"The best preparation for a geneticist of the future is to study physical sciences (physics, chemistry) and mathematics, as well as biology. Don't worry about how much time it will take. The whole journey will be stimulating. If it isn't, choose another interest."– Dan Nathans's reply to an inquiry from a 13- year-old aspiring geneticist in England (1995)
Restriction enzymes are the essential tools, the workhorses, of the molecular biology of the gene; mapping, sequencing, cloning, and other procedures would be inconceivable without them. It was Daniel Nathans's brilliant work that first demonstrated the immense utility of restriction enzymes for analyzing genomes, greatly accelerating the expansion of modern molecular biology.
Daniel Nathans was born in Wilmington, Delaware on October 30, 1928. He was the youngest of eight children of Russian Jewish immigrants Samuel and Sarah Nathans. Like many families, the Nathanses fell on hard times during the Great Depression, but Nathans would later remember only the good humor and warmth of his parents and siblings. He attended Wilmington public schools and held various part-time jobs from the age of ten. Like his siblings, he went onto the University of Delaware, studying chemistry, philosophy, and literature, all of which he enjoyed. He decided to go into medicine, he noted later, because his father "had his heart set on having a physician in the family, and I was his last chance." As Nathans was attracted to the natural sciences, liked what he saw of his family physician's life, and had no firm career plans, he thought medicine would be a good choice.
After receiving his BS in Chemistry from the University of Delaware in 1950, Nathans went to the Washington University School of Medicine in St. Louis, planning to return to Wilmington and enter general medical practice. Although he enjoyed all aspects of his medical training, he was especially drawn to laboratory research after his experience working with eminent pharmacologist Oliver Lowry during the summer of 1951. By the time he received his MD in 1954, Nathans had resolved to pursue a career in academic medicine, where he could teach and do research in addition to treating patients. He served an internship at Columbia Presbyterian Hospital under Robert Loeb's supervision, which he later called "one of the most valuable years of my life."
Wanting a break before his medical residency, Nathans became a Clinical Associate at the National Cancer Institute at the National Institutes of Health in Bethesda, Maryland. There he split his time between caring for patients receiving experimental cancer chemotherapy and research on recently discovered plasma-cell tumors in mice, similar to human multiple myeloma. Struck by how little was known about cancer biology, he became interested in protein synthesis in myeloma tumors, and published his first papers on this research.
While in Bethesda, he met and married Joanne Gomberg, a lawyer. Their family soon included three sons.
Nathans returned to Columbia Presbyterian for a two-year residency in 1957, again on Robert Loeb's service, still thinking he would pursue an academic medical career that combined teaching, research, and patient care. He continued working on the problem of protein synthesis as time allowed. In 1959, he decided to work on the research full time and became a research associate at Fritz Lipmann's lab at the Rockefeller Institute in New York. It was an exciting time to be at the Rockefeller. Biochemists, microbiologists, and geneticists were rapidly forging the new discipline of molecular biology during the 1950s, resolving central questions about how the genetic material DNA directs living cells to manufacture the enzymes and structural proteins they need. Researchers had identified the structure of DNA, discovered the role of transfer RNA (tRNA) and the cell structures known as ribosomes in protein synthesis, and clarified the biochemical steps of the process. However, there was still much to discover about how genetic information was translated, and how that translation could be changed by outside factors. In the stimulating environment of Lipmann's lab, Nathans at first continued his effort to synthesize protein from myeloma cell extracts. Another postdoctoral fellow persuaded him to pursue the problem with cultures of E. coli bacteria, as they are easier to work with and had been extensively studied. In collaboration with Norton Zinder, Nathans showed that RNA from the RNA bacterial virus (phage) f2 could support synthesis of the virus's coat protein in a cell-free system. It was the first example of a purified RNA directing the synthesis of a specific protein, and supported the emerging idea that RNA might act as a "messenger" between cellular DNA and the protein synthesizing "machinery" of cells.
His three years at Rockefeller finally convinced Nathans that he was better suited for the science of medicine than for the practice of medicine, and he looked for a university research and teaching post. One of his medical school mentors, W. Barry Wood, had become chair of the microbiology department at Johns Hopkins University (JHU) and offered him a faculty post, which he accepted in 1962. Nathans continued researching protein synthesis, including a study on how antibiotics such as puromycin block that process. His research direction began to shift in the mid-1960s, when his department lost its two virologists and he was asked to give some lectures on animal viruses. Preparing for these, Nathans became interested in tumor viruses; like bacterial viruses, they promised to be excellent models of genetic mechanisms in the cells they infected. In 1969 he spent a six-month sabbatical at the Weizmann Institute in Israel, learning cell-culture techniques and getting acquainted with simian virus 40 (SV40), a small tumor virus.
While he was in Israel, Hamilton Smith, a JHU colleague, wrote to him about a new enzyme he'd found in Haemophilus influenzae bacteria, which seemed to cut the DNA of other species at particular points. Nathans recognized that such an enzyme would be useful for making uniform fragments of a small virus DNA that could then be mapped, i.e., the precise molecular structure determined. He brought some SV40 back from Israel and immediately set to work testing Smith's enzyme and several other known restriction enzymes on the virus. As he hoped, the Haemophilus restriction enzyme cut the SV40 DNA into eleven specific fragments. In an elegant series of experiments, he and his graduate student Kathleen Danna went on to deduce the physical order of the fragments and to discover the point where DNA replication started. In subsequent work, Nathans and his students used physical maps of the SV40 genome to map sites of transcription and genetic variation. Restriction enzymes rapidly became ubiquitous tools of molecular biology, essential for physical mapping of genes, for sequencing, and for recombinant DNA technology. Nathans and Smith shared the 1978 Nobel Prize in Physiology or Medicine with Swiss researcher Werner Arber, who in the early 1960s had predicted the existence of bacterial enzymes capable of cleaving foreign DNA at specific sites.
Nathans continued to work on the SV40 genome into the 1980s, using restriction enzymes to create mutant forms of the virus in which certain DNA segments were deleted. These mutants were reintroduced into the host cells and assessed for biological activity. In the latter part of his career, hoping to learn more about how cancerous processes--which are characterized by rapid, uncontrolled cell growth--began, he shifted from tumor viruses to the study of cultured mouse cells, investigating the effects of substances called growth factors on cell reproduction. He and his co-workers isolated and characterized some of the first cellular genes that were activated when cells were stimulated to grow and divide.
Though widely acknowledged as an outstanding researcher, teacher, and mentor, Nathans was also an able administrator--thoughtful, fair, deliberate, and clearheaded. (One colleague noted that Nathans had "the highest signal-to-noise ratio of anyone" he'd ever known.) He was director of the Microbiology Department at JHU from 1972 to 1982, and then served as Senior Investigator of the Howard Hughes Medical Institutes unit there from 1981 to 1999. He served on many national scientific committees and as Interim President of JHU during 1995-96, guiding the institution through a time of difficult transitions. Although dedicated to his scientific research, Nathans also enjoyed reading history and fiction, and spending time with Joanne and their three sons. (Eli is a lawyer turned historian, Ben is a Russian historian, and Jeremy is a molecular biologist and neuroscientist.)
After his year as JHU interim president, Nathans returned to his research, but was diagnosed with leukemia the next year. He died on November 16, 1999.
Nathans received many awards and honors, including the Selman Waksman Award in Microbiology in 1967, the Nobel Prize in 1978, election to the National Academy of Sciences in 1979, and the National Medal of Science in 1993, along with six honorary doctorates. In January 1999, Johns Hopkins University established the McKusick-Nathans Institute of Genetic Medicine, a multidisciplinary clinical and research center named for Nathans and pioneering medical geneticist Victor McKusick. Nathans published 138 articles and book chapters during his career.