Expanding the genetic code
If one could rationally expand the set of amino acid building blocks, one could add new chemistries to proteins—both as biological probes, as well as to create proteins with novel functions, to explore the chemistry–biology interface.
Abstract
My interest in the biological sciences began during my third year of graduate school at Caltech. I had just completed a detailed study of the thermal and photochemistry of 1,1-diazenes in the Dervan lab. However, rather than write my thesis, I decided to remain at Caltech and take on a project focused on generating sequence-specific DNA cleaving molecules. Having never taken courses in biology and having no experience in DNA chemistry, this challenge was a bit daunting, but after a number of wrong turns, we managed to generate a series of poly-pyrrolebased amides that had quite impressive selectivity. At the time we had to write five proposals for our thesis at Caltech (a good thing) so in addition to the proposals I had formulated around reactive intermediates (which I would still like to do), I began to explore the chemistry–biology interface. I turned to proteins which had a bigger set of building blocks then DNA, and thus were more attractive to a young physical organic chemist. And as a chemist, the first question that came to mind was why God chose these particular 20 amino acids as the building blocks for life, many of which are devoid of interesting functional groups. It struck me that if one could rationally expand the set of amino acid building blocks, one could add new chemistries to proteins—both as biological probes, as well as to create proteins with novel functions. So, I began to teach myself the key elements of the central dogma that translated the genetic code to protein sequence and formulated an in vitro plan to site-specifically introduce novel amino acids into proteins. Toward this end, I thought it might be useful to learn some protein chemistry and therefore applied to the Walsh lab (then at MIT) for a postdoc. However, while I was writing my thesis opportunity knocked and I accepted a position at Berkeley. Nonetheless, I decided to spend a year or so in the Walsh lab to learn basic molecular biology and protein chemistry.