I was deeply disappointed by the obituaries in the mainstream and scientific press concerning Sydney Brenner, the Nobel laureate who died in April at the age of 92 in Singapore. They completely missed the point. Consequently, I feel compelled to pen a short eulogy to one of the greatest scientists who ever lived and with whom I had the honor to interact over many years.
Brenner’s pioneering use of the nematode Caenorhabditis elegans to understand biological functions (for which he ultimately won the Nobel Prize) was far from his most important scientific contribution. As recounted in The Eighth Day of Creation,1 Sydney, working with Francis Crick and others, made fundamental contributions to the development of the central dogma, postulating, and then demonstrating, the existence of mRNA, and identifying the triplet nature of the genetic code. The concept of mRNA, tRNA, and the translation of mRNA into protein is as important now as it was then; details of these processes are still being worked out.
As recombinant DNA methods became established in the mid-1970s, the safety issues of these new techniques were far from clear. The principal scientists in the business, including Sydney, met at the historic Asilomar Conference on Recombinant DNA (February 1975) to debate the issues and establish a framework of risk for different kinds of cloning experiments. Sydney’s clarity of thinking was fundamental in establishing this risk assessment and implementing it in the U.K.
I met Sydney on several occasions in the early 1980s when I worked at Celltech and later GlaxoSmithKline in the U.K. Conversations with Sydney and Peter Goodfellow persuaded me to go west in 1993 to San Diego and set up R&D at Sequana (one of the first genomics biotech companies). Sydney was based at the nearby Salk Institute and had an apartment in La Jolla by the ocean. We spent many hours talking over dinner about the development of genomics as a scientific endeavor.
I’d never met anyone with a brain database as big as Sydney’s and an operating system that allowed almost instant recall and interpretation of data. He also had a wicked sense of humor and an acerbic wit (see GEN, May 2019). I relish one comment he made when a leading scientist moved from one organization to a start-up biotech company: “Well, that should put the average IQ up at both places!”
Sydney was eminent without being pompous, and he could not abide scientists, laureates, or any others who were full of self-importance. He turned down a British knighthood (as you might expect), but he was a Companion of Honour (there are only 65 of them at any one time in the U.K.).
In the early 1990s, DNA sequencing was used to get a better understanding of the number of genes in the human genome. The cataloguing of mRNAs coding for all proteins was called expressed sequence tag (EST) sequencing. Sydney was a strong proponent of EST (popularized by Craig Venter).
Sydney’s ingenuity was also evident in developing the concepts of multiplex parallel sequencing. Sydney was a founder of Lynx Therapeutics, which was bought by Solexa (a British company that developed dye-based chain terminators) in 2005. Lynx deployed the concept of massively parallel signature sequencing, allowing the analysis of millions of individual DNA molecules in a single assay. Lynx’ Megaclone system pioneered the use of bead technology to capture and analyze these multiple DNA molecules. Together, Lynx and Solexa formed the basis of the next-generation sequencing platform acquired by Illumina in 2006. Given his many other accomplishments, it is easy to overlook Sydney’s fundamental role in the development of this transformational technology.
I remember fondly one particular conversation with Sydney, holding a glass of wine, watching the sun set over the Pacific Ocean after the draft human genome sequences had been published, he said that he was reading the human DNA sequence from the beginning of chromosome 1 all the way to the end of chromosome 23. At the time, I wasn’t sure that was true; in retrospect, I suspect it was. It sums up the man: he was so inquisitive about how the whole genome all fitted together. He recognized that the Fugu genome is eight times smaller than the human genome but has essentially the same number of genes—another genius insight.
So, how do you capture the essence of the man? Listen to the wit and humor in his voice, enjoy his anecdotes for people and places,2 and remember his scientific contributions. It’s not all about C. elegans. He helped shape today’s genetics and genomics through his pioneering work on transcription and translation. Fundamental, don’t you think?
1. Horace Freeland Judson, The Eighth Day of Creation (Cold Spring Harbor Lab Press) 1996
2. Sydney Brenner, Loose Ends. Current Biology (1994-2000).
Timothy J.R. Harris, PhD, is currently a venture partner at SV Health Investors and a consultant to various biotechnology companies. He is a founder and board member of Rheostat Therapeutics.