A curious boy from Perth Amboy
Stanley Norman Cohen was born on 17 February 1935 in Perth Amboy, New Jersey, the son of Bernard and Ida (Stolz) Cohen. He is sometimes confused with Stanley Cohen the biochemist, who shared the 1986 Nobel Prize for discovering nerve growth factor; the two are different men. This Stanley Cohen grew up in a Jewish family in a small industrial city on Raritan Bay, and the papers he later gave to the National Library of Medicine preserve, alongside his high-school yearbook, a programme from the second national convention of United Synagogue Youth, the Conservative movement’s youth organisation, in 1952.
He was a restless, many-sided teenager. According to the library’s biographical note, he was a successful debater, played the banjo and ukulele, and even published popular songs. At Rutgers University, where he graduated in 1956, he first intended to become a physicist before turning to medicine. He earned his M.D. at the University of Pennsylvania in 1960.
From the clinic to the laboratory
Cohen spent the next several years in clinical training, internships and fellowships at Mount Sinai Hospital in New York, University Hospital in Ann Arbor and Duke University Hospital, and at the National Institute of Arthritis and Metabolic Diseases, where he decided to combine patient care with basic research. As a postdoctoral researcher at the Albert Einstein College of Medicine in New York he studied how genes are switched on and off in the bacterial virus lambda.
In 1968 he joined the faculty of Stanford University’s School of Medicine. There he took up a problem with obvious medical urgency: antibiotic resistance. Bacteria often carry their resistance genes on plasmids, small, self-copying circles of DNA that live alongside the main chromosome and can pass from one bacterium to another. To understand how plasmids worked, Cohen needed a way to take them apart, put them back together and grow them in living cells. In 1972 his laboratory found a simple method, treating the bacterium E. coli with calcium chloride, that allowed the cells to take up plasmid DNA and pass it on to their offspring.
Working with Norman Davidson and Phillip Sharp at Caltech, Cohen’s group used electron microscopy to map the structure of resistance plasmids, showing how separate segments of DNA combined to form the plasmids that carried drug resistance. Early attempts to study the pieces were frustrating: the only way to break plasmids apart was to shear them mechanically, which produced random fragments that were of little use. What he needed was a way to cut DNA precisely.
Sandwiches in Honolulu
In November 1972 Cohen travelled to Hawaii for a U.S.–Japan meeting on plasmids. Also presenting was Herbert Boyer of the University of California, San Francisco, whose laboratory had been studying a restriction enzyme called EcoRI. Boyer showed that EcoRI cut DNA at a specific sequence and left short, single-stranded “sticky ends” so that any two pieces cut by the same enzyme could stick together. Cohen described his method for getting plasmids into bacteria and cloning them.
Late one night, over sandwiches, a scene that has become one of the founding legends of biotechnology, the two men realised that their techniques fit together like halves of a key. With Boyer’s enzyme they could cut and splice DNA precisely; with Cohen’s plasmids and transformation method they could put the result into bacteria and let the bacteria copy it. They agreed to collaborate.
The experiment that changed biology
The work moved back and forth along the highway between Stanford and San Francisco. Cohen’s team, including Annie Chang, isolated plasmids and sent them to Boyer and Robert Helling, who cut them with EcoRI; the fragments came back to Stanford to be joined and introduced into E. coli. The key vehicle was one of Cohen’s plasmids, pSC101, which EcoRI cut at only one site and which carried a gene for resistance to tetracycline. Bacteria that took up a recombinant plasmid could be picked out simply by growing them on tetracycline. In the spring of 1973 the first experiments succeeded, and in November the four scientists published “Construction of biologically functional bacterial plasmids in vitro” in the Proceedings of the National Academy of Sciences.
They quickly pushed further. They joined DNA from a Staphylococcus plasmid to an E. coli plasmid and showed that it was copied in E. coli, proof that genes could cross the boundary between species. Then, in work published in 1974 with John Morrow and others, they inserted genes from the African clawed frog, Xenopus laevis, into bacteria, which faithfully replicated the animal DNA. The long-held assumption that genes were locked within their species had been broken. Molecular biologists now had a way to isolate, copy and study any gene, the technique soon known simply as DNA cloning.
Promise and alarm
The power of the new technique alarmed scientists as much as it excited them. Cohen was among the signatories of the 1974 “Berg letter” which called for a voluntary pause on certain kinds of recombinant DNA experiments until their risks could be assessed, and he took part in the 1975 Asilomar conference that drew up the first safety guidelines. As the debate moved into government, he became a prominent voice arguing that the hazards had been overstated and that containment rules for low-risk experiments should be relaxed, warning against heavy regulation of basic science.
Recombinant DNA had become a public controversy. The city of Cambridge, Massachusetts, debated banning the research; Congress considered legislation. In 1976 the National Institutes of Health issued formal guidelines, overseen by a new Recombinant DNA Advisory Committee, and over the following years many of the strictest containment requirements were relaxed as experience showed the feared dangers had not materialised. Cohen’s position, that the risks of most experiments were small and the potential benefits enormous, was largely borne out.
Cohen and Boyer had not initially thought of patenting their work. Encouraged by Stanford’s technology-licensing office, they filed a patent application in 1974, administered by Stanford on behalf of both universities. Three patents were granted, in 1980, 1984 and 1988, and they were licensed non-exclusively at modest fees to hundreds of companies. The Cohen–Boyer patents became among the most lucrative in university history and helped persuade universities worldwide to take the commercial value of their scientists’ discoveries seriously.
Birth of an industry
In 1976 Boyer co-founded Genentech with the venture capitalist Robert Swanson to use recombinant DNA to make human proteins. Cohen, who consulted for the rival company Cetus, chose to remain an academic. Within a few years Genentech had coaxed bacteria into producing the human hormone somatostatin and then human insulin; in 1982 recombinant insulin, made under license by Eli Lilly, became the first genetically engineered drug approved by the U.S. Food and Drug Administration.
The products that followed have touched hundreds of millions of lives: insulin for diabetics, human growth hormone, clotting factors for haemophilia, the hepatitis B vaccine, drugs for cancer and immune disorders, and the enzymes, crops and diagnostic tests of agricultural and industrial biotechnology. The modern understanding of human genes, from the Human Genome Project to genetic medicine, rests on the ability to clone DNA that Cohen and Boyer first demonstrated. As the immunologist Hugh McDevitt put it, Cohen’s cloning technology has helped biologists in virtually every field.
A life at Stanford
Cohen has spent his entire independent career at Stanford, becoming professor of medicine in 1975 and of genetics in 1977, chairing the department of genetics from 1978 to 1986, and holding the Kwoh-Ting Li professorship since 1993. He returned to the questions that had started him off, how plasmids are inherited and evolve, and how bacteria share genes for antibiotic resistance, and developed methods for following gene activity in animal cells. In later years his laboratory turned to the molecular basis of degenerative neurological diseases.
His honours include election to the National Academy of Sciences in 1979, the Albert Lasker Basic Medical Research Award in 1980, the Wolf Prize in Medicine in 1981, the National Medal of Science in 1988 and the National Medal of Technology, shared with Boyer, in 1989. He and Boyer also shared the Lemelson–MIT Prize in 1996, the Albany Medical Center Prize and the Shaw Prize in 2004, and he was inducted into the National Inventors Hall of Fame in 2001.
In later decades Cohen continued to publish on plasmid biology, on mobile genetic elements such as transposons that can “jump” between bacterial strains, and on how cells control the decay of messenger RNA. He also developed techniques that use “reporter genes” to track gene activity in animal cells. His papers, spanning nearly seventy years from his schooldays to 2016, are preserved at the National Library of Medicine. He was elected to the American Philosophical Society in 2006, received the Double Helix Medal in 2009, and in 2016 was given the Biotechnology Heritage Award.
Legacy
Unlike many scientific revolutions, the one Cohen helped start can be dated almost to the month: before 1973, there was no practical way to move a specific gene from one organism into another and make copies of it; afterwards, there was. Nearly every biology laboratory in the world now uses the basic tools he and Boyer assembled, often without a second thought.
Cohen has always emphasised that the discovery came from curiosity rather than a commercial plan, from wanting to understand how bacteria resist antibiotics. That a question about plasmids, pursued for its own sake, ended up creating an industry and transforming medicine is perhaps the strongest argument there is for basic science.
Sources & further reading
Stanley Norman Cohen, Wikipedia · Herbert W. Boyer and Stanley N. Cohen, Science History Institute · Stanley N. Cohen Papers, biographical note, National Library of Medicine · Stanley N. Cohen, National Inventors Hall of Fame · Researched from the sources above and checked against them. Spotted an error? Tell us.
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