NSCASCPAPER CLASSIC PNAS

Danna and Nathans: Restriction enzymes and the boon to modern molecular biology

n 1971, a paper published in PNAS proteins and viral RNA. Although he time,’’ said Danna, currently an associ- (1) helped jump-start the era of never obtained a Ph.D., the work gave ate professor at the University of Colo- modern molecular biology and bio- him confidence and experience with bio- rado (Boulder). ‘‘You would try hard to technology, eventually giving rise to chemistry, leading to a faculty position solve a problem and then go to him if Imany of the genetic advances that seem so in the microbiology department at The you needed help.’’ commonplace today. The article, written Johns Hopkins University School of by Academy member Daniel Nathans and Medicine (Baltimore) in 1962. In A Clear Vision his then graduate student, Kathleen Nathans’ own words, he became ‘‘a one- Smith and his postdoctoral student Kelly Danna, exposed the marvelous utility of man ‘Division of Genetics’ ’’ (3), which made rapid progress with their indepen- restriction enzymes. In the accompanying gradually morphed into a sizable group, dent study of the Hemophilus influenzae Perspective highlighting this classic work including graduate student Kathleen restriction enzyme, concluding in 1970 of scientific literature, Rich Roberts pro- Danna, fellow professor Hamilton O. that the enzyme cleaved DNA only at vides a historical account of the scientific Smith, and Smith’s postdoctoral student sites with a specific arrangement of base discoveries leading up to the PNAS paper Thomas Kelly. This combination of tal- pairs. However, after publishing their and the unparalleled scientific advances ents would prove highly fruitful in the findings (4), the scientists abandoned made after its publication. years to come, as Roberts asserts in his the subject of restriction enzymes and Perspective. went on to other research. Leaving Medicine for Research ‘‘I did my nice piece of biochemistry and, for some reason, I wasn’t interested The road to the discovery of restriction A Colossal Understatement in the actual application of the enzyme,’’ enzymes began in 1945, when Nathans After some departmental shuffling, said Smith, an Academy member and cur- enrolled in an undergraduate chemistry Nathans was asked to teach medical stu- rently the scientific director at the Insti- program at the University of Delaware dents about animal viruses. The topic tute for Biological Energy Alternatives (Newark). Lingering in Wilmington, DE, intrigued him, so he switched tracks in (Rockville, MD). ‘‘I just more or less pub- the same town where he was born and his research to study a relatively simple lished my work and put it on the shelf.’’ raised, Nathans initially lived at home tumor virus, simian virus 40 (SV40). To However, Nathans and Danna contin- and commuted to class by hitchhiking. learn how to grow and handle SV40, ued work on the enzyme, with a differ- He was the last of eight children born to Nathans went on sabbatical to The ent spin than that of Smith and Kelly. Russian Jewish immigrant parents, who Weizmann Institute of Science in Reho- ‘‘If you look back on it, it seems like encouraged his natural interest in sci- vot, Israel, in 1969. Roberts chronicles such a simple notion. But the fact is, I ence. Nathans claimed that his father the developments that Smith made dur- think Dan saw the utility of this much saw him as ‘‘the last chance to have a ing Nathan’s absence, noting that Smith more clearly than even those of us who doctor in the family’’ (2). corresponded with Nathans to keep him were very close to the work,’’ said Kelly, ‘‘Becoming a physician also seemed abreast of the research on endonucleases. an Academy member and currently the more attractive to me than any other al- In what proved to be a colossal under- director of Sloan–Kettering Institute ternative I knew about,’’ Nathans noted statement, Nathans wrote in a personal (New York). ‘‘Clearly, he must have had (3), so he applied to medical school and letter to Smith that the finding ‘‘could a vision at the very beginning of this received a scholarship at Washington be useful for many things.’’ Nathans’ that just the simple idea of being able to University (St. Louis). However, an in- research team would begin a few prelim- separate the fragments of viral DNA tense summer session of research con- inary experiments, he noted in the let- into specific pieces would have enor- vinced Nathans that his future lay in ter, ‘‘if everybody is interested to see if mous applications,’’ said Kelly. research and teaching rather than in it looks promising.’’ medical practice. After he received his Upon his return to Johns Hopkins, A Lasting Legacy medical degree in 1954, an internship at Nathans began studying the effect of Throughout his life, Nathans continued to Columbia-Presbyterian Medical Center in Smith’s enzyme on SV40. Danna soon play an integral part in molecular biology New York, followed by 2 years as a clini- joined the project, and the work became and genetics research. After an extremely cal associate at the National Institutes of the subject of her dissertation. Nathans fruitful career at Johns Hopkins, spanning Health (Bethesda), confirmed Nathans’ sensed Danna was ready for a change— years as the department chair and includ- desire to focus on research. an earlier dissertation project had ended ing a period as university president as well Much to the surprise and dismay of in chaos, with pulverized rat liver spilled as numerous accolades, Nathans suc- his father, Nathans left medicine and across Danna’s laboratory bench. Al- cumbed to leukemia in 1999. However, as began his basic research career at The though Nathans was a rather serious Roberts outlines in the Perspective, the Rockefeller University (New York) in and formal person compared with oth- legacy of Nathans’ 1971 PNAS paper is 1959. However, tired of sitting through ers in the laboratory, the two worked readily visible in almost all areas of mod- endless lectures, Nathans abandoned his well together. ern biotechnology. Ph.D. program at Rockefeller and ‘‘He was always available, but he Christen Brownlee, started laboratory research on bacterial didn’t breathe down your neck all the Freelance Science Writer

1. Danna, K. & Nathans, D. (1971) Proc. Natl. Acad. 3. Odelberg, W., ed. (1979) Les Prix Nobel. The Sci. USA 68, 2913–2917. Nobel Prizes 1978 (Nobel Foundation, Stock- 2. DiMaio, D. (2001) in Biographical Memoirs, ed. holm). Berry, R. S. (Natl. Acad. Press, Washington, DC), 4. Kelly, T. J. & Smith, H. O. (1970) J. Mol. Biol. 51, Vol. 79, pp. 262–279. 393–409. © 2005 by The National Academy of Sciences of the USA

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