwestern Medical Center) • Dr Vernon Chinchilli, PhD (Penn State College of Medicine) • Dr Duanping Liao, PhD (Penn State College of Medicine) • Dr Judith A James, MD, PhD (Oklahoma Medical Research Foundation) • Dr Quan-Zhen Li, PhD (University of Texas Southwestern Medical Center) • Dr Diane Kamen, MD (Medical University of South Carolina) • Dr Mariko Ishimori, MD (Cedars-Sinai Medical Center) BIO Dr Olsen undertook an undergraduate degree in Biology at Brown University followed by an MD and MS in Immunology at University of Chicago. She subsequently trained in internal medicine at the Medical College of Virginia, before training in rheumatology at UT Southwestern Medical Center. CONTACT Nancy J. Olsen, M.D. Penn State Hershey Rheumatology 500 University Drive Hershey, PA 17033 USA T: +1 717-531-4921 E: nolsen@pennstatehealth.psu.edu W: http://www.pennstatehershey.org/ findaprovider/provider/2062
Dr Olsen’s work into determining an effective early intervention for SLE offers a lot of promise for affected patients, who will hope that the trial will live up to its name and give them all something to smile about.
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COMMUNICATION RESEARCH NEWS
The importance of… explaining science simply Science can be a complicated mistress. Whether it be understanding the cosmic influence of quarks and gluons, or the biological reasoning behind using Drosophila melanogaster (fruit flies) as a model for research, explaining science in layman’s terms is vital to bridging the gap between research experts and the wider public. Improving this access is more important now than ever before, especially in light of the increasing numbers of sensationalised science stories splashed across the news. But how can you, as a researcher, condense the complexities of your work into a format that makes sense to everyone?
context of research and why it relates to them. When communicating with the public, make sure you condense your work into a format that clarifies your area of research within science. Explain why it will benefit the general public in the long run, before going into further details. Brevity is key.
Here are a few ideas to think about when communicating your research directly to the public.
3. Utilise social media Love it or hate it, social media is the best method for reaching the public quickly and directly. Whether it be Facebook, Twitter, Instagram, or one of the many other platforms, social media provides an effective way for the public to really engage with scientific news and stories whenever they want.
1. Use analogies Analogies are a great tool for breaking down complex processes, simplifying them into an easier-to-understand and more relatable topic. For instance, immunological research could be simplified by relating immune functions to the military, highlighting important immune cells as ‘foot soldiers’, and the destruction processes they are involved in as ‘going to war’. Try to think around the topic of your research, explaining it in a way that makes sense to somebody without a scientific background.
watch videos to get the information they require – primarily due to ease, convenience and accessibility. Why not turn your research into an animated video to accompany a written article? Having an engaging, explanatory video based on your research will improve your online presence and help your work to reach a much wider audience. For more information on improving your online presence through social media platforms or through animated videos, please visit www. researchfeatures.com.
4. Animate your research Studies show that animated videos are fastbecoming a highly effective way of engaging the public. Many people now
2. Provide context It is all well and good explaining the complex methods involved in research but, a lot of the time, many people struggle understanding the
Explaining science in layman’s terms is vital to bridging the gap between research experts and the wider public
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