A New York family devoted to public health
William Howard Stein was born in New York City on June 25, 1911, the second of three children of Fred M. Stein and Beatrice Borg Stein. His father was a businessman with a strong sense of civic duty who retired early in order to give all his time to health causes, among them the New York Tuberculosis and Health Association and Montefiore Hospital. His mother devoted most of her life to improving the lot of New York City’s children. Both parents encouraged him from childhood to go into medicine or a basic science.
He went first to the Lincoln School of Teachers College at Columbia University, a progressive school that encouraged the creative arts, music and writing, and where he took his first chemistry course. At about sixteen he moved to Phillips Exeter Academy in New Hampshire, a far stricter school, where he said he learned standards of precision in writing and in work that served him well for the rest of his life.
A shaky start, then biochemistry
Stein studied chemistry at Harvard and graduated in 1933, in the depths of the Depression, after what he cheerfully called an enjoyable but not academically distinguished college career. His first year of graduate study at Harvard went so badly that he nearly gave up on science. Someone suggested he might like biochemistry better than pure organic chemistry, and in 1934 he moved to the Department of Biological Chemistry at Columbia University’s College of Physicians and Surgeons, then led by Hans Clarke.
Columbia was, in his words, an eye-opener. Surrounded by lively teachers and fellow students, he found his calling. His doctoral thesis, completed in 1937, analysed the amino acids in elastin, a protein then thought to play a role in heart disease. While still a graduate student, in 1936, he married Phoebe Hockstader, whom he later called an enormous support throughout his life. They had three sons, William Jr., David and Robert.
Partners for life at the Rockefeller Institute
In 1937 Stein joined the laboratory of Max Bergmann at the Rockefeller Institute for Medical Research in New York. Bergmann, a German Jewish protein chemist who had left Germany after the Nazis came to power, believed that knowing the exact amino acid make-up of a protein was as basic to biochemistry as knowing the elements in a simple compound was to chemistry. In 1939 a young chemist named Stanford Moore joined the group. Moore and Stein began a collaboration that would last the rest of their lives; Moore later said that in those early years they worked out a system of collaboration that lasted a lifetime.
The Second World War interrupted their protein work. Moore went to Washington, while Stein stayed with Bergmann’s group, which worked for the federal Office of Scientific Research and Development; Stein studied how chemical blister agents damage the body. Bergmann died in 1944. When the war ended, the institute’s director, Herbert Gasser, invited Moore and Stein to stay on with freedom to pursue any biochemical problem they chose.
Building the machine
The problem they chose was measurement. To understand a protein you needed to know how much of each of its twenty kinds of amino acid it contained, and no accurate method existed. Following a suggestion from the British chemist Richard Synge, they began separating amino acids on columns packed with potato starch, measuring each fraction with a colour reaction using the chemical ninhydrin. To handle the hundreds of fractions, they invented a drop-counting automatic fraction collector, a device that Stein noted later became standard equipment in biochemical laboratories around the world.
The starch method worked, but analysing a single protein took about two weeks. They switched to ion-exchange resins, which cut the time to about a week, and then, with their colleague Darrel Spackman, automated the whole process. In 1958 they unveiled the first automatic amino acid analyzer, a machine of pumps, columns, a heated reaction coil, a photometer and a chart recorder that ran overnight and drew the results as a series of peaks. What had once taken weeks of skilled work could now be done while the scientists slept.
Stein was clear about why they did it. They needed to know the amino acid composition of proteins, to separate fragments in good yield and to purify proteins, and since no methods existed, they had to invent them. The instrument was soon commercialized by Beckman Instruments and spread to laboratories everywhere.
The partnership itself was unusual. Moore and Stein worked side by side for some four decades, published together and shared their honours, including the American Chemical Society’s award in chromatography and electrophoresis in 1964 and its Richards Medal in 1972. Stein credited the enlightened administration at Rockefeller, which let them follow the problems they thought important, and later generous support from the National Institutes of Health. He also stressed that none of it could have been done without a large group of devoted and highly skilled colleagues in the laboratory.
The first enzyme spelled out
With their new tools, Moore and Stein set out to determine the complete chemical structure of a protein. Frederick Sanger had sequenced the hormone insulin by painstaking manual methods. Moore and Stein, with a team of skilled colleagues, chose ribonuclease, an enzyme that breaks down RNA. By 1960 they had worked out its full sequence of 124 amino acids, the first enzyme ever to be sequenced and the first protein sequenced with the help of automation.
They went further. They noticed that certain chemical groups in the enzyme’s active site, the small region that actually does its work, were unusually reactive. By tagging those groups chemically, they could locate them in the sequence. As the Swedish Academy put it when awarding the 1972 Nobel Prize in Chemistry, this gave a detailed picture of the active site of ribonuclease long before its three-dimensional structure had been determined. Their work showed how a protein’s chemistry explains how it functions, and they went on to study a series of other enzymes.
Why it mattered
The automatic amino acid analyzer changed protein science from an art into a routine. It made it practical to analyse the composition and sequence of protein after protein, laying groundwork for later automated sequencers and for the protein chemistry that biotechnology depends on. Stein also used the analyzer to study the amino acids in human urine and blood plasma, and the measurement of amino acids in body fluids became an important tool in medicine, used for example in investigating inherited disorders of metabolism. The column chromatography and automated fraction collection that Moore and Stein refined became everyday techniques in biochemistry, part of the toolkit used to purify and check proteins, including protein medicines.
Their sequencing of ribonuclease, together with Christian Anfinsen’s work on how the same enzyme folds, also helped establish the central idea of modern biochemistry: that the order of amino acids, written in the genes, determines what a protein is and what it does.
Jewish life and public service
Stein was born into a Jewish family in New York, and his parents’ civic work centred on institutions such as Montefiore Hospital, founded by New York’s Jewish community. He carried on that commitment as an adult. He served as a trustee of Montefiore Hospital and, from 1957 to 1970, on the medical advisory board of the Hebrew University–Hadassah Medical School in Jerusalem. His mentor Max Bergmann was himself a Jewish refugee from Nazi Germany, part of the wave of émigré scientists who helped make American biochemistry world-leading.
He also gave years of service to science itself. He chaired the editorial committee of the Journal of Biological Chemistry from 1958 to 1961 and became its editor in 1968, caring deeply about how scientific knowledge is shared. He served on the council of the NIH institute for neurological diseases and blindness from 1961 to 1966 and chaired the U.S. National Committee for Biochemistry in 1968 and 1969. He taught as a visiting professor at the University of Chicago in 1961 and at Harvard in 1964, and gave the Harvey Lecture in New York in 1956. He and Phoebe often welcomed visiting scientists from around the world into their home. He is counted among Jewish Nobel laureates by the Jewish Virtual Library.
Paralysis, courage and legacy
In 1969, after developing a fever while attending a scientific meeting in Copenhagen, Stein was struck by sudden paralysis, diagnosed as Guillain–Barré syndrome. He remained quadriplegic for the rest of his life and in 1971 had to give up the editorship of the Journal of Biological Chemistry. Colleagues remembered that his spirit and sense of humour endured, and he remained a guiding presence for younger scientists at Rockefeller who continued the work on ribonuclease.
In 1972 he shared the Nobel Prize in Chemistry with Stanford Moore and Christian Anfinsen. In 1973 Columbia University and the Albert Einstein College of Medicine of Yeshiva University gave him honorary doctorates. William Stein died of heart failure in New York on February 2, 1980, at the age of 68. His legacy is a set of tools so successful that they became invisible: the machines and methods that let scientists and doctors read the building blocks of proteins every day.
Sources & further reading
William H. Stein, Biographical (autobiography), NobelPrize.org · Press release: The Nobel Prize in Chemistry 1972, NobelPrize.org · The First Automated Amino Acid Analyzer, The Scientist · William Howard Stein, Jewish Virtual Library · William Howard Stein, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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