Head of Neuroscience and Mental Health at The Wellcome Trust; Professor of Neuroscience, University of Edingburgh, UK
Breaking the Wall of Research Funding. What Funding Can Do to Enable - and to Disrupt - Research Excellence.
Excellence, excellence, excellence – in a time where the talk of “excellence” in education and research is abundant, we need to ask about the challenges facing funders: under what conditions can different funding mechanisms help promote excellence – and when might these actually hinder breakthroughs? The neuroscientist Richard Morris (1948) has built his career examining the neural mechanisms of learning: twenty-five years ago, he devised what has come to be known as the “Morris Water Maze”. This is a key behavioural protocol for testing spatial memory in rodents that is widely used today to investigate the role of the hippocampus and other brain structures in the formation of spatial memories. Today, Morris works also at the Wellcome Trust, the largest medical charity for biomedical research in Great Britain, which awards over 600 million Pounds each year for innovative health-related research. As Head of the Department of Neuroscience and Mental Health, Morris oversees a wide portfolio, while also continuing his interest in how the latest advances in behavioural neuroscience can assist applied and translational projects in the realms of cognition, learning and memory.
20 years ago I realized that things would never be quite the same.
In the opening line of his poem, Burnt Norton, the English poet, T.S. Eliot, wrote, “Time past and time present, are both perhaps present in time future, and time future contained in time past.” These words of this very famous poem resonated a new way on this day in this city, as we reflect on the past, consider the present, and try to build our future.
I am here today as both a scientist, in fact a neuroscientist working at the University of Edinburgh, and also as a representative of major international funding organisation: The Wellcome Trust in London. My contribution this evening will reflect that dual role.
So, first neuroscience: A field of research practiced by many talented researchers here in Berlin. It is the science of what the brain does and how it does it. We want to know a great deal about the brain, how it self organises itself through development to become the astonishing one and half kilogram entity that it is. To understand how a neuronal activity patterns represent information in mediating functions, such as perception, memory, motor action, as we have heard. We need to get a much better handle on what goes wrong in neurological and psychiatric diseases. The brain is an immensely complex organ, and the challenge it presents are both formidable and exciting.
Many biological, biomedical funding bodies recognize understanding the brain as one of the frontiers that is before them. But just as mountaineers climb Mount Everest because it is there, so do many scientists study the brain, because of their curiosity to find out how it works. Curiosity is the motivation- so much of our work. I don’t think we should be ashamed of it.
The Einstein Foundation, sponsoring this meeting, will recognise that it was the spurt of Einstein’s interest in the photoelectric effect and special relativity, when as a young man he thought by night about physics but worked by day in the Zürich patent office. Scientific curiosity aside the unmet demands of neurological and mental health disorders, which cause untold suffering for millions around the world, points to a second very important motivating purpose behind so much neuroscience research that we seek to fund, as we have seen in Miguel Nicolelis’ and Martin Schwab’s talks today. Findings of clinical relevance can emerge from many different directions, including basic science. It is by harnessing the multidisciplinary efforts of so many that we can hope to make progress.
My own field of research is memory. Memory is absolutely fundamental to human life. Qualitatively distinct types of memory enable us to change our behaviour in response to experience, to acquire and use a repository of knowledge, to recollect events from the past, and to plan for the future. All of these forms of memory are key to our individual existence. But certain things have happened to you and to you only: that you have a particular and unique set of social relationships and social memories, that you alone can recollect your past, and that such recollections are integral to your ability to plan for the future.
So, T.S. Eliot’s words, of which I began this lecture, are essential to what we call episodic memory - one of about five or six different forms of memory, a specific form that enables us to enrich our sense of the present by mentally travelling backwards and forwards in time.
The use of memory is changing. With a great deal of human knowledge now externalised and sort on demand through social engines on the Web. But nonetheless, the loss of personal memory is greatly feared by all of us. The inability to recollect the events of our life can develop from a minor irritation to a condition that completely undermines normal existence, as in Alzheimer disease: a condition rightly recognized by the Federal Government of Germany as needing, and now receiving, substantial further research investment.
One specific issue in this large field of memory concerns the role of context. Certain forms of memory are said to be context independent: motor skills, for example. Learn to play tennis in one place, and you can readily transfer that motor skill to another place. But, other forms of memory are intimately bound up with the place where they happened. An example of this is a car crash: you see one on your way home from work, tell your family, and they may ask, “Was anyone hurt?” But they all immediately go on to ask, “Where did it happen?” The memory of events is immediately and automatically tied to the places and contexts where they have happened.
I think nowhere does the notion of context and memory ring more clearly more in our minds than here in the shadow of the fallen wall. But how does the link from the memory of events to the context in which they occur actually happen? The answer that is emerging from modern neuroscience, but one which we need to fill in many more details, has to do with a specific part of the brain, the hippocampus, contained within the medial part of the temporal lobe on the sides of the brain. It has neurocircuitry within it that processes both spatial maps on the one hand, and one-shot mechanisms for remembering unique events.
Through a whole range of extremely ingenious single-unit recording experiments, using multiple single-unit recording technologies of the kind that we have heard from Nicolelis today. A number of experiments have identified that there are particular cells in the hippocampus, which respond to the particular place you are in in the world. It responds to the direction in which you are facing, and other cells in an adjacent region build a map of the kind of grid, a kind of metric, in which this spatial information is actually processed.
So in a laboratory: as a laboratory animal moves freely around an environment, we are able to listen in to these different cells and build a sense of the way in which that animal is mapping his environment. Now, through modern neuroimaging techniques, we are also getting a handle on that in the human brain.
But imagine then that some event happens also, such as the animal finding food or water, or being threatened in some way by a predator. It turns out that the encoding of memory for events is also processed in the hippocampus. So, unlike the learning of motor skills, which requires practice, what you have in this system is a situation in which it can learn in one trial. It can automatically bind the memory that you have for the particular event you have seen to the context in which it is actually happening. The hippocampus fulfils this ‘binding task’, and so can answer our family’s question of where a car crash or some other surprising event of the day happened.
There is lots of detail that could be fleshed in about the specific neurons that are involved in this: the local circuits, the neurotransmitters, and the molecular mechanisms. I think it is a big challenge to try to work that out. As we do so, we will get a handle onto fundamental disorders like Fragile X, schizophrenia, and Alzheimer’s disease.
I began this lecture by noting that I wanted to reflect on science in the shadow of the Berlin Wall, from the perspective of working for a major funding agency as well, as that of being a working scientist. In key questions for a funding agency are: what research should we fund? How do we find the break-through scientists to do it? Where and with what infrastructure will they actually go about it?
The Wellcome Trust will be known to some, but perhaps not to all of you. Based in the United Kingdom, it is the largest biomedical charity in Britain, and now the second largest in the world after the Gates’ Foundation. Our mission is to support research on animal and human health, and last year we spent over 700 million Euros on diverse aspects of biomedical research. The Trust is independent of government, and independent of any specific pharmaceutical company including the one that resulted in the legacy to create the Trust left upon the death in 1936 of Sir Henry Wellcome, the co-founder of the Burroughs Wellcome Company. Those funds have been invested to build up an asset base. It is ethically invested in whose dividends under the control of the independent trustees and governors who yield the funds that we deploy for research.
Importantly, an ever-enlarging proportion of our research funding is now going abroad to Africa, India, Vietnam, Laos, Malaysia, and other countries in the developing world. Of recent research in which the Wellcome Trust is involved, perhaps the best known is the human genome project - through its laboratory in the Sanger Centre in Cambridge. Wellcome did the European-end of that big international project.
Now devoted to more biological aspects of gene sequencing, gene function, the Sanger Institute is endeavouring to take the fruits of that genetic research forward to benefit human health in such fields as cancer, diabetes, and Malaria. From the neuroscience department, which I have the privilege to lead, we have recently funded new projects concerned with neurogenetic conditions, such as Alzheimer’s disease, Parkinson’s disease, and motor neurone disease: all of which take advantage of these massive in-house gene sequencing facilities. Without that infrastructure, even the brightest people will be unable to make progress.
In the neurosciences, Wellcome has been the pioneer of non-invasive brain imaging through its facility in London, affectionately called “the functional imaging laboratory, or the FIL”, which is the home of statistical parametric mapping. The FIL has yielded major insights about brain activation patterns and diverse aspects of cognition, including memory, as I have touched on. They include current research on brain activation patterns in decision-making, which we see as a very important aspect of cognition and also social interactions.
The FIL has also been home to certain infamous studies, such as the work as Eleanor Maguire on London taxi drivers. This research, involving both structural and functional imaging, has revealed changes in the size of the hippocampus in linear proportion to the number of years that a London cabbie has been driving around the city, and activation patterns in the hippocampus and neighbouring regions when they are faced with taking a novel route between two places. So, the notion that is emerging from that human research is that the structure of our brains can change in certain ways as a function of how we actually use it.
But what of the future? The operating environment for Wellcome, and for other funding agencies, is a challenging one. We live in a world of unstable financial markets, of unpredictable changes in climate, of energy insecurity, food and water insecurity, with the threat of pandemics as well as we have just heard of political issues and political change.
Clearly, we cannot tackle all the scientific aspects of this, but we feel we must aim to make a difference by finding clearly defined scientific and geographical niches. Certain unmet needs that we see include the major global health challenges, which will be a big focus of Wellcome’s funding in the years ahead: cognition, as I have touched on, and also infectious diseases.
The strategy that the Governors of Trust have recently endorsed, involves an increased focus on the individual as well as a number of other aspects, which I don’t time to go into. I would just like to end by referring to that.
The focus on the individual is, I believe, a particularly interesting one. It brings me to a key point. Applicants for research grants and funding agencies, play a curious game with each other, because we have known for a long time within Wellcome, as have the UK Research Councils, that the elaborate plans laid out in many grant applications are frankly somewhat disingenuous. Not only will parts of the work have already been done, but also other parts will never be done, because research is, by its very nature, impossible to plan in any detail.
So while there may be merit in requiring grant applicants to lay out in elaborate detail, as in the NIH style or even EU Framework Project style with milestones and deliverables, we are wondering if there isn’t a place for more trust in research funding? Why not identify the best researchers, using a diverse array of metrics, and then fund these people and the infrastructure that they need to get on with things?
A quote that the Director of the Wellcome Trust is fond of using from Joshua Lederberg in 1991, reads as follows: “Simply put, the best way to administer a creative research environment is to find people of great talent and reasonable ambition, whatever their specific disciplines, and leave them to their own devices.” (Applause from audience)
In a new policy that was laid shortly after this first Falling Walls meeting, the Wellcome Trust moved to an approach that focuses more on the brightest and best in our universities and research institutes. The policy is somewhat analogous to that of the Howard Hughes Foundation in the United States. We shall support these people in well-resourced facilities, and the details of this policy will be laid out in Nature and Science this coming Thursday.
So, to conclude: I shared with you that neuroscientists are beginning to unravel some of the secrets of the neurobiology of memory, focusing today on the initial of what we call contextual binding: events and places. I have also tried to share with you that one major funder of research is seeking to breaking the wall of fictitious grant applications towards a system that has to do with people and places. Like others in this meeting, I see many exciting research possibilities ahead, but quite where things will go is a little unclear. We should never forget, the wise words of that great American baseball player Yogi Berra, who famously said, “Predictions are hard, especially about the future.” Thank you.