Shortly after receiving the 2002 Nobel Prize in Medicine or Physiology, I congratulated Sydney Brenner with a magnum of 1995 Chateau Latour. He said, “Oh Ron, it's lovely but a bit young. Let's wait and we'll toast when it's ready.” Well, a bit like the wine, when Sydney finished his medical training he was too young to practice medicine. He was told “you're not ready.” Though born, raised, and educated in South Africa, the capricious absence of a job took him to Oxford in 1952, where he received a PhD in Physical Chemistry in 1954. But the milestone event of his training was perhaps the April 1953 drive he made to the Cavendish Laboratory in Cambridge, England to see first-hand the new Watson and Crick model for the structure of DNA. In his own words, “This was it … the curtain had been lifted and everything was now clear as to what to do.” With research in his blood, he moved back to the Department of Physiology in the Medical School in South Africa in 1954, where he began work on a bacteriophage system, which might be useful in cracking the genetic code. Solid progress led Brenner back to the MRC Laboratory of Molecular Biology (previously the Cavendish Laboratory) in 1956, where he joined the unit for Molecular Structure and was director from 1979 to 1986. This transitional move landed him in the emerging epicenter of molecular biology. As luck would have it, he wound up sharing an office with Francis Crick (for 20 years), where an earthly form of the Vulcan mind meld would allow them to conceptualize how information stored in DNA is transformed and ultimately translated into proteins. This work propelled Sydney into a role as one of the most influential scientists of our era.
While Crick was a theoretician, Sydney was an experimentalist whose skills were further honed by work with François Jacob and Matt Meselson. By focusing on bacteriophage as a model and by working with acridine dye–induced mutations, Brenner developed the concept of frame-shift mutations. This, in turn, provided the genetic proof of a triplet code. Subsequent work on induced protein chain termination mutations allowed him to use the same technology to establish collinearity of the gene with the growing polypeptide chain as well as establishing messenger RNA as the mediator. Not done yet, mutations outside of the coding sequence led to the discovery of “stop codons.” The resulting interlocking concepts represent an enormous advance and, for me, are my favorite discoveries from the entire Brenner opus.
By establishing the flow of genetic information from the DNA template to an RNA intermediate and via the triplet code from mRNA to protein, Brenner confirmed Francis Crick's “Central Dogma,” DNA→RNA→Protein.
In 1962, Brenner expanded his interests beyond genetic coding to consider the larger problem of organismal development with a focus on the nervous system. This fit well into his earlier medical training in anatomy, physiology, and cell–cell communication. He chose as his model the translucent nematode, C. elegans, whose simple brain is comprised of only 302 neurons. Using genetic dissection as a molecular scalpel, Brenner and his colleagues, in particular John Sulston and Robert Horvitz, not only produced a complete blueprint of the nervous system but went on to discover novel developmental mechanisms such as programmed cell death. This opened new frontiers in understanding animal development and was recognized by the 2002 Nobel Prize in Physiology and Medicine. In addition to the Nobel Prize, Sydney received numerous other awards including the Albert Lasker Awards for Special Achievement in Science and Basic Medical Research, and the King Faisal International Prize for Science, Krebs Medal, Royal and Copley Medals of the Royal Society, Harvey Prize, Kyoto Prize, and Gairdner Foundation International Award. He was also a member of the Royal Society of London, foreign associate of the US National Academy of Sciences, fellow of the American Association for Cancer Research, and foreign member of the Academy of Science, Paris, and fellow of the American Association for Cancer Research Academy.
In the mid-nineties, Francis Crick convinced Sydney to join the Salk faculty, reuniting the dynamic duo as perhaps the most interesting colleague one could wish for. Scientific royalty was in our midst, and they loved to hold court. While I stored Sydney's celebratory bottle for all these years, we never got to share it—so we will open it in his honor at our next annual Sydney Brenner lecture. In the meantime, let's all raise a glass to Sydney.
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