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Researcher Spotlight: Professor Andrew Wilkie

2 Jun, 2014

Professor Andrew WilkieProfessor Andrew Wilkie is the Nuffield Professor of Pathology at the University of Oxford and Honorary Consultant in Clinical Genetics at the Department of Clinical Genetics, Oxford University Hospitals NHS Trust. With 21 years of funding from the Wellcome Trust under his belt we thought it was about time we shone the spotlight on him to find out more about his work and his hopes for the future…

What are you working on?

I’m interested in genetic errors that cause human malformations – especially those involving the skull. I want to find out more about the origins of specific malformations in particular children, so that we can make better diagnoses in the clinic. But I’m also interested in the underlying general principles of disease – for example which molecular pathways are involved, and why characteristic patterns of mutation arise.

What does your average day involve?

I’m in the very fortunate position of being involved in the entire investigative process. So I might be sitting in the clinic with my surgical colleagues, providing genetic advice for parents when they bring their children for assessment (Oxford is a wonderful place to be based for this work, because families visit us from all over the UK). I might be talking to one of the postdocs or students working in my research lab about the latest batch of samples that they have been sequencing, trying to find a new disease gene or mutation pattern. Or I might be sitting in the clinical diagnostics laboratory, checking the data and signing off reports where the research discovery has now matured into an NHS diagnostic test. These are the exciting bits – like everyone else I also spend ages leading a couch potato life in front of my laptop engaged in seemingly endless rounds of draft writing, editing and reviewing, not to mention keeping on top of the flood of emails. But committee meetings are my real bugbear!

Child_with_Apert_syndromeWhy is your work important?

Having a child with a serious skull malformation is a life-changing event: mothers and fathers carry a mental image of what parenthood will be like, and that can morph from the moment of birth into a seemingly endless round of hospital visits and associated constant anxiety.

Answering the “why” question is important at several levels. It can be empowering to the family; a diagnostic “label” often opens the door to additional social and educational support; and it is essential for proper genetic counselling so that individuals in the family can choose if they wish to have further children without running the risk of the condition occurring again.

What do you hope the impact of your work will be?

Two things; one predictable, the other not. Finding new genes for diseases brings new diagnostic possibilities for patients all around the world. The beauty of genetic diagnosis is that technically, it’s not that difficult once you know where in the genome to look and what to look for. For the families that turn up positive, that can make a big difference.

The unpredictable bit is that my work has helped uncover a new mechanism for genetic diseases arising in older fathers. We know this explains the origins of several rare malformations but there are hints that it might impact on a much wider range of diseases – from autism to cancer. We can’t be sure yet, but new gene sequencing technologies are making these questions more accessible to study, so ask me again in 20 years if I’m still around…

CT_scan_of_a_child_with_severe_craniosynostosisHow did you come to be working on this topic/in this field?

Originally, once I had finished my training in Clinical Genetics, I expected to return to the subject matter of my doctoral work. But in the meantime the juicy bits had been taken on by other very competent people! So I had to come up with something completely new.

In 1990, just before finishing my doctorate, I attended an EMBO symposium on the Molecular Biology of Vertebrate Development. Then, whilst working at Great Ormond Street Hospital, I saw some babies with Apert syndrome – a severe type of craniosynostosis (premature fusion of the sutures that separate the bones of the skull), which is easily recognised because the digits of the fingers and toes are also fused together – and thought that one might be able to apply basic concepts from the developmental biology of the limb to understand the cause of this condition.

Add to that the fortunate coincidence that Oxford, my Alma Mater, happened to have a specialist craniofacial unit and I had the opportunity to return to the wonderful (then new) Institute of Molecular Medicine, and the ingredients were in place. I even managed to get some fellowship funding – see below – despite the referees being generally rude about my application (one described it as a “back of the envelope job”).

How has Wellcome funding helped you?

I am now in my 21st year of continuous funding from the Wellcome Trust; during that time I have risen through the ranks of Advanced and Senior Clinical Fellowships, then Programme grants to a recent Senior Investigator award. In fact, over my career as a whole, about 85% of my funding has come from the Trust. Last year I was fortunate to be elected as a Fellow of the Royal Society and had the extraordinary privilege of adding my signature to the Charter Book, which contains the names of many of the scientific giants of the past 350 years. I will admit that this is a dream come true; one that would, literally, have been impossible without the Wellcome Trust.

What’s the most frequently asked question about your work?

“Can genetics lead to a cure?”

Working on malformations doesn’t make “cures” easy, because the faults in the genetic programme affect the formation of organs at early stages of development.

There are obviously enormous challenges in coming up with safe means to identify and treat these types of problem in utero. Nevertheless, I am starting to “think the unthinkable” in my own research and look at whether we could target some milder types of craniosynostosis that arise postnatally. But a strong sense of humility is in order and I don’t anticipate the surgeons being put out of business for a while.

Which question about your work do you most dread – and why?

When will the human genome sequence yield the health benefits that have been promised?” – although the question causes me more annoyance than dread.

Annoyance because thousands of people with Mendelian disorders and cancers already benefit daily from improved genetic knowledge to diagnose, prevent and treat these conditions in themselves or their families. Rather, the “failure” of human genomics implicit in the question arises from the (in my opinion) persistent overselling of its translational applications to prediction in common complex diseases.

Back in the 1920s Ronald Fisher realised that genetic diseases came in fundamentally different flavours – and that was before the chemical nature of the gene was even known. But then, he was a very clever man.


Tell us something about you that might surprise us…

As an essential sanity check, I head up to Scotland for a week each winter to climb a few Munros. Just me, my tent, the mountains and (but not guaranteed…) liberal quantities of snow and ice. My brain empties out all the accumulated **** as I focus on the immediate tasks required for comfort, survival, and, hopefully, a few more ticks in Munro’s tables.

What keeps you awake at night?

Sorry, I don’t like to whinge but… writing grant applications. There’s something deeply oxymoronic about the whole process, because most really interesting science is inherently unpredictable within the five-year timescale covered by most long-term support.

Grant-writing is really a combination of fortune telling and salesmanship, neither of which I feel especially comfortable with.

I put my survival in the system down to a combination of bloody-mindedness – I have this in spades – and a large dose of luck (and, of course, the Trust’s excellent judgment!).

The other thing that keeps me awake is all those families for whom I’ve not yet been able to make a precise genetic diagnosis: this means that the genetic counselling I have given them is likely to be a combination of fortune telling and salesmanship…

What’s the best piece of advice you’ve been given?

Perhaps my parents’ advice to apply to study medicine at university. Although at school my strengths were clearly in maths and sciences, I didn’t have any strong sense of where this could take me as a career.

Provided that you have the basic intellect, there is something to suit everyone in medicine, because different branches require such different personalities and mental processes. The better pay and greater job security is an advantage too.

The downside is that it’s most unlikely that I would be allowed anywhere near a medical school nowadays – my general cluelessness (not to mention oddballness…) would be sniffed out immediately and stamped on (writing “Medecine” on the university admissions form was a bit of a give-away).

The chain reaction question, posed by Dr Bungo Akiyoshi is “What problems would you work on if you were to start over your career again?”

I am still fascinated by the developmental processes that give rise to both normal and abnormal phenotypes, so if I was starting now I would probably still work on the same questions – but I would aim to get a really thorough grounding in bioinformatics. This is an essential skill for every young researcher, both to make the most of their own data and to harvest the richness that lies in cyberspace.

You can find out more about Prof Andrew Wilkie’s work via his department website or by reading his papers Craniosynostosis and Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease

Image credit: “a white munro” by Stu Smith on Flickr, CC-BY-ND-2.0

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