I was born in Wolverhampton in the West Midlands of England in 1947. My father was a journalist and my mother trained in architectural drawing, but stayed at home to look after her three children. None of my extended family was academically inclined, though my grandfather (who regrettably I never met) was an engineer, inventor and eccentric. As a child quite a lot of my free time was spent bird-watching, fishing and keeping pets (tortoises, rabbits, mice, a dog and various found animals). The other major occupation was sport – particularly cricket and field hockey.
These distractions continued into secondary education at a small country grammar (i.e. state funded) school. Academic work, by contrast, was less addictive and my attentiveness and performance fluctuated. Art was an exception as I developed an interest in drawing, which paid off as I later illustrated a series of children’s books by my father – about a talking Irish dog. Of the other school subjects on offer, biology and chemistry stood out as they related to my extra-curricular interests. For example, I obtained chemicals to use at home and recall that the effect of sodium hydroxide on a wooden table-top impressed both me and my parents.
School biology lessons never really caught my imagination, but I happened to see on television a series of lectures in which Maynard-Smith, Korner, Perutz and Crick talked about their work. This would have been around 1962 when the Nobel Prizes for the structures of DNA and globin were awarded. DNA in particular fascinated me and, as it was not yet on any school curriculum, I wanted to find out more. The way forward was obviously to study biochemistry at university, and I was accepted at the brand new School of Biological Sciences at Sussex University. Fortunately John Maynard-Smith was dean and Asher Korner ran the biochemistry course. This was more like it.
During a genetics course I learned that Max Birnstiel in Edinburgh had purified the DNA encoding a single gene and I decided to apply there for a PhD. At the time it was not known whether all cells of the body had the same genome. I studied a dramatic case where gene copies are hugely amplified in a single cell type – the frog egg. As it turned out this is a rare exception rather than the rule, as the vast majority of cells retain the entire unaltered genome, regardless of whether they are blood cells, liver cells, neurons etc. I moved to Joe Gall’s laboratory at Yale as a postdoctoral researcher and continued working on gene amplification. Here I encountered a very distinct and stimulating research style, based on genuine curiosity, clear thinking and simplicity of expression, which I have tried to emulate since. From there to Zurich, Switzerland where, fuelled by discussions with Hamilton Smith, discoverer of type 2 restriction enzymes, and Ed Southern, inventor of the eponymous blot technique, I realised that restriction enzymes could be used to map methylated sites in the genome. This triggered my laboratory’s later involvement in the discovery of CpG islands. In DNA methylation I had found an unstudied aspect of DNA that I could really get my teeth into.
After moving to Edinburgh University for my first proper job, I became interested in how the DNA methylation signal is read. My group found proteins that bound to DNA only when it was methylated and implicated them as mediators of the repressive effect on transcription. One of these proteins was MeCP2 and we were busily learning more about it when a “bolt from the blue” changed our research agenda. Huda Zoghbi’s laboratory identified that mutations of the MECP2gene were the elusive genetic cause of Rett syndrome. This severe disorder was named after Andreas Rett – a Vienna-based paediatrician and, coincidentally, my laboratory was in Vienna when we first isolated the MeCP2 protein. Andreas Rett was still working in that city, but we never met, as Huda’s crucial link between our work and his took place after Dr Rett had passed away.
Despite moving from place to place somewhat during my career, Edinburgh has been a recurrent theme. My four children were born there and my wife is a geneticist at the university. Since the Scottish Enlightenment of David Hume and Adam Smith, Edinburgh has been a refreshingly non-conformist part of the United Kingdom, where questioning orthodoxy has often led to discovery. I try to be part of that tradition. Our finding that Rett syndrome in mice can be reversed by putting back the missing MECP2 gene overturned the prevailing view that this was a condition rooted in irrevocable developmental defects. In fact there is a real prospect that one day this distressing disorder will be treatable. The goal of our field now is to make that prospect a reality.
27 September 2016 Hong Kong
