Psychiatric disorders are the disorders of what makes us human, they’re the disorders of social interactions with other people, of how you perceive the world and I found that absolutely fascinating. And the idea that you might be able to interrogate that from a biological point of view was really attractive.
To what extent do you think genes predetermine our happiness?
From a research point of view we think about it the other way round: which genetic variants would predispose you to getting depression, for example. It’s easier to study that way: you can recruit a really large number of people who have depression, but measuring how happy people are is quite difficult.
There’s definitely a role for genes in predisposing people to developing depression, although it’s not as strongly heritable as some of the other psychiatric illnesses (like schizophrenia). The way I’d tend to think about is that your genetic make-up sets your brain up to be potentially more or less resilient to things that you might encounter during your life. It’s not that your genes make you unhappy, but your genes might give you a brain that’s more vulnerable to stress, for example, or many of the other things we know can predispose people to becoming depressed. It seems likely to me that, even if you’re not clinically depressed, your genes probably have some influence on how happy you are because most of the psychiatric illnesses are a continuum – it’s not a hard line as to whether you’re depressed or not.
Do these gene markers that make you more or less resilient operate in any one part of the body? Are they neurological?
You can’t really categorise genes that way. And depression, for example, is a really complex illness – it’s a lot about the interaction between the rest of the body and the brain. Less and less we’re thinking of the brain as a discrete, isolated organ that doesn’t talk to the rest of the body. Instead, we’re increasingly trying to understand the relationship between the brain and, say, the hormonal system or the vascular system, and how these different systems interact with one another.
What is the clinical definition of stress? Does stress make you sad? And, if so, why is the lack of stimulus depressed people experience also likely to make you sad?
A colleague of mine, Cath Harmer, has done a lot of work suggesting that people who are vulnerable to depression tend to have a ‘negative bias’. For example, if you encounter a relatively neutral event – like your friend passing you in the street without acknowledging you – people with depression might be more inclined to interpret that negatively: ‘Oh, they saw me and they’re ignoring me’ rather than ‘Oh, they must not have seen me.’ If you have that negative bias pervading your life, that can lead to depression. Cath has shown that treatments that work for depression seem to quickly reverse this negative bias. The hypothesis is that once people no longer have this bias then their symptoms ease.
With stress, there are a lot of things you can measure – a lot of physiological signatures of stress responses; the classic one would be levels of the hormone cortisol. What should happen when you encounter a stressful event is that your cortisol should rise and fall away slowly. The stress response is there to ensure that your body becomes alert and ready to respond when your encounter something dangerous – it’s a very immediate response to something in the environment that’s stressful. However, if you have too much stress repeatedly then that’s really bad for your body. Your body is not designed to be in that hyperalert state over a sustained period of time. There’s evidence that people who suffer from depression have altered cortisol responses.
What is your general research focus?
I’m interested in understanding how genetic factors influence whole brain function, particularly in the kind of brain functions that are problematic for patients with psychiatric disorders.
The idea is, if we understand how genes (and the proteins that they make) influence whole brain function, then maybe we can find good targets for treating the symptoms of psychiatric illnesses. My work has evolved over the years; I now work on a number of genes that are of interest with respect to whole brain function. However, there is one particular gene that I’ve been working on since my PhD, called COMT. It breaks down a chemical called dopamine in the brain – dopamine is really important in lots of different brain functions. One of the things that makes COMT good to study is that in the normal human population there is natural genetic variation in the form of COMT that people have and that translates into how active the enzyme that the gene encodes is. So you can have genetically high, intermediate or low activity. We’ve used this genetic variant as a proxy for COMT activity and dopamine levels in the brain.
Over the course of my research, I’ve shown that if you lower the activity of this enzyme it increases dopamine levels in certain parts of the brain. The nice thing is that the effect of COMT is relatively specific to the parts of the brain that are important for higher cognitive functions: things like decision-making, working memory. The reason that’s interesting is that these are the kind of functions that are impaired in psychiatric illnesses. Therefore, the hope is that if you could lower the activity of this enzyme, you can improve these aspects of brain function.
In order to have optimal brain function you want not too little and not too much dopamine, but somewhere in the middle. We’ve shown previously that if you have low dopamine to start with, the drug enhances working memory performance. But if you have high dopamine to start with – if you already have fairly optimal levels – the drug actually makes you worse. If we can fine tune the amount of dopamine that somebody has in the brain region then we should be able to optimise his or her cognitive function.
One of the things that really interests me about this field is that even the work that we’ve done so far shows quite clearly that this wouldn't necessarily just benefit people who have some kind of medical diagnosis, but also people who are fully healthy but who just happen to have the form of the gene that gives them lower dopamine. One would predict that the cognitive enhancing effects of these drugs should be there in healthy people as well.
But whereas in patient populations you have a very clear deficit in something that causes significant problems for the patients concerned – working memory or decision-making capacity, for example – in healthy people, it’s less clear that it would be a good idea to take drugs to improve working memory all the time. These drugs might help you to focus and attend to something really specific. But if you're doing something in which you need to be a bit more mentally flexible, change what you’re doing or learn about changes in rules or changes in the environment, then enhancing attention and focus might be detrimental. So in healthy people, who do not have particular problems with working memory and attention, I’m less clear that taking such a drug chronically would be a good idea at all. While you might enhance attention, it’s probably going to be at the cost of some other brain function – because you’re already relatively optimally balanced anyway.
But there are difficult ethical questions – if you had a really difficult 12-hour surgery, would you want to give it to the surgeon? Would that be an acceptable use of it? Where do you draw the line?
Where would you like your research to go, in the course of your career?
Ultimately, if we can develop a drug that enhances cognitive function to treat cognitive problems – in particular for schizophrenia but also other psychiatric illnesses – that would be my goal, that would be great. Then the work that we’ve done would be therapeutically useful. I think that’s the goal of anybody working in this department – to make the lives of patients better.
But stepping back from that just understanding how genes influence your response to things that are in the environment and how they make you more or less resilient to environmental factors – that would be a supplementary goal.
What gives you most job satisfaction?
I love data – I’m a real nerd. And I like the process of trying to understand what the data mean.
One of my favourite things, which happens very rarely in science, is the brief period where I’ve analysed something and I know something that nobody else in the world knows – it normally lasts about two minutes… because I get really excited and have to go and tell somebody! I love the process of trying to synthesise information coming from various sources into some kind of coherent hypothesis and then interrogating that hypothesis and seeing if it holds up or not.
The other thing I really like is bouncing ideas off a wide range of people and interacting with a wide range of people. Oxford’s great for that; almost anything you could conceive of, if you wanted to do a study with some technique you’ve never tried before, there’ll be someone here you can talk to. I’ve never once approached someone and said ‘Do you want to collaborate?’ and had someone say ‘No.’ It’s a very open place.
So those two things: interacting with other people to develop new ideas and then shutting myself away in my office and playing with data.
Was it difficult for you when you were starting out to know where to go and what to specialise in?
I’ve never known what I’m going to do! I did my undergraduate degree at Bath University. Until the age of 18 I was completely convinced that I wanted to be a vet. And I got to the stage of applying to uni for veterinary science and then one morning I woke up and thought ‘I don’t want to be a vet! I don’t know what I want to do...’ So I applied for biology, which I really enjoyed, and then over the course of my degree it evolved into a four-year course with a year spent in industry working at SmithKline Beecham (now GSK). That was a really transformative year. I had a fantastic mentor. I got to do what was essentially a year of pure research, which I loved. My mentor suggested I apply for a PhD, which had never occurred to me.
I applied to PhD programmes in my final year and was fortunate to get onto the Wellcome four-year doctoral programme in neuroscience here (including an MSc). At that point I was interested in neuroscience but I hadn’t done very much. I was really a molecular biologist by training. But the MSc year was brilliant in exposing me to totally different kinds of science going on in Oxford and I think as a result of that my DPhil ended up being very interdisciplinary.
The nice thing about the Wellcome scheme is that the research money is awarded to the student. That meant I was free to go and do whatever I was interested in doing and I knew I was interested in relatively clinically focused neuroscience.
I was fascinated by psychiatry because psychiatric disorders are the illnesses of what makes us human, of social interactions and how you perceive the world around you. The idea that you might be able to interrogate that from a biological point of view was really attractive to me.
When I finished my DPhil I spent some time working in the US at the National Institute of Mental Health, with colleagues who have become long-term collaborators. Then I returned to Oxford where I’ve been ever since, albeit working in several different departments to learn different techniques. My research is still quite multidisciplinary, and I have a number of wonderful collaborators that make this approach feasible.
The master’s course was really good at facilitating that collaborative approach because it is run across multiple departments, and covers all aspects of neuroscience, but I think that is a strength of Oxford actually, and, because the University is so large, anything you might want to do, there’ll be someone here doing it. I love that even now I am still able to learn new things and use novel technical approaches to answer the research questions that I have, and to develop new ideas.
I’ve never encountered competition between groups within the University. I have seen that elsewhere, but not here. I think people’s interests are diverse enough that people aren’t treading on each other’s toes, they’re not applying for money to do the same thing. So people are quite open to the idea of collaborating with others because they’re not going to be in competition with them – it’s going to be a genuine and mutually beneficial collaboration. It’s a good place to be, I enjoy it.