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Andrew Wilkie

In conversation with John Reed

(i)

The work of a medical geneticist

On psychological profiling I always score very strongly at the introvert end of the personality scale. My world is quite internalised: a lot of my life I live in my head.

In my work I am motivated by trying to help people, but it is a small-scale thing. Much of the work involves studying families with rare genetic disorders. I really want to help these particular families, to give them better information and tests. And the fact that the disorders may be rare and on a global health scale not necessarily very important doesn’t especially bother me.

The work that I do then combines these two aspects, introversion and helping people, quite felicitously.

I am a medical doctor. Having obtained my basic medical training I specialised in a field called clinical genetics, which concerns individuals who have genetically based disorders. These are conditions that are part of your inherited makeup and might be shared with relatives. Clinical genetics is the medical discipline of advising such people and their families about the diagnosis, what could have caused it, whether it could happen again, and what tests are available. I specialise in disorders affecting development of the skull and the limbs, so I see patients and families with these problems. And then in the laboratory we work on their genetic material to try to pinpoint exactly what has caused that particular collection of physical features. The payoff from this goes in two directions. First it can provide better information for families and be helpful in that way. Second it also enables us to learn more about how the human body normally develops.

There is a possibility of cures down the line for some genetic conditions, but those I work on are present at the time of birth; there are often quite severe physical abnormalities in the development of the growing baby inside the womb. So I think that the notion that there is going to be any simple treatment is a bit fanciful; that is not what drives me to do this work.

How did you get into this particular area of science?

By a very haphazard process. Apart from a short series of undergraduate lectures I’ve never done a formal course in genetics. In life it is such a matter of chance actually finding what is right for you. It is very difficult – you go to school and do A-Levels and you are supposed to decide what degree to do and you get channelled down a pathway that may not be right. I suspect a lot of people never discover their true niche. In my case I was good at maths and science at A-Level but what in many ways really interested me at that age was wildlife, the environment and conservation issues. Those are things that I still feel really passionately about. But I didn’t have the courage to decide that this was what I was going to work on because they seemed a bit woolly and non-academic. I come from a background where both my parents were medically qualified; my dad was a distinguished physiologist, he had an FRS. So there was a lot of both covert and overt pressure channelling me down an academic pathway.

Actually I didn’t have any idea what to do at university. So my parents said, ‘If you don’t know what to do, do medicine.’ So that is what I did, medicine at Cambridge. In my final year, whilst I was supposed to be reading for a Biochemistry degree, I spent an awful lot of my time in the genetics library reading various obscure papers on evolution that had very little to do with my course and certainly weren’t helping me get the best mark in the final exam. That was the time when a guy called Carl Woese was producing evidence for a third domain of life, the Archaebacteria, which no one had suspected before and I found this idea that there were three domains rather than two very intriguing.

After that, and the one time in my life that I have really felt completely lost, I came over to Oxford for the three-year clinical course. I started off with the worst thing that I could possibly do, which was the surgery attachment. I didn’t have the faintest idea why I was there. As a student on the wards you are suddenly in this very hierarchical realm of white coats and I couldn’t stand it. At the end of the surgery attachment I failed the final test and I just don’t fail things; it is not something that I’m allowed to do! To fail this thing was a huge shock. So the early period of being a clinical medical student was very challenging.

Paradoxically once I had stabilised a bit the new component that it gave me, and which has been incredibly important, was learning about people. I had a very sheltered background, a hot-house public school education and I was an only child. The great thing about clinical medicine is that when you put on that white coat you can ask people the most intimate questions and they will answer because it is in the context of a medical consultation. You meet people from all walks of life and you really find out about the diversity of human experience.

Another theme to highlight is that there may be one or two key people who are a huge influence on your professional life and its direction. The professor of medicine at Oxford was David Weatherall: at the time he was doing some of the very early work showing how the study of genes could be used to identify the causes of genetic diseases. A few years previously he and his group had been the first to identify a defect in the DNA of a human with a genetic disease. With the strands of genetics and evolution that I had brought from my final year in Biochemistry, and the influence of this man, I started getting interested in how you could bring genetics and disease together. And it is rather nice for me that his office is literally next-door here so I feel I have made a professional journey and yet he is still around.

What is the actual nitty-gritty of the process of what you do? What sort of mental processes does it require? Is it a creative enterprise, is it logical analysis?

One can characterise it as being like a complex crossword puzzle. I’m not a hugely inventive, creative or technology-driven person but I am very analytical and persistent. I tend to think on a small rather than large scale and am good at details. The starting point is the patient in the clinic, often with a rare syndrome, and a description of what features the patient has from looking at photographs of them. It is then a matter of pattern recognition to make a correct diagnosis. Children with genetic conditions provide experiments of nature and each of them is telling you something about how genetic mistakes affect normal development. By seeing patients oneself it also stimulates questions in your own mind: How could this pattern of problems arise? What is this person telling us about the underlying causes?

An important component of the work is taking the family history, finding out if other people in the family have been affected by the condition. Sometimes there is just one affected person and you can’t make very much of the information. But if several people in the family have been affected then if you obtain samples from them you can start to work on the problem in a logical way: you suppose that all these affected people must have the altered gene in common. The crossword puzzle element comes in because you start off saying ‘This condition could be due to a single letter change in the six billion which is the genetic make-up of each of us.’ And how do you go from ‘It could be one of six billion,’ to ‘It is this particular one’? The first stage is this process of looking at families and finding a piece of chromosome that is shared, within a single family, by all the affected people but is not present in the unaffected people and then working from that to saying ‘What are the genes on this part of the chromosome?’ The next stage is to work from a part of one chromosome down to a single gene and maybe just a single chemical change in the DNA. Here, the international Human Genome Project, which has given us the DNA sequence, is very important.

So what is your role more specifically now in this process?

I am one of only two clinicians in the lab so at the patient end of things, where a lot of the projects originate, I am the contact person. I do a lot of the dealing with people and obtaining samples from them. Then raising the grant money, which is an extremely competitive process. At one end there is the strategic direction of where the science is going and at the other, personally looking at day-to-day results as they come in, helping to troubleshoot, making suggestions, trying to have bright ideas about how to get round problems; looking at new data and thinking about what the logical next step is to take this further. Writing papers, again we all have strengths and weaknesses: I would characterise perhaps my biggest strength is writing papers for publication. Ultimately the way you are known for your science is not that you did a very good experiment on the bench, it is what actually gets put in print.

(ii)

The moral, the social and the intellectual

I have a rather clear distinction between ‘work’ and ‘outside of work’. By the time I’ve been away on holiday for a week I’m not sure that it would be a big problem for me if I never returned! I don’t have any particular fears about retirement because I don’t feel that work is so much a part of my core being that if I stopped doing it I wouldn’t be a whole person. It is strange really, I see it as being in a box. But the things that really interest me outside work…I relax through bird watching, which I wouldn’t say I did at a hugely intellectual level.

Another thing is going to wild places, camping, mountains. I get something very deep from this but it is not intellectual at all – or if it is, then it is the very different, challenging environment where the weather may turn bad and if you slip you could kill yourself. What they have in common, because I often do it on my own, it is yourself against some sort of problem where you have to weigh everything up and come to some judgement about what to do. You can completely empty your head of all the kind of rubbish that normally churns around inside and focus on something very basic – what you are going to do in the next 12 hours. What mountain are you going to climb? What is the weather looking like? How many Mars bars are you going to put in your rucksack? I don’t have to do it all the time but there is clearly something very renewing about it.

Morally what do you think this work has done to you?

As a clinical geneticist you come up frequently against a conflict between what might be in your own interests in terms of getting samples and what might potentially be in the best interests of the individual. One of the satisfying things about genetics as a part of medicine is that on the one hand although it is highly technical, involves a lot of lab work and if you do well you get a publication in a good journal, on the other it does involve a lot of face-to-face contact with people and a sensitive handling of those situations. So in terms of a moral journey I think the focus on individuals and individual autonomy is sharper than it was 20 years ago.

Has that shaped your moral outlook more generally?

More important, at least for the person I was 25 years ago, was my general clinical training. This was essential in helping me understand what makes people tick. It is easy to imagine another pathway, if I’d just gone into basic science, where I’d never have come across that.

I suppose that I am a moralistic person. I’m generally a pessimist. Combining my interests in astronomy and evolution, the more one knows about the earth the more hugely insignificant both humankind and oneself seem in the overall scheme of things. I find the course that the human species is taking at the moment profoundly depressing. It is the sort of thing that if you dwelt on it too literally you would just top yourself! So I have ways of dealing with it; another mental box.

In my own personal behaviour I am quite an ascetic person. I don’t aspire to lots of material things. That is easy for me to say because I live in a nice house and have a lovely wife and two lovely children, but I am not always wanting more. I find the venality of society...the way it seems to be so focused on wealth and always getting more...I do find it quite repugnant.

And is your pessimism associated with a feeling of impotence?

Yes, and in a sense that is part of my character. There is a type of person who has a ‘can do’ philosophy and wants to solve the problems of the world. That is not me at all. I will just work away on my little bit, which is hopefully helpful for a few people. It is a small person approach to things I’m afraid but that is the way I am so I might as well acknowledge it!

We don’t have a television at home and that’s something that my wife has perhaps an even stronger stand on than myself. When I stay in a hotel for a night and put the television on I find it quite intrusive. Sometimes it’s intriguing to see these things in almost real-time but there is something quite odd about having the horrors of the world brought to your cosy sitting room where you can watch them sitting on your cosy chair. It is quite bizarre, quite desensitising of people because it is reality and unreality at the same time.

You spend most of your days thinking about the human body and human species, building blocks, like machines in a way. It strikes me as an odd thing for a human being to be doing. Does that spill over into your general perception?

One of the things that I have found remarkable in my own life is having children and the way this little thing pops out suddenly! But it is a miracle shaped by at least a billion years of evolution. You hear about ‘designer babies’ but it is absolute rubbish. Any scientist who tells you that we are even 1% of the way to understanding how it all works is pulling the wool over your eyes (and their own). It is so bloody complicated. What I do is so far removed from describing a human being as a whole that they are like two different universes.

What has your work done to you socially?

I’m not a particularly sociable person but the work involves running a group of people who are working in a small space, they are often on short-term contracts, there is a lot of pressure and the pay is not especially good. When you start off as an independent scientist there is no training, you are completely thrown in at the deep end. One of the biggest transitions that you have to make is from being the bench worker producing results for yourself to the person who hires the first research assistant and then you are supervising them as well. I found that a huge challenge.

I think that the lab that I have is a happy place where people get on and I enjoy the sense of community. The other context for socialising is that as you get an international profile and get invited to meetings, that gives you the chance to meet your peers around the world. A lot of the time going on these trips is just hard work but you do have some lovely experiences, you meet some great people and feeling part of a wider scientific community is very satisfying.

What is the nature of these relationships in work?

It is pretty professional really. I don’t have a lot of friends, not because I’m some ‘saddo’: it is just not something that is an important part of my psyche. I’ve got half a dozen good friends but I don’t need to have the feeling that people like me.

My friendships are with medics or scientists mostly. It’s interesting when you’ve known someone for a long time to see their trajectory...but the person who is my best friend is Jane my wife. She is a hugely important person. So the sort of conversations that you might have with a friend I have with Jane. We talk about everything and because she is a children’s nurse, she is not into the minute details of genetics but I bore her with it anyway. As we don’t have a television people say ‘What the hell do you do in the evenings?’ – well the answer is that we actually talk to each other!

My friends, I might see or talk to these people, even good friends, three or four times a year. In my younger days one of my main outlets for such friendships was going off camping, which is pretty intimate when you are lying next to someone in a tent. But I don’t think I could tolerate that now. And Jane won’t go camping with me either! (The last time she did, she had to be rescued by helicopter, but that is another story...) So if anything I have got more isolated.

I had a very isolated childhood. Both my parents were out at work and I got very used to my own company. It is only since I have had children myself that I realised what a very strange childhood I had. One thing that I decided, it was almost in the marriage contract, I was quite happy not having children but if I was going to have them it had to be two and not one.

I don’t dwell on the past. Excessive rumination can be bad for your health!

(iii)

Conversation, tastes and the future

Conversations?

I am quite good on a one-to-one basis like this but hopeless at small talk. But the situations where I get into conversations are quite limited. There aren’t lots of times when I’m going out with a friend and having a conversation apart from with Jane.

What do you converse about, what is the point of it?

Generally speaking it would not be intellectual or highly philosophical. It is usually fairly pragmatic things about how your life is going, comparing notes about kids, that kind of thing.

Have you had decisive conversations with people, conversations that have changed your outlook or direction?

I’m not the person for that moment when the scales fall from your eyes. So I suspect that it is a more incremental or cumulative thing rather than ‘Oh, I hadn’t thought of that!’ and you go off in another direction and your life changes. So I can’t think of any striking instances.

Would you like to have more conversations with a wider variety of people?

When I go out to dinner and meet interesting people that is fun, but if I’m being honest it is not something that I think ‘I wish I did this more often.’ Jane, she is always saying, ‘We don’t have enough dinner parties, we’ve got to fix up something,’ and it’s down to her that I’m not some sort of ghastly recluse! So, yes, I am quite happy to participate and enjoy it. But at the same time it is not something that I’m going to actively go out and seek.

And the things you actually do go out and seek, the bird watching?

Ah, solitude! I guess you could characterise it is a rest from the constant chatter of human existence and I suspect that is pretty important for me.

Tastes, aesthetics, are your tastes and senses an important part of you?

The most important aspect is visual. Something I have had a long-standing interest in is visual arts: not that I am in any way artistic myself...I can’t draw to save my life. But it is a strand that has gone through my life that I find deeply satisfying. In terms of what those tastes have been...the period of art that I get most from extends from about 1800 to 1950. Music is something else. I listen to a lot of music, mostly rock and classical…a current favourite is Bruckner.

What is it about this particular period of art that interests you or excites you?

I’m not very interested in literal, visual interpretations and I’m an atheist so all the centuries of Virgin and Child do nothing for me. What does interest me is the way in which you can represent an image or an emotion through paint applied often in quite an economical way. And the physical colour and texture of the paint as well...that has an emotional resonance in me. Something I do like to buy is original prints or paintings. It is ideal because you can spend quite a bit of money, yet it is low consumption, doesn’t clutter the house up and you can enjoy it.

With the pictures is it the immediate, aesthetic experience or more intellectual?

Because I’m more a visual than aural person I think I can probably rationalise a little bit more why a particular picture is good rather than why a particular piece of music is good, but at the end of the day my response is aesthetic. And again if other people think it is a piece of crap that doesn’t bother me at all because the reason I have got it is because I like it.

One of my favourite artists is Edvard Munch. Clearly when you look at Munchs in a museum, you are looking at his pictures with the knowledge of the kind of person he was and the society he was brought up in etc. and that is an important part of the deal. But the sort of paintings I can afford to have on my wall are not your Edvard Munchs. They are by people who are more or less successful British artists trying to plough their little furrow and they might have very interesting and bizarre lives but if so I’m not aware of it.

Someone who I think was a superb technician was Francis Bacon. His outlook was extraordinarily bleak and despite the slightly bleak things that I have said, I don’t get a huge hit out of looking at loads of mutilated forms so as to get all depressed. But what I do like is that if you actually stand in front of one of his pictures and look at the way it is painted it is just brilliant. So behind his genius was not just an outlook, an oeuvre, that was different and might do something for you or might not, but he was also technically brilliant. And that part of it I can appreciate and get a lot out of. And again going a little bit away from the intellectual to the aesthetic and seeing the paint applied to canvas in a certain way can give me huge satisfaction.

Do you talk to other people about art or music?

No, it’s a very internal experience. I feel really stupid talking to other people about it. I don’t say, ‘Oh yeah that’s a very nice picture, that’s a very nice piece of music.’ I don’t want to tell other people ‘You don’t like that picture – well you should like it.’ If they don’t like it they don’t like it. I find that type of conversation a bit navel-gazing.

The future. What does it hold for you, how do you think about it and its uncertainties?

Work-wise I don’t think much beyond the next five years as grant money tends to come in five-year tranches. At the moment my major grant runs out this October and the work of almost the entire group depends upon renewing the funding.

The way I work is in a kind of tree: you make discoveries and then that takes you somewhere else. I am not someone who in five years is going to say ‘Right, I’ve done this I’m going to work on something completely different.’ It’s all building on what we have done already and then you make a new discovery and you take it in a new direction.

I can be a bit more specific in terms of goals because at the end of the day what you are measured on is your publications. At the moment I have something like 100 publications, but there are 25 papers that I have written where I am the first or the senior author that are in good journals. I see that as the core of what I have done, these 25 original discoveries. I’m about half way through my professional career and if, through the rest of my career, I could get another 15 I would be very happy. It’s a bit like climbing Munros in Scotland.

What a lot of scientists tend to do at my stage is to stop doing so much direct bench work-related science, and start to get into science politics, the management of science. I know enough about myself to feel that that is not where my abilities lie and it is probably better, both for me and the rest of the world, if I stay doing what I’m best at which is this. But the scientific process is very tough and just because you have got a reputation the papers do not write themselves, you still have to go on making the discoveries and it is not easy. Every time when you have sent off the last good paper you think ‘Christ what the hell next!’

What about more broadly, personally?

The most important thing for me personally – more so than work goals – is seeing my two boys develop as people, they are aged six and eight at the moment. Getting them through the next 10 to 15 years – it is so hard to find in life the match between your own abilities and what is out there to do. I’d just like them, however they end up, to feel that they had given things a try and they were happy. I think I have ended up in that situation. When I look back at the way I was, it’s amazing!

What I really hope for is that when I retire I will still be physically in good enough shape that I can go on walking in the mountains and that I will then have time to do more things, learning about the rest of the world, that I haven’t had time to do during my working career: reading War and Peace, cosmology, geology, possibly music...

April 2005