Albert Lasker Award
for Special Achievement in Medical Science

Groucho Marx may hold the distinction of being the funniest comedian who ever lived, but Sydney Brenner, this year's recipient of the Lasker Special Achievement Award, holds a loftier title—the funniest scientist who ever lived. Like Groucho, Sydney is famous for his flamboyant energy, his creative one-liners, and his insightful monologues on every subject imaginable—not to mention his bushy eyebrows. Fifty years ago, Groucho Marx taught Americans the meaning of the Yiddish word chutzpah when he refused membership in a Beverly Hills country club because he didn't care to join any club that would elect him as a member. Like Groucho Marx, Sydney Brenner is the personification of chutzpah.

What other scientist would have the chutzpah to present a lecture at Harvard wearing a splashy Hawaiian shirt?

What scientist would have the chutzpah to submit a manuscript to the Royal Society with a fake reference tucked away in the middle of the text, "Leonardo da Vinci (personal communication)"? And when called on the carpet by the editor, fired back that there's a new Italian postdoctoral fellow working in the lab.

What scientist would have the chutzpah to refuse a knighthood from the Queen of England? I doubt that even Groucho Marx would have the chutzpah to refuse the club at Buckingham Palace.

The mind boggles to realize that Sydney Brenner, the scientist, can outwit Groucho Marx. In describing Groucho Marx, Woody Allen said: "Groucho is simply unique in the same way Picasso and Stravinsky are, and I believe his outrageous disregard for order will be funny a thousand years from now."

Francis Crick describes Sydney Brenner in much the same way: "Sydney is unique, both in his characteristic sense of humor that colors his many unusual insights and in the breadth and importance of his biological discoveries. There is simply nobody else quite like him." This is high praise from the High Priest of Biology.

So who is Sydney Brenner and what are his scientific achievements that place him in the company of Picasso, Stravinsky, and Groucho Marx? It is intimidating to attempt to summarize in several minutes the 50-year career of a scientific giant like Sydney Brenner. It may not be possible, but let me try. This will be a real act of chutzpah on my part!

Like everything else about Sydney, his early life was unusual. He was born in 1927 in a small town outside of Johannesburg, South Africa—far removed from the academic centers of the world. His parents had emigrated to South Africa in 1910 from Latvia and Lithuania. His father was a shoemaker who worked every day until he was over 80. His father could neither read nor write, but he could speak multiple languages. Despite these humble beginnings, Sydney taught himself to read the newspaper by age three. By age four, he had become a voracious reader. By age six, he had discovered the adult section of the public library, where he read his first chemistry books. By age 10, he was doing chemistry experiments at home, extracting pigments from leaves and petals. His brilliance was obvious to everyone, and he soon won a scholarship to medical school at the University of Witwatersrand in Johannesburg, entering at the tender age of 14.

Histology was his favorite course, and he became fascinated with cells and chromosomes. While a medical student, he read every book he could find on cytogenetics and even built himself a centrifuge so that he could determine the chromosome number of Elephantulus—a tiny mouse-like shrew. Scientists typically learn science by working in the laboratories of scientists. But this was not Sydney's style: he taught himself science. Who else could possibly teach Sydney? Teaching himself science is a recurrent theme in Sydney's career, as you'll hear more about in a moment.

In order to graduate from medical school, students in Johannesburg had to pass an exam in which they had to correctly diagnose an unknown sick patient. In the last year of his six-year curriculum, Sydney was sent off to the bedside of a man with diabetic ketoacidosis and told to smell the patient's breath. When asked what he smelled, he replied "McClain's toothpaste!" He failed the exam and had to wait another year to graduate.

This delay worked to Sydney's advantage in several ways: first, he was only 20 years old, which was below the legal age to practice medicine in South Africa; and second, the extra year gave him the opportunity to continue his cytogenetic experiments and the leisure to read every biology book and journal that he could get his eyes on. He became wildly excited by papers from the U.S. and Europe describing how bacteriophages could be used to study genes. Sydney sensed the emergence of a new field—soon to be known as Molecular Biology, which was much more challenging to him than practicing medicine. But there was one major problem. Science in South Africa in the early 1950s was scientifically primitive: there were no Ph.D. programs for Sydney to enter. So in 1952, he left Johannesburg to take a graduate degree in biochemistry at Oxford.

Sydney's timing could not have been better. He arrived in Oxford a few months after Jim Watson had arrived in Cambridge. According to Watson, he and Sydney "added badly needed doses of genetic fresh air to the British biological world." When Sydney heard about the Double Helix, he rushed to Cambridge to see the newly constructed DNA model and to meet the pair of young geniuses who conceived it. At their first meeting, Francis Crick was greatly impressed with Sydney's quick analytic mind, and he set about to recruit him to the MRC Laboratory at Cambridge. When Sydney joined the MRC staff several years later, there was no space for his office so he moved in with Crick, a temporary arrangement that continued for the next 20 years, much to the benefit of the scientific world.

Between 1954 and 1966, Sydney emerged as one of the handful of heroes who presided over the golden age of molecular biology. With Crick, Sydney deduced the triplet nature of the genetic code and coined the term codon. On his own, he worked out the fundamental nature of mutations, showing that single base changes in DNA lead either to altered proteins or to the absence of proteins—the so-called frameshift, suppressor, and nonsense mutations. With François Jacob, he conceived the idea of messenger RNA, the transcript that conveys the genetic information in DNA to the protein synthesizing machinery of the cell, and he went on to perform ingenious experiments to prove its existence. The discovery of messenger RNA is one of the most thrilling pieces of detective work in the history of biology, involving a dramatic series of twists and turns. The action began at Oak Ridge, Tennessee; moved to the Pasteur Institute in Paris; then to Sydney Brenner's rooms at King's College; then to a party at the Golden Helix, Francis Crick's home in Cambridge; then to Matthew Meselson's laboratory at Caltech; and culminated in a "eureka moment" when Sydney and François Jacob were relaxing on the beach near Los Angeles. Out of the blue, Sydney sprang up from the sand and screamed out to Jacob: "It's the magnesium! It's the magnesium." For those interested in the unabridged version of this historical event, I refer you to Horace Freeland Judson's The Eighth Day of Creation and François Jacob's The Stature Within. For his pioneering work on the genetic code and the discovery of mRNA, Sydney received the Lasker Award for Basic Research in 1971.

In the mid-1960s, Sydney made the daring decision to launch a new program in developmental biology designed to learn how a multicellular animal develops from a single fertilized egg. His Grand Scheme was to find an animal in which he could trace the birth and death of every one of its cells. In typical Brennerian fashion, Sydney read extensively, taught himself zoology, tried many pilot experiments involving a multitude of different organisms, and finally settled on a tiny roundworm that lives in the soil called Caenorhabditis elegans, or C. elegans for short. He chose this particular worm because it was small, translucent, anatomically simple, and suitable for electron microscopy. It was also easy to cultivate in the laboratory and to manipulate genetically. Up to 100,000 worms can be grown in a single Petri dish the size of a silver dollar. Each parent worm gives rise to more than 250 progeny with a generation time of only 3.5 days, much shorter than that of the fruit fly. The appeal of C. elegans lies in its simplicity. Compared to a typical human who has more than a trillion cells, C. elegans has only 959 cells in its entire body. Yet, C. elegans has a range of differentiated cell types and does all the basic things that animals do—it moves, it eats, it defecates, and it has sex.

Once Sydney settled on C. elegans, it took about 10 years to prove to other scientists that useful biology would emerge. By 1974, Sydney had succeeded in isolating and mapping the chromosomal location of 300 mutations that altered the movement or the morphology of the worm. All of this initial work was done by Sydney himself, but he soon began to attract top-flight postdoctoral fellows from around the world. The field grew rapidly, from one scientist 30 years ago to over 2000 today, all of whom are descendants of Sydney—his students, his student's students, and even great grandstudents.

The development of C. elegans has been scrutinized to a degree unmatched by any other multicellular organism. Since 1974, more than 10,000 genetic variants of C. elegans have been produced in over 100 different laboratories throughout the world. It is the only animal in which the complete lineage and fate of every cell is known. C. elegans is the only animal in which the three-dimensional wiring diagram of the nervous system has been mapped at the electron microscopic level. In 1998, it became the first animal whose genome was sequenced. C. elegans has also proved to be a medical Rosetta Stone, providing clues to cancer, Alzheimer's disease, and diabetes.

Sydney's dream for the Grand Scheme has come true. The worm has achieved its place in history, along with the fruit fly and the mouse, as one of the three animal models that are revealing the basic principles of multicellular life.

Sydney's skills have not been limited to the laboratory. He is as shrewd a politician as he is a scientist. During the early hysteria of the recombinant DNA controversy, Sydney's was the sane voice that soothed the politicians and scientists who worried that the gene-transformed bacteria would escape from the labs and find their way into public places like Central Park. Sydney made the crucial suggestion to use enfeebled strains of bacteria that could not survive outside the lab. He became convinced that this approach would work after testing genetically crippled bacteria on himself. He drank a cocktail full of disabled bacteria and then measured how much of it came through his intestines. None survived. Now recall that in 1975 human experimentation with recombinant DNA was outlawed. Sydney obtained permission for his experiment by telling the British authorities that the enfeebled bacteria would be tested on "an upper primate." Now that's chutzpah !

Sydney Brenner is an indefatigable raconteur who is legendary for his trenchant wit and his marvelous impiety. When asked by the Educations Committee of the British Parliament how much mathematics do students need to learn to do biology, Sydney replied: "The ability to count to 20—that's all—there are 4 bases and 20 amino acids. You might have to go to 64 at some stage. There are 64 codons in the genetic code." Sydney has recently published a collection of his humorous views on biology in a book entitled "Loose Ends," which I recommend to everyone. It's loaded with delicious anecdotes.

After 50 years in science, Sydney remains as dynamic as ever. He recently invented an ingenious technique to clone DNA on the surface of microbeads sitting in a test tube. This is a far cry from the traditional method of cloning that involves growing bacteria in an incubator. The basic idea is take a complex mixture of DNA, such as all the genes in the brain, and cut it into one million different fragments. Each fragment is then copied 100,000 times and attached to a single microbead. The result is a library of 1 million microbeads, each one of which contains 100,000 copies of a unique piece of DNA. Since the entire library of 1 million microbeads is contained in one test tube, it can be rapidly probed and sequenced. And in true 21st century fashion, Sydney has started a biotech company (Lynx Therapeutics, Inc.) to bring his invention to the masses.

In the 20 years that Sydney shared an office with Francis Crick, they concocted ingenious schemes to explain the workings of nature. Some of their schemes were more rational than the actual scheme that God chose. The take-home lesson is clear: If Sydney had shared an office with God during the Creation, the Universe would be a much more rational place.