Nobel laureate Sydney Brenner, who escaped poverty in his native South Africa to become one of the heroes of molecular biology’s golden age and, with the help of a translucent soil worm, provided vital clues to understanding diseases such as cancer, Alzheimer’s and AIDS, died April 5 in Singapore, where he had helped develop scientific institutes. He was 92.
His death was announced by the Agency for Science, Technology and Research in Singapore. The cause was not immediately known.
Dr. Brenner was a critical player in the decades of discovery propelled by James Watson and Francis Crick’s solving of the DNA structure in 1953. His insights were essential to developing what is now known as the “central dogma” of biology: the idea that our DNA code instructs the building of proteins that sustain life in our cells.
His scientific home for nearly four decades was the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, where for years he shared an office with Crick. They kept a sign on the wall pronouncing that “Reading Rots the Mind,” which belied, in the trademark irreverence of both scientists, their dazzling work in pushing the frontiers of their profession.
(In later years, Dr. Brenner submitted a manuscript to the Royal Society in London with a fake reference — “Leonardo da Vinci (personal communication)” — tucked in the text.)
In an address bestowing on him the prestigious Lasker Award for medical science — Dr. Brenner’s second — Nobelist Joseph Goldstein described him as “chutzpah” personified. Dr. Brenner’s biographer, Errol Friedberg, noted that his disdain toward rules made him the “scourge of universities and institution administrators.”
Any conflicts tended to be overshadowed by the major advances Dr. Brenner made in molecular biology. At the Cambridge lab in the late 1960s, he undertook an ambitious search for a model organism to study complex animal development on a genetic level — uncharted territory at the time.
He found his match in Caenorhabditis elegans, a millimeter-long, transparent roundworm that would lead him to the 2002 Nobel Prize in physiology or medicine for “seminal discoveries concerning the genetic regulation of organ development and programmed cell death,” which “have shed new light on the pathogenesis of many diseases.”
Dr. Brenner, then affiliated with the Molecular Sciences Institute in Berkeley, Calif., shared the honor with John E. Sulston of the Wellcome Trust Sanger Institute in Cambridge, England, and H. Robert Horvitz of the Massachusetts Institute of Technology.
With the three men as its champion, C. elegans pushed forward a new understanding of how our cells are programmed to proliferate, specialize and die. It became the first animal to have its complete genome sequenced — an important precedent for the Human Genome Project.
The humble worm’s DNA has turned out to be surprisingly similar to our own, helping us understand how our cells grow uncontrollably to cause cancer and why they die in excess in neurodegenerative disorders, heart attacks and AIDS.
Picking the right animal to work on in biology, Dr. Brenner saw, was as important as asking the right questions.
“Without doubt,” he remarked in his Nobel lecture, “the fourth winner of the Nobel Prize this year is Caenorhabditis elegans; it deserves all of the honor but, of course, it will not be able to share the monetary award.”
Sydney Brenner was born Jan. 13, 1927, in Germiston, South Africa, to Jewish emigre parents from Eastern Europe. His father, a cobbler, could neither read nor write, although he could speak English, Yiddish, Russian and, after moving to South Africa in 1910, Afrikaans and Zulu.
Young Sydney’s first home was in the back of his father’s shoe shop, two rooms he remembered smelling perpetually of leather. The public library became a haven, and it was there he found “The Science of Life,” the book that first turned him on to biology. Too poor to buy his own copy, he reported the book missing to the library instead and accepted a small fine.
Dr. Brenner entered medical school at the University of the Witwatersrand in Johannesburg at age 15. He did not like clinical practice, falling in love instead with the research lab.
In 1952, he won a scholarship to study with chemist and future Nobel laureate Cyril Hinshelwood at the University of Oxford in England. He received a doctorate in 1954.
In England, Dr. Brenner reunited with May Covitz Balkind, a fellow Witwatersrand student who had traveled to London to study psychology.
They were married from 1952 until her death in 2010. Survivors include three children and a stepson.
Under Hinshelwood, Dr. Brenner joined a burgeoning group of thinkers who were forming the new field of molecular biology. On a cold morning in April 1953, he and three colleagues crammed into a car and drove to the Cavendish Laboratory in Cambridge, England, to see Watson and Crick’s model of the DNA double helix with their own eyes.
The moment was “the watershed in my scientific life,” Dr. Brenner wrote in his Nobel autobiography.
Dr. Brenner joined the Cavendish Lab in 1957 and, in a collaboration with Crick that year, they deduced that DNA was read as a triplet code, with each unit of three bases (named A, T, C, or G) corresponding to one of 20 protein building blocks. The lab formally merged later with biology groups at the university to become the Medical Research Council Laboratory of Molecular Biology.
With future Nobel laureate François Jacob at the Pasteur Institute and Matthew Meselson at Harvard, Dr. Brenner proved in 1961 the existence of “messenger RNA.” The molecule, they found, is a key intermediary between DNA and protein — a translated version of the genetic code that is sent out to direct synthesis in the cell’s protein-making factories.
Dr. Brenner’s greatest skills, as he described in his 2001 memoir, “My Life in Science,” were in “getting things started.” For him, the fun of science was in “the opening game.”
And so with a basic understanding of DNA worked out by the late 1960s, he turned his sights toward a new project: studying the development, especially the brains, of higher organisms.
After abandoning more exotic animal models, Dr. Brenner looked to roundworms, recruiting his children and friends to collect soil from their backyards and on holidays abroad. He settled upon C. elegans: a fast-growing, self-fertilizing, transparent creature with a simple nervous system that could be seen under an electron microscope.
Dr. Brenner’s team mapped the entire cellular anatomy of the worm’s brain and spinal cord, from tip to tail. Worms with strange morphologies or behaviors, such as abnormal locomotion or feeding, were of special interest. From these specimens, Dr. Brenner worked backward to figure out which faulty neurons might cause the behavior, and then which genes in those neurons had been mutated.
Sulston, advised by Dr. Brenner in Cambridge, developed techniques to trace all of C. elegans’s cell divisions from the fertilized egg to the 959-cell adult. The feat has yet to be repeated in another organism. Horvitz, also a researcher on Dr. Brenner’s team, went on to identify key C. elegans genes involved in controlling cell death.
In addition to his work in research, Dr. Brenner held leadership positions at the Medical Research Council in Cambridge.
In 1996, he founded the Molecular Sciences Institute in Berkeley. He remained director there until 2001, when he joined the Salk Institute for Biological Studies in San Diego. His old friend Crick, who died in 2004, was also working at the Salk Institute.
Dr. Brenner also helped launch the Institute of Molecular and Cell Biology in Singapore, where he became an honorary citizen.
In the 1990s, Dr. Brenner wrote a column in the journal Current Biology called “Loose Ends” (later renamed “False Starts”). The most popular of his pieces were his “Uncle Syd” columns, a series of letters to his imaginary advisee, “Dear Willie,” with practical-joke ideas and career tips for the young scientist as he rose from graduate student to retired professor.
To busy scientists seeking a polite way to turn down time-consuming invitations to meetings, he suggested the following reply: “Dear X, I regret I am unable to accept your invitation as I find I cannot attend your meeting. Yours sincerely.”
Colleagues lauded him as “the funniest scientist who ever lived,” a title Dr. Brenner much preferred to “the father of the worm.” Behind the wisecracking exterior was a scientist who believed fervently in solving problems but who knew when to move on from a conundrum and leave it for younger minds to fiddle with.
“I’m a strong believer that ignorance is important in science,” he told the New York Times in 2000. “If you know too much, you start seeing why things won’t work. That’s why it’s important to change your field to collect more ignorance.”