On the Track of DNA Methylation: An Interview with Adrian Bird

The day school let out for the summer, my daughter and I packed our bags for Britain, where we had lived for a few months in 2006. Annie was eager to reconnect with her friends there, and I had arranged to conduct three interviews. In desperation and with the clock ticking, I struggled to fit my bulky recorder into my wheelie when it dawned on me that the ‘‘talk app’’ on my daughter’s iphone should be up to the job. You can imagine the reluctance and skepticism on the part of my 15-year-old, but she managed to get into the spirit and acquiesced. First up on my schedule was Adrian Bird (Image 1), who holds the Buchanan Chair of Genetics at the University of Edinburgh and is also Director of the Wellcome Trust Centre for Cell Biology. Long before the word ‘‘epigenome’’ was coined, Bird began mapping the distribution of DNA methylation (occurring at the cytosine of CpG dinucleotides) in the genomes of a variety of species. His work emerged just as agarose gels, restriction enzymes, and Southern blots were being developed. Bird later spawned the idea of CpG islands, pockets of DNA rich in unmethylated CpGs and frequently found in conjunction with the promoter regions of mammalian genes. Bird’s observation provided a roadmap for disease gene discovery for about 15 years, until human genome draft sequences began to emerge. Bird’s laboratory then went on to identify proteins that bound to methylated DNA, one of which (MeCP2) was discovered years later to be defective in Rett Syndrome, a rare X-linked disorder in which affected girls develop autism and a distinctive set of behaviors. This astonishing turn of events propelled Bird to extend his studies on MeCP2 to a murine model for Rett Syndrome, ushering in new ideas about therapy for this devastating illness, but still leaving open the question of MeCP2’s role in the brain. Bird and his wife Cathy Abbott, also a geneticist, invited me to spend the night prior to the interview with them (future interviewees, take note!), and I was delighted to do so. Still jet-lagged, I traveled by train, leaving behind the uncharacteristic sun of Cambridge to find cold rain penetrating the skylights at Edinburgh’s Waverley Station. It felt very cozy to share the evening with them and their children, Tom and Annie: chatting, watching some Twenty20 (an abbreviated form of cricket), playing Uno, feeding the three guinea pigs, and experimenting with the iphone’s tape app, which, to our delight, worked. Gitschier: My first question is a twopart, integrated one. How did you get interested in methylation, and what was the state of the art at the time you started working on it? Bird: I first got interested when I was in Zurich doing a post-doc. Gitschier: Whom were you with there? Bird: Max Birnstiel. I had been in the States doing a post-doc [with Joe Gall at Yale] on gene amplification in frog oocytes. When I went to Max’s in Zurich, he had a visitor named Ham Smith. Gitschier: What year approximately was this? Bird: 1973–1974. Ham was on sabbatical, and the first thing he did was to make a restriction enzyme, HpaII—Haemophilus parainfluenzae II. I was making ribosomal RNA genes, just for something to do really. We knew there was a difference between the amplified ribosomal RNA genes, which were extrachromosomal in the oocyte, and the chromosomal ones, and that the difference was due to methylation. Don Brown and Igor Dawid had shown that chromosomal rDNA had 5-methylcytosine and the amplified didn’t. Image 1. Adrian Bird. doi:10.1371/journal.pgen.1000667.g001