A curious boy in Boston and Washington
Walter Gilbert was born on March 21, 1932, in Boston, Massachusetts, into a Jewish family. His father, Richard V. Gilbert, was an economist then at Harvard University; his mother, Emma Cohen, was a child psychologist who, as he later recalled with amusement, practised giving intelligence tests on him and his younger sister. She taught the two children at home for their first few years, and they raided the adult shelves of the public library for things to read.
In 1939 the family moved to Washington, D.C., where his father went on to work in the New Deal administration and, during the Second World War, at the Office of Price Administration; later he headed a planning group advising the government of Pakistan. Walter went to public schools in Washington and then to Sidwell Friends School. As a boy he belonged to a mineralogical society and an astronomical society. In his last year of high school, 1949, he was so taken with nuclear physics that he skipped school for long stretches to sit in the Library of Congress reading about Van de Graaff generators and simple atom smashers. In Washington the family also became friends with the radical journalist I. F. Stone, and Walter met Stone’s eldest daughter, Celia, when they were both eight.
A theoretical physicist
Gilbert went to Harvard, majoring in chemistry and physics, and graduated in 1953, adding a master’s degree in physics in 1954. That same year, at 21, he married Celia Stone, who became a poet; they have two children, John and Kate. For his doctorate he went to the University of Cambridge, where he studied the theory of elementary particles under Abdus Salam, a future Nobel laureate, and received his PhD in 1957. At Cambridge he also met a young American biologist named James Watson, who a few years earlier had helped discover the double helix structure of DNA.
Back at Harvard, Gilbert spent a postdoctoral year, worked as an assistant to the physicist Julian Schwinger, and in 1959 became an assistant professor of physics. For several years he taught a wide range of theoretical physics courses and supervised students working on the mathematics of particle scattering. But, as he later wrote, his interests gradually shifted from the mathematical formulations of theoretical physics to an experimental field.
Into biology: messenger RNA and the first gene switch
The turn came in the summer of 1960, when Watson, by then at Harvard, told him about an experiment he and François Gros were running to find messenger RNA, the short-lived copy of a gene that carries instructions from DNA to the ribosomes, the cell’s protein factories. Gilbert joined in for the summer and found the laboratory work so exciting that he never really went back. He went on to show that a single messenger molecule can serve many ribosomes at once, and that a growing protein chain stays attached to a transfer RNA molecule as it is built, a key step in understanding how cells make proteins. For most of the 1960s he and Watson ran a laboratory together. Harvard made him associate professor of biophysics in 1964 and professor of biochemistry in 1968.
In the mid-1960s Gilbert and his student Benno Müller-Hill achieved something many thought impossible. The French scientists François Jacob and Jacques Monod had predicted that bacteria use special proteins, called repressors, to switch genes off when their products are not needed, but no one had ever isolated one, because cells make them in tiny amounts. Gilbert and Müller-Hill identified and purified the lactose repressor of the bacterium E. coli, reporting it in 1966: the first gene control protein ever isolated. They later bred bacterial strains that made thousands of times more of it, and in the early 1970s Gilbert isolated the stretch of DNA the repressor binds to. It was a concrete demonstration of how genes are turned on and off, the basic logic behind development, health and disease in every living thing.
Reading the letters of DNA
In the mid-1970s Gilbert and his graduate student Allan Maxam developed a fast chemical method of DNA sequencing, published in 1977. The method takes a piece of DNA labelled at one end, uses four chemical reactions that each break the molecule next to one or two particular bases, and then sorts the fragments by size on a gel. Reading the ladder of fragments from bottom to top spells out the sequence of letters. Before this, determining even a short stretch of DNA sequence was painfully slow work.
At almost the same time, Frederick Sanger in Cambridge developed a different method based on copying DNA. Together, the two techniques launched the era in which scientists could read genes directly. For their contributions to determining the base sequences of nucleic acids, Gilbert and Sanger shared half of the 1980 Nobel Prize in Chemistry; the other half went to Paul Berg for work on recombinant DNA. Sanger’s approach eventually proved easier to automate and became the standard, but the Maxam–Gilbert method was the first to be widely adopted, and in 2017 the American Chemical Society honoured the 1977 paper as a chemical breakthrough. The ability to read DNA that both men pioneered now underlies genetic diagnosis, cancer genome testing, forensic science and the rapid identification of new viruses.
Genes in pieces and the origins of life
Gilbert also shaped how biologists think. When researchers discovered in 1977 that the genes of animals and plants are split, with coding segments interrupted by long stretches that are cut out of the messenger RNA, Gilbert coined the words that are now in every biology textbook: “exons” for the parts that are expressed and “introns” for the intervening regions. In a 1978 essay in Nature titled “Why genes in pieces?” he suggested that split genes might speed up evolution by letting cells shuffle useful building blocks into new combinations.
In 1986 he gave a name to another big idea, the “RNA world”, the hypothesis that early life relied on RNA molecules that could both carry genetic information and act as enzymes, before DNA and proteins took over those jobs. The idea had earlier roots, notably in the work of Carl Woese, but Gilbert’s short paper made the phrase famous, and it remains a leading framework for research into the origin of life. He also helped develop practical tools of genetic engineering, showing in the 1970s that blunt-ended DNA fragments could be joined efficiently, and in the late 1970s, with Lydia Villa-Komaroff and Argiris Efstratiadis, he worked on bacteria that produced the mammalian hormone insulin.
Biotechnology: from the laboratory to medicines
In 1978 Gilbert joined Kenneth Murray, Phillip Sharp, Charles Weissmann, Heinz Schaller and others in founding Biogen, one of the first biotechnology companies. He took leave from Harvard and served as its chief executive in the early 1980s, building a research network in Europe and the United States and taking the company public in 1983. Biogen’s two early successes came from its founding scientists’ work: a genetically engineered alpha interferon, licensed to Schering-Plough and sold as Intron A for conditions including hepatitis B, hepatitis C and certain cancers, and genetically engineered hepatitis B antigens that were used in vaccines given to millions of infants. In 1998 the company received the National Medal of Technology, in particular for its role in developing hepatitis B vaccines, the first vaccines made with recombinant DNA.
Gilbert’s time as a business leader was not easy. Biogen lost heavily in the mid-1980s, critics said he lacked business skills, and the board replaced him as chief executive; he returned to Harvard in 1985. But his strategy of licensing the company’s inventions kept it alive, and Biogen went on to develop Avonex, approved in 1996, one of the first treatments shown to slow disability in multiple sclerosis. Gilbert later co-founded Myriad Genetics and in 1996 Paratek Pharmaceuticals, which works on new antibiotics, and served as an adviser and board member to many young companies.
Championing the human genome
Gilbert was one of the earliest and loudest voices for reading the entire human genome. At a planning meeting in Santa Fe, New Mexico, in March 1986, he made the case that the complete human DNA sequence should be the central goal of human genetics, at a time when many scientists thought the project too costly, too dull or simply impossible. In 1987 he proposed a company, Genome Corporation, to sequence the genome and sell access to the data, an idea that alarmed colleagues who wanted the information to be free; the company never got off the ground.
In a 1991 opinion piece in Nature he predicted, correctly, that a finished genome sequence would turn biology into a science in which computer databases were as essential as laboratory chemicals. The publicly funded Human Genome Project, launched in 1990 and completed in 2003, made the sequence freely available to every researcher in the world. It is now the reference used to diagnose inherited diseases, match cancer patients to targeted drugs and study human evolution.
Jewish roots, character and controversy
Gilbert was born into a Jewish family; his mother was born Emma Cohen, and his wife Celia is the daughter of I. F. Stone, the celebrated Jewish American journalist. He has not written publicly about religious practice, and his own short autobiography for the Nobel Foundation speaks of family, books and science rather than faith. He is counted among Jewish Nobel laureates in chemistry by reference lists of Jewish laureates.
Colleagues describe a combative, fast-thinking scientist who relished argument. He was an outspoken critic in the long dispute over fraud allegations involving a paper co-authored by David Baltimore, and he chaired Harvard’s Society of Fellows. In the late 1980s he also joined the early controversy over the cause of AIDS, saying publicly that it had not been proven that HIV caused the disease, a view that was widely criticised; in later years he said that the success of antiviral drugs had changed his assessment.
Later years and legacy
Gilbert retired from teaching at Harvard in 2001 and began a second career as an artist, working mainly in digital photography and combining art with science. He was elected a Foreign Member of the Royal Society in 1987 and has sat on the Board of Scientific Governors of the Scripps Research Institute.
His legacy runs through almost every corner of modern biology. He helped prove how genes are switched on and off, co-invented one of the first practical ways to read DNA, gave biologists the words exon, intron and RNA world, helped turn genetic engineering into an industry that makes vaccines and medicines, and argued early and hard for the human genome sequence that doctors and scientists everywhere now rely on.
Sources & further reading
Walter Gilbert, Biographical, NobelPrize.org · Press release: The Nobel Prize in Chemistry 1980, NobelPrize.org · Biogen Inc. company history, Reference for Business · Biogen, Wikipedia · Walter Gilbert, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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