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First Base 

By Kevin Davies

Kevin Davies, Ph.D.Editor-in-ChiefDecember 15, 2002 | There are some years when the announcement of the Nobel Prize is tainted by controversy surrounding some aggrieved scientist who feels he (it's usually a "he") was denied due recognition. This year, however, the committee got it right by finally awarding a share of the physiology or medicine prize to Sydney Brenner, at the tender age of 75. Since bursting onto the scientific stage almost half a century ago, Brenner has repeatedly stamped his indelible mark on biology with his visionary brilliance. In this high-throughput, post-genomic era of Big Science, we may never see his like again.

The son of Lithuanian immigrants, Brenner left his native South Africa to study at Oxford in 1952. A few months later, he was driving to Cambridge for a viewing of Francis Crick and Jim Watson's hallowed model of the double helix — the greatest day of his life (at least until the Nobel ceremony this month).

A self-proclaimed "failed thoracic surgeon," Brenner spent the '50s hanging around with a "radical evangelical sect" of physicists, led by Crick, with whom he shared both an office for 20 years and several epic discoveries. One of these discoveries was the veritable "eureka moment" in Brenner's rooms at King's College, Cambridge, England, on Good Friday, 1960, when with a yelp he conceived the existence of messenger RNA. The following year, Nature published a breathtaking report from Brenner, Crick, and others, proving that the bacterial genetic code was read in triplets — a paper considered by many to be the most elegant biological experiment of the 20th century.

For these achievements (and others), Brenner was feted with two Lasker Awards (in 1971 and 2000) but shut out from Nobel consideration in the 1960s because of the arbitrary limit of three recipients per prize. It is for what Brenner did next that he finally wins the prize — establishing the little-known nematode Caenorhabditis elegans as one of the premier models of animal development.

This microscopic worm has revolutionized scientific understanding of neurobiology, Alzheimer's disease, cell death, and many other fields, and it was the first multicellular organism to have its genome sequenced by a team lead by Brenner's protégé, John Sulston. Brenner chose Caenorhabditis after carefully considering — and rejecting — a menagerie of other candidates, eventually opting for the sinewy C. elegans over its cousin, C. briggsae, because, he says, it was the more photogenic (sliced under the electron microscope).

Genome Delicacies 
As J. Craig Venter readily acknowledges in Part II of our exclusive interview, Brenner was an early advocate of sequencing cDNAs in the mid-1980s (as an alternative to wasting years sequencing "junk DNA"), a strategy that Venter exploited and transformed into a slick industrial operation. "Sequencing large genomes has nothing to do with any intellectual endeavor," Brenner insists. "The creative work was done earlier by Fred Sanger and by others who improved the technology. The rest is about two things: money and management."

Interestingly, Brenner declines to join the chorus of criticism of Venter, whom he considers "more Faust than Mephistopheles" — someone who accepted the restrictions dictated by commercial organizations in return for the unparalleled investment of resources that he could not find in the public domain. (Venter says as much in our interview.)

A few years ago, Brenner took issue with those in silico sycophants who "believe that computers can extract biological significance directly from DNA sequences. This approach has generated two new areas of activity. One — bioinformatics — is simply pretentious; the other —

Communism and biochemistry were two disciplines that disappeared in 1990, but only one is worth bringing back. 
functional genomics — is ridiculous. ... There is already a perfectly good name for the science of studying gene function; it used to be called genetics." A key limitation of sequence data is that the switching information that dictates the precise timing, location, and duration of gene expression — Brenner dubs this the "left-hand value" of the gene by analogy with the address of a computer location — cannot be deduced from DNA sequence alone. The value of traditional wet-lab experimentation is a pet theme of Brenner's, who is fond of saying that communism and biochemistry were two disciplines that disappeared in 1990, but only one is worth bringing back.

Brenner has steadfastly maintained the need to look beyond mere genome sequence analysis. To wit: "Many people and many computers will play games with these [genome] sequences, but we will have to find out by experiment what the sequences do and how the products they make participate in the physiology and development of the organism. ... We must understand what cells can do because all of what we are is generated by cells growing, moving, and differentiating." These words, quite remarkably, were written almost a quarter of a century ago, yet read like a manifesto of what we hail as systems biology.

Brenner was one of the first to appreciate the importance of computers in biology, specifically to help log the reconstruction of the nematode's nervous system, even as most of his colleagues sneeringly suspected that anybody interested in computing was choosing "an easy way out of a responsible job." Brenner taught himself computer programming, which in turn inspired a view of complex biological systems that culminated with his creation of the Molecular Sciences Institute in Berkeley, Calif., some 25 years later.

By contrast, Brenner takes a dim view of the necessary level of mathematical training required by biologists. All that was required, he told a British parliamentary committee, was "the ability to count to 20 — that's all — there are 4 bases and 20 amino acids," although he did concede that, "you might have to go to 64 at some stage" (representing the total number of triplet sequences or codons — a term Brenner coined — in the genetic code).

Brenner remains an inspiring intellectual force in the community. Last August he served up another delicacy as senior author on the Science publication detailing the sequencing of the pufferfish genome, a favorite among geneticists because of the genome's highly compact nature. He is also principal scientific advisor to Lynx Therapeutics Inc.

Undoubtedly one of the smartest, Brenner is also one of the funniest scientists who has ever lived. His endless supply of anecdotes can be found in his frequent columns — often signed "Uncle Syd" — for Current Biology and, lately, The Scientist, as well as a memoir published last year called My Life in Science. He once buried a reference in the middle of an otherwise erudite manuscript submitted to the Royal Society of London that read: "Leonardo da Vinci (personal communication)." When the journal's editor complained, he argued that this was simply a new Italian postdoc in the lab.

In presenting Brenner with his lifetime achievement Lasker Award two years ago, the Nobel laureate Joseph Goldstein quipped that some of Brenner's ingenious proposals to explain the workings of nature "were more rational than the actual scheme that God chose. ... If Sydney had shared an office with God during the Creation, the Universe would be a much more rational place."

Kevin Davies, Ph.D.
Bio·IT World 

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