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The Institute for Translational Medicine & Therapeutics (ITMAT) in Edinburgh 2017

Supported by the Royal Society of Edinburgh

and the British Pharmacological Society

Big Data and the Development of New Medicines

Friday 17 March 2017 at the Royal College of Physicians of Edinburgh

Report by Jennifer Trueland

Introduction

Professor Sir John Savill FRSE, Chief Executive, Medical Research Council, UK; Professor of Experimental Medicine, Vice-Principal and Head of College of Medicine & Veterinary Medicine, University of Edinburgh

Sir John welcomed the international audience to the Royal College of Physicians of Edinburgh to the first ITMAT (Institute for Translational Medicine and Therapeutics) conference to be held in Europe. ITMAT, based at the University of Pennsylvania, was the world’s first institute for translational medicine, and its conferences are internationally renowned. He reflected on the changes he has seen in his career in medicine, from 1981, when he qualified, when medicine was largely ‘experience-based’, to practice based as far as possible on evidence. In the last five years, however, it’s become clear that we have to move into another new era, one of data-driven medicine: at a population scale, he said, we can distil experience and evidence and deliver the very best diagnosis, prevention and care through data-linkage at scale. “Here in the UK, we’re extremely well placed to do that,’ he added. The meeting’s other big theme would be how this data-driven approach would fit in to translational medicine. Sir John praised his colleagues on the organising committee for drawing up an exciting programme and thanked the speakers for travelling from around the world to take part in the meeting.

Session 1: Infrastructure

Chair: Professor Moira Whyte, Sir John Crofton Professor of Respiratory Medicine and Director of MRC/University of Edinburgh Centre for Inflammation Research, and Head of University of Edinburgh Medical School

Dr Mattias Uhlen, KTH Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), Stockholm

Precision Medicine and the Human Protein Atlas

Dr Uhlen is founding Director of the Science for Life Laboratory in Stockholm, a national centre for molecular biosciences, and a collaboration between four Swedish universities. Founded in 2010 with financial support from the Swedish Government, it expanded quickly and now involves some 900 researchers. It has a focus on ‘omics’, including bioinformatics, big data, infrastructure and system biology.

Dr Uhlen also talked about SCAPIS (Swedish cardiopulmonary bioimage study), which combines the use of imaging technologies, large-scale omics and epidemiological analyses, with the aim of improving risk prediction of cardiopulmonary disease and optimising the ability to study disease mechanisms.

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He began, however, by talking about the Human Protein Atlas, a project which started in 2003 with the aim of using an antibody approach to explore the human proteome. Funded generously by the not-for-profit Wallenberg Foundation, it is an open access knowledge base that maps the spatial distribution of human proteins. Although its main focus has been immunocytochemistry, immunohistochemistry, transcriptomics and targeted proteomics, it has also been integrating a number of techniques, including DNA sequencing, mass spectrometry and cytometry (CYTOF). This allows them to look at populations of patients “very nicely”, he said. They can map where the proteins are in the cells, tissues and organs.

A flagship paper on the project appeared in the journal Science two years ago, reporting on the tissue-based map of the human proteome. One of the areas of interest was around tissue-enriched proteins. The media found it very interesting that there are more tissue-enriched proteins in the testes than in the brain, for example, he said.

The atlas is an ongoing process and they are now working on 44 normal tissues, including specialist tissues such as the eye and the hair. People can go to the atlas and find out how their favourite protein is expressed in different parts of the body, he said. A brain atlas (mouse) was launched in 2015, to allow more detailed study (120 annotations) of the mouse brain, which allows them to do 3D reconstructions of the whole brain.

In December 2016, they launched a completely new atlas, called the cell atlas, which has localised 12,003 proteins to 32 cellular structures. Essentially it’s looking at where the proteins are in the cells. This new atlas has defined 14 organelle proteomes and people can look under different categories at the types of cells they are interested in, by exploring the atlas under the various headings. It’s also possible to look for cell variations – around 16% of all proteins show single cell variations, he said, and half of those are correlated to the cell cycle, most commonly for those localised to the nucleus, cytosol, mitochondria and nucleoli. The cell atlas is an open access database, based on hundreds of thousands of images, and people can interrogate knowledge-based chapters to look at cell line transcriptomes, organelle proteomes, multilocalising proteins and cell-to-cell variation.

In the past few months, there have been press releases showing emerging human cell atlas initiatives, from the Allen Cell Atlas Institute in Seattle (funded by Microsoft’s Paul Allen) and the Biohub Cell Atlas (Standford, USCF, UC Berkeley), funded by the Facebook founder Mark Zuckerberg and his wife; and the Wellcome Trust is also funding a human cell atlas, which is an international effort. “There are a lot of cell atlas initiatives now and we’re quite pleased about that.” Dr Uhlen didn’t think a year ago that Microsoft and Facebook would be involved, but is shows, he said, that biology is moving into big data.

The protein atlas has started to integrate data from different resources to give a fuller picture. The latest has transcriptomics data, for example, from its own institute and also from Japan, which allow valuable comparisons and a good understanding of how each gene or protein expresses in different parts of the body. The take-home message, he said, is that almost half of genes are expressed in all tissues of the human body, very few proteins are unique for one tissue and, from a pharma perspective, many drug targets are actually localised to all tissues. The atlas has around 200,000 visitors per month, mostly from the United States, with China in second place, and the UK in third. More than 200 countries visit the atlas.

One of the concerns is the validation of antibodies – the project has its own, but also uses commercially provided antibodies. Dr Uhlen has been involved in a committee to improve on that, culminating in a paper in Nature Methods that gives five ‘pillars’

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for validation of antibodies, with the main message being that the specificity of antibodies is dependent on application and context.

He outlined future plans, which include launching a pathology atlas this year, which will show which proteins have alternative expression in disease, with a particular focus on cancer. There are plans to launch a metabolic atlas next year, showing which metabolic pathways are active in different tissues and diseases; and a plasma atlas in 2019, showing which proteins are present in plasma under normal and pathological conditions. The pathology atlas will include ‘omics and clinical data from more than 9,000 patients, and will show prognostic genes in 17 major major cancer types, based on protein levels. They have used more than 200,000 core hours at the Swedish Supercomputer Center.

Dr Uhlen then turned to the KTH Centre for Applied Precision Medicine (KCAP). This was started in 2015, funded by philanthropists. The ambition is to combine traditional diagnosis with advanced imaging and combine it with ‘omics technologies. The aim is to take advantage of biobank resources in Sweden to develop and apply new technologies for personalised medicine through biomarker discovery, to allow stratification of patients and studies of normal physiology and disease pathology. They are interested in detecting early signs of disease, but also in where it is possible to create individualised treatments and also to carry out yearly analysis of health status.

They have a good baseline, he said, because they have looked at around 3,000 people, spending around £3,000 on each with comprehensive tests such as full-body imaging. It will be possible to follow these patients on national registers, which is easy in Sweden because each person has a unique number.

For the first pilot, they selected 101 people from the SCAPIS cohort – healthy individuals with comprehensive baseline data. They have been asked to provide samples and questionnaires every three months during the first year, and every six months in the second year. The questionnaires include 140 questions on things such as health, family history, lifestyle, occupational and environmental exposure, psychosocial wellbeing and socioeconomic status, plus 35 questions on diet/food frequency. Dr Uhlen described the process as throwing all the ‘omics technology they could at the people, but then combining it with questionnaire data – such as whether they had divorced – but also including information from things such as activity bands. “It’s been an amazing journey for us,” he said.

He shared some early results from the first year and a half of the project, including some individual cases – including a baker who had been eating a lot of bread, but cut it down after discussion with a nurse in visit one, and improved his blood pressure by visit three, and BMI by visit four. The results have huge potential in looking at the correlation between the protein data and health, for example, or to look at what’s happening with the immune system, or the impact on gut bacteria (microbiome). The result is that there’s a lot of data that needs to be sorted out and made useful – to get knowledge from it and apply it.

In conclusion, Dr Uhlen said, this is a European effort to systematically map proteins, which are the building blocks of humans. They are doing it by investigating the human spatial proteome in cells, tissues and cancers and integrating transcriptomics and proteomics. They are very excited about the pathology atlas, to be launched this year, and have a focus on validation of antibodies. Eventually, they hope to put it all together, and integrate all ‘omics data, to develop true precision medicine. “Hopefully we can help patients in the future,” he said.

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Q & A

Asked whether he plans to sequence everyone in the cohort, or just the outliers, Dr Uhlen said he is willing to take advice, but that for the pilot of just 100 people they have done full human sequences. With data from 30,000 individuals, however, there should be more selective sequencing, perhaps on the basis of the imaging data.

Asked what they do if they find patients who have undiagnosed conditions, Dr Uhlen said there are ethical questions about whether they can tell someone if they have cancer, for example, but that this is a work in progress.

Asked whether it is possible to measure the impact of exposure to environmental factors with proteomic analysis, he said that he hopes they will eventually be able to move into that, but acknowledged that questionnaires are subjective. It’s possible to be objective with things such as measuring sugar levels in people’s diets, he added.

Dr Ian Dunham, Scientific Director of Open Targets

Improving Target Identification and Prioritisation through Open Targets: An Integrated Programme of Experiments and Bioinformatics

Open Targets is a public–private initiative that aims to transform drug discovery by enabling the systematic identification and prioritisation of targets. It’s necessary, said its Scientific Director, Ian Dunham, because improving target identification should make it more likely that candidate drugs make it through all stages of trials and into the clinic. The problem is that many drug discovery programmes fail, he said, for a number of reasons at all stages of the process (from pre-clinical to phase III).

Causes of attrition include clinical safety, commercial reasons and regulatory reasons; but by the time a potential drug reaches phases II and III, the most common reason for attrition is lack of efficacy – a long way into the process. The bottom line is that it’s expensive and a waste of resource, he said. Picking the right target at the beginning of the process could transform this situation.

Open Targets (partner organisations are GSK, Biogen, The Wellcome Trust Sanger Unit, and the European Bioinformatics Institute) focuses in pre-competitive research to enable the systematic identification and prioritisation of targets. It is committed to rapid publication, and making data, methods and results publically available as soon as possible, and it believes in non-exclusive partnerships that foster the free exchange of ideas and expertise.

Essentially, Open Targets wants to bring lots of information together – in an open way – to assess which potential targets are most likely to be successful, before they actually go into the drug discovery pipeline, and to create a web-based resource. They also want to create a web-based resource that people can use to help begin their drug discovery process. Identifying targets that are likely to be successful – or unsuccessful – at an earlier stage of the drug discovery process can potentially save time, money and, ultimately, lives if good therapies reach the clinic more quickly.

There are two areas. The first is a bioinformatics area that is about integrating the data relevant to making a choice of target, including genetics in humans and mouse knock-outs, and also includes drug information. The idea is to bring all that information together into one place to allow people to make informed decisions. The second is an experimental aspect to improve the baseline of data that’s available, that’s physiologically relevant and can be done at scale and to address specific therapeutic areas. All of this is brought together in the target validation platform.

There is a portfolio of experiments taking place now, using a number of techniques (e.g., genetics, human cellular experiments) in several therapeutic areas, including oncology, immunology and neurodegenerative diseases. Dr Dunham gave one

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example of an experiment that is building data around cancer cell lines, layering information on a number of factors including mutations and drug sensitivity. Essentially, they are looking to answer questions such as why the cells are cancerous, and whether they have sensitivities that might be exploited to find an effective treatment.

Dr Dunham then spoke about how they go about building the target validation platform. They talk to users about how they work and what they want from a database. This includes looking at the types of data they use, what they do with it, how they quantify it, treat it and trust it, what technologies and outputs they use and how they define success.

They found that what users want is easy access to all relevant evidence for associations between potential drug targets and disease, and they want to be able to identify and prioritise targets; for example, through the use of scoring systems and lists. This requires the modelling of complex research approaches; an intuitive interface that allows the right tasks to be accomplished; timely, relevant and integrated content; and sustainable infrastructure.

There are already databases out there that process raw data, Dr Dunham said, so they took an evidence model, which focuses on what the evidence is that a target is associated with a disease (based on evidence from a number of sources). They take all the evidence and try to build a matrix of how targets are involved in disease. This also provides what are effectively suggestions of where there might be a correlation between a target and a pathway – in much the same way as Netflix suggests what movies you might like, based on what you’ve watched before.

There have been five releases of the target validation platform so far (as at March 2017). It contains information that can be interrogated in different ways to help researchers make decisions about what areas to look at and which targets would potentially be effective. The technology is cloud-based, the software is open-source and uses various search mechanisms, and information can be updated rapidly; they are working towards continuous integration.

Q & A

Asked whether the ‘Netflix’ analogy simply means that people’s prejudices are reinforced, rather than suggesting interesting new areas for research, Dr Dunham said it is a criticism they are aware of, and that there are a number of issues, such as a lack of good data on what are failed targets. What the platform is trying to do is enable researchers to use their own intuition and skills to identify targets and use the platform to help them do that.

Asked about what other datasets would enhance predictions, he said that being able to systematically have information about genetic roles in longitudinal progress would be fantastic.

Asked whether content experts are involved – i.e., people who know about particular disease areas – Dr Dunham said they are still evolving and would be delighted if people wanted to get involved.

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Professor Sir Rory Collins, Director of the UK Biobank and Professor of Medicine and Epidemiology, University of Oxford, and Professor Cathie Sudlow, Chief Scientist with UK Biobank

UK Biobank, a Resource for Genetic Epidemiological Research

UK Biobank is a resource that is largely driven by the MRC and the Wellcome Trust, although more funders are coming on stream, such as Cancer Research UK, said Sir Rory. It aims to improve the prevention, diagnosis and treatment of a wide range of conditions, and does so with the help of half a million altruistic individuals who have consented to take part and share their information for research purposes.

Sir Rory outlined the benefits of prospective cohorts for studying the causes of different diseases. For example, risk factors can be measured before the disease develops, appropriate controls can be selected from the same population and the person with the disease (so confounding by other factors is less extreme) and the effects of an exposure, (for example, smoking), on many different diseases can be assessed. They can also be cost-effective in the long term. But prospective cohorts need to be large, since only some of the participants will develop any given disease during the follow-up. Exquisite detail can be good, but large numbers are needed to plot risk, he said, giving an example of information needed to decide whether to treat someone’s blood pressure based on risk factors such as age; you need a lot of people to get meaningful results. UK Biobank combines detail and scale, he said.

The UK Biobank prospective cohort involves 500,000 men and women in the UK, who were aged between 40 and 69 when they were recruited during 2006–10. This cohort gave general consent for all types of health research by both academic and commercial researchers, and follow-up through all health-related records.

Participants answered extensive baseline questions (via computer touch-screen) and submitted to a variety of measurements, with biological samples stored for future experiments. Questions were wide-ranging and included areas such as socio-economic status, lifestyle, environmental factors and family history, while baseline measurements such as height and weight, waist size, blood pressure and heel ultrasound were taken from all.

Some large subsets of the half million took part in an enhanced baseline assessment process and underwent additional tests. For example, 175,000 had their hearing tested, and their vascular reactivity. Likewise, the cohort provided samples (eg blood, urine, saliva) that could be used for a variety of assays.

It was important to collect a lot of samples, said Sir Rory, and to store them, because future developments would mean that more tests could be made in the future when assays become cheaper and more effective. There were also phased enhancements; for example, 200,000 participants completed internet diet diaries, and all half million participants were genotyped using a bespoke array.

The information is already being used, said Sir Rory, and the quality and scale is already helping researchers. Data on all participants is due to be published in April 2017.

There are a lot of advantages in doing assays on all half million, he said, because they support many different comparisons, minimise depletion, improve quality control and are cost effective. They are expensive and typically restricted to standard assays – but things will become easier and cheaper as time goes by.

Non-standard tests are already being done on some subsets. For example, a fifth of participants are undergoing imaging of a variety of sites, including brain/heart/body MRI and carotid ultrasound. Baseline assessments are also being repeated in these people to monitor change over time.

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Professor Sudlow said that Biobank really begins to fulfill its potential when you follow up the half million people and find out what happens to their health, making it into a truly prospective study.

There are participants throughout the UK, although most are in England, which has some challenges for follow-up. Data linkage can be challenging because there are different datasets involved at national and regional levels, and UK Biobank has to work with different data providers. It can be a lengthy process to move from raw data to de-identified, clean data that is useful for researchers, and it has to be done annually.

The UK Biobank uses information from death registers and registers covering specific diseases, such as cancer, to get retrospective as well as prospective information about participants. They also tap into hospital admissions information to get coded diagnostic information across a wide spectrum of diseases.

The ‘Holy Grail’ has been to get information from primary care, where an enormous range of diseases is managed, she said. Although some progress has been made – particularly in Scotland and Wales – there are still challenges. But where the links are there, information is provided not just on diagnosis but also on prescriptions. In England, they are making some inroads by working with some computer system suppliers to get the same level of information as in Scotland and Wales.

It’s important to do things at scale, because of the number and range of conditions identified. Including data from primary care could actually double the numbers of patients identified with diabetes, for example, and 50% more cases of stroke and quadruple numbers of dementia cases could be picked up. Specificity is also important, and it’s also crucial to ‘future-proof’ the data so that more detailed phenotyping is possible in the future, said Professor Sudlow.

UK Biobank has been assessing how accurate these data sources are, is developing algorithms to define outcomes, and is creating state-of-the-art coded linked data, taking in deaths, cancers and hospital episodes. It is also starting to develop more complex algorithms, and is piloting integrating additional coded data, moving to detailed sub-classification of disease and incorporating ‘unstructured’ data from sources including medical records.

Professor Sudlow concluded by saying that that all researchers could use the resource if the research question was in the public interest, and encouraged everyone to visit it.

Q & A

Asked how they decide when to use the stored samples, Sir Rory explained that they are working out what the policy should be. Where possible, he said it is ideal to do things across the whole cohort. It is important to gain interest beyond government and charity funding to drive more assays to share data with researchers around the world.

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Session 2: Translational Science A

Chair: Professor Sir Munir Pirmohamed, Head of the Department of Molecular and Clinical Pharmacology, University of Liverpool

Dr Patrick Vallance, President of Pharmaceuticals R&D, GlaxoSmithKline UK

Chemistry, Biology and Medicine: Translation in Making Medicines

There is no shortage of data available, said Dr Vallance; the challenge is ensuring it is used. He quoted Forbes Magazine in 2015, which said that less than 0.5% of all data is ever analysed and used. Three years ago GSK looked at how much of its own data it could use easily, and found in R&D it was around 20% – it’s now around 90%, he said, but it demonstrates the ‘mountain that has to be climbed’ to get good information in the right format.

He said there are four fundamental decisions that have to be taken when making medicine: these concern getting the right target, getting the right molecule, the clinical biological experiment, and demonstrating the clinical effect and value.

The target is the most important first question, he said; it has to be something that makes an impact on disease and is safe. Target selection is crucial and sets a course for a number of years, and usually takes place in academia. It costs well over a billion pounds to make a medicine and takes a decade – and there’s a high failure rate. The cost and time taken must change, and should change, in an era of biological advances.

Dr Vallance spoke a little about Open Targets (see above) as covered by Dr Dunham, saying there is a great deal of information out there, including the protein and cell atlas, and UK Biobank. He said the UK has great potential to pull together publicly-available data, and that when data from companies comes on board as well, that will be helpful.

He explained that genetic validation improves the effectiveness and efficiency of medicine discovery and development. Around 10–15% of targets have genetic data at the moment; increase that to 50% and you can expect a 13–15% cost reduction; increase it to 100% and you can expect to cut costs by a quarter. Genetic validation improves your chances, he said, and this is something that companies are looking at.

Considering the molecule, you have to think about what you are going to do with it. A lot of this involves knowledgeable and experienced chemists who have ‘seen it all before’ – so what GSK is trying to do is gather all that information and make it available without having to rely on the individual chemist, and to supplement that with informatics tools.

It’s hard to be totally open with your chemistry, because that’s the intellectual property, but in some areas you can be open, said Dr Vallance. For example, GSK has released all its compounds tested against malaria and made the information publicly available so that people can use this to work on possible treatments. This is a good approach for neglected disease areas, he said. As a result, around 70 groups have been working on it, people have been trained in it, and GSK now has potential treatments in the pipeline as a result.

When you have your validated target, and your well-designed molecule, you want to test it in the clinic as quickly as possible. Dr Vallance gave an example of testing a new inhaler by measuring what the patient is doing in real time – e.g., are they using the medicine; do they feel better; does their condition improve? A test with real-time monitoring of COPD patients found they could get answers a year earlier than with traditional methods.

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Novel partnerships are expanding capabilities; for example, recruiting trial patients through social media. Proving the efficacy of medicines can take a long time and it can be hard to get patients involved in clinical trials. GSK has been testing its treatment in real world settings, working with GP practices – and such projects involve large data-handling expertise.

Dr Vallance concluded by pointing out that it is crucial that companies release their clinical trial data and that open innovation builds trust. This is a public good, but companies also find it useful because they can, for example, work out pitfalls before designing their own trial. Safety is also important, and social listening has potential for telling companies about their products. The US is looking at how it can use this as a research strength and the UK needs to build on its own expertise in this area.

Q & A

Asked whether there is potential to simplify the regulatory regime around clinical trials, Dr Vallance replied that trials can be a bottleneck in the whole process, and he is in favour of action to make the process simpler.

Asked about the prospects for new treatments for brain diseases such as autism, he acknowledged that there have been failures for “obvious reasons”, including insufficient knowledge of brain biology and difficulties with diagnosis of many brain diseases such as depression. He said he is optimistic, however, because genetics is opening up a whole new set of possibilities for brain disease, and will hopefully drive a new wave of neuro drug discovery.

Professor Andrew Morris FRSE, Professor of Medicine and Vice-Principal Data Science at the University of Edinburgh and Chief Scientist, Scottish Government Health Directorates

Options & Opportunities for Health Data Science in the UK

Professor Morris spoke about gearing up the UK for quality healthcare and research, using data science as a catalyst for change. He said the challenges include raising the proportion of mathematicians and statisticians who are involved in healthcare research.

We are in the age of the fourth industrial revolution – a new revolution about how we learn from data in real time, he explained. It’s revolutionary because of the speed at which change is happening, and because it’s pervasive, taking place in almost every country, and it’s changing the way that products are made and systems are run and how we interface with society.

He spoke of the change from the mid-20th Century, when we had ‘one computer; many users’, to the point now where we have ‘one user; many computers or devices’ – we have moved to intelligent environments. The question is how to apply this fourth industrial revolution to healthcare, to speed up the translation of research from cell to community, and to get better quality at reduced cost.

He spoke about how the NHS in Scotland is using informatics to support patient care. He said that Scotland has a good track record of collaboration across the major centres and has benefitted from the unique patient identifier, but that there is a need to move from measuring activity to measuring processes and meaningful outcomes for patients.

Professor Morris gave several examples of how digital health is already working across Scotland, including the Emergency Care Summary, which is a basic record taken from GP systems that can be accessed in the health service Scotland-wide. There is also a nationwide approach to digital radiology – a single PACS, with 24,000

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users in 38 hospitals, and a national diabetes system that has shown improved outcomes in terms of amputation, for example.

Scotland now has national-level data resources for five million citizens, he said, and it works on the principle of ‘collect data once; use it often’. There are many examples of how Scotland is using data to improve care and health, from the micro to the macro; for example, in prevention of disease, earlier diagnosis and developing more effective and safer treatments.

There are many studies showing that the approach is working; for example, in stratifying retinal screening based on risk. Scotland is also making progress in the field of improved nationwide pathways. Data linkage is also driving efficiency in clinical trials, he says. Scotland is also using the population-level approach to develop precision medicine based on phenotypes.

Other initiatives include the Stratified Medicine Scotland Innovation Centre. There’s an opportunity to scale across the UK via the Farr Institute, he said, which includes infrastructure, staff and collaboration, underpinned by high-performance super-computing. Crucial elements have included public and patient involvement, partnerships with industry and international partnerships.

Professor Morris stressed that the UK will have to make some bold decisions if it wants to be known as a health science nation, and create a UK-wide health science ecosystem. There are a number of big issues and challenges, including the fact that there’s a complex environment, which doesn’t necessarily allow interoperability without additional effort; another issues is that there is a tidal wave of data, and medicine is becoming data intensive, whether it’s the genome or predictive analysis. The third big issue is ‘direct-to-patient’, he said – how do you harness this way of getting patients directly on to clinical trials?

The fourth big issue is digital maturity of health systems – we want to get to personalised medicine and prescriptive analytics, but how mature are our health systems? The UK is currently far behind the US, but there have been positive policy moves, such as the recent Wachter Review into digital health in England. There are also issues around ontology and variability of prescribing. The sixth issue is interdisciplinarity – there needs to be a confluence of activity, he said. The biggest issue is public trust, and it’s important to address this and show that data is being used in a responsible way.

There are promising initiatives in the pipeline, including the National Institute for Health and Biomedical Informatics Research, due to be launched next year. Key principles include building on existing investments, going ‘molecule to man’ – well beyond the electronic patient record, bringing data scientists into the heart of medicine, creating a large informatics ecosystem that works at detail and scale, and predicated on team science, valuing technical services. Core activities of the new body, which will be a separate legal entity along the lines of UK Biobank, will include leadership, developing skills and capacity, creating partnerships and improving public trust.

There is an opportunity for the UK to lead the way in the fourth industrial revolution, Professor Morris concluded.

Q & A

Asked how to ensure standardisation of prescribing, for example, Professor Morris explained that it is possible to learn from other industries where there are, for example, defined and embedded data standards; such as the mobile telephone industry where companies compete, but also collaborate on standards.

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Professor Dame Anna Dominiczak FRSE, Regius Professor of Medicine, Vice- Principal and Head of College of Medical, Veterinary and Life Sciences, University of Glasgow

Translational Research in Academia

Dame Anna spoke about the Queen Elizabeth University Hospital site in Glasgow, which involves the NHS, Glasgow University and industry working together; this, she said, is what translational medicine is all about. While the targets may be found in academia, it’s important that lab discoveries make it to the patient – and that knowledge from the bedside makes it back into the lab.

She pointed out that there are many areas of excellence in Scotland and in Glasgow, and that many great teams in translational centres of excellence are led by clinician scientists. These cover all sorts of clinical areas including heart disease, immune disease and cancer. Translational centres need ‘all the ‘omics’, she said, and there will be more in the future, and all the information is needed to phenotype the patient.

Scotland has a large number of patients with chronic disease, and Glasgow in particular sees much ill health. Glasgow Biomedicine – Partnership in Clinical Research is a one-stop shop for clinical trials across Glasgow and the West of Scotland, and covers 52% of Scotland’s population.

There are 1,301 clinical studies, 311 of which are commercially sponsored, while 990 are non-commercial and academic-led. They have a broad portfolio, ranging from oncology and child health to anaesthetics and mental health, and have conducted several first-into-man studies. There are good links across Scotland via NHS Research Scotland.

Scotland’s linkage of health records means there is excellent information on people ‘from womb to tomb’, and the CHI number (unique clinical identifier) is a great strength that Scotland should ‘shout about’. You can get fantastic information from linking datasets, and the Farr Institute has helped them do that across Scotland, Dame Anna added.

She spoke about how the Stratified Medicine Scotland Innovation Centre came into being – approximately £20 million of funding was awarded; in part, she believes, because of strong endorsement from Patrick Vallance, and others, who recognised that Scotland is in a strong position because of its leadership in electronic public health records.

The centre is a public/private partnership and, four years in, is already running successful programmes in a number of clinical areas. The vision is to transform management of chronic disease globally by accelerating biomedical research, high- quality healthcare provision, and economic growth. The process allows drug trials to be done smarter using precision medicine, and collaboration means it’s possible to find a trial for every oncology patient.

Dame Anna gave three exemplars of precision medicine activities, covering rheumatoid arthritis, ovarian cancer and multiple sclerosis. The Centre covers all of Scotland, so patients can take part wherever they are in the country, and the idea is to give treatment where it will do best. Other trials are being taken forward thanks to other funders.

What they have created is a precision medicine ecosystem, Dame Anna explained, including patients, clinicians, researchers and the clinical laboratory, and including a wide range of techniques. It’s not all about ‘omics, she added – things such as better imaging need to feed in, and the new Imaging Centre of Excellence, which is adjacent to Stratified Medicine Scotland, and which includes the UK’s first 7Tesla MRI scanner in a clinical setting, will be part of the ecosystem. While NHS Scotland is crucial to the Scottish Ecosystem for Precision Medicine, it is also linked with the

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UK Catapult for precision medicine. She said everyone should align and work together.

Dame Anna then spoke a little about global efforts to promote precision medicine, saying that Scotland had been chosen as a case study at the WISH Precision Medicine Forum last year. She said that US colleagues had visited the centre and were jealous of the opportunities for having links with the whole of the Scottish NHS. We need to stay at the forefront of this activity and not let anyone overtake us, she said.

Health economics are important, Dame Anna concluded, and precision medicine prevention innovation has the potential to make savings on ineffective medicines, for example. There are potentially big gains to be made in precision medicine for chronic diseases such as diabetes, because the ageing population will be living with these diseases for longer. She said the future is to focus on chronic disease and stop specialising as much as we have in the last few decades – and understand, for example, that many of the ‘omics are the same in, for example, cancer, cardiovascular disease and inflammation. If everyone came together, they would be even better at delivering precision medicine for patients.

Q & A

Asked about how to ensure there are meaningful numbers of patients for clinical trials, Dame Anna replied that collaboration is invaluable. She also warned against people working in silos, and said multi-morbidity will be even more of a focus as the population continues to age.

Session 3: Translational Science B

Chair: Professor Sir Nilesh Samani, Professor of Cardiology and Director of the Leicester Biomedical Research Unit in Cardiovascular Disease, University of Leicester

Professor Esther Lutgens, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam

Immune Checkpoint Regulators in Cardiovascular Disease

Professor Lutgens outlined some of her research into atherosclerosis, a lipid-driven immune disease. She focused on her lab’s work into how CD40L-CD40 interactions drive atherosclerosis, and whether inhibition of these could work as a therapy for the condition.

Short-term anti-CD40(L) antibody treatment has been tested in phase I and II trials in MS, Crohn’s and some blood malignancies, she said, but long-term blockage of CD40-CD40L will result in immune suppression, which isn’t desirable. But there are knowledge gaps in considering it as a therapeutic target in atherosclerosis, including which signalling pathways are involved, which cell types that express CD40(L) are involved in atherosclerosis, and how the co-stimulatory interactome works in atherosclerosis.

She outlined her lab’s work into CD40-TRAF interactions in a mouse model, with the conclusion that CD40-TRAF6, but not CD40-TRAF2/3/5, signalling drives the activation of macrophages and is, therefore, a likely area for exploration in drug discovery.

A virtual ligand screen has identified some 800 compounds, which have been narrowed down to seven, then to two promising small molecules. It has been found that TRAF-STOPs have a powerful impact, decreasing CD40-induced monocyte

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recruitment and macrophage activation – significant in atherosclerosis. In mice, TRAF-STOP treatment decreases atherosclerosis, both in those that already have it and those that don’t; it also reduces inflammation, and further work suggests that it could also be a treatment for obesity.

Dr Lutgens concluded that small molecule mediated inhibition of CD40-TRAF6 interactions is a promising therapeutic strategy for the treatment of atherosclerosis, but also in other conditions including obesity, peritonitis and sepsis.

Q & A

Asked if she had thought about getting industry involvement during this ‘long journey’, Dr Lutgens replied that it is important to do enough ‘science’ before seeking investment.

Asked about the next steps, she said this will involve working with industry, making the treatment orally available and dealing with toxicity.

Professor David Porter, Jodi Fisher Horowitz Professor of Leukemia Care Excellence and Director, Blood and Marrow Transplantation, University of Pennsylvania Health System

Use of Genetically Modified T Cells to Treat Cancer

There is a need for curative therapies to address the cancer epidemic, said Professor Porter, and immunotherapy, perhaps in combination with other therapies, could mean that we start to become better at curing patients.

Ultimately, he said, targeted cellular immunotherapy could overcome many limitations of conventional chemotherapy and other forms of adoptive immunotherapy. Genetically modified immune (T) cells with redirected specificity to tumour antigens may combine the advantages of antibody therapy, cellular therapy and vaccine therapy.

Cell surface proteins are targets for new therapies, as they can be targeted to kill the cell with immune (T) cells. He spoke about his work with CD19, which he called an ideal tumour target in B-cell malignancies. CD19 is expressed in most B-cell malignancies and is an ideal target because it is generally restricted to B cells and B cell precursors. Also, antibodies against CD19 inhibit tumour cell growth – and patients can live relatively normally without them.

He spoke about targeting cancers with chimeric antigen receptors (CARs). These combine an antigen recognition domain of antibody with intracellular signalling domains into a single chimeric protein, and gene transfer to express CARs on T cells in a stable way confers novel antigen specificity.

Professor Porter described a study with more than 350 patients, including adults and children, with a number of conditions, and went into some detail about CLL (chronic lymphocytic leukaemia). CLL is a cancer of white blood cells and is usually slow growing, but can be aggressive and life-threatening; it results in an accumulation of malignant B cells.

Although survival varies (from two years to more than 20 years) it is incurable except with bone marrow or stem cell transplantation, which carries risks, and is not suitable for all patients. The prognosis is predictable, based on many factors including biomarkers and how patients respond to therapy, and patients with multiply relapsed or refractory diseases, or high risk features, have poor prognosis. We’ve been needing new treatments for these patients, he said, adding that median survival is a year.

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He described the impact that treatment with CTL019 therapy has had on some individual patients in the trial, including one with advanced disease who achieved complete remission by day 31, and who is still in remission more than six years later. He also spoke about the impact that CTL019 infusion has had on bulky tumours, reducing them significantly.

Overall, there has been a complete response in 11 out of 43, and a partial response in 10 out of 43 patients – meaning that almost half (49%) responded to the therapy. Then the CTL019 therapy was tested in patients with relapsed refractory ALL (15 children and five adults) the results were even more significant, with 90% achieving complete response. This is a hugely promising therapeutic area and CAR-T cell trials have now gone global, taking place in 25 centres in 11 countries.

Overall, he said, it appears that in ALL, a third of patients who achieve remission may relapse; in CLL, there are fewer relapses, but not enough patients who achieve remission. There’s still a lot of work to be done, he added. This could include identifying new targets, using a combination of CAR-T cells directed at more than one target, combining CAR-T cells with targeted therapies, and developing universal ‘off-the-shelf’ CAR-T cells.

Professor Porter concluded with a call to arms, saying that everyone around the world should be working towards large-scale, reproducible manufacturing of high- quality cells at low cost. Clinicians, patients, big data, engineers, cell biologists and everyone else need to be involved.

Q & A

Asked about cost per patient, Professor Porter explained that it is currently very expensive, but added that the cost for caring for these patients is also expensive. Working out which patients are most likely to respond would make it more cost-effective.

Asked if the aim is to develop a cell that could be given to everybody, he said that while some headway is being made with donor T-cells, the expectation is that they would be rejected; they would have to be genetically modified, and that this is more likely to be the bridge to the solution rather than the solution itself.

Professor Mukesh Jain, Director of Case Cardiovascular Research Unit, Case Western Reserve University

Novel Insights into Metainflammatory Disease

Professor Jain spoke about the Kruppel-like Factors (KLFs) as important determinants of cellular inflammation and metabolism, and the potential of this information for developing therapies for a wide range of conditions.

Two of the major forces shaping human evolution are nutrient scarcity, which prompts energy storage and conservation, and infection, which is why we have an immune system for pathogen clearance. Immunity and metabolism are linked, he explained, and are involved in many conditions, including cardiovascular disease, cancer and neurodegenerative conditions.

KLFs are key in immunity, metabolism and the cardiovascular system. In the immune system, they regulate myeloid, T-cell and endothelial/epithelial quiescence and activation, and they are dysregulated in patients with acute and chronic inflammation.

He spoke about thrombosis, a major source of illness and death, and a condition for which those who suffer from metabolic syndrome and other inflammatory conditions are at greater risk. Although there are treatments, there are risks of recurrence, and safer drugs are needed, ideally ones that alter thrombosis, without affecting

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haemostasis (the process that stops bleeding). He described research that shows that KLF2 regulates myeloid cell activation, and that it antagonises major inflammatory pathways, suggesting that targeting neutrophils may be an effective strategy to treat thrombosis without altering haemostasis.

Professor Jain then spoke about some of his work around KLFs and metabolism. Fasting has been a fundamental response for survival: it induces adaptive metabolic changes, and confers health benefit, even improving healthy life span. KLF15 co-ordinates the fasting response, he said, and so could have a role in how we age. Experiments in the lab show that KLFs regulate how nutrients are used and change in different physiologic states, and that they regulate lifespan and healthspan across metazoan life. Therefore, targeting KLFs may be a useful strategy for diseases of ageing, he said.

He mentioned the Harrington Project, a $300m US and UK initiative to accelerate medical discoveries to clinical proof-of-concept. It combines profit and not-for-profit elements and aims to help physicians translate the knowledge they get from real-life clinical practice into therapies that improve patient outcomes. He said he is confident it will extend into other countries.

Session 4: Translational Science C

Chair: Dean Denis F Kinane, Professor of Periodontology and Pathology, University of Pennsylvania School of Dental Medicine

Dr Nick Stroustrup, Department of Systems Biology, Harvard University

Integrating Diet, Environment and Random Chance in Ageing

Dr Stroustrup spoke about working with the nematode C. elegans to study ageing, lifespan distributions, and the biological processes that determine them. When we will die is a question as old as time, and we still haven’t answered it today, he said. So why is it such a hard question to answer? One reason is that lifespan is determined by diverse physiological processes that interact with each other in ways we don’t fully understand.

C. elegans is a microscopic creature that shares many genetic similarities to humans. It provides a useful testbed for studying the basic biology of ageing because, in the lab, it’s possible to run the equivalent of large clinical trials on them, measuring the impact of interventions ranging from diet to drugs and toxins. Could it be a way of developing new approaches to pre-clinical trials, he asked. It’s valuable for trying out statistical approaches and analysing datasets, he said. But it’s also potentially a much quicker way of answering basic research questions than running large-scale trials on traditional lines.

We can’t predict lifespan because we don’t really understand the basis of the physiology, or it might be because it’s random. Dr Stroustrup described setting up, what is effectively, a lifespan machine that can measure when a nematode is active and when it is nearing death. This means that they can see the impact that different interventions have on lifespan. For example, they have found that when they put the temperature up, C.elegans dies more quickly than at lower temperatures, and this can be modelled mathematically. Comparing the lifespan distribution of this group with another that hasn’t had the intervention shows that while it shortens lifespan, it doesn’t change the distribution. Regardless of how long an animal would have lived with one condition, the new lifespan is a simple proportion, or scale factor, of what it would have been. The same survival curve is present – just stretched or compressed

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across time. Other interventions in ageing have similar effects. Different phenotypes get the same results.

It’s reasonable to think that a number of molecular mechanisms contribute to lifespan, he said; for example, the mechanisms that cause cancer or diabetes. Some factors such as temperature might affect molecular mechanisms, but others probably don’t affect all of them. So it’s possible to produce a model with molecular mechanisms associated with ageing, and possible interventions, showing temporal scaling, getting the uniform effect on lifespan distribution.

Their thinking then turned to whether there is some structure underneath – some interaction between the molecular mechanisms because the risks might not be independent of each other. Many questions remain, but Dr Stroustrup and his colleagues have a platform for studying the systems biology of ageing; and they can do it because they have a system for carrying out such large clinical trials with interventions that manipulate the ageing process. They are starting to find that there may be something very special about the systemisation of the mechanisms of ageing: a lot of outcomes that the research community is looking at in lifespan health might have as much to do with statistical physics as they do with molecular biology.

Q & A

Asked about limited heterogeneity in simulated trials, or the issues of including other labs to deal with this, Dr Stroustrup replied that if you scale up in a single lab, you can control for the effects that you might see if you were involving lots of labs.

Asked if charts showing increases in human longevity would fit the model, he said that the human data doesn’t really work because people haven’t tried in humans to do any of the interventions that he is doing in the lab – and he isn’t doing any of the interventions that have extended lifespan in humans. The lab world is ‘pure’, while humans are ‘messy’, so there’s not really that overlap, he added.

Dr Meirav Pevsner-Fischer, Department of Immunology, Weizmann Institute of Science, Israel

The Role of the Microbiome in Health and Disease

The microbiome is present in any part of the body that is exposed to the environment, for example, the gut and the skin, explained Dr Pevsner-Fischer, adding that her lab mostly studies the interaction of the gut microbiome in health and disease. Our bodies are heavily colonised with bacteria, she said – we have as much bacteria in our body as our eukaryotic cells, raising the notion that we are actually human superorganisms in which the microbiome and our cells comprise one unit.

It’s been recognised for some time that the microbiome is involved in human functions such as digestion, vitamin synthesis and protection against pathogens, but new techniques have opened up the way to study its role in more depth. For example, we can sequence its composition without having to culture it, and sequencing fees have dropped. We also have better facilities, such as germ-free labs to grow mice with no bacteria, and anaerobic chambers that allow us to grow and study bacteria that wouldn’t otherwise survive outside the gut.

Dr Pevsner-Fischer gave an example of the impact of the microbiome, saying it is now known that our gut bacteria have a role in whether or not we are obese. When germ-free mice are given transplants of ‘lean’ microbiota they are normal weight, but grow obese when given microbiota from an obese mouse.

We now know that each of us has our own specific microbiome signature, as individual as a fingerprint. That means that it could hold the key to truly personalised

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medicine. The microbiome is our second genome, she said, and has an impact on our health profile. She described some work to look at personalised nutrition based on a prediction of glycaemic response, which found that individuals have a highly variable response to identical meals.

Blood glucose levels are increasing rapidly – as shown by the rise of Type 2 diabetes and prediabetes and impaired glucose intolerance. Hyperglycaemia is linked to multiple diseases, including metabolic syndrome, cardiovascular disease and colon and pancreatic cancer, so it’s desirable to maintain normal blood glucose levels. Dr Pevsner-Fischer pointed out that changes to nutrition – such as dietary advice to cut down on fats and increase carbohydrate – have contributed, as have increases in sugar consumption and in the use of artificial sweeteners.

They measured the post-meal blood sugar levels of individuals, because spikes in glucose levels after meals result in the insulin secretion that directly affects fat storage and weight gain. They found that different people have vastly differing responses to the same meals, and suggested that the microbiome is a determinant of our unique food response.

The personalised nutrition project is based on the idea that diets to maintain normal blood glucose levels have to be personally tailored. People taking part were profiled and questioned, subjected to continuous glucose monitoring and kept diaries; the only exclusion criterion was diabetes. Their microbiome composition and function was also measured. More than 900 people took part and nearly 50,000 meals were measured in the main cohort.

Individuals themselves responded consistently to the meals, but the group response varied hugely. For example, one individual had an extremely high response to bread, while others had very little response. The researchers found that variability of response had some associations between microbiome features; for example, high levels of actinobacteria were associated with a high response to glucose and bread.

Using a variety of factors, they have developed a model that predicts the response an individual is likely to have to any given meal, and work continues to feed in more factors and improve its accuracy. Giving personalised diet sheets based on foods that are good for them as individuals is successful she said, because it improves the post-meal response and has a favourable effect on overall blood glucose fluctuations.

Dr Pevsner-Fischer concluded that the microbiome is a determinant of health, and that it is our second genome.

Q & A

Asked if there are ways to alter the microbiome, Dr Pevsner-Fischer cited changes to diet or faecal transplantation.

Asked if the ‘blunt instrument’ of faecal transplantation will be refined, she said she hopes so, because compliance is not optimal at the moment.

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Closing Remarks

Professor David Webb FRSE, President of the British Pharmacological Society and Christian Professor of Therapeutics and Clinical Pharmacology at the University of Edinburgh

Professor Webb described the meeting as an incredibly stimulating day, and thanked Professor FitzGerald for bringing ITMAT to Europe for the first time. He also thanked the speakers, the organisers and the audience.

Evening Speech

Professor Garret FitzGerald, Professor of Medicine & Systems Pharmacology & Translational Therapeutics, and Director, ITMAT, University of Pennsylvania

Professor FitzGerald spoke about his first visits to Edinburgh from a schoolboy playing rugby to a respected academic being awarded an Honorary Degree. It was partly his long history with the country that made him delighted that the first ITMAT meeting ‘on the road’ was in Scotland, he said, adding that it was greatly to the organisers’ credit that it had been such a wonderful meeting.

Speaking at the time of the Rugby Six Nations tournament, he said that although rugby is an “important distraction”, we can’t ignore the strange times in which we are living. He said that Brexit and the ascension of Donald Trump have caused dismay in many people in science. “As in the UK, we fear for the US in our ability to recruit and retain foreign talent,” he said. He expressed concern that the regulatory frameworks around medicines, for example, might be under threat, and said that some in the Trump regime are committed to undermining action on climate change.

“At this time of political and cultural dislocation, it is important to engage with the political process and to speak up for and remain true to our core values: a belief in facts, transparency, diversity and inclusion, an emphasis on modesty, and inquisitiveness, persistence and empathy.”

He said it is important to develop scientist politicians, and said that scientists are privileged to be part of their community. “But along with privilege comes responsibility to deliver,” he added.

“This is actually part of the translational science that was so nicely illustrated today. For those of us who have suffered illness or the loss of loved ones, or who have crossed that boundary from the healthy to the seriously ill, who have lived in the valley of death, translational science provides hope and a distant tomorrow that certainly helps today.”

This is the thought that motivates scientists to go on seeking solutions, he said, to work harder, and to read and digest the literature in a different way, and to draw on colleagues and connections – and to understand Martin Luther King’s description of the “fierce urgency of now”.

The rapid emergence of translational medicine tools and technologies give the prospect of great new diagnostics and therapies, but also present ethical and economic challenges – to ensure they are safe, and that there is an equitable distribution to society as a whole.

Opinions expressed here do not necessarily represent the views of the RSE, nor of its Fellows. The Royal Society of Edinburgh, Scotland’s National Academy, is Scottish Charity No. SC000470