This is Oral History Interview #38 on May 4, 1979. Dr. Sondra Schlesinger, Professor in the Department of Microbiology and Immunology at the Washington University School of Medicine interviews Dr. Daniel Nathans, Professor and Head of the Department of Microbiology at the Johns Hopkins University School of Medicine and a member of the Washington University School of Medicine class of 1954. Dr. Schlessinger interviews Dr. Nathans about his life and scientific work.
Dan, an obvious first question, of course, is why you wanted to go to medical school, but in answering that maybe you could also tell me when you started medical school, whether you had any interest in scientific research, even before medical school.
I got into medicine really for what turned out to be a very poor reason. I was always interested in science and mathematics and in college I majored in chemistry and it seemed that it was always my family’s intention that I should go to medical school. In fact, to them an interest in science meant only one thing, mainly medicine, becoming a doctor. And actually that was attractive to me, although I really had no basis on which to make such a judgment. In any case, I decided I would go to medical school and I applied to a number of schools including Washington University and, I might add, including Washington University quite by chance. It was in essence picked out from a list of private medical schools in the United States. I knew absolutely nothing about the school and having been accepted, I then inquired among the faculty at the University of Delaware where I went to undergraduate school and I learned that it was a very lucky choice, that it was an outstanding school, widely recognized. To top off the offer of acceptance, I also took the offer of a scholarship, one of the Jackson Johnson scholarships that are given regionally, and of course that delighted me also and I then accepted So in answer to your question, my decision to go to medical school was really based on what turned out to be an ill-informed decision to become a family physician.
Had you done any research as an undergraduate?
I did a little bit, in chemistry. As I look back on it I am not sure I’d call it research today, but it was something enjoyable; it was a laboratory project.
And how about here at Washington University?
Well yes, at Washington University really is when I grew up scientifically I would say. I came here in 1950 and what I found out very quickly was that basic medical sciences interested me very much. I began with, first of all, gross anatomy, which Mildred Trotter taught. A magnificent course, very thorough and one which related anatomy to medicine in really a wonderful way and she of course was a very vigorous teacher with just a tremendous enthusiasm which she communicated to the students. Even though I have gone into a completely different area of science, I was really very enthusiastic about that course and learned a great deal. In fact, when I look back on it I did an immense amount of work. I read Morris’ Anatomy and if it wasn’t quite clear in Morris’ Anatomy I read Gray’s Anatomy and I knew all the nerves and muscles and God knows what all. But that is the kind of atmosphere there was in that course. I think at the same time I also took the biochemistry course.
And that was Carl Cori teaching?
Carl Cori was the Head of the Department and he gave a series of lectures on carbohydrate structure and metabolism and it was just beautiful. And having had a chemistry background I felt very well attuned to what he was talking about and I enjoyed that enormously. There were other fine lecturers in that course. Of course this was a time, as you remember, before much was known about DNA. Just in the recent past it has been discovered that DNA was the chemical substance of heredity but its structure wasn’t known. Actually, I don’t remember very much about the lectures on nucleic acids; my recollection is [that] they got short shrift. That is a kind of interesting curiosity, but intermediary metabolism, amino acid metabolism, got a great deal of attention and it was given as a rigorous course. I enjoyed it enormously and that helped open up new interests for me.
For my own interests, I am curious to know what microbiology was like at that time.
I will come to that a little later. But just let me continue chronologically. I don’t remember all the courses of the first year. I remember physiology, particularly renal physiology, which was the interest of the chairman of the department whose name I don’t recall at that moment. I found that interesting but clearly it was the chemical aspects of biology that most interested me. I took microbiology in the second year and at that time [Jacques] Bronfenbrenner was chairman of the department and he was a very colorful, interesting man. My recollection is that he gave almost all the lectures in the course himself. He sat behind a desk at the front of the class and systematically went through microbiology, but it was a medical microbiology and immunology course. That was the last year that he taught the course and I remember our class gave him a gold watch at the end of the course which he was very touched by.
But of course, the course changed drastically because Arthur Kornberg came as chairman of the department in the following year and I didn’t, of course, have much contact with him. In fact, I was completely unaware that in the future I would be very much interested in the things that he was doing right at that time on that very floor. I was also, I must say, completely unaware of the eminence of the contributions of the people in microbiology in regard to bacteriophage research – just oblivious of that completely.
A real turning point for me was at the end of my first year of medical school. I had gone home to Wilmington, Delaware at the end of the year and was going to come back to St. Louis for the summer, for let’s say personal reasons, mainly a young lady who was here. I also was unhappy with the arrangements that I had made at home. And having gotten a letter from the Dean of Students, Thomas Hunter, saying how well I did in the first year of medical school, I decided I would impose on him and ask him if there was any possibility of getting a laboratory job for the summer, for my coming back to St. Louis. He turned my letter over to Oliver Lowry, who at that time was Chairman of the Pharmacology Department. Dr. Lowry wrote to me and offered me a position in his lab for the summer which I immediately accepted and promptly went back to St. Louis. That was really a wonderful summer. I can now call Dr. Lowry “Ollie” and at that time of course all the students called him “Ollie” and everybody in the department called him “Ollie.” That really opened up for me a picture of what doing research was like, how enjoyable it was, the kinds of questions that could be asked and sometimes answered, but mostly just the joy of research which, of course, comes from his every pore. He is a magnificent teacher. I worked on the distribution of ascorbic acid in the adrenal cortex as an independent project, but one in which he was interested and started me on by working side by side with me at the bench. I learned how to do the micro-dissections that he does. The cortex was really ideal for that, because it had very distinctive morphological layers which could easily be determined. I learned how to dissect those layers of rat adrenal cortex and do micro-chemical analyses of various kinds.
That was my first experience in research and clearly it was something that I enjoyed. I decided that I really was much more suited to the science of medicine than to the practice of medicine. As time went on, including other experiences in research in the Pharmacology Department, that feeling became confirmed and I thought what I would really like to do was to be in internal medicine at an academic center, where I could do biochemical research on disease problems. That was my intention for quite some time.
There were other people who also had a hand in my training and influenced me in sometimes obvious and sometimes subtle ways. At that time at Washington University, it was really a wonderful academic atmosphere, one which I often look back on with very warm feelings and tremendous respect for the faculty that was here. It was a very devoted faculty, clearly, and now that I am on the other side of the fence, I appreciate that even more than I did at that time. [It was a] very scholarly group, including the clinicians, very scholarly group, and particularly I am more familiar with the people in the Department of Medicine – Barry Wood was chairman of the department at that time and Carl Moore, who was head of the hematology division and sort of a co-director of the medical service. He and Barry Wood traded off rounding on the medical service there and having responsibility for it. Of course I got to know Barry Wood much better later on, after we were both at Hopkins in the same department, and I perhaps can tell you about that a little bit later.
Barry Wood was a very unusual man. He had a way of inspiring younger colleagues that is really unsurpassed in my experience. Well, I can’t divide up my feelings about him into a student period and a colleague period, but the time I was a student it was clear he had just tremendous skill in bringing out the best in students, of not only arousing our interest in medicine but just bringing out the best performance, mostly by his example. He was always very well-prepared; his lectures were just models of clarity, as were Carl Moore’s, as a matter of fact. That clearly affected me – that was something I found very attractive, being an academic physician. And that was my intention really, at the time that I graduated, to go into a department of medicine where I could teach and take care of patients and also do research.
Well, I am going to ask you what happened. After medical school; did you go through an internship and residency period?
Yes, I became a medical intern after graduation from Washington University, at Columbia Presbyterian Medical Center. Robert Loeb was the Chairman of the Department [of Medicine] at that time, and I remember still the thrill of hearing that I was accepted there. That was the start of the intern matching plan – I think that very year may have been the first year, and I was very pleased about that. There I found – well first of all, for the interest of Washington University group – I found I was extraordinarily well-prepared compared to my colleagues who were interns on the same service. I felt quite confident, and as time went on it was clear that sort of the fundamental scientific grounding in medicine that was the kind of education that Washington University gave and I gather still gives, really was very effective in terms of applying what you knew to the real problems in medicine.
I enjoyed my internship very much. In fact, I look back upon it as one of the most valuable years of my life – being in a large hospital in a major city and seeing people as they walk in the front door with primary complaints is an experience that I wouldn’t trade for anything. I think what you learn about human strengths and human weaknesses, the ability to bear suffering, or not bear suffering is gotten in no other way that I can think of. Of course I developed skills in scientific medicine as well as in the art of medicine and it was still my intention at the end of that [year] to go on into a department of medicine. Shall I go on?
At the end of my internship I decided [that] I wanted a break from clinical medicine and I applied to the National Institutes of Health for a clinical associateship and I went there in 1955 as a Clinical Associate in the National Cancer Institute. This was a time when the NIH was still a small place. The clinical building had just gone up and at the time I came was only a fraction occupied by beds or by investigators. I was among the first group to take care of cancer patients. That was a very striking experience for me. I spent that first year more or less as a resident on the cancer service rotating through the different services primarily involved in chemotherapy of cancer. That was also the time when the systematic study – clinical study – of chemotherapy for solid tumors and for leukemia was getting underway and I helped take care of those patients. That was a tough job. But it was a very exciting one; at the same time rather a depressing one, because in those early days progress was extraordinarily slow in finding combinations of cellular poisons that would kill tumor cells more rapidly than they would kill normal cells. But during the second year there I got to do a research project primarily. I worked with John Fahey, who was interested in immunology – in particular at that time in fractionating immunoglobulins with the recently-developed DEA cellulose method. The people who had developed the methods, [Herbert A.] Sober and [E. A.] Peterson, were in a different section of the Cancer Institute. I decided to look into the problem with myeloma because Michael Potter had just begun his work on induced myelomas in mice, and I became interested in that and I had decided to try to answer the question: Is myeloma protein actually produced in the myeloma tumor? I must say in retrospect I did it in a rather roundabout way because of my biochemical bias.
At that time was it known that the myeloma protein was an immunoglobulin?
It was known that it was like an immunoglobulin, yes, but it wasn’t clear that the plasma cells were actually producing the protein, or the immunoglobulins, for that matter. So I did a pulse-label experiment in which I pulsed the animals with a radioactive amino acid and then followed it into the intracellular protein and into the extracellular protein by purifying the myeloma proteins that were present in tumor tissue and that were present in the serum. These showed a very nice precursor product relationship in the lag in the time for the appearance of the protein in the serum. But the main thing is that I enjoyed it very much and I got interested in the problems of protein synthesis. Still, I thought I would go back to a clinical department and so at the end of that two years at NIH, I went back to Columbia as a resident in medicine. I spent two years there on the medical service, the first year as a regular resident, the second year partially doing research, and partially in the residency. Having gotten interested in protein biosynthesis, which at that time as a complete mystery, people were talking about—
This was now about 1958, is it?
Well, let’s see. I went back to Columbia in ’57, so this is ’57-’59 [that] I was there as a resident. At that time in the protein biosynthesis field, it wasn’t known that ribosomes had anything to do with protein synthesis and people were thinking that all the amino acids must sit down in some kind of structure at a particular time and then get zipped up and form protein. Nobody had the faintest notion about how the genetic material, how DNA, might direct the sequence of the amino acids in the protein. I don’t mean to imply that I was thinking in those terms, I certainly wasn’t that sophisticated.
No, but neither messenger RNA (mRNA) nor transfer RNA (tRNA) were known at that time.
No. I realized later, thinking about genetic codes – just the rudiments of genetic codes and how they might operate. But in terms of the biochemical pathway from a free amino acid to a polypeptide chain really nothing was known at all. So I became attracted to that as a result of this little project on the myeloma protein biosynthesis and during my last year of residency I decided I wanted to work on that problem. After thinking about a number of labs and applying to two labs, one of which accepted me and that’s the one that I will tell you about, I went over to Fritz Lipmann’s lab at the Rockefeller Institute.
At that time the Rockefeller Institute had just started, under Detlev [W.] Bronk, to become a University and they started with a Ph.D. program, including one that was designed for M.D.s. I initially was intending to get into that program, had been accepted into that program, and to work with Fritz Lipmann. Lipmann accepted me, I think, because he himself was a M.D. and he rather liked having some M.D.s in the laboratory, but I guess the primary reason is that Robert Loeb wrote him a letter and on the basis of that he took me.
I decided not to get into that program because finally, after a lot of thought, I decided that I really didn’t want to meet anybody’s course requirements, that I had had enough courses and enough examinations and I just wanted to do research and I could learn what I needed to know around that research problem. And so after I described to Dr. Lipmann what I done at NIH he suggested that I continue with that and look at protein synthesis and extracts of the myeloma tumors and see if I could get those extracts to make the protein. So that’s where I started. I got some mice from Mike Potter and started transplanting the tumors at the Rockefeller and then started making extracts and looking at protein synthesis in those extracts. By that time of course, tRNA had been discovered, a cell-free system for protein synthesis had been established in Paul Zamecnik’s lab, and it was known that the ribosomes were involved, the microsomes in the animal cell extracts, and something about activation of amino acids was understood, attachment of amino acids to tumors.
That work was of course done here at Washington University when Paul Berg was here – the activation of the amino acid.
Yes, I know that work very well and I think what Paul showed was fatty acid activation in general also applied to amino acid activation which was a new mechanism at that time. So I started work with the myeloma cell extracts and was never able to make the myeloma protein.
How were you assaying the myeloma protein?
I was incorporating labeled amino acid into protein and then adding carrier and fractionating by column chromatography and looking for radioactivity in the carrier peak. But what I did come up with was the requirement for a soluble extract of cells which was required for amino acids to go from amino-acyl-tRNA into protein – what are now called the elongation factors – and started purifying those factors. Actually at that time we thought it was a single protein which somehow was involved in going from amino-acyl tRNA into protein.
At about that time Jeffrey Zoombay, another post-doctoral fellow, came to Lipmann’s lab and he began working with E. coli and was interested in protein synthesis in E. coli. It seemed to me that I really ought to shift my interests to looking for a similar protein factor in E. coli extracts because it is much easier to work with – the ribosomes were clean and starting to get defined through the work of [A.] Tissier and [J. D.] Watson. So I switched to E. coli and found that also in E. coli there is a requirement for a soluble factor to go from amino-acyl-tRNA into polypeptides in the presence of ribosomes and many other things, and so my problem in Lipmann’s lab was to purify that. That was a difficult problem and in retrospect it was difficult because there were multiple factors involved and they were being fractionated. It really took another post-doctoral fellow to find that out, named Robin Monroe who was in Lipmann’s laboratory. He found you can divide this so-called factor into two fractions and these became known later on, as you probably know, as the elongation factor G with a GTPase activity that it has in the presence of ribosomes and the elongation factor T which again is subdivided into two different fractions.
In line with that same interest I picked up on the puromycin problem. Puromycin had recently been found by [Michael B.] Yarmolinsky to block protein synthesis and actually he made a very nice observation, that is, in looking at the structure of puromycin he saw that it was analogous to the pre-prime terminus of tRNA with amino acid on it. He found that it inhibited protein synthesis and I subsequently found, and other people as well, that it inhibited this step from tRNA to polypeptide and that the puromycin actually became attached to the carboxyl terminal of the growing peptide chain and thereby terminated the protein synthesis. Well, to get off the deep science track, it was really that experience in Lipmann’s lab which I found very enjoyable and very stimulating – a really very invigorating atmosphere there and at the Rockefeller Institute generally.
That made me decide that that is what I wanted to do and I preferred that to having responsibility for taking care of patients. So I decided as a result of that experience that I would not go back to a clinical department, which was my intention all along, but would go into some science department where I could have the opportunity to continue this kind of research and also teach. Two possibilities arose, in terms of job possibilities. One was here at Washington University. Ollie Lowry offered me a job in the Department of Pharmacology. Of course I was very much interested in that possibility. The other was also a connection at Washington University, namely from Barry Wood, who by that time had moved to Johns Hopkins, first as Vice President for Medical Affairs and then he later became Chairman of the Department of Microbiology at Hopkins. After thinking about it a good bit – and it was a very difficult choice – I decided to go to Hopkins, and I went there in 1962 at the beginning of that academic year and I have been there ever since.
Now when you started at Hopkins did you start working on protein synthesis?
Yes. I continued with protein synthesis. First of all, I continued with puromycin problems and it was really there that I found that puromycin became attached to the carboxyl terminus of the growing polypeptide chain.
I left out something very important [done] at the Rockefeller in terms of my own research interest. During the last year that I was there – I spent three years in Lipmann’s lab – Norton Zinder and a student of his discovered the male-specific bacteriophages for E. coli, one of which turned out to be an RNA phage, as you well know. Just about the same time, Marshall Nirenberg published a very interesting paper in the Biochemical and Biophysical Research Communication where he showed that a very crude extract of E. coli when supplemented with exogenous RNA was markedly stimulated in its protein synthesis. That came on the heels of the discovery and perhaps more at that time, the idea that messenger RNA actually carried the genetic information from gene to ribosome where it was translated into protein.
It occurred to me in conversation actually, with Edward Wright, who at that time was a good friend and fellow student at the Rockefeller – in fact we had been together on the house staff at Columbia – that Zinder’s phage RNA might well be a messenger and that the thing to do was to get some of that RNA and use the Nirenberg-type extract and see whether or not you could make a viral protein using that messenger. Of course I had facility in using a protein synthesis extract and so I suggested to Norton that we ought to do this experiment. He thought that was a good idea and so we got some RNA and together with another student of Lipmann’s and another fellow of Norton’s, [J. H.] Schwartz, we proceeded to do that experiment. [This was] to incorporate amino acids into protein under the stimulus of added phage RNA and an E. coli extract and then to analyze the product by two dimensional tryptic fingerprint and compare the ninhydrin-stained spots, which was the carrier co-protein that we used as the carrier, with the radioactive spots on the same paper. The result was happily very clear cut that since we used lysine, arginine and trypsin in every spot, it was labeled and it corresponded exactly to the reference of tryptic peptides. So, it was quite clear that the RNA was capable of functioning directly as a messenger and of course at that time we thought that perhaps that meant that all RNA viruses operated that way there in the viral genome was a messenger directly.
So I continued working on that problem when I went to Hopkins. I was particularly interested in seeing what else was made in response to the added phage RNA because I had found in those studies with Norton that histidine was incorporated into protein under the stimulus of this RNA and yet histidine did not occur in co-protein and therefore the indication was that were other things coded in this viral genome which were not the co-protein. And so I, and subsequently my students, spent some time in identifying those other products as synthetase or replicase of the virus and the so-called maturation or A-protein of the virus.
That carried through to an interest in the regulation of the synthesis that these proteins in infected cells and the finding that the co-protein served as the inhibitor of translation of the synthetase in vitro, and actually it had already been implicated in the affected cells by Norton and Harvey Lodish, who was a student of Norton’s. So my initial research was really a continuation of that work – first on puromycin and then on the RNA phage genome as a messenger. I got involved in isolating the ____(?) mutants and first defining the gene products with those ____(?) mutants, and then doing these other things.
So now I guess the next question is how you went from RNA phage to SV40 [Simian Virus 40]?
Yes, well there is a bit of a story connected to that. Some time in the mid-’60s our department lost its animal virologist, Bob Wagner – [and] Bernard Roysin(?) had left, a man named Allen Levy had left – and I was asked by Barry Wood to give a lecture on tumor viruses to the medical students. I didn’t know anything about tumor viruses. So I began to read about tumor viruses and went back to the old literature and I had a really good time reading about tumor viruses. Not only did I have a good time, but I became very much interested in tumor viruses, particularly in two aspects. It was quite clear that tumor viruses, like the phages that had been so well studied, were beautiful models of genetic mechanisms in mammalian cells. So from that point of view they seemed really right for studying such mechanisms by the techniques that were so successful with phages. Secondly, that they did wondrous things to the growth of animal cells and they could do it in culture, which made a deep impression on me. Again, a relatively simple model system for trying to understand cell growth and its controls and tumor genesis. So I decided then and there that I really ought to go into this more deeply and I had to get to a lab where they were actively working on such problems, so I could learn some techniques and have time to think about the problems, have time to read and talk to people.
You know, taking a sabbatical with young children takes some planning and when you have a laboratory that has fellows and students in it, it also takes some planning before one can really get away, so finally I got away in 1969. I spent the first six months of ’69 at the Weizmann Institute of Science [in Rehovot, Israel].
Had you made the decision before then that SV40 was the proper vehicle?
No. I hadn’t at that time. But I had more or less decided that I wanted to work with the DNA tumor virus and my reasoning was that having worked with a RNA phage I was very much aware of the technical problems of preparing intact RNA and how careful one had to be at every step in handling it, whereas duplex DNA could be handled even crudely and aside from the shearing problem, it would remain perfectly active. That had a bearing on my choice and actually at the time that I went I thought it would be either a _____(?) virus or an adenovirus. My thinking was first, that I wanted a virus that was easy to prepare, but most important – and this really came from my work with the RNA phage – I wanted the simplest biological entity that had the phenomenon of interest because I thought there just [would] be fewer extraneous problems to deal with and I wanted to get right to the heart of the matter more quickly.
So I wrote to Leo Sachs at the Weizmann Institute, he was the Head of the Genetics Department, and told him of my interest and asked if I could come for six months and he wrote me a wonderful letter and said, “I’ll be delighted to see you,” and that was that. I got a scholar grant from the American Cancer Society and so during the Christmas holidays and December of ’69 my family and I took a Christmas cruise to Naples and then flew to Israel. Well, it was a wonderful experience all around, both for myself and for the family. First, of course, to be in Israel, the first time for me. My wife had been there for an extended period in her earlier years.
Scientifically it was a wonderful place to be and I was given generous space, a lab of my own. One of the problems I had was that I couldn’t speak Yiddish and I couldn’t speak Hebrew. The ladies in the kitchen let me know very quickly that it either had to be Hebrew or Yiddish. They didn’t understand English. But I managed to do what I wanted to do in the lab. I think probably I tried to do more than I should have on a sabbatical, but I certainly managed to learn some very practical things about tissue culture and preparing for parvoviruses which was the main interest there for Ernest Winocour, who came back soon after I arrived and actually my scientific discussions and work really centered around Ernest more than anyone else in that department.
I also had time to think about what I wanted to do, which was my primary reason for going – how I wanted to get into the tumor virus area. I very quickly decided SV40 was the most tractable virus to work with for reasons that many other people were quite aware of but I was not. Along about this time I got an interesting letter from my colleague, Hamilton Smith, who was in the same department as I at Hopkins, telling me about an interesting enzyme that he had found in Haemophilus influenzae which he came upon accidentally during some investigations of possible in vitro recombination of Haemophilus DNA, and he was using transformation to look for in vitro recombination between pieces of Haemophilus DNA. In one of his experiments he used as a control a radioactive DNA from a coliphage – D-22 – and lo and behold, extracts of Haemophilus, which he was investigating for recombinational activity, rapidly degraded that coliphage DNA, but they didn’t seem to touch Haemophilus DNA.
He realized that this had biochemical properties or restriction enzyme and he wrote to me about this and told me about his initial studies on trying to determine whether that enzyme was cutting foreign DNAs at specific sites. Well, at that very time I was thinking about how to approach the genetics of SV40 in a sort of combined genetic and chemical way. I also had done some experiments with the RNA phage which involved fragmentation and testing of fragments.
Had you ____(?) ?
It was done biologically, you can get defective particles out of these cells that have a piece of 2/3 length of the molecule and with a man named [Yoshiro] Shimura, who was a fellow with me at Hopkins, we found that 2/3 made the synthetase, a replicase, in vitro, but didn’t make the co-protein. So this sort of general approach of trying to locate genes by looking at the activities of fragments was sort of on my mind and it just immediately occurred to me when I found out from Ham Smith about this restriction enzyme, because I really knew very little about restriction enzymes at that point, that this was a possible way to do just that with duplex DNA. That these were, in essence, trypsins and chymotrypsins for DNA.
So I began to read literature on restrictions and modifications and it turned out that Werner Arber, who did the fundamental work from a molecular point of view on a phenomenon that had been known since the early ’60s [and] discovered by a number of people including Salvador Luria and Bernardi(?). What our bearing found was that restriction modification involved DNA; non-genetic changes in DNA, modifications or cutting. He had predicted that these enzymes must recognize specific nucleotide sequences and he had suggested that if that were the case they could be very useful for the agents for analyzing DNA, even down to the sequence level.
I became very excited and really planned out a series of experiments and prepared some radioactive SV40 DNA and I carried it all home with me. This was just about the end of my time there – [I carried it] through Europe and so on and finally got it home. When I got back to Baltimore a medical student, Stuart Adler, came knocking on my door and wanted to work with me. I suggested to him that we prepare, even if in crude form, all the known restriction enzymes and see whether they cut SV40 and perhaps we could get specific fragmentation and then look at the activities of those fragments. That is what he did. In the meantime I was learning how to prepare SV40 in quantity. I did most of the setting up of tissue culture work and had a great time, really. I got the tissue culture going and started preparing SV40 DNA and in the meantime he [Stuart Adler] was preparing the extracts. We got some of Ham Smith’s restriction enzyme. And so he [Adler] did just that – using sucrose gradients to assay activity on SV40 DNA of these various restriction enzymes. What he found was that three out of the four he tested cut SV40. Smith’s enzyme obviously made many breaks. The E. coli B enzyme made one break, the P-1 enzyme made one break, and the K enzyme didn’t touch it at all.
We published a little abstract in the Federation Proceedings in 1972. So that really set the course of what we had to do. Obviously, we had to separate those fragments in case of enzymes that made multiple cuts, and we had to find out what part of the DNA molecule they came from and create a map that way – a physical map – and then see how we could use that map to localize different functions. Kathleen Danna, who was a graduate student in the lab, had been working on the RNA phage problem, became interested in this and so she took it up and found that one could separate the DNA fragments on acrylamide gels by electrophoresis, as had been done with real virus RNA duplex segments. [We] determined the size of the fragments [and] their order in the genome. We did the post labeling experiment to determine the origin of DNA replication and then collaborated with George Khoury and Malcolm Martin at NIH to do transcription studies using fragments to determine where messengers mapped. In essence, it’s been going in this direction since.
In the few remaining minutes of this interview, could you give me some ideas on the things you are doing now?
Yes. We have become interested in the regulatory elements that may be present in the SV40 genome that control rates of the DNA replication and control expression of early and late genes. Our approach has been to construct mutants in a segment of the DNA which is outside the coding region of the nucleotide sequence. In fact, right at the start point of the early and the start point of the late genes, where the origin of replication is known to map, where the beginnings of messengers are known to map. And we are creating mutations, either single base pair substitutions at specific sites in that region or small deletions, and then determining what physiological effect those mutations have and in that way, trying to define at the sequence level, what signals there are that apply to those processes.
Any results yet?
Yes. David Shortle who is a student in the lab, a M.D., Ph.D. student, first developed a very nice method for making point mutations in DNA at pre-selected restriction sites.
How does that work?
That works by using a restriction enzyme to nick at a specific site and then to make a small gap at that site and then to use a chemical mutagen specific for single-stranded nucleotide residues. In order to modify those residues you can use bisulfide which deaminates C-residues and single-stranded polynucleotides to U. Well, that creates, in essence, a base pair substitution at that point, which is fixed, which cannot be corrected by cellular enzymes. Then he [Shortle] applied that to the region where the origin of DNA replication maps and has obtained some very interesting mutants, some of which are deficient in DNA replication and some of which over-produce DNA by something like threefold over the wild-type rate. Each of these is a single base pair substitution, all within about a half dozen nucleotide residues of each other. What it amounts to is that an operational definition of the cis-element which we call the origin – the origin of replication – that controls the rate of DNA replication.
Well thank you very much, Dr. Nathans. Dorothy, I believe you had some questions you wanted to ask.
[2nd Interview begins – Dorothy A. Brockhoff interviews Dr. Nathans]
I am going to have to get much more elementary. I am going to start out by using some quotes that I found in Time Magazine, which is one of the things that your PR department sent in finding out whether Time is correct in trying to zero in on why you got the Nobel Prize. If we can explain to the general reader what the work actually consisted of, that is where I would like to start.
I brought this quote from Time [Time, Oct 23, 1978, p. 90]. “Scientific work does show that a specific restricting enzyme group of virus, SV40, known to cause cancer in animals,” [ed. note: but not in man] “into eleven defined fragments.” Then, it says that you “later described the way SV40 was split when two other enzymes were used.” And it says, “by analyzing the fragments produced by all three enzymes you [Nathans] was able to map the SV40 genes.” Do you think this is now a correct summary of your work? Is that what you would say if a layman came up to you and said what was the basic summary of your work?
Well, it is an accurate statement about the beginning of this work on the use of restriction enzymes to analyze simple chromosomes. The general notion is that the enzymes which were discovered by Hamilton Smith [ed. note: Johns Hopkins University School of Medicine] and really were implicated in this kind of function by Werner Arber, [ed. note: University of Basel, Switzerland] who also shared the Nobel Prize. This was, I think, the first use of those enzymes as genetic tools to cut gene segments out of a larger chromosome and to use those segments to try to map the functions of the genes. This has really been extended very greatly subsequent to that early work in a large number of laboratories, to a point where one can use those fragments to get at the ultimate kind of map of a chromosome, namely, exactly what the order of the basic chemical units are, that determine the biological activity of the chromosome.
Then the layman would say, “Why is it important to get such a map?”
Yes. You know, before the early 1940s our conception of a gene was some kind of ill-defined entity which somehow or other determined heredity characteristics of all living organisms, including man. It was an abstraction which was deduced from looking at the characteristics of living forms and how they related to the parents’ characteristics. Then in the early ’40s it was discovered by Oswald Avery and his colleagues at the Rockefeller Institute that the chemical substance that determined that was DNA. Then the structure of DNA was determined, I should say induced, by [James] Watson and [Francis] Crick. So the next natural step was to try to dissect the DNA that made up the genetic material much more finely and in that way to understand how it works. One of the key elements in that further understanding of how DNA works was to be able to dissect very large pieces of DNA, which are very difficult to analyze, into small pieces, which are much simpler to analyze. But it wouldn’t do just to break the DNA anywhere because you can imagine that if you had a huge string and you just came along and broke it up randomly, you would end up with a collection of pieces that were distributed in all specific sizes, from all particular regions of that original length of string. Whereas if you had a way of cutting, let’s say, three inches from one end, five inches, nine inches, so that you’re very specific, then you would get a whole collection, which is a relatively small number of pieces, each of which was a particular size. That essentially is what restriction enzymes do.
By separating those pieces you now have either individual genes, or very small collections of genes, or specific pieces of genes and those can be analyzed in great detail both from a chemical point of view and a biological point of view. What that means in a broad sense is that even if you can’t examine the genetics of an organism you can analyze the DNA and try to understand something about its genes and how they function. I might say a very important subsequent step in this process of analyzing very complex chromosomes by looking at individual pieces, was the recombinant DNA method, which certainly has as one of its elements the use of restriction enzymes but has a whole new influx from a different pathway of microbial genetics which allows one to isolate from any living organism very specific gene segments for further analysis.
Let’s continue with Time’s explanation. They say that scientists have found about 100 restriction enzymes. How are they able to locate these particular enzymes and do you think many more will be discovered in the coming year? That was my question when I read the [figure] 100. Do you think we’re just on a threshold of discovering many more or is this probably the optimum number?
Let me just answer sort of by historical description of what happened. What happened was a certain small number of enzymes were discovered in some particular bacterial species and then another one was discovered in a different bacterial species and then there was a more or less systematic search through the known bacterial species for restriction enzymes. As a result, over 100 different enzymes were discovered. So, I’m sure we haven’t exhausted the total number. I would doubt that we are going to find a thousand more, for example. Not only that, but this is a little bit more sophisticated argument: DNA is made up of only four basic units. It can only be arranged in a finite number of ways. If you look, say, at four at a time, or six at a time, which is what these enzymes see when they attack DNA. So since there are only a finite number of these combinations of four or six, if we discover more enzymes, or as we discover more enzymes, more and more of them show the same kind of cutting activity as one already discovered.
This was the question I was particularly interested in: they went on to say (these were the writers at Time) that you were cited, that is by the Nobel Prize people, for your “brilliant discussion of other possible applications of the enzymes to genetics.” I wondered if you could elaborate on that.
Well, let’s leave out the adjectives that they used (laughter), I think what they were referring to is in the first full-length paper that we wrote in 1971, which detailed the way in which one of the enzymes, actually the enzyme that Hamilton Smith discovered, cuts the viral DNA into specific pieces. We also, Kathleen Danna and I, discussed possible ways in which the enzymes could be used in understanding the chromosomes of viruses and probably more complicated things and how they might be used to analyze mutants of the virus. [We discussed] how Smith’s methods, and this was perfectly obvious really, could be used to discover more enzymes, and how these pieces obviously would be important for analyzing DNA to the ultimate level that I mentioned, of nucleotide sequence.
I know one reporter was hitting away, as Time indicated, on all the practical aspects of this kind of work. Could you perhaps touch on that for the layman? What lies ahead?
Well, it occurs to me that I may not fully have answered your other question about practical applications, but let me do that here. I think that the most important outgrowth of the work that I am involved in, the work on recombinant DNA – which as I mentioned, is really a new development – is the deeper understanding of how complex chromosomes are organized and how they function, including the chromosomes from man. As you may know, encoded in the DNA of our chromosomes, are programs for how we develop from a single egg into an adult, programs for how cells become brain cells, intestine cells, or blood cells. These are all genetic programs that preexist in the DNA and we know almost nothing about these programs, how they operate. I think the major contribution of all of this field that we are talking about, which includes the use of restriction enzymes, is in the insight it’s going to give into those kinds of fundamental problems and of course into the problems of disease that are related to abnormalities in development or changes in cells that lead to different kinds of diseases like cancer. We already are getting some very major insights into those problems.
Now at a more practical level, that is to say perhaps you have in mind in thinking about your last question, particularly with recombinant DNA technology added on to the use of restriction enzymes, it is possible to isolate genes (and this is called molecular cloning) which codes for proteins that are biologically very active and very useful, such as insulin for example, which you read a great deal about. Clearly it is just a matter of time, I think very little time, before insulin is produced in one of these, so that it will be available for medical use. I see also the possibility of making new kinds of proteins with perhaps new kinds of biological activity, some of which might be inhibitors of some proteins that are related to the way diseases are produced. For example, diseases of the autoimmunity, immunology, immunity against your own tissues. Because we now know how to modify genes so that you can produce products that are slightly different from the normal products in predetermined ways, and I see this as becoming increasingly important. It has often been discussed – the manufacture of some viral and bacterial vaccines would probably be helped by use of this kind of methodology. The diagnosis of certain genetic diseases is already being aided by the use of restriction enzymes to analyze the DNA of the fetus. I think gene therapy which has been discussed for a long time has a way of treating certain genetic disorders.
What do you mean, gene therapy?
I mean adding to the cells of an individual who has a genetic disease, genes which will function in place of the genes that are defective in his cells. I think that has now become a real possibility for the future, that is to say perhaps a decade from now.
Do you see this as a practical application for the treatment of cancer too? That has been one of your interests, hasn’t it?
Yes, it is my interest. I would say that I myself cannot, from the vantage point of this time in history, see specific practical applications such as the treatment and prevention of cancer. I do, however, see advances in understanding how cancer comes about. I think this kind of approach is going to contribute very greatly in trying to understand how a normal cell changes from a normal cell to one that becomes different which we call cancer. There is some change, which at least in some forms of cancer is very likely to be a genetic change, and we need to determine what that change is. Perhaps, and I say “perhaps,” by understanding that we will be able to do something to prevent that change from occurring or to correct it if it does occur. But again I repeat, I don’t now see how we go from studying the mechanism to an application of it.
Are you concerned now with all the fuss and furor about the discussion whether there should be research in recombinant DNA and so forth – the moral implications? Have you addressed yourself to this any more, talked about it, written about it?
Well, I was involved in the early letter that was published in Science and other journals that called attention to possible or conceivable biohazards involved in recombinant DNA. What I had in mind, and I think what many of the other signers of that letter had in mind, was that people who do recombinant DNA experiments ought to have some experience in handling microbes in the same way that people who handle known pathogenic microbes have. You know there are guidelines for ways of handling organisms, say, that cause pneumonia or that cause typhoid fever and tuberculosis. People are trained to do that, and people who don’t have a big governmental apparatus looking over their shoulders and things have worked out very well. It occasionally happens that there’s a laboratory infection, but it’s extremely rare and I don’t think there is an instance where there has been an epidemic as a result of a laboratory infection. That is what I had in mind in voicing that initial concern about recombinant DNA, but what happened was—
You voiced that in a letter you said?
Together with another group actually, chaired by Paul Berg.
Was it published?
Yes it was published in ’74. But what actually happened was the development not of what you’d call guidelines in the strict sense, but actually regulations, governmental regulations, very detailed regulations, I think. In my view, regulations which were all out of proportion to any reasonable assessment of the conceivable risk. I think things are now coming back into a balance, things are much more rational now. We still have not quite reached the level which I think the situation calls for, but under a recent revision of the NIH regulations, it’s now possible for university investigators to do most of the experiments that they’d like to do. That is, they don’t now need facilities which it’s just inconceivable universities can build and operate in the university center. I am hoping the next step will be to change the regulations, the guidelines, in much the [same] way (as I mentioned) that we do for known pathogenic organisms, so that individuals know that they need a certain kind of training, an institution takes responsibility for seeing that those individuals have the appropriate kind of training, [and] the appropriate kind of facilities, and we proceed to do our creative science without the encumbrances of a really huge bureaucracy, and at great expense, I might add.
I wanted to go back now to the very beginning. I read that you came from a family of eight children. I wondered what your parents did, what your father did to support a family of that size, and if you were the only particular child who went off into the direction of science?
Well let me start a little bit there. My parents were both immigrants from Russia. In the early part of this century there were several waves of Eastern European Jews who came to the United States. They came because in Russia, and in much of eastern Europe, they were confined to ghettos. Opportunities for education were extremely limited, and in my father’s case there was an additional factor, namely that his father, who was a Talmudic scholar, was an extremely orthodox man. He wouldn’t allow my father to have secular books in the house and so my father left home. I think he was sixteen.
What was your father’s name?
Samuel. He left home when he was sixteen and got a job and decided to emigrate, and accumulated enough money to bribe his way across the border into Germany and then came to the United States, where he had an older brother living in Boston.
When was this?
In approximately – I don’t know the exact date – 1909. Soon thereafter my mother, who incidentally is a first cousin of my father, came to this country from the same area of Russia. She was eighteen at the time. She was a seamstress in Russia. She traveled alone and came to her sister who lived in a small town in Pennsylvania.
What was your mother’s name?
And she moved to Hazleton?
Yes. In the new country my parents re-met (as I said, they were first cousins) and married and lived in Philadelphia initially. And that is where the small army of children started, and I’m the last one. Actually, there were nine children, but one of my sisters died in infancy.
Did you grow up in Philadelphia?
No. I was born in Wilmington, Delaware. By the time I came along my family had moved to Wilmington. My father had a small grocery store. You asked how he supported the children, I will never know that. I can tell you some of my recollections about that period. He had a small grocery store and it was absolutely wiped out during the Depression years. He was unemployed for I don’t know exactly how long – I guess three or four years. [He was] much too proud to take relief money. At that time my older brothers and sisters were bringing some money [home]. We owned an old house that was attached to the grocery store. But I can never remember the store actually operating, at least at the time when I was old enough to notice these things.
When were you born?
I was born in 1928.
So you remember a little about the Depression.
Oh, yes. I remember about the Depression. I remember our house was in terrible shape; rain leaking in, ceilings falling down. We just didn’t have the money to fix it up. I learned later from my mother that she and my father often went hungry to provide enough for the children.
Was she trying to work, too, as a seamstress in this country?
No. She was too busy rearing the children. She had worked, yes. When she first came to this country she worked as a seamstress, but after the children started coming she stopped working – she helped in the grocery store. Finally, my father got a job with the Allied Kid Company in Wilmington as a laborer there.
What’s the Allied Kid Company?
It’s a leather factory. Curiously enough I remember that time as an extremely happy one. I was very well cared for, as you can imagine, as the youngest child in the family with everybody looking out for my welfare. It was an extremely warm atmosphere. I only have fond memories of those years.
Your father was not strict in the sense that his father had been? About books?
No. On the contrary. I think he was basically an agnostic. He stopped attending the synagogue. Stopped sending his children for religious education.
So you weren’t brought up—?
No. I received no religious education whatsoever.
Have you abided by that since then or have you felt the interest, after you went to Israel, to become involved?
I’ve always felt Jewish, aside from the religious aspects – I’ve never been a religious person. But from the view of historical context, of social customs, of certain attitudes, I’m very much Jewish.
Did the other children in the family go on to the university, too?
Yes. Almost all of my brothers and sisters went to the University of Delaware, which was the state university, very close to Wilmington where we lived, and of course, relatively inexpensive.
How did you ever scrape up the funds? Did you work part-time while you were going to school?
I began work when I was in the sixth grade. Ever since that time, throughout my schooling, I’ve worked at some job or other. I used to like to go to the Jewish Community Center and I began sports there – swimming, basketball and so on. Wonderful place – and I used to get odd jobs there. I was towel boy for a while – in the locker room, for quite a few years, starting, I think, in sixth grade. And then I worked at a wallpaper store on weekends, after school, and in the summer. As I look back on it, I’m very grateful for the kind of relationships that I developed during those years and how well I was treated.
Grateful? You mean you learned a lot about people?
No. What I mean is I’m grateful for the warmth of the relationships with the people I worked for and with. It was all very enjoyable to me. It seemed like that was the way everybody lived – of course you worked after school, of course you worked on weekends, and so on.
Did you have a scholarship at the University of Delaware?
I think that was the first year that a man named Silverstein, who owned a chain of drugstores in Delaware – the _____ [name of store is unintelligible] stores – set up a scholarship fund.
_____ [name of store is unintelligible] stores?
Yes, and I’ll come back to that. He wrote me a letter – and my name got into the newspaper. I saw a notice for the scholarship in the Wilmington newspaper, in my senior year of high school, so I applied for it and I got the scholarship – and that was very generous scholarship. It paid tuition, for _____(?). So that’s how I managed. Now my sisters and brothers who preceded me had a tougher time – it was mostly working that got them through.
Did they all get a university education.
I think all but one of my siblings went to the University and all but one finished.
Tell us about the letter.
After my name appeared in the paper—
After you won the Nobel Prize?
Yes. I got a wonderful letter from a man named Samuel Silverstein from Philadelphia. He said that he noticed my name in the paper and that he now was eighty-four years old and that my name seemed familiar to him. As since he was “preparing to meet his Maker,” (he had a wonderful sense of humor – very humorous man) – as he was preparing to meet his Maker and would like to enter those pearly gates he wanted to be able to say that he did a good turn in his life and therefore was writing to me to find out (quote) “whether you are the boy who won the ______ [name of the drugstore chain] Scholarship in 1946.” It was just delightful! I enjoyed so much being able to write to him and tell him that I am the boy! And also, _____(?).
That brings us to the Nobel Prize. There have been descriptions in some of the literature out here on how you reacted when you heard about it – champagne corks were popping in the laboratory and so forth and so on. I believe one of the writers in the Johns Hopkins magazine said that your reply when you were first informed over the telephone was, “Well, I’ll have to have verification,” which he seemed to think was typical of the way you would react. On the other hand, Smith is supposed to have said, “Wow!” when he was told about it. I wonder if the stories are true.
The quotes are not quite literally correct. I think she’s very accurate in other ____(?). (Laughs) I was finishing breakfast on that morning, the phone rang [and] I picked it up. The woman said “This is so-and-so from the Associated Press.” [ed. note: Dr. Nathans continues to tell of his notification that he had won the Nobel Prize, but the tape is difficult to understand except for an occasional word] And she said it was just a press release. My reaction was, “Well, I’ll tell you what. You come down to my laboratory in about two hours. By then I’ll know whether it’s true and I’ll be prepared to give you a statement.” (Laughs) At least Hancock [ed. note: Johns Hopkins magazine editor] got the spirit of my reply.
You said you have had many fantasies but you’d never had any fantasy about winning the Nobel Prize.
(Laughter) I knew you’d ask me that. I’m not going to tell you what fantasies I’ve had. I’ll leave it to your readers’ imagination.
But you never wondered about the Nobel Prize in all the time you—
No. My feeling was that the area that I was working in was clearly of such long-term significance that sooner or later the Nobel committee had to take notice. Who they decided represented those advances most appropriately for the Nobel Prize was quite another question. That was their business, not mine.
How has your life changed? Or has it changed since you’ve won the Nobel Prize?
Well, it hasn’t changed in a fundamental sense. How I spend my time has changed. But in the fundamental sense, I still have the same interests, the same intentions in terms of what I want to do, mainly to do research and continue teaching. It’s changed my schedule a lot. There are a lot of invitations to go here and there and give talks, dinners to attend and so on, university functions. I not only cannot turn them all down, but I don’t want to turn them all down. But as a consequence, I find [that] my time is spent doing those things or thinking about those things so that I have much less time to do science and research.
You went to Sweden to get the [Prize]. What was that like? You made an acceptance speech. Could you briefly describe [that]?
It was a wonderful trip. I went with my wife and our three sons, and two of my brothers and a sister and the dean of the Hopkins medical school, who was my guest. We spent about eight or nine days there. It was just beautifully done – a wonderful combination of formality and meticulous planning – services that were available to us all the time. And a real personal warmth from the people who were on the scientific committee at the Karolinska Institute for the physiology or medicine prize. And we just enjoyed it tremendously. It’s sort of a national pageant there and this week or so is set aside. It was just done so beautifully. Every moment was enjoyable.
Is it possible for us to get a copy of the comments that you made?
Earlier, when you were talking with Dr. Schlessinger, you mentioned the number of doctors here at the university who had an important influence on you. I was wondering, are there any other people that you did not mention in your interview with Dr. Schlessinger who had a profound influence on your life, whether they were scientists or whomever they might be? I think the readers would like to know something about them, if there were such people.
I am trying to think who I mentioned.
Well, you mentioned the Coris, Dr. Cori, and you mentioned specifically Dr. Lowry and I noticed you spent a lot of time talking about Barry Wood. I wondered if there were others besides this fellow at the Rockefeller, Lipmann.
I think those are the principal people. There were faculty members at the University of Delaware, not so much in science as it turns out, [but] people _____(?) science and philosophy – which actually for me was the most rewarding and enjoyable part of my undergraduate education – not the science, biology and chemistry. [They were] people whom I got to know, liked and respected.
Would you care to mention any of their names? Would they be names that the readers might recognize?
I don’t think so.
They were in other fields?
Yes. I majored in chemistry and of course took all the biology that is needed to get into medical school. But I also managed to study philosophy and political science at more than an elementary level, and enjoyed it very much.
Because of your interest in political science, etc., are you active in any of the committees of concerned scientists about the image of science today and what’s happening and so forth?
I haven’t been very active over the years. I think I am getting more active now as a result of invitations that have come to me. I think in the future I’ll be more active still.
What do you think about the image of the scientist today? There have been some programs here on Channel 9, the educational television station. They seem to think, particularly since the Three Mile Island incident, that people are turning away from science, they are getting skeptical, they are getting worried. What do you think?
You know, clearly people are worried about technology and what it does to their lives and rightly so. Yet my experience during this recombinant DNA debate was that there is an enormous reservoir of good will for scientists and the feeling that they are trustworthy and not narrowly selfish as is sometimes the image that people might be concerned about. I did not sense that all. Similarly, in my contacts with congressional committees, I also got that feeling. But there is no question that people worry about what technology is doing to the quality of their lives and I am worried, too.
I think it is something that we have to be constantly concerned about. First of all, we don’t have all the answers and the insights that it takes to know what some given kind of technology is going to mean for our lives. We have to figure out the best way we can to balance the benefits and risks of technological change. Things are changing so rapidly – that’s an obvious concern to people. Our lives are changing so rapidly compared to all the previous centuries for which we have records. That creates anxiety and uncertainty about the future. That is a real issue. I don’t have any simple answers to this. There is no way I can see in which we suddenly cut off technology. We have got to decide each issue as it comes up, but hopefully not from a narrow point of view of the immediate benefit of that technology as opposed to the possible long-term harm of that technology. At the same time, we have to be well-informed; that is actually the burden of the comments that I made at the Nobel banquet.
Scientists have an obligation to inform the people in a democratic society. Ultimately, it’s the people who make decisions of this kind. They have to be well-informed in order to make intelligent decisions. There is no easy way for them to be sufficiently informed to make an intelligent decision, but we have to do our best when we have knowledge that is applicable to particular problems and to convey that in a clear and relatively uncomplicated way. I think people who get interested in those problems have to educate themselves. They can’t just make emotional statements; that is not sufficient. They have to educate themselves and make responsible statements. I think the press has to be the go-between in this kind of communication in a more responsible way than it has been.
Well, do you have some sort of, I wouldn’t say an affinity for the press, but some sort of understanding of the press since I read that you married a lady who was a reporter at one time. Is that true?
I guess you could say she was a reporter. At the time we met, she was working in Washington. Yes, she was reporting on social legislation – federal legislation in the social welfare field.
I just wondered whether you dealt as strictly with the press as some scientists do. Some scientists are very contemptuous of the press.
Let me say that I have not so much been contemptuous of the press as disappointed by the quality of most of the reporters that I’ve had contact with. I think part of the problem is the intense pressure that they’re under to produce an article at some time in the immediate future. But by and large, I’ve found that they’ve been so concerned about producing that product to meet the requirements of their job that they’ve compromised on quality of that product – with rare exceptions.
Who were the exceptions?
I met a man from the Wall Street Journal – not recently, several years ago – at the American Cancer Society, at a _____(?) conference. He was interested in getting some insight into problems he was going to write about. Now I grant you that he didn’t have to produce an article for the news page of the Wall Street Journal. He was intending to write an in-depth review of a particular area. But he was an intelligent man. I’ve talked to Mr. Schmeck—
Hal [Harold M.] Schmeck.
—of the New York Times. Again, I thought he was a very sensitive person who was interested in getting an accurate and interesting story. But those are exceptions. It concerns me that people who are informing those on whom the ultimate decisions rest in a democratic society are [so poorly prepared]. Let me mention one other person, Elise Hancock.
The lady that wrote the story—
The editor of the Johns Hopkins magazine. She is very bright and [has] a lot of insight.
Was she helpful in interpreting your work to the layman?
Yes. I think she wrote a beautiful article after very brief interviews with me and with Hamilton Smith. She dug out the original papers. She asked for the original literature to read and so on. She did a beautiful job.
It came to me while you were talking – for a long time you weren’t sure whether you were going to go into clinical practice or whether you were really going to stay in research, or go into research. As you look back on it, are you glad you made the decision that you did?
Oh yes. It was absolutely the right decision for me. I’ve been very content with my choice. I felt extremely fortunate in having the opportunity to do the things that I’ve done. I think in discussing my family background you can readily appreciate that it’s not an opportunity that my parents had.
Do you have any advice to young people interested in a career in research? I guess you get asked this very often.
I think it is a very important question, because I find that young people today are too concerned about the security aspects of their career choice. I was surprised to find when I gave a talk recently before a group of Westinghouse science winners in Washington – we had dinner preceding my talk – that that was the topic of conversation that interested them. I think that people have to follow their interests. That is not to say that you don’t have to give some thought to what the opportunities are going to be, and obviously we all need shelter over our heads. But I think they have to put the emphasis where it really counts and that is to do something that interests you, that excites you, and that is going to give you satisfaction. I have always felt that for myself that I did not want to spend 90 percent of all my hours earning enough money to enjoy the rest of the time. I wanted to do as my primary occupation something that really excited me. I am happy with my choice.
The editor of this magazine gave me a stipulation when I came over to her. She wanted to know, and I don’t know how to ask this, other than to put it in those same words she did. She said, “What does it take to be a Nobel Prize winner? Do you think that the people have certain characteristics in common?” I was thinking about that a lot last night, and I would guess hard work is certainly one, and a lot of ability. Can you think of any other qualities that come to mind?
I have no way of answering that. I think it is a very diverse group of people and I think, by and large, creative people who do the things that they are interested in doing.
Do you plan to write any kind of book, such as The Double Helix?
I have no such plans.
You have written a great many publications; I noted that in our write up that we are going to do on you.
About average, I’d say, for somebody in my stage.
They are mostly scientific. You don’t write for any of the more popular magazines?
They are all scientific. I did accept an invitation to give a talk at the Honors Program here – my first such venture.
Have you given any thought to what you are going to say there?
Yes, but you will have to wait.
I guess that is it then. Thank you very much.