Biologist, Nobel winner helped crack genetic code
Sydney Brenner, a multitalented biological-research giant who helped decipher the genetic code, discover how its information is put to use and lay the groundwork for DNA sequencing technology, died Friday. He was 92.
Brenner was also famed for research on a tiny worm, Caenorhabditis elegans, which became a model organism for studying animal life. Many of its genes turned out to have human equivalents, leading to insights into human biology.
For the C. elegans research, Brenner, John Sulston and Robert Horvitz shared the 2002 Nobel Prize in physiology and medicine. It also earned Brenner an informal title he didn’t much care for: “father of the worm.”
Brenner’s seven-decade career spanned the globe, and he was active in science until the end. He spent the last part of his life in Singapore, where he advised that country on its biotechnology policy.
The South African native also performed research in the United Kingdom and in San Diego, where he served on the faculty of the Salk Institute and Scripps Research. Brenner’s research led to the formation of several companies, including
the San Diego biotech CombiChem.
“He was one of the most important figures in molecular biology for the last 50 years,” said genome expert J. Craig Venter, who knew Brenner for decades. “There wasn’t a major breakthrough in the early days that he didn’t play some role in. He was a walking history of the whole field.”
Venter said that while the worm research was significant, it was far from Brenner’s most important contribution to science.
He said Brenner’s work on the genetic code was fundamental. He teamed up with scientists led by Francis Crick, who with James Watson discovered the double-helix structure of DNA.
In a 1961 paper, the team outlined the “triplet” code by which DNA spells out the instructions for proteins. A sequence of three DNA letters specifies one of 20 amino acids, the building blocks of proteins, along with a “stop” sequence signaling that the protein is complete.
Certain three-letter sequences are redundant, spelling out the same amino acid. Scientists at Scripps Research led by Peter Schultz took advantage of that redundancy to engineer bacteria that produce a 21st amino acid, giving it the power to make proteins not found in nature.
In related work, Brenner helped discover messenger RNA, the carrier molecule that copies the DNA code and carries it into the cell for protein synthesis. The discovery of the so-called mRNA led to development of “antisense” drugs by the Carlsbad firm Ionis Pharmaceuticals. The drugs intercept mRNA to block or alter protein production.
Later, Brenner’s discoveries became the basis for what is known as “next-generation sequencing,” which offered greatly improved speed over existing technologies. It combines reading multiple copies of DNA in parallel with repeated sequencing to reduce errors.
The technology was used in a company he co-founded, Lynx Therapeutics, which was acquired in 2005 by Solexa. In 2007, Illumina purchased Solexa, making its next-generation technology the core of its products.
Brenner joined the Salk Institute in 1976, and also served on the faculty of Scripps Research.
“We at Salk join countless other scientists and researchers around the world in mourning the passing of Sydney Brenner,” Salk President Rusty Gage said in a statement. “Along with raising the field of molecular biology to maturity, Sydney was a generous and dedicated mentor, colleague and friend. He was an inspiration to generations of scientists and he will be greatly missed.”
At Scripps Research, he collaborated extensively with Richard Lerner, its former president, and faculty member Kim Janda, among others. CombiChem, the San Diego biotech company, was founded by a team including Janda and Scripps Research colleagues Dale Boger and Chi-Huey Wong.
In 1992, Brenner and Lerner proposed a method in molecular synthesis that employed a “bar code” tag that precisely described the steps used to create each molecule.
The method married DNA with combinatorial chemistry, a way of rapidly making many kinds of molecules in vast quantities. The DNA, added step by step in the synthesis, served as the tag. So when scientists found a rare “hit” in a molecule, they didn’t have to figure out how it was produced.
That proposal was ahead of its time. But genetic technology has matured since then, partly due to Brenner’s work on DNA sequencing. This method of making “DNA-encoded libraries” is now used by drug companies as a way of cataloging the vast numbers of molecules they work with, so the rare “hits” can be easily replicated.
Everybody uses DNA-encoded libraries today,” Janda said. “And that’s something Sydney came up with.”
Born in Germiston, South Africa, in 1927, Brenner earned degrees in medicine and science in 1947 from Johannesburg’s University of Witwatersrand, the Salk Institute said in a biography. Brenner moved to Oxford University in 1952 to pursue his doctorate in physical chemistry.
While at Oxford he became engrossed in DNA and developmental genetics research. He joined the University of Cambridge in 1956 and shared an office with future Nobel Laureate Crick for nearly 20 years.
Brenner’s co-discovery of messenger RNA led to his first Lasker Award in Basic Medical Research; he later received a second Lasker Award in honor of his outstanding lifetime achievements.
“We all owe much to Sydney. With his passing we have lost a great scientist and a good friend,” said Salk professor Terrence Sejnowski.
Brenner is survived by daughters Belinda and Carla and son Stefan. His wife, May, died in 2010.