The youngest child of immigrants
Daniel Nathans was born on October 30, 1928, in Wilmington, Delaware, the last of nine children of Samuel and Sarah Nathans. His parents had come to the United States early in the twentieth century, as he later wrote, as part of a wave of Russian Jewish immigrants seeking freedom and opportunity in the New World. His mother, Sarah Levitan, arrived at eighteen. His father had rebelled against an orthodox family, left home in his mid-teens and made his way to America a few years later. The couple married in Philadelphia in 1910.
Daniel arrived on the eve of the Great Depression. Soon after, his father lost his small business and was out of work for a long time. In his Nobel autobiography Nathans remembered a house that was cold and leaky, and added that he only learned later that his parents had sometimes gone hungry. Yet they kept their good humour and their hopes for their children, and he recalled only fond memories of an affectionate family. From about the age of ten he worked after school, at weekends and in the summers to help out.
From medicine to the laboratory
Following his older brothers and sisters, Nathans went to the University of Delaware, living at home and, according to his student and biographer Daniel DiMaio, commuting by hitchhiking. He studied chemistry, philosophy and literature and graduated in chemistry in 1950. To his father, an interest in natural science meant medicine, and Nathans won a scholarship to the medical school of Washington University in St. Louis. A summer of research with the pharmacologist Oliver Lowry convinced him that research and teaching suited him better than practice, though he did not abandon medicine at once.
After his medical degree in 1954 he spent a year as an intern at Columbia-Presbyterian Medical Center in New York under Robert Loeb, a year he called one of the most valuable of his life. He then worked as a clinical associate at the National Cancer Institute in Bethesda, caring for patients receiving experimental chemotherapy and studying how tumours of antibody-producing cells make protein. There he married Joanne Gomberg after what DiMaio calls a whirlwind courtship. Two more years of residency in New York followed, and then, much to his father’s bewilderment, he gave up clinical medicine for full-time research.
Learning how cells make proteins
In 1959 Nathans joined the laboratory of Fritz Lipmann at the Rockefeller Institute in New York. These were the years before messenger RNA and the genetic code were understood, and he set out to learn how cells string amino acids into proteins. He identified bacterial elongation factors that add amino acids to a growing protein chain, and worked out how the antibiotic puromycin stops the process. With Norton Zinder he showed that RNA from a bacterial virus could direct a cell-free extract to make the virus’s coat protein, the first example of a purified messenger directing the synthesis of a specific protein.
In 1962 W. Barry Wood, a former teacher from St. Louis, recruited him to the Department of Microbiology at the Johns Hopkins University School of Medicine in Baltimore. He stayed for the rest of his life. When colleagues who taught animal virology left in the late 1960s, Wood asked Nathans to teach medical students about viruses. He accepted with trepidation, knowing little of the subject, but he was soon struck by the dramatic way tumour viruses change the cells they infect. He chose the simplest such virus he could find, SV40, whose genome is a small ring of about 5,000 base pairs of DNA, and in 1969 he went to the Weizmann Institute of Science in Israel to learn how to grow it.
A letter from Baltimore
While he was in Israel, a letter arrived from his Hopkins colleague Hamilton Smith. Smith had found an enzyme in the bacterium Haemophilus influenzae that destroyed foreign DNA but left the bacterium’s own DNA alone, and he had early evidence that it cut DNA at specific sequences. Bacteria use such restriction enzymes to defend themselves against viruses. Nathans saw at once what they might do in a scientist’s hands. As he later recalled, the letter set him thinking that restriction enzymes could be used to dissect the genome of a small virus and learn how it works.
He came home with radioactively labelled SV40 DNA in his luggage. With a medical student, Stuart Adler, he tested every restriction enzyme then known. Smith and his postdoctoral fellow Thomas Kelly then showed that the Haemophilus enzyme really did cut DNA at short, defined sequences. Nathans called such enzymes the trypsins and chymotrypsins of DNA, comparing them to the enzymes biochemists had long used to cut proteins into manageable pieces.
The first map of a genome
With his graduate student Kathleen Danna, Nathans showed that Smith’s enzyme cut SV40 DNA into eleven specific pieces, which they separated by size using gel electrophoresis. Their 1971 paper in the Proceedings of the National Academy of Sciences, DiMaio writes, ushered in the modern era of genetics. In its discussion Nathans predicted, with characteristic understatement, almost everything that followed: that the pieces could be used to map genes, to locate mutations, to detect differences between DNA molecules and to obtain fragments small enough to read letter by letter.
With Danna and George Sack he then worked out the order of the fragments around the viral ring and produced the first cleavage map of any genome. His laboratory used it to locate the point where the virus starts copying its DNA, showing that copying runs in both directions, to map the virus’s early and late genes, and to create mutants by deleting or altering chosen pieces. Other scientists quickly adopted the method. Nathans shared his reagents freely, and that generosity helped other groups determine the complete sequence of SV40 DNA.
How it changed the world
Restriction enzymes turned DNA from a long, featureless thread into something scientists could cut, sort, map and rejoin. Nathans admitted that he did not foresee the recombinant DNA revolution, but the methods his laboratory developed in the early 1970s became part of its foundation, as Paul Berg, Stanley Cohen, Herbert Boyer and others learned to splice genes from one organism into another. That is the basis of genetic engineering, which lets bacteria and other cells produce human proteins such as insulin and many modern medicines.
The same idea of cutting DNA at fixed sites and comparing the pieces became one of the first ways to tell individuals apart by their DNA and to trace inherited disease genes, and it shaped early efforts to map the human genome. DiMaio, who trained in his laboratory, put it simply: challenge a student to design a molecular genetics experiment that uses neither restriction enzymes nor molecular cloning, and you might as well ask for bricks without straw. Nathans was also quick to see the risks. He signed the 1974 letter calling for a pause on certain recombinant DNA experiments until their safety was understood.
Jewish roots
Nathans began his Nobel autobiography with his parents’ journey from Russia, describing them plainly as Russian Jewish immigrants. His father’s break with an orthodox upbringing, the family’s poverty in the Depression and the scholarship that carried the youngest son to medical school are a familiar story of the Jewish immigrant generation in America, in which free public schools and state universities opened the professions to children of working families.
He does not appear to have written about religious practice, and his own account of his background centres on family rather than faith. His 1969 sabbatical at the Weizmann Institute in Rehovot, Israel, where the decisive letter reached him, was supported by the American Cancer Society. His connection to Israeli science thus sits at the very start of the work that made his name.
A modest laureate
Nathans shared the 1978 Nobel Prize in Physiology or Medicine with Werner Arber, who had predicted restriction enzymes, and Hamilton Smith, who found the first one that cut at specific sites. He greeted the news with characteristic scepticism, insisting on independent confirmation before he would comment, and he said that his wife Joanne’s main job was to make sure his head did not get too big for his hat. That day he postponed the departmental celebration until he had taught his regular laboratory class for medical students. At a university assembly in his honour he politely declined to answer a question on public policy, reminding the audience that a Nobel Prize did not make him an instant expert on everything.
He was gentle, soft-spoken and scrupulously fair, and his advice was sought by students, technicians, presidents and, on one occasion, the Vatican, when he was asked to advise the Holy See on scientific matters. He served on the President’s Council of Advisors on Science and Technology and received the National Medal of Science in 1993. He directed the Hopkins Department of Microbiology from 1972 to 1982, and from 1995 to 1996 he served as interim president of Johns Hopkins University. Colleague Jeremy Berg said Nathans had the highest signal-to-noise ratio of anyone he had ever met.
Last years and legacy
In his last decades Nathans studied how cells respond to growth signals, isolating some of the first genes switched on when cells are told to divide. As he neared seventy he told DiMaio he was looking forward to more teaching, new research and what he called a privileged life, but not long afterwards he was diagnosed with acute myelogenous leukaemia. He kept coming to the laboratory between rounds of chemotherapy and died at home in Baltimore on November 16, 1999, aged 71. He was survived by Joanne, a lawyer for the City of Baltimore, their three sons, Eli, Jeremy and Benjamin, and seven grandchildren.
Earlier that year Johns Hopkins had named the McKusick-Nathans Institute of Genetic Medicine in honour of him and the medical geneticist Victor McKusick. It was a fitting pairing: the man who first mapped a genome with restriction enzymes beside a founder of medical genetics. Genetic engineering, DNA testing and genome mapping all still draw on the simple, powerful idea Nathans took from a colleague’s letter in 1969: that nature’s molecular scissors could be used to read and rewrite the code of life.
Sources & further reading
Daniel Nathans, Biographical, NobelPrize.org · Daniel Nathans, Biographical Memoirs of the National Academy of Sciences, vol. 79, by Daniel DiMaio · Daniel Nathans, Wikipedia · Jewish Nobel Prize Winners in Physiology or Medicine, JINFO.org · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.