A naturalist from New York
Marshall Warren Nirenberg was born in New York City on April 10, 1927, into a Jewish family. His father, Harry Edward Nirenberg, was a shirtmaker; his mother was Minerva Nirenberg, née Bykowsky. He had a sister, Joan. When Marshall developed rheumatic fever as a boy, a serious and often heart-damaging illness in the years before antibiotics, his parents moved the family south to Orlando, Florida, in the hope that the warm, subtropical climate would help him recover.
Florida made him a naturalist. “Florida was a natural paradise in those days” he recalled in 1992. As a teenager he wandered its lakes and woods with notebooks, keeping careful records and sketches of plants, insects, spiders and birds. The National Library of Medicine, which holds his papers, traces his lifelong habit of keeping meticulous scientific diaries to those boyhood field notes.
From caddis flies to cancer cells
After finishing high school in 1945, Nirenberg enrolled at the University of Florida in Gainesville, earning a bachelor’s degree in zoology and chemistry in 1948. He returned for graduate work and in 1952 received a master’s degree in zoology with a thesis on the ecology and classification of caddis flies, small moth-like insects whose larvae live in streams.
His interests were already moving from whole organisms to the chemistry inside them. Late in 1952 he went to the University of Michigan in Ann Arbor, where he studied biological chemistry under James F. Hogg, and in 1957 he received his PhD with a dissertation on how tumour cells take up hexose sugars. That same year he moved to the National Institutes of Health (NIH) in Bethesda, Maryland, as an American Cancer Society postdoctoral fellow in the laboratory of DeWitt Stetten Jr. at what was then the National Institute of Arthritis and Metabolic Diseases. He joined the institute’s staff as a research biochemist in 1960. It was there, as a young and almost unknown scientist, that he set out to answer one of the largest questions in biology.
The problem of the code
By the late 1950s it was clear that DNA carried hereditary information and that its structure was a double helix. What nobody knew was how that information was turned into the proteins that do the work of living cells. DNA is written in an alphabet of four chemical letters; proteins are built from twenty amino acids. Somehow, through an intermediary of RNA, sequences of letters had to specify sequences of amino acids. Theorists including George Gamow and Francis Crick had argued that the code probably used “words” of three letters, which would give 64 possible combinations, but the actual dictionary was a complete blank.
In 1959 Nirenberg began working on the relationship between DNA, RNA and protein. He was soon joined by J. Heinrich Matthaei, a postdoctoral researcher from Bonn. Their approach was to build a cell-free system: they broke open Escherichia coli bacteria and kept the cytoplasm, with its ribosomes and enzymes, working in a test tube. They destroyed the bacteria’s own DNA with an enzyme, so that protein would be made only if they supplied a message themselves, and then fed the system synthetic RNA of known composition.
3 a.m., May 27, 1961
The key experiment used polyuridylic acid, or poly-U, an artificial RNA made of a single repeated letter, uracil, supplied by NIH colleagues Leon Heppel and Maxine Singer. In each test tube, one of the twenty amino acids was tagged with radioactive carbon and the other nineteen were left unlabelled; by changing which one was “hot” the scientists could see which amino acid the message caused to be built into protein. At three o’clock in the morning on May 27, 1961, Matthaei ran the test with radioactive phenylalanine. The control tube without poly-U showed a background of about 70 counts; the tube with poly-U showed some 38,000 counts per milligram of protein. A string of uracils had made a chain of phenylalanine. The first word of the genetic code, now written UUU, had been read.
In August 1961 Nirenberg, then thirty-four and little known, presented the result at the International Congress of Biochemistry in Moscow, at first to a small session. The biologist Matthew Meselson, who was in the audience, told Francis Crick, and Crick arranged for Nirenberg to give the talk again to an audience of about a thousand. He became famous almost overnight. The New York Times later wrote that biology had reached a new frontier, describing “a revolution far greater in its potential significance than the atomic or hydrogen bomb.”
Racing to read every word
The discovery set off what became known as the “coding race.” Nirenberg’s main competitor was Severo Ochoa of New York University, a Nobel laureate with a large laboratory, who quickly began similar experiments. Nirenberg’s team was small, but colleagues across NIH, aware that they might help produce the first Nobel Prize for an NIH intramural scientist, put their own work aside to help him. DeWitt Stetten Jr. later called the collaboration “NIH’s finest hour.” Using other synthetic RNAs, the group showed that a run of cytosines (CCC) coded for proline and a run of adenines (AAA) for lysine, and by mixing letters in known proportions they narrowed down the composition of many other codons.
Mixtures could not reveal the order of the letters, however. The decisive advance came in 1964, when Nirenberg and his postdoctoral fellow Philip Leder devised a simple binding test: a three-letter piece of RNA would attach to a ribosome and pull in only the transfer RNA carrying its matching amino acid, and the complex could be caught on a filter. With this method the laboratory assigned about fifty codons. By 1966 Nirenberg’s group had worked out the codons for all twenty amino acids, with confirmation and the remaining details coming from the chemical syntheses of Har Gobind Khorana’s laboratory in Wisconsin. The code turned out to be essentially the same in bacteria, plants and animals, including humans: one language for nearly all life on Earth.
Nobel Prize and a warning
Honours followed quickly: the National Academy of Sciences Award in Molecular Biology in 1962, the National Medal of Science (awarded for 1964 and presented by President Lyndon Johnson at the White House in February 1965), and in 1968 the Albert Lasker Award and the Louisa Gross Horwitz Prize. In October 1968 the Nobel Prize in Physiology or Medicine was awarded jointly to Nirenberg, Khorana and Robert W. Holley “for their interpretation of the genetic code and its function in protein synthesis.” Nirenberg was the first NIH scientist to win a Nobel Prize. He turned down professorships at several universities and an offer to work with François Jacob at the Pasteur Institute in Paris, preferring the steady research support of NIH. From 1962 he led the Section on Biochemical Genetics at the National Heart Institute, and from 1966 its Laboratory of Biochemical Genetics, a post he held until his death.
Nirenberg was one of the first scientists to warn publicly about what his discovery might make possible. In an editorial in Science in August 1967, titled “Will Society Be Prepared?”, he predicted that humans might one day program cells with synthetic genetic messages, and argued that decisions about using such power “must eventually be made by society, and only an informed society can make such decisions wisely.” The piece started a public debate on genetic engineering years before the technology existed; Joshua Lederberg, among others, criticised its language as likely to alarm the public.
A second career in the brain
Having helped solve the code, Nirenberg changed fields in the late 1960s and spent roughly three decades on neurobiology, reasoning that the brain, like DNA, is a system that processes information. He had never done tissue culture before; the NIH neurophysiologist Phillip Nelson taught him, and in return Nirenberg taught Nelson molecular biology. Together they cloned lines of neuroblastoma, a nerve-cell tumour, selecting cells for particular neural traits. His laboratory built a bank of these lines and supplied them to scientists around the world for decades.
With Werner Klee of the National Institute of Mental Health, he developed a cell line rich in morphine receptors and used it to show how morphine suppresses the enzyme adenylate cyclase and how cells compensate, work that offered a molecular explanation of opiate tolerance and withdrawal. He also studied how nerve cells form synapses, and in the late 1980s, after another switch of organism, his laboratory identified a family of new homeobox genes in the fruit fly Drosophila, named NK-1 to NK-4, which help control the development of the nervous system. He was still studying the wiring of Drosophila embryos in the last years of his life.
Shy titan, Jewish scientist, citizen
Nirenberg was famously modest. Asked in 2007 by the journalist Ed Regis why the public tended to credit Watson and Crick with cracking the code, he answered: “Personality, I guess. I’m shy, retiring. I like to work, and I’ve never gone out of my way to try to publicize myself.” He recalled that Crick once told him he was foolish for never seeking the limelight. In 1961 he married Perola Zaltzman, a Brazilian chemist who also worked at NIH; she died in 2001. In 2005 he married Myrna Weissman, a professor of epidemiology and psychiatry at Columbia University, and gained four stepchildren.
He was born and raised in a Jewish family, and is counted among the Jewish Nobel laureates, but the surviving record says little about religious practice; his public life centred on science. He did, however, use his standing on behalf of persecuted colleagues. In 1969, with Christian Anfinsen, he protested the purge of scientists in Brazil; in 1975, with the Committee of Concerned Scientists, he wrote to the Soviet authorities seeking the release of Mikhail Shtern, a Soviet endocrinologist arrested after applying to emigrate to Israel. He signed appeals against nuclear war, against the Strategic Defense Initiative in 1986, for the Chemical Weapons Convention in 1997, and in support of stem cell research in 2001.
Last years and legacy
Nirenberg remained a laboratory chief at the National Heart, Lung, and Blood Institute for the rest of his life, also holding adjunct posts at the University of Maryland and George Washington University. He was elected to the American Philosophical Society in 2001 and was a member of the Pontifical Academy of Sciences. He died of cancer at his home in New York on January 15, 2010, aged eighty-two. NIH director Francis Collins called him “one of science’s great titans.” His sister Joan remembered: “His curiosity was unbounded.”
The genetic code he began to read in a Bethesda laboratory in 1961 underlies nearly all of modern biology and medicine: genetic testing, recombinant drugs such as human insulin, the reading of the human genome, and mRNA vaccines all depend on knowing which three-letter word means which amino acid. Nirenberg never became a household name, but every textbook table of the genetic code is, in large part, his work. His laboratory notebooks and papers are preserved at the National Library of Medicine, which presents them online in its Profiles in Science series.
Sources & further reading
Marshall Warren Nirenberg, Wikipedia · The Marshall W. Nirenberg Papers: Biographical Overview, NLM Profiles in Science · Beyond the Laboratory, 1967–2002, NLM Profiles in Science · Nirenberg and Matthaei experiment, Wikipedia · Marshall Nirenberg, Forgotten Father of the Genetic Code, Dies, Scientific American · Nobel-winning scientist Nirenberg dies at 82, NBC News / AP · Researched from the sources above and checked against them. Spotted an error? Tell us.
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