Reprogramming the genetic code.

When Maria Leptin called to say that I had been awarded the 2010 EMBO Gold Medal, I was delighted and surprised. The roll call of past winners is impressive, and I had been at the Laboratory of Molecular Biology (LMB) when Jan Löwe had received the award in 2007 for his elegant work on the bacterial cytoskeleton (Michie and Löwe, 2006). I also knew that several other LMB scientists, including Barbara Pearse, Hugh Pelham and Matthew Freeman, had previously won this prestigious award for their seminal contributions to molecular biology (Pelham, 1989; Freeman, 2002). Like many scientists that I know I invariably find the experiments we are about to do the most compelling, and our curiosity and optimism about the future, and the limitless possibilities that it offers, is perhaps part of what drives us continually forward into the unknown, but makes it difficult for us to sit down and write reviews about what we have already done. However, the recognition of our laboratory’s work by this medal provides a ‘still point’ in which I can reflect, and allows me the opportunity to provide a personal account that recognizes the contributions to science made by the many talented and generous people that have educated and mentored me, and that I have had the privilege to work with. I hope that this review can honour, in a small way, the debt of gratitude I feel for the ways in which they have enriched my life in science. I was naturally drawn to chemistry at school because it provided a systematic explanation for how all matter behaves in terms of simple sets of rules governed by invisible particles and captured in the periodic table. I had fantastic teaching in both chemistry and physics, and was taught by Mr Liasis, Mr Manthorpe, Mr Teh and Ms Pountney over the years. It was clear to me that I wanted to do chemistry at University and I was lucky enough to be accepted to Oxford. At Oxford I was tutored by Peter Atkins and Gordon Lowe, who appeared to take the view that they were teaching us to be scientists and that the examinations at the end of the degree were incidental distractions that bright people would somehow get through. Their tutorials were aimed at getting us to think, sometimes in unusual ways, and I have not yet forgotten the surreal image of Peter Atkins reclining on his office chaise longue, a glass of dry sherry in hand and his leather trousers creaking, while he shone a lamp on my face and demanded that I explain how I would establish the laws of thermodynamics on a desert island using only a coconut (of course I had a truly marvellous proof, but there is insufficient space for it here!). While tutorials were fantastic entertainment, the lecture courses were generally more prosaic, traditional and thorough. Later in the course I specialized in organic chemistry and was given tutorials with John Sutherland who, like Gordon Lowe, was continually able to relate the chemistry we were learning to biological processes. I decided to do a part II research year with John, whose laboratory then worked on both engineering penicillin biosynthesis to make new antibiotics and the chemical origins of life (Powner et al, 2009). I worked on engineering an enzyme that naturally expands the five-membered ring of penicillin to the six-membered ring in a cephalosporin, so that it would accept new substrates and make new types of cephalosporin antibiotics. This experience got me hooked on a combination of chemistry and molecular biology and the idea of doing more research. In 1996, I moved to Yale to study for a PhD, since a US PhD allowed me to complement a thorough training in chemistry I had received at Oxford with the opportunity to take biology classes. After the first year at Yale, I had taken most of the biology courses and felt equally comfortable with both chemistry and biology. I decided to work for Alanna Schepartz at Yale, who had a great project that had been pioneered by a graduate student in the laboratory, Neal Zondlo. Neal had shown that it was possible to dissect out the DNA-binding residues of a helical protein and transfer these residues in register onto a small stable scaffold protein to generate a new functional chimeric protein with exquisite DNA-binding affinity and specificity (Zondlo and Schepartz, 1999). With Robert Grotzfeld, I developed combinatorial approaches, using phage display, to extend the approach Neal had developed. I went on to show that we could make high-affinity binders for protein and DNA targets using this approach (Chin et al, 2001; Chin and Schepartz, 2001a, b). Since the approaches we developed were new to the laboratory, I learned a lot about how to do experiments and how to get things to work from scratch, which has been very valuable. In 2001, I finished my PhD and went off to Scripps for a postdoc with Pete Schultz. From then on my research has Received: 8 March 2011; accepted: 27 April 2011; published online: 20 May 2011 *Corresponding author. Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. Tel.: þ 440 122 34