UNIVERSITY OF WISCONSIN-MADISON ARCHIVES
ORAL HISTORY PROJECT

Interview #529
LEDERBERG, JOSHUA

LEDERBERG, Joshua (1925-2008)
Professor of Genetics
At UW: 1947-59

Interviewed: 1998	
Interviewer: Barry Teicher
Length: 5 hours, 49 minutes

Family background; Stuyvesant High School; Early interest in science; Columbia College; Francis J. Ryan; Navy V-12 training program; Columbia University College of Physicians and Surgeons; Early work with neurospora; Work at Yale with Edward L. Tatum; work with George Beadle; Discovery of recombination in bacteria; Cold Spring Harbor Symposium; Challenge by Andre Lwoff and Max Delbruck; Position at UW; Candidates; Interview; Hiring concerns; Job offer; Arrival in Madison; Ira Baldwin; Rudolph Froker; Department of Agricultural Genetics; Jim Crow; Recombination research; Karl Paul Link; Transduction; Norton Zinder; Lambda; Larry Morse; Immunogenetics; Phase variation; Tetsuo Iino; Cell motility; Bruce Stocker; Replica plating; Esther Lederberg; S. G. Bradley; David Skaar; Aleck Bernstein; Bob Wright; Boris Rotman; Tom Nelson; Summer research at Berkeley; Roger Stanier; Protoplasts, L forms and penicillin; Fulbright fellowship in Australia; McFarlane Burnet; Work with NASA; Moon infall; Carl Sagan; James Watson and Bill Hayes; Numerical Analysis Laboratory; Teaching; Department of Medical Genetics; John Z. Bowers; Kimball Atwood; Stanford University; Arthur Kornberg; Nobel Prize; Trip to Sweden; Honorary degree; Reflections on career at UW

First Interview Session (June 19, 1998): Tapes 1-2

Tape 1/Side 1

00:00:00	Question: Could you discuss briefly your early schooling and a little bit about 	your family background? Answer: Joshua Lederberg (JL) was born in 1925 in 	Montclair, New Jersey, to parents who had recently emigrated from Israel. His 	father was a part-time rabbi, taught Hebrew, and supervised the ritual slaughter.  	His family had moved to Washington Heights in Manhattan by 1925. JL attended 	New York public schools, which were instruments of Americanization and upward 	mobility and were very much in keeping with the melting pot tradition in 	America.

00:02:01	No question: JL was a precocious child and even though this caused some difficulties at times, he had some very wise teachers who were sympathetic and made accommodations for his intellectual gifts. That degree of insight and compassion has always impressed JL. He was academically inclined and spent a great deal of time reading. He learned more from the public library than from school.

00:03:00	No question: In 1938, through an entrance examination, JL qualified to enter Stuyvesant High School, which had been founded in 1918 as a special school for science academic development. Stuyvesant housed academically talented youth, and because of that JL felt less lonely than he had in grade school. The teachers were good as well, and were extremely sympathetic to the intellectual nurturance of their students. Besides after school clubs and activities, Stuyvesant also had advanced placement courses, which was unusual for the time. JL estimates that half to two-thirds of his classmates were, like him, second-generation Jewish immigrants. Today you would find similar phenomena, except the students would be Asian rather than Jewish.

00:05:10	Question: Were there any teachers that played a particular role in your training? Answer: Because he was so self-directed, JL cannot directly recall any teachers at Stuyvesant who played significant roles in his intellectual development.  However, the teachers played an important role in creating a nurturing environment, which was important to JL. In terms of curriculum, there were lots of electives. JL focused on chemistry and some biology. He talks briefly about the chemistry set he owned in grade school.

00:06:37	Question: What about the role of religion in your early life and education? 	Answer: The discussion turns to the role of religion in JL’s early life. His father 	was an orthodox rabbi and while JL had a good deal of sympathy for the 	fundamental ethical and philosophical traditions of Judaism, he had difficulty 	connecting them to the ritual practices that go back to the Middle Ages. Over 	time he and his father came to respect their differences.

00:07:50	Question: Did you have any career aspirations early on? Answer: JL knew he was going to become a scientist from the time he was literate. One possible explanation for this early interest in becoming a scientist, he notes, is that this was an alternative to orthodox religion, in that Jews had folk heroes like Albert Einstein who, while not deeply observant, were highly respected, proud of their Jewish origins, and a credit to the Jewish people.

00:09:11	Question: Why did you select Columbia? Answer: After graduating from Stuyvesant in 1941, JL enrolled in Columbia College. Originally he assumed he would be attending City College until, at the very last moment, he won a scholarship to Columbia. He selected Columbia partly because of his limited knowledge of other possibilities, but partly out of opportunity. He also had an eye on Columbia because he knew that individuals like T. H. Morgan and E. B. Wilson had been there and that they reflected the tradition of Columbia being a great center for research in biology. In high school JL received no advice from his teachers about which college to attend, since they all seemed to assume he would attend City College. City College had some good teachers and a superb peer group, but very limited laboratory facilities and only the semblance of a research program, especially when compared to the active research programs at Columbia.  JL cannot remember the details relating to the scholarship he received from Columbia, but he assumes he had received advice in this area from his mentors at Stuyvesant. One other possibility was that there was a competitive entry into an organization called the American Institute Science Laboratory, which was later incorporated into the New York Academy of Sciences. AISL won a grant from Westinghouse and IBM to establish a laboratory where high school students could actually dabble in research. JL notes that he graduated from high school in February of 1941 but was not able to enter Columbia until September, partly because he was too young but also because it was midyear. Thus he ended up spending much of his spring working at the AISL.

00:13:26	Question: When you enrolled at Columbia did you declare a major immediately? 	Answer: Upon entering Columbia, JL had determined that his majors were going 	to be biology and chemistry. He enrolled in a number of graduate courses as a 	freshman which, he said, was for the best, since he was not mature enough to 	appreciate the humanities—which he put off taking until later in his 	undergraduate career. JL notes he did exceptionally well in the sciences, but the 	rest of his cultural experiences were not that far ahead of his chronological age.  	Because of his age, there was some initial skepticism on the part of his professors 	in the graduate courses he was enrolled in, but that soon disappeared.

00:14:42	Question: Hans Ris was at Columbia, was he a post-doc at that point? Answer: 	One of the people at Columbia JL had occasional contact with was Hans Ris, who 	later enjoyed a successful career at UW. He was among those who initially 	looked askance at JL because of his age. Over time Ris came to accept him.

00:15:32	Question: Were there any courses or instructors that particularly influenced you? 	Answer: Regarding instructors, the one outstanding mentor JL had at Columbia 	was Francis J. Ryan. One of the first courses he took was taught by Franz 	Schräder, E. B. Wilson’s successor. Schräder was a rather stiff, Germanic type.  	When JL wanted to do experiments with mice, Schräder was not overly 	enthusiastic about the idea. Salome Waelsh, who suffered discrimination because 	she was a woman, befriended JL and gave him the mice he needed to conduct his 	experiment. He explains the experiment he was working on, which in the end did 	not work out. Just three months ago, JL notes, a paper was published that, in 	effect, reproduced the experiments JL had done at that time.

00:17:42	Question: You served in the V-12 hospital corps? Answer: JL entered Columbia in September of 1941 as a civilian. The Navy advertised an officer training program called V-12. You entered the program through competitive examination and if you were accepted the Navy would put you in uniform and support your education.  Later you would have an obligation to service. JL qualified as a pre-med, and eventually a medical student. He was accepted into the program in 1942, with the agreement that he would not be called into active duty until July 1, 1943—at which point he was to be immediately sent back to Columbia College’s V-12 program. The only problem was in early June JL received his orders, which said he was to report to Holy Cross College in Worcester, Massachusetts for his pre-medical training. He soon learned, however, that he had received the wrong orders, and when the situation was corrected he was indeed sent to the V-12 program at Columbia. For the duration JL lived in the barracks in Hartley Hall on the Columbia College campus. Occasionally the Navy would pull JL out of school for a quarter and have him serve as a hospital corpsman at St. Albans Naval Hospital. He was assigned to the clinical laboratory, where he served as the parasitologist and did laboratory diagnoses. Occasionally he took care of patients, but his main job was in the laboratory.

00:21:47	Question: You graduated from Columbia then? Answer: JL started attending 	Columbia Medical School in October, 1944. Columbia Medical School had a 	very fine reputation and was located in the neighborhood JL grew up in. His idea 	was to obtain a degree that not only allowed him to practice medicine, but 	conduct research in neurology. In the meantime, he had become deeply imbued 	with pursuing genetic work back at Columbia. As it turned out, he continued 	working in Ryan’s laboratory in Morningside Heights on the main Columbia 	campus while simultaneously attending medical school.

00:23:44	No question: Returning to Francis Ryan, JL notes he was at Stanford doing work with George Beadle and Edward Tatum during JL’s first year at Columbia. JL had heard about Ryan and was aware of the fact that Beadle and Tatum were studying biochemical mutants in Neurospora. As soon as Ryan returned to Columbia, JL camped on Ryan’s doorstep “and gave him no peace” until he let JL work in his laboratory. JL calls Ryan the most important mentor in his life, both during his college days and beyond. Some of the reasons Ryan proved so helpful was that he provided JL with discipline, readily exchanged ideas, and taught him how to conduct experiments and record his results—in other words Ryan taught him “what it meant to confront a scientific issue in a highly professional way.” When Ryan died at a relatively young age the number of testimonials about his role as a teacher “was absolutely legendary.”

00:24:56	Question: Another person who makes a brief entrance into your life later on is 	Kimball Atwood, wasn't he a student of Ryan's as well? Answer: The discussion 	turns briefly to Kimball Atwood, who also worked with Ryan. Atwood was at 	Columbia doing experimental work at the same time as he was attending New 	York University Medical School. At one point, after JL had enrolled in medical 	school, he and Atwood roomed together. Later Atwood again worked with Ryan 	on periodic selection in the chemostat and some other “very fine experiments” 	which, JL notes, had nothing to do with medicine. JL cannot understand why 	Atwood bothered attending medical school, since he had little interest in it and no 	intention of using his medical education.

00:26:08	Question: Your first publication was with Ryan? Answer: JL’s first publication, 	“Reverse-mutation and adaptation in leucineless Neurospora,” was with Francis 	Ryan. JL began as a dishwasher and assistant in Ryan’s lab, and Ryan gradually 	let him do more things, including sharing ideas with him. Ryan had observed a 	phenomenon of what was called adaptation, where leucine-requiring strains of 	Neurospora when planted in a leucine-free media would not grow, or grow to a 	very limited degree, because they did not have the leucine they needed to make 	their protein. But occasionally an event would occur where an outgrowth of 	leucine-independent organisms grew very happily without leucine. So the 	question became was this really a reverse mutation? Although this seems very 	commonplace today, it was a new concept at the time. JL was assigned the job of 	investigating whether it was a reverse mutation, which basically involved doing 	back crosses between the adapted strains and the wild type strains to make sure 	there was no hidden leucine-dependant genetic material in those strains. The 	answer, JL discovered, was that there wasn’t, and the best they could tell the 	adaptive change was a mutation in the same gene that had mutated in the first 	place.

00:27:51	Question: Were there any other professors? Answer: JL names some other professors he worked with at Columbia. Ryan was the person he spent the most time with, however. At Columbia Medical School no one professor stands out.  The students “were herded into a very large lecture room,” but still he got to know some members of the faculty, such as David Rittenberg, David Shemin and Sam Graff.

00:28:49	No question: Most of JL’s work in medical school was pretty didactic, and he 	cannot recall developing any deep intellectual relationships. There was also a 	different peer group, and while they were smart they were not primarily 	scientifically oriented. Some of his classmates later became important in 	academic medicine, but they were the exceptions rather than the rule.

00:29:35	Question: What happened that caused you to take a leave from school and transfer to Yale? Answer: There were two reasons why JL took a year’s leave from Columbia Medical School and transferred to Yale. One reason had to do with the fact that World War II ended, which allowed him more flexibility in pursuing his medical education. The second reason is he already had begun experiments looking for recombination in bacteria and wanted to continue. The work was more or less an extrapolation of work he had done with Ryan on Neurospora reversions, which had been influenced by Avery, McCarty and MacLeod’s paper on DNA causing genetic transformation in pneumococci.

00:30:40	End of side.

Tape 1/Side 2

00:30:40	Question: So what seemed to you was the most burning question? Answer: The most burning question in biology at the time was the authentication that a chemically defined substance was the carrier of genetic material (Avery et al, 1941). This needed to be approached from a variety of perspectives. At first JL tried transforming Neurospora with extracts of wild type Neurospora. He attempted this in Ryan’s laboratory and with Ryan’s strong 	encouragement. JL extrapolated those experiments into one trying to transform Neurospora, which for a variety of technical reasons did not work. He then thought he could perhaps turn this around and see if bacteria could change genetic material by mating as do other organisms. The textbooks dismissed this possibility, but as JL started to delve into the matter he began to realize there was no intellectual foundation for the claim that bacteria were asexual. He was reinforced in this approach by Rene Dubos, who had just left Rockefeller University for Harvard and who had laid out arguments pro and con for sexuality in his book, The Bacterial Cell, thus confirming JL’s inference that there was no hard evidence one way or the other, and that it was a problem worth pursuing with powerful genetic methodology—which he had learned from working with Ryan.

00:32:55	No question: The experiments got underway without giving clear-cut results.  	When the war ended one of the scheduling options presented to JL was an elective 	quarter. This was done partly to give the overworked medical faculty a rest.  	Francis Ryan proposed to JL that he consider working with Edward L. Tatum, 	who had just moved from Stanford to Yale. Very importantly, Tatum had just 	developed some mutant strains of Escherichia coli that would be ideal for the 	experiments JL was planning to conduct. Instead of just asking Tatum for the 	strains, Ryan suggested to Tatum that he take JL into his laboratory. JL wrote a 	letter outlining the research proposal and Tatum accepted him for the quarter 	beginning in March or April, 1946.

00:34:31	Question: Let's talk a little about Tatum and his background? Answer: The 	discussion turns briefly to Tatum and his background.  Tatum’s father, Arthur L., 	was a distinguished professor of pharmacology in the medical school at UW.  	Tatum had been raised in Madison and done his undergraduate and graduate work 	at UW.  He had worked with E. B. Fred and William Peterson for his doctorate, 	which was on nutrition in lactobacilli, and he was among the first to discover that 	bacteria needed vitamins for their growth.  JL notes that Tatum was doing a post-	doc after completing his graduate work with Fritz Kögl on the nutrition of fungi 	when he received word that George Beadle was starting a program of research on 	the biochemistry of eye colors in drosopha, in which he was working out the 	genetic control and gene-enzyme relationship.  This was in 1936-37.  In 1937 	Beadle ended up recruiting Tatum to come to Stanford and work out pathways of 	eye pigment biosynthesis.  This had nothing immediately to do with Tatum’s 	background in microbial nutrition, JL notes, but the latter had everything to do 	with the transition to research on Neurospora.  Beadle eventually became 	frustrated with the complexities of working with eye pigments and decided to 	shift to Neurospora, where Tatum’s background in nutritional requirements of 	fungi fitted perfectly into that scheme.  Thus in January or February of 1941, 	Beadle and Tatum started their experiments on looking for biochemical mutants in 	Neurospora—and by June or July they had collected a good sampling of them.  	They published their first report in October or November in the Proceedings of 	the National Academy of Science, which made for a very quick breakthrough.

00:37:35	Question: What compelled him to come to Yale? Answer: Tatum, who had been denied promotion to associate professor at Stanford, possibly because there was at the time a fair amount of prejudice against chemists in biology departments, accepted Yale’s offer to a full professorship. He set up his program at Yale and JL was one of his early recruits. Tatum was only at Yale for a couple of years before accepting an offer to return to Stanford.

00:38:41	Question: Let's talk about your collaboration with Tatum?
	Answer: JL came to Tatum’s lab at age 21 with a prepared proposal and a definite protocol for his experiments. Working with Tatum, JL learned a lot about conducting experiments. Tatum was a very insightful investigator and had “a green thumb.” It took only six weeks to complete the experiments. By the first of July, JL “was ready to talk about them.” The opportunity to do so came at the Cold Spring Harbor Symposium, held in early July, 1946. JL did not think they were going to get the chance to talk about the experiments at the Symposium, but Al Hershey talked about recombination of bacteriphage and some of those in attendance started saying how unfortunate it was that bacteria did not do things like that. At this point Tatum and JL could not keep their experiment quiet any longer. JL notes how try as he might, he could not think of another experiment “that would nail it down any further than we had.” He knew that they had reproducible phenomena, that they had done experiments with more and more markers, and that they had clear segregation of unselected as well as selected markers. One of the joys of this kind of experiment, JL notes, is that you can do it overnight, meaning you can conduct numerous experiments in a month, if need be.

00:41:15	No question: Tatum managed to secure a place on the program, and there was a great debate following their presentation. The informal, post-session seminar lasted three to four hours. Andre Lwoff argued that JL had not proven he had gotten single cells that had the characters of two parental cells, and he was just dealing with contaminated mixed cultures that were cross feeding each other. That had been, JL notes, one of his initial concerns. Indeed, he designed his first experiments to make sure that would be readily detected if it occurred.

00:43:05	No question: The way the discussion ran was Lwoff said you had to isolate single 	cells, and JL responded by saying there was other evidence that these were pure 	clones and could not possibly be mixtures, after which Lwoff said he could not 	believe it till JL isolated single cells. Eventually Max Zelle raised his hand and 	said he would show JL how to isolate single cells, or they would isolate them 	together—which is exactly what happened. JL had overestimated the complexity 	of isolating single cells and found it easy to do, and he has done it routinely many 	hundreds of times since. Most accepted the results of JL’s experiment. The main 	holdout was the Cal Tech group. Max Delbrück in particular expressed great 	skepticism. JL said Delbrück, who was doing research on phage at the time, said 	essentially that JL had not done the experiments he, Delbrück, wanted him to do.  	JL notes that many of the top people in the field were supportive and encouraged 	him in his work. Regarding the experiment itself, technically it could have been 	done fifty years earlier, but there had not been the correct approach in thinking 	about bacteria as genetic entities. JL explains how, historically, the discovery of 	recombination could have occurred.

00:45:56	Question: When you started this experiment were you confident it was going to 	work? Answer: JL said that when he began the experiment, he had no idea if it 	was going to work. He merely wanted to test the proposition. He was prepared 	for the long haul and was startled when he achieved such immediate success.  	This early success, he notes, was “pure luck.” JL did not know how lucky he was 	in coming to Tatum because he not only had interesting mutants, but the very 	strain he had chosen, E. coli K-12, which was just one of the stock culture 	collections out of Stanford, proved to be almost unique due to a number of 	properties that lent itself to this kind of experimentation. In retrospect, for the 	way they did the experiment, if random strains had been chosen the chance of 	success would have been one in twenty. JL notes that he was well aware of the 	prospects of strain specificity. For all he knew there were male strains and female 	strains and he would have had to mix them with the right gender combinations.  	He was again surprised when it worked with a single strain. JL has no idea how 	persistent he would have been had the experiment not met with early success.

00:48:41	Question: You understood the enormity of what you'd done when you did it? 	Answer: JL immediately understood the importance of the experiment. He 	remembers linking it to what Avery and his people had done. He views himself as 	a genetic counterpart to Avery’s biochemical work.

00:49:21	Question: Where were the results published initially? Answer: The first 	appearance in print was in Nature, which was published in November, 1946. It 	was a very brief article summarizing what they had spoken about at Cold Spring 	Harbor. In the spring of 1947, the proceedings of Cold Spring Harbor were 	published. JL notes he did all the experiments by himself and he brought the 	concepts of the experiment to the lab. Tatum provided the strains and the lab 	space, as well as guidance and oversight. They talked over the results and 	reviewed the manuscripts together. JL did the preliminary writing and Tatum 	polished it up. JL and Tatum alternated senior authorship for the first couple of 	papers. JL does not recall Tatum ever publishing anything afterwards on 	recombination.

00:49:59	Question: Did Dr. Tatum think it was going to work?
	Answer: The issue when JL approached Tatum initially about the experiment was not did Tatum think the experiment would be a success. Rather, the issue was did Tatum think JL had a 	good experimental test. And they were going to find out something one way or another about nature by applying that test. In that sense the experiment would work, since it would answer the question of whether or not one can find genetic recombination in bacteria.

00:51:42	No question: The issue was that nobody in natural history had seen any clear evidence of reassortment of genes. Is there anything else in the natural history of bacteria, the question became, that might lead one to guess whether recombination is occurring? JL discusses some research published in 1941, which demonstrated how, when one does serological typing of what were then called species of Salmonella, one can see some natural historical suggestion that some kind of reassortment of immunogenic factors was taking place within the Salmonella group  That was the only hint he had at the time. This was also the reason that the next organism after E. coli JL wanted to study was Salmonella.

00:53:28	Question: At this point you're deciding not to go back to medical school? 
	Answer: Returning to the summer of 1946, because so many issues needed to be resolved in relation to his and Tatum’s recombination experiment, JL elected to ask Columbia Medical School for another year’s leave of absence. This was the year he worked out the linkage map of E. coli and published it in Genetics.  During this same time period, he met Esther Zimmer and they were married in December, 1946.

00:56:00	Question: Did you work with Tatum any more after that initial experiment? Answer: JL notes that Tatum was an extremely important and supportive influence during this period. Among other things, Tatum got him the fellowship that enabled him to come to Yale in the first place, then arranged that the fellowship be renewed the following year. JL comments that he could not have done his experiments had it not been for Tatum’s deep involvement and support. Still, Tatum was not immediately involved in the experimental or the intellectual work.  He was much more of a biochemist than a geneticist so even though he was concerned about gene-enzyme relationships, he was not thinking about mapping or several of JL’s other interests and concerns. JL briefly discusses what he sees as Beadle’s and Tatum’s most significant contributions to science.

00:57:58	Question: You wrote your dissertation on your experiments?
	Answer: JL’s dissertation was a compilation of the work he had already completed. In 1947 he was faced with a new crisis: does he return to medical school or not—and if he does not then what does he do next? At some point during that summer, Tatum received a solicitation from Alexander Brink of the University of Wisconsin asking about prospective candidates for a position in the Agricultural Genetics Department. Tatum sent Brink JL’s name along with some background material.  It was not until July of 1947 that JL was personally contacted about applying for 	the job. It was around this time that Tatum suggested that if JL was interested in securing a job, he might want to finalize his dissertation. Tatum then arranged with the Yale authorities for JL to register retroactively as a graduate student, so that all the time he was at Yale he was in an informal status as a visiting medical student from Columbia. In order to complete the retroactive registration, JL had to come up with an $800 tuition fee.

00:59:42	End of side.  End of tape.

Tape 2/Side 1

00:59:42	Question: Let's talk briefly about your experiment with Tatum, how did you feel about it? 
	Answer: The discussion returns to the 1946 experiment and JL’s thoughts when the first positive results came in. Fear, he says, was probably his dominant emotion. The fear was of having his expectations raised only to have them dashed later by not being able to replicate the results. Thus he tried restraining his emotions and assumed it was probably a mistake or an artifact. He was especially fearful that his judgment might be clouded by his high expectations. After repeating the experiment four or five times, there was no escaping it: the experiment was a success.

01:00:52	No question: From there JL allowed himself to think about its implications and ask the question “What do you do next?” He was eager to talk with others and get their input and suggestions, and indeed he did just that. The Cold Spring Harbor Symposium was a wonderful opportunity because essentially everybody in the field congregated for the first time since the war. The Symposium was important in two ways: first, it gave JL access to supportive and critical judgments made by people he respected and admired; and second, the debate that followed the presentation settled the matter once and for all. Had his findings first appeared in a journal, for example, the debate on a matter this controversial might have dragged on for months.

01:02:50	Question: Do you know why the decision was made to seek someone more theoretical to fill Cole's position? 
	Answer: A position in the Agricultural Genetics Department at the University of Wisconsin came open when Leon Cole retired.  The decision was made to replace him with a person more versed in basic, as opposed to applied, genetics. JL suspects that Cole might have been responsible for this decision to some extent. Although he did not know it at the time, several other names were submitted for the position. These included Max Zelle, J. M. Severens, John R. Laughnan, Adrian Srb, A. H. Doermann and David Regnery. JL later came to know some of these candidates very well. David Regnery ended up at Stanford University and was on the faculty there for some time. Adrian Srb went to Cornell, where he had a distinguished career in Neurospora genetics. Gus Doermann did some fine work on T-phages, and worked on Neurospora as well. Max Zelle is a bit surprising in that he did not make a strong mark scientifically, although he assumed some important administrative positions in biology and medicine in the Atomic Energy Commission.

01:05:02	No question: Prior to JL’s interview, Tatum told him a lot about UW and how 	much he had enjoyed living in Madison. JL, who had never visited the Midwest, 	had never met any of the people he would be working with in Madison. He was 	excited about going for the interview, especially in light of the fact that there were 	no other jobs available in bacterial genetics—nor was there a guarantee that there 	would be a job in this area in the foreseeable future. The only alternative he had 	at the time was to return to medical school.

01:06:40	Question: How did you get to Madison? 
	Answer: JL left for the interview in Madison by train. He brought his wife, Esther, and many people commented on what an asset she was to the 21 year old candidate’s credibility. JL was impressed by the friendly nature of the people in the Midwest. He thought, correctly, that he could enjoy Madison very much. JL’s first impression of Brink was as a very responsible, albeit initially formidable personality. JL came to like him immediately. Though forewarned, he was still somewhat dismayed by the lab facilities and he found himself working in primitive quarters for quite some time.

01:09:05	No question: Regarding his appointment into a college of agriculture, he says he 	was not the least bit dismayed about conducting basic research in a department 	that featured applied research. Besides, he notes, the University and the College 	of Agriculture already had outstanding reputations. JL knew a fair bit about the 	College’s work in various areas so he knew he would have intellectual 	companionship, even if he was on the basic side of the spectrum.

01:10:54	Question: At what point did you decide that you wanted the job in Madison? 	Answer: Even though he wanted the job in Madison as soon as he was greeted 	there, he was still torn about returning to Columbia and finishing medical school.  	He does not recall making a final choice until the very last moment. There were, 	in addition, other matters he needed to consider. He had applied for a Merck 	Fellowship that would have provided financial support for his time at Columbia, 	and at nearly the last minute the Jane Coffin Childs Fund said they would arrange 	some funding for him. JL was disappointed to learn he did not get the Merck 	Fellowship, as he had considered returning to Ryan’s lab and continuing his work 	on E. coli, while at the same time completing medical school.

01:13:11	Question: Was Brink the one who offered you the job? 
	Answer: Regarding the Madison job, JL’s correspondence indicates that he vaguely agreed to a verbal offer in Madison, probably from M. R. Irwin, and that this was followed up by a formal written offer. The salary offer was for $3500, roughly twice what he had been making as a fellow. He was hired as an assistant professor and as such was expected to teach and conduct research. During his first years at UW he started a course in genetics and microorganisms, which was cross listed with bacteriology. He also lectured occasionally in other courses.

01:14:15	Question: The question relates to whether JL was aware of concerns people had about JL’s hiring, concerns which focused on his age, his unfamiliarity with farms and agriculture, his “aggressive” personality and the fact he was Jewish.  Answer: JL notes that he was totally unaware of any of these concerns. In retrospect he understands that some of the people he had contact with on a daily basis might have had some misgivings about hiring a Jew, but if they did they never betrayed those feelings to him. Regarding his so called aggressiveness, JL said it stemmed from his relentlessness about the logic of the situation, in that he did not hesitate to speak his mind if the situation called for it. Over time he learned there were other ways to get one’s point across. He could take as well as give, he notes, and in the context of scientific discussion he always expected to be dealt with critically, openly, and forcefully—and he did not hesitate to treat others in a similar fashion.

01:18:00	No question: JL reflects on his relationship with the University of Wisconsin and 	how things might have worked out better than they eventually did. He also notes 	that he might not have been aggressive enough when it came to matters relating to 	resources, such as space and help. He notes that he did not push hard enough, and 	too often took “no” for an answer and let it stand at that. There were others on 	campus, he notes, who were more diligent in pressing for their needs. The net 	result was that instead of being as aggressive as perhaps he should have been, he 	ended up leaving and going to other places where he did not have to argue as hard 	for his needs.

01:19:23	End of side.  End of tape.  End of interview.

Second Interview Session (September 30, 1998): Tapes 3-5
			
Tape 3/Side 1

00:00:00	Question: Could you discuss briefly the Merck Fellowship you applied for? 	Answer: JL briefly discusses the Merck fellowship he applied for at 	approximately the same time he applied for the job at UW. The Merck 	fellowship, JL notes, was a newly instituted program of post-doctoral fellowships.  	He hoped the fellowship would finance his return to New York City to continue 	his medical studies at the Columbia College for Physicians and Surgeons. JL was 	not awarded a fellowship. That left him in a quandary as to how he would be able 	to afford to return to medical school. At that time he was also afforded the 	opportunity to accept a position at the University of Wisconsin. At the last 	moment, the Jane Coffin Childs Fund in New York City made an offer for a 	research fellowship that would have helped out considerably, yet it would have 	been difficult to cover tuition and living expenses with what the Childs fund was 	offering. In the end, JL decided to accept the job in UW’s Department of 	Agricultural Genetics.

00:02:34	Question: Why did Max Delbruck challenge your findings? 
	Answer: The discussion returns to Max Delbrück’s challenge of JL's recombination findings at the 1946 Cold Spring Harbor Symposium. JL recalls that Delbrück did not say much, critically or otherwise, during his presentation. Thus Delbrück was not a factor in the overt debate. It was only somewhat later, when JL wrote Delbrück for advice on some aspect of the work, that Delbrück wrote back saying he did not 	believe a word of the recombination theory and did not want to discuss it. Delbrück noted that JL was not doing the experiments on the kinetics that he wanted him to do. JL does not recall ever having a clear message from Delbrück of what, exactly, he had in mind.

00:04:24	No question: JL remembers Cal Tech, where Delbrück was from, as being rather 	quizzical about his findings from the outset. He later learned, from a letter Ray 	Owen had written Alexander Brink regarding JL's possible hire, that everybody at 	Cal Tech was opposed to his theory—a fact that puzzled Ray Owen. People at 	Cal Tech, JL notes, sometimes had difficulty understanding there might be 	important discoveries being made elsewhere.

00:05:40	Question: What about Hinshelwood and his concern regarding the experiment? 	Answer: The discussion moves to C. N. Hinshelwood, a very influential figure in 	science. Hinshelwood wrote "a curious book" in the mid-40s on the chemical 	kinetics of the bacterial cell. In it he denied the existence of genes in bacteria. It 	was evident in the book that he had not given much thought to recombination.

00:07:47	Question: What was happening in genetics in 1946 that prompted Brink and the Department of Agricultural Genetics to hire someone with JL's background and expertise? 
	Answer: The most visible and important innovations in genetics during the early 1940s, JL notes, were in the field of Neurospora. Also, the biochemical kinetics represented by Beadle and Tatum were making a stir, in that they offered the possibility of understanding pathways of gene action and brought genetics closer to biochemistry. Tatum was, in a way, an exemplar of that, and had he been available at an affordable rank, Wisconsin would have gone after him. Bacterial genetics almost didn't exist, with the exception of JL's 1946 work. There had been a few studies in mutation in bacteria, but the conclusions were less than far reaching. There was also work on phage, but the genetics of phage was, again, a recent phenomenon, and it is unlikely its results would have spread very widely at that point. In terms of the overall discipline of genetics, the part that had a chance to ripen and sink in since 1941 was the biochemical genetics of Neurospora.  Indeed the record has shown that some of the other candidates for the UW position had come from that field, which presented a very legitimate alternative.

00:09:56	Question: How did you approach the housing situation? Answer: JL and his wife, 	Esther, arrived in Madison prior to the start of the fall semester in 1947.  There 	was a tremendous housing shortage in Madison at the time, due to the large 	number of GIs on campus.  JL and Esther moved first into emergency housing at 	the Truax Field barracks, along with numerous graduate students, for the first 	couple of weeks.  They then had a rental for a year before moving into Eagle 	Heights, which was a new housing development on campus.

00:11:10	Question: You were hired for a nine month appointment? 
	Answer: JL's original 	appointment was for an academic year. This was quickly changed to a twelve month appointment. Starting at a salary of $3,500, JL soon got a raise to $4,800, which was for a twelve month appointment. Compared to what he had been living on, JL had no complaints about what he earned at UW.

00:12:19	Question: Ira Baldwin was dean when you came to Madison, could you talk about 	your association with him? 
	Answer: The discussion moves to various individuals in positions of power during JL's years in Madison. Ira Baldwin was dean of the College of Agriculture at the time JL was hired. As a new hire, JL had little to nothing to do with the dean. E. B. Fred was president from the time JL arrived on campus nearly to JL's departure in 1958. Again, JL did not have many dealings with Fred and that level of administration until when he wanted to establish a new program in a new department. When he wanted something, JL generally worked through the department heads, Brink and Irwin.

00:14:54	Question: What about your interactions with Elvehjem? 
	Answer: JL knew Conrad Elvehjem more as a professor than as Graduate School dean. JL saw people like Baldwin, Fred and Elvehjem as very correct, polite and reserved—something he did not fully appreciate until he had achieved similar status. Indeed, there is something inherent in these jobs that make one careful about what one says. JL also notes that the Madison administrators were men of their word who did not go back on their promises.

00:16:22	Question: Talk about your association with Froker? 
	Answer: The one other administrator discussed is Rudolph Froker, who succeeded Ira Baldwin as dean of the College of Agriculture. JL saw a little bit more of Froker than the others. Froker, JL notes, saw his job as running the Ag School and the Ag Experiment Station and serving the needs of agriculture for the state of Wisconsin. He thinks Froker might have been a little puzzled about his appointment. In hindsight, JL sees Baldwin as perhaps being more research oriented than Froker. JL relates an incident in which a professor was seeking support from the Ag Experiment Station to conduct research on plant improvement through protoplast fusion. JL thought it was a good idea and made some intervention to try and get the project some support. It was turned down, however, which, JL notes, may in part color his reaction.

00:18:24	Question: Where did Froker stand on the applied versus basic research? 
	Answer: Regarding the applied versus basic research debate, JL thinks that applied research, aimed at making a good name for the school in terms by showing what it could do for the farmers of the state, was what Froker saw as his mission. JL is certainly not opposed to that mission. In fact, it might be the only politically viable stance to take. There was no question that you could get a Baldwin or an Elvehjem interested in a scientific development, whereas Froker was someone who came with a different perspective.

00:19:45	Question: You were hired to take Cole's position, you did not have much 	association with professor Cole? 
	Answer: When JL was hired, he took the position that had been held by Leon J. Cole. Cole had retired the year before and died a few years later. JL has a vague recollection of meeting him once or twice after arriving on campus, but he remembers Cole's spirit as being "all over the place." Brink and Irwin frequently referred to Cole and his vision of incorporating more basic science into the Department’s overall activities. JL came to learn that Cole had even written a paper about bacteria in 1916, and while it was rather primitive it was still ahead of most thinking at the time. The very fact that Cole worked in the area of bacteria at all set him apart from many others at the time. Cole, JL notes, was very sympathetic to an eclectic view of what genetics needed, and he certainly had a vision of the ever growing importance of genetics in biology and human affairs.

00:21:54	Question: Talk about your first impressions of Brink and your relationship with 	him over the years? 
	Answer: The discussion turns to members of the Department of Agricultural Genetics in 1947. Almost everybody in the Department was much older than JL when he arrived on campus and was thus, in his view, venerable. This was certainly the case with Alexander Brink, with whom JL had an avuncular relationship of sorts. Like so many others in the Department, Brink dealt with JL kindly and generously. Brink, who took a serious view of science, had, in his work, "spanned the gamut of some very important applications in breeding work," in addition to studying cattle poisoning from sweet alfalfa and other practical work. With his work on transposable genes, Brink was on to the same line of work as Barbara McClintock. McClintock won a Noble prize for her work, and, JL notes, it would have been totally credible for Brink to have shared the prize with her.

00:24:52	No question: The discussion of other members of the Department begins with 	Lester Casida, whom JL characterizes as a bit of an anomaly because he was more 	of a reproductive physiologist than a geneticist. Casida conducted important 	research that was published in basic science and application journals.

00:26:23	Question: What about Arthur Chapman? 
	Answer: JL did not have much contact with Arthur Chapman, Delmer Cooper, Norman Neal and Gustav Rieman, perhaps because they spent a good deal of time in the farm fields conducting their research. JL knew Richard Shackelford a little better. He describes Shackelford as a lively person, whose main line of work was mink breeding. He was interested in pigment mutations and hair color and he was as much a geneticist as a breeder. Shackelford, JL notes, uncovered some interesting developmental mutations in mink.

00:28:36	Question: Could you talk about your first meeting with Jim? 
	Answer: The discussion turns to Jim Crow, whom JL first met at Cold Spring Harbor in 1947. Crow was extremely lively and had a breadth of interests. He was a fruit fly geneticist who later went into human genetics. He is very articulate, thoughtful and generous. During JL's first year in Madison another vacancy occurred, and 	the Department wanted to find somebody who could teach formal genetics. This was to be a joint appointment with Letters and Science. JL brought up Jim Crow right away, and the Department liked Crow from the outset. JL thinks his being in the Department was part of the draw, in that they had a lot of common and fundamental interests. Crow was also an excellent teacher, and JL often comes across people who had their first genetics course from Crow and remember him clearly.

00:30:39	End of side.

Tape 3/Side 2

00:30:39	No question: Continuing with the discussion of Jim Crow, JL notes that Crow taught the introductory course in genetics, which was in all likelihood cross listed in zoology. Crow's research was in population genetics in Drosophila, and he conducted experiments on natural selection with cages with artificial populations of various mutants and how they evolved over time. JL explains how Crow's research expanded when he ran into certain kinds of mutants that showed departures from normal Mendelian behavior. Crow worked with Larry Sandler, one of his early students, on a phenomenon called meiotic drive, which is a situation in Drosophila genetics where you do not get one-to-one ratios because the presence of the gene actually alters the details of spermatogenesis and competition between sperm, with some carrying and some not carrying the gene. JL says it was lucky Mendel did not run into that early on or he never would have discovered his laws because they would not have applied. Crow was interested in anomalies like that. He also became more and more theoretical about how mutations affect any reproductive process and enter into the mathematical theory of natural selection. He did a good deal on the foundations following Sewall Wright, R. A. Fisher, and others in the elaboration of that theory.
							
00:32:21	No question: This then drove an interest in his part in human genetics and human 	evolution from a similar perspective—such as studies of mutation in a human, for 	which he is still regarded as a world expert. He also became more and more 	involved in advisory work to the government. JL believes he was chairman of 	several successions of the National Academy committees on biological effects of 	atomic radiation, which were very important in setting standards of radiation 	exposure. So he had a very broad ranging set of interests. In addition, JL said he 	talked over his own experiments with Crow all the time, and vice versa.

00:33:16	Question: In terms of the department as a whole, how would you characterize it? 	Answer: JL thinks the Department of Ag Genetics functioned well and that Brink 	and Irwin were both good managers. Both men practiced shared decision making 	with members of the Department.  It was not necessary to take everything to a 	formal vote, as there was enough informal consensus to run the Department.  	Thus, both Brink and Irwin could speak authoritatively whether or not there had 	been a formal vote on the matter under discussion.

00:34:27	Question: Were there any problems or issues in the department during your years 	that you recall? 
	Answer: The issue of funding in Ag Genetics is discussed. JL says he was more fortunate than most because he had access to NIH grants, which provided a major part of his funding during his years on campus. People doing more applied work received funding through the Agricultural Experiment Station. These funds were usually a little on the scarce side. In addition, there was less of a merit system involved, which might have proven a little discouraging for those doing cutting edge work. Again, JL was not involved much in the administrative end of the budget. He had much to do in the lab and focused his energies there. He got more work done in his years at Wisconsin, JL notes, than at any comparable period in his career.

00:36:20	Question: When you came to Madison, did you bring any research with you? Talk 	a little bit about the lab conditions. 
	Answer: The discussion turns to JL's research. JL’s first lab at Wisconsin "was pretty primitive." It had no air conditioning and "was not much more than a couple hundred square feet, all together." It had facilities for glassware washing, autoclaving and media preparation and the like. His lab also contained two lab benches, and for a long time JL did not have a hood. It was difficult to do much chemistry under those conditions, but he was able to do microbiology. Probably the most irksome thing, from JL's perspective, was the summers. It was not just a matter of personal comfort, but the agar plates would not jell. The temperatures were around 35-40 degrees centigrade. Nevertheless this period proved to be the most fruitful of his career.

00:38:12	No question: The work JL brought with him to Madison was the work he had 	done his dissertation on, which was the discovery of the recombination of 	bacteria. He spent the 1946-’47 academic year working out how to do linear 	mapping from the crosses of different E. coli strains. After that there was the 	question of "what do you do next with that system?" That was still a time when, 	although the strains were publicly available, there was no competition. Luca 	Cavalli was just beginning to conduct experiments in this area and it would be 	two or three years before anybody else really picked it up.

00:38:56	No question: A line of inquiry JL had in mind to start with, and which had its 	beginnings at Yale, was to work out still more sharply the actual physical or 	physiological system—the mechanics—of recombination. Could you see the cells 	joining up with one another under the microscope? What was the fertilization 	process like at that level? This proved very difficult because it was a rare 	phenomenon with the strain he had at that time. You could tell from the 	frequency of recombinance when you made mixed cultures that only about one 	out of a million cells in a culture would participate. So how are you going to go 	around looking for unique morphology when you have a haystack of a million and 	one needle in that haystack and no obvious way to pick it out morphologically?  	JL says they ran a blank on that for quite a while, but then several things started 	happening in very quick succession. One was the discovery that there were, in 	fact, mating types in E. coli. In one level this was not a very great surprise, 	because JL had started his work with Neurospora where there were well 	established mating types and you can only get a cross if you mix a plus and a 	minus strain together. In the Neurospora case you don't talk about one as being 	male and the other female, you just have arbitrary alternate types.

00:40:46	No question: With E. coli it turned out there was a polarization that, besides there 	being a mating type difference, that the plus cell, called the F+ cell for fertility 	factor, was actually contributing genetic material to an F- cell which was 	receiving it. JL knew that because the contribution was often much less than the 	complete genome. As a result, there existed progeny that were the result of a 	quarter, a third, a half of the genetic material of the donor of the F+ cell being 	represented in the overall progeny of the fertilized F-cell.  So he started calling 	them male and female. This was greatly helped by Cavalli's discovery of a strain 	that showed a very high frequency of recombination—which got as high as 1 	percent or even a few percent, making it so JL could at least start dreaming of 	being able to see the conjugal mechanism under the microscope.  Eventually he 	succeeded in doing that and actually finding pairs of cells stuck to one another.  	He describes using a strain of E. coli other than K-12 where, when looked at 	under the microscope, one could see the cells that would agglutinate with one 	another.  But every now and then you would be able to see a clear mating pair 	where there was a plumb one and a thin one stuck together. You could then 	isolate and follow that pair and their offspring under microscopic control. The 	result was a good correlation between the occurrence of these pairs and the 	occurrence of genetic recombination in the progeny.

00:43:13	No question: This was one line of research that put physical meaning into the very 	abstract recombination process. Until then it had been a black box where you put 	two genotypes into the black box and ended up getting different genotypes out of 	it. This way you could get a little more insight into what was going on in 	between.  However they were still unable to get a clear picture of exactly how the 	DNA was transferred from one cell to another because for most of their lifetime 	these pairs, although they are swimming together, maintained a physical gap 	between them. For a while, JL thought maybe one of them was getting stuck on 	the flagella of the other. We now know it is not the flagella, but other much 	shorter hairs that are all over the surface of the cell, which apparently are the 	recognition sites for F+ and F- cells. Thus "he" recognizes "she" through the 	mediation of these hairs. Looking at the problem today, from the best we can tell 	the hairs allow the two cells a little later on to get very close to one another—and 	then something else happens and there is a pore opened up as the cells are in close 	approximation and a single strand of DNA unravels from the double strand and 	works its way through to the recipient cell and increasing amounts of it appear in 	the donor cell that initiates fertilization. The conjugal mechanism, JL notes, has 	ended up rather more complicated than he had initially expected. His visual 	model had been that the two cells actually fuse with one another, as in fungi and 	protozoa. The complete fusion is not seen, however. To this day, JL is attempting 	to find systems where complete fusion occurs-but that is not the standard even in 	E. coli crossing. This issue became very complicated with the contributions of 	other workers. JL mentions some, including Bill Hayes' discovery of the F 	system. He also discusses experiments conducted by François Jacob and E. L. 	Wollman, in which they timed the progressive entry of different genes from the 	donor cell into the F- cell. At first JL resisted this approach, thinking there might 	be other explanations for the genetic ratios they were getting, but over time he 	came to accept it. That was the underlying platform of JL's continued research on 	E. coli recombination upon his move to Madison.

00:47:38	No question: There were equally exciting things going on as well. Once you have a cross breeding mechanism in bacteria, the question becomes what can you use it for? One issue JL brought with him from Yale was to use the genetic control of enzyme reactions. In particular, he decided to concentrate these efforts on lactase.  The enzyme was easy to measure and it was one that under some conditions is not vital to the life of the organism, so that lactase negative mutants would be perfectly viable and you could grow them and study them and compare them with the wild type, lactase positive. Shortly after arriving at Wisconsin, JL asked Karl Paul Link for assistance and Link got one of his graduate students to prepare a substrate that would give rise to a color reaction when the enzyme was present. What resulted was a very sensitive and very keen assay for the enzyme. JL very quickly found a great many mutants that were defective in lactose metabolism.  At about the same time Jacques Monod, and joining with him shortly thereafter, François Jacob, was beginning to work on the same system. Originally they were doing this without reference to recombination. Starting in the early '50s, they began embracing a program quite similar to JL’s, but whereas JL's approach was to learn how many different kinds of mutants he could find and could he classify them in having different impact on the formation of the enzyme, their approach was to go into much further depth on the phenomenon of enzyme induction—about what happens within the cell when lactose or other inducing substrates are added to the bacteria and the enzyme starts to be formed. JL ended up with numerous anomalies and they ended up with a very pretty picture. Their pretty picture is mostly right, but there are still some anomalies that have not been explained very well.

00:50:39	No question: The contributions that came out of his work encompass two 	important points. The first is JL found, on introducing this colorimetric assay for 	the enzyme, that there was a baseline level of enzyme formed. It was only about 	1 percent of the maximum level, but it was not zero. That told JL that the 	inducing substrate was not carrying information necessary for the specificity of 	the enzyme. It was acting as a trigger for the production of the enzyme, but its 	production was going on anyhow at a low level without the inducer. That was a 	new concept at the time, because most theories of enzyme induction thought the 	substrate played an active role in shaping the enzyme around it. This was, then, a 	departure from that point of view. The other, which went even further, was that 	among the first mutants JL isolated was one that he called a constitutive mutant.  	This is a mutant that went full blast in making top levels of the enzyme even 	without an inducer. This just reinforced the idea that the cell already had all of the 	information needed to make the enzyme, and the role of a substrate was as a 	physiological modulator of level of production. This was eventually internalized 	by everybody, but JL thinks his early experiments in this area set the trend of 	thinking in that direction. JL started those experiments in 1947. Much of this 	work is summarized in the 1951 Cold Spring Harbor Symposium.

00:53:44	No question: JL notes there are some anomalies that led to some amusing 	consequences, because besides using lactose he started using other sugars and 	looking for fermentation defective mutants with respect to those sugars. There 	was one that, oddly enough, was a non-fermenter, or a very slow fermenter on 	glucose, but fermented very rapidly on maltose. The question was: if you had a 	glucose negative mutant how come it was fermenting maltose? In 1950 JL was a 	summer lecturer at the University of California and he met Mike Doudoroff, who 	was a member of the biology department or biochemistry department and who 	was very much into fermatative metabolism. Doudoroff was quite skeptical about 	what JL told him, but when he viewed the cultures, he and his students went to 	work on it and discovered a new pathway. It turns out that in E. coli a major 	pathway for the utilization of maltose is to use one of the two glucose residues—	maltose is glucose linked to glucose—to synthesize the starch from it, and use the 	other one and release not glucose but glucose six phosphate. (JL notes that it 	might possibly be glucose one phosphate.) This was a new pathway that was 	picked up as a result of the anomalies generated by these units.

00:55:47	No question: There were a number of things that JL stumbled onto in the process 	of this other more designed line of work.  He has already mentioned the F factor, 	it turns out these mating types were controlled by a unique genetic element which 	was not in the chromosomes, but were floating around in the cytoplasm. The F 	factor, as later work has shown, is controlled by a little ring of DNA which 	replicates along with, but is not part of, the bacterial chromosome. JL says it may 	in fact be present sometimes in multiple copies. So this is a whole new class of 	genetic elements, and it was a prototype for what JL later called "plasmid".

00:57:05	No question: Another thing they stumbled onto—which was the result of astute 	observation by JL's then-wife Esther—was the presence of phage plaque 	appearing on plates of certain kinds of crosses. They had no idea where these 	were coming from. At first Esther thought it was a contamination. JL suggested 	following that up, and they found that standard strains of E. coli were carrying 	embodied within their genetic structure a bacterial virus, which they called 	lambda. At first they thought this was another cytoplasmic factor, and they 	compared it to the kappa that T. M. Sonneborn had been working with in 	paramecium. That proved to be not quite correct. They soon discovered that if 	you do crosses between lysogenic strains—the ones carrying this phage—and 	sensitive strains,  the lambda segregates as if it's on the chromosome—it was 	linked to a factor called galactose. There was no question that the capacity to 	produce lambda was linked chromosomally, thus in some way you had something 	that could be transmitted through the medium, enter the target cell, and then 	become incorporated into the chromosome.

00:58:46	No question: This also ended in some parallel thinking about genetic transduction.  	The French group concluded that cytoplasmic factors—the ones JL called 	plasmids—often, or maybe even always, had a Jekyll-Hyde existence in its being 	able to go into and out of chromosomes. They coined the term "episome" for that 	transition, which was a perfectly legitimate concept except others started getting 	confused and using episome to mean transmissible particles whether they got into 	the chromosome or not, and it got to be a little bit messy. This eventually got 	straightened. Plasmid is an overarching set of extra chromosomal genetic 	elements. Some of these can interact with the chromosome, and in the case of 	lambda they do. In the case of F sometimes they do and sometimes they do not.  	So when F gets into the chromosome it is stabilized and has a high frequency of 	recombination associated with it. If it stays out in the cytoplasm, it allows 	conjugal transfer, but transfer of the chromosome only at a very low rate and 	transfer of the plasmid itself at a very high rate. They were, thus, able to tie 	together a number of aspects in what might be called infective heredity.

01:00:42	End of side.  End of tape.

Tape 4/Side 1

01:00:43	No question: The discovery of lambda, which is a prototype for a large number of 	other viruses that can have a lysogenic stage—with lysogenic meaning capable of 	producing the phage, where the virus is integrated within the chromosome, and 	then relating that to the overall plasmid concept—was, JL thinks, important 	elaborations of cell biology that have had very broad ramifications even beyond 	microbiology. Indeed, we use these concepts every day when we think about 	cancer viruses and so on. But they were unexpected by-products, in that they 	were not in any way looking for them. These were things simply stumbled into in 	the course of other work.

01:01:39	No question: The discussion turns now to transduction, which was the outcome of 	a very explicitly designed experimental effort, but which had an outcome they 	were not counting on. JL had begun his research with E. coli because everybody 	was using E. coli, in that it is convenient, it grew on simple media, and the strains 	JL worked with were totally safe—although it has relatives that are dangerous.  	But it does not have any great medical interest. It is not, by itself, a source of 	disease. It can be used technologically for producing various kinds of gene 	products, but that did not occur until many years later.

01:02:51	No question: JL had had his eye on Salmonella as a near neighbor, a close cousin 	of E. coli. He saw it as something that, once they had the tools, should be worked 	on genetically as well. Thus working with Salmonella was on his agenda when he 	began his work at Wisconsin. In 1948 JL recruited his first graduate student, 	Norton Zinder. JL suggested that Zinder work on recombination in Salmonella.  	Salmonella, JL notes, is in many respects just like E. coli. Its most obvious 	difference is that the entire lactase gene and its control elements are deleted from 	it. Another reason to look at Salmonella, besides its importance in food poisoning 	and typhoid fever and related diseases, was a lot of serological work had been 	done on it. The serology of the Salmonella group had a special interest because 	the pattern of distribution of different antigens in its natural history was a mosaic 	kind of matrix that struck JL as indicating that recombination must be taking place 	to account for the various combinatorial varieties of Salmonella strains that are 	found in nature. This was an idea JL had before he did his first E. coli experiment	—in that yes, there should be recombination as part of the natural history of 	bacteria.

01:05:00	No question: JL got Zinder to start working in that area. JL then wrote Kaare 	Lilleengen, who had a library of different strains of Salmonella typhimurium he 	was happy to share with JL, together with a few bacteria phage which he had also 	isolated.  JL thought these might at a minimum be useful as resistance markers.  	Zinder and JL set up protocols exactly analogous to those of E. coli.  They had a 	tough job getting a new library of mutants, and that inspired developing some new 	experimental methodology for acquiring mutants.  JL remembered a lecture in 	medical school which noted that penicillin only worked on growing bacteria, so 	he thought maybe he could exploit that.  The question relating to that became: 	"How do you isolate a needle in a haystack when the needle is a nutritional 	requirement?" It is easy to isolate the hay, he notes, but how do you isolate the 	cell that is not growing? Penicillin, JL concluded, only attached cells that were 	growing.  This worked, giving JL a new method for isolating auxotrophs, which 	was invaluable in developing the library of Salmonella mutants.

01:06:38	No question: Zinder continued his work, trying crosses, while JL was very rigid 	and said he would not believe it unless Zinder could show he had double mutants 	on both sides, because if you only have a single mutant requirement it may revert 	spontaneously and be an artifact. The best basic method, as in E. coli, was to 	have growth-dependant strains that would not grow in minimal medium, mix 	them up, and see if there was any bacterium that would grow in minimal medium. 	But then you want to make very sure that your controls are completely negative, 	that they will never revert. If you only have a single mutant, then you can almost 	always get rare reverse mutations that confuse when you get crossing. JL did not 	want to go wrong on that, so when Zinder showed him results with some of his 	single mutant strains that looked like they were giving recombinant prototrophs 	much more frequently than could be accounted for by reversion, JL would point 	out that these results were not to be trusted and that Zinder needed to work with 	double mutants. When Zinder tried it with double mutants, however, it did not 	work. Zinder finally found one particular double mutant that did work, with 	another double mutant strain, and this was a mutant that had both a tryptophane 	requirement and a tyrosine requirement. This seemed to work quite well. The 	background was completely negative and they never saw any reversions, and 	when you mixed the culture they gave a result.

01:08:21	No question: It became apparent at this point that they had a new system, but was 	it exactly the same as the E. coli system? One of the very first things one does, 	and JL did it very early in the E. coli work, was to see whether the filtrates of the 	parent cultures, or even the mixed cultures, could induce change as compared to 	the intact cells. In other words, are the units of interaction both in intact cells, or 	can you get something that will pass through a filter that will still interact? Lo 	and behold, JL notes, unlike E. coli the filtrate worked. There was much more of 	it in a mixed culture, although you could get a little activity with a filtrate on one 	of the pure strains. Here JL and Zinder had a clean enough system that JL felt 	confident that a result that had one bacterial strain with just one marker and a 	filtrate—he got such a big difference between reverse mutants and the effect of 	the filtrate—could now be trusted. He was unwilling to trust it when he was 	mixing the two cells together, because for one thing he was not sure how much 	continued growth was occurring, but this was a much cleaner result.

01:09:53	No question: At this point, they were "coming down the home stretch" with totally 	new phenomena which were very different from E. coli.  But filtrates of mixed 	cultures could transform single mutants and could be any one of a number. The 	only double mutant they could transform was the tyrosine tryptophan. At some 	point they "smelled a rat." There was something very special about that double 	mutant, and they had to have stumbled on it in order to get the total picture.  It 	was at this point that JL said he went around in circles for a while, because there 	had been a lot of talk about L forms. People in the field had been publishing 	pictures about very curious morphologies of bacteria under certain conditions, but 	also in phage lysates—very bizarre shapes and forms. They were offering hints 	that maybe these were gametes of some kind, and formally this statement was 	correct.  JL and Zinder had a filtrate, it had granules in it, and if they put it in a 	centrifuge and spun it down hard the filterable activity, the FA, could have this 	transforming activity.  JL had it in his head, however, that this might have 	something to do with the L forms. Zinder was trying to struggle with it and hone 	in on exactly what was in the filtrate. They were getting there, because they were 	actually doing physical fractionation and some people, perhaps even Zinder, were 	remarking that maybe it was phage.

01:11:45	No question: At the 1951 Cold Springs Harbor Symposium, JL presented these 	results on behalf of the whole group, which was again a hodgepodge of 	everything they had been working on for the last four years. Zinder followed that 	further and said that if it was phage, they should be able to grow it. That 	eventually is what materialized.  They now had a situation where they could take 	a phage, grow it on one Salmonella strain, and the phage filtrate, by itself, would 	transfer activity to a recipient strain and give this prototrophic progeny.  This was 	a new phenomenon and they gave it a new name—transduction. This became 	another very powerful tool for genetic analysis. Transduction has been found in 	numerous other species. So what was the "rat" about the tyrosine phenylalanine?  	It turns out they are very closely linked.  The other markers are sort of scattered 	around the chromosome. It turns out that the size of DNA, which is packaged in a 	phage particle in transduction, is about 1 percent of the genome. So if you happen 	to have two markers that are within a segment that is 1 percent, they will go 	together and you get co-transduction of two separate markers. Co-transduction is 	also used as a tool: if you want to establish close linkage, show that they are 	transduced together.

01:15:00	No question: Larry Morse was in the lab at the same time and he thought he 	would see if lambda could transduce. He set up some experiments and found the 	answer was generally no—with one outstanding exception, which was that if you 	took a galactose positive lysogenic strain and gave it a shot of ultraviolet light it 	activated the prophage, the prophage started multiplying, started producing many 	copies of itself, and what they then discovered was a very high frequency of 	transduction of the gal marker—but no other marker in E. coli. Gal and lambda 	are very closely linked on the chromosome. They now knew that the transducing 	particles were defective. The transducing particles made a little mistake in what 	piece of the chromosome they had integrated. Instead of being the intact lambda 	and nothing else, it was kind of a shift where they had a defective lambda and a 	piece of the gal that went along with it. That is a specialized transduction and it 	only works for a marker very closely linked to the prophage itself. In generalized 	transduction any piece of bacterial DNA at random can be packaged into an 	occasional phage particle. Thus, within a short period of time they discovered 	two new mechanisms of recombination.

01:17:20	Question: Let's go now to immunogenetics. 
	Answer: The discussion moves to JL's work in immunogenetics. JL now had a new mechanism for genetic analysis 	which could be applied to Salmonella. At this point, they started looking through the serological factors and found a connection at the Center For Disease Control in Atlanta, which was the United States reference center for Salmonella infection work. The Center was particularly helpful and provided JL with all the re-agents he needed. They started looking at this mosaic structure of different serological types. JL found it easy to take any two Salmonella of different serology, grow phage on one and apply it to the other, select against the existing strain so you got rid of the unmodified bacteria, and under the influence of the transducing phage find exactly the new ones that you expected. So if you have somatic antigen x and y, and flagella antigen a and b, you start out with x cum a, and another strain y cum b, grow the phage on the latter, and you can get an x cum b very readily. You have to select against the x cum a with anti-a antiserum just to get rid of the majority of parental cells that are still there. JL notes that you almost always do this in bacterial genetics because the sex life is not that active and they do not need sexual reproduction for the most part to produce new progenies, so you have to somehow get rid of the existing types then see what new ones are going to be present—which is quite routine in this kind of work. So you could essentially generate any serological type you wanted, whether it already existed or not.

01:21:29	No question: Another biologically even more interesting phenomenon was there 	to be analyzed, this one with the help of Tetsuo Iino, a graduate student from 	Japan. The issue here is a phenomenon called phase variation. This has to do 	with there being two different antigenic phases of Salmonella bacteria in the 	flagella. JL gives an example of this phenomenon. In the mosaic descriptions of 	different Salmonella strains, JL notes, you write down the somatic antigen of each 	of the two alternative phases that go along with it, which are interconvertible, in 	that a cell flips from being what is called specific phage into so called group 	phase, and vice versa. But it always alternates between the same two alternatives, 	thus you cannot predict what the second phase is going to be from what the first 	phase was. You can predict what the second phase is going to be, but only if you 	know the history of that particular strain.

01:23:58	No question: So what it looked like was two alternative states that the bacterium 	could be in and that the genetic potentiality was there for either or both, but that at 	any given moment it was expressing either one of the other. JL wanted to 	correlate that at a genetic level and see what he could find out about mechanism.  	He was able to do that and establish that there are two separate genes, one for the 	specific phase allele and one for the group phase allele. Thus if you start out with 	an I, you could, using different Salmonella strains, alter that to be a, b, c, d, e, f, g	—any of the alternatives depending on the donor. He discusses some possible 	variations. You now have established two different genes—one controlling the 	specificity of the flagella when it is in the group state, and the other establishing 	the specificity of the flagella when it is in the non-specific state. JL ended up 	showing that there was an alternation of states that later on were then shown to be 	a DNA inversion. Mel Simon, JL notes, gets the most credit for a detailed 	examination of that phenomenon. So there is a specific enzyme that looks for 	certain sequences in the flanks of this DNA segment, and is able to cut the DNA 	and let it reseal in the opposite sense. This can go in one direction—and back 	again, back again, back again. This is what happens once every thousand 	divisions, and it is a way in which the bacteria can randomize what they expose to 	the outside world. They are not stuck with one overcoat, and if antibodies start 	developing against that overcoat they can go to the alternative one.

01:26:15	No question: It has turned out to be a frequently used trick, and there must now be 	hundreds of examples of phase variation based either on DNA inversion or some 	other physical movement of a piece of DNA from one part of the chromosome to 	another part. It is an ancient trick that has been well learned and used in many 	other contexts. JL thinks it is its biological function for the bacteria. They can 	draw upon an archive of alternative specificities that has been selected for in 	history as being a good set of choices. But they do not expose their hand until 	they are forced to, and an antibody is present that selects against an existing 	strain, so they go to an alternative one. This was another study that came out of 	being able to start to use the tool of transduction analysis. One final word about 	Tetsuo Iino: he successfully completed his dissertation, returned to Japan, and 	subsequently became a professor of genetics at Tokyo University. He had a long 	and distinguished career and much of his work was in the general area described 	above.

01:28:23	End of side.

Tape 4/Side 2

01:28:24	JL's work with Iino got them into the genetics of flagella and of motility in 	Salmonella, and that led into something else unexpected. One of the 	characteristic experiments would be to take the non-motile mutant, which might 	be one that was lacking both of the two loci previously mentioned—the group 	phase and the specific phase—or having a mutant that barred motility altogether, 	and then transducing motility from a competent motile strain into the non-motile 	one. This could easily be selected for by using a nutrient agar medium, but using 	very, very soft agar, so that motile cells could quite literally swim through it—	actually at a rate of one or two millimeters an hour, which is an immense distance 	when compared to the bacterial size—and then leaving their progeny behind or 	accompanying them as they swim. They keep multiplying as they go, and you get 	a cloudy swarm, or a cloudy growth, through the bulk of the agar, if it is a straight 	forward transduction of motility. If you have a large inoculant of non-motile cells 	and just a few motile ones coming along—JL calls those initials—these would 	appear at the edge of the static growth as new swarms that would break out from 	the edge and then gradually that cloud would go through the entire medium.

01:30:07	No question: You pick up strains that had migrated through the agar and they are 	very active, motile strains, and retain that characteristic later on. JL was looking 	at some of those plates in his lab when Bruce Stocker dropped in. The very first 	day Stocker arrived, he noticed some things on JL's plates that JL had overlooked.  	In addition to the swarms, there were little clusters of colonies they came to call 	trails, because they looked just as if something had been moving through the agar 	but left droppings behind. That indeed proved to be the case—it was a cell that 	had become motile but had left behind descendants that were non- motile, and 	eventually petered out to where there was no swarm, no permanently motilized 	culture derived from it. Stocker instantly reached the conclusion, which turned 	out to be a correct one in the end, that this was a form of transduction in which a 	gene had been transferred which was somehow impaired in its ability to replicate, 	but could confer the physiological property of motility on the cell that was 	carrying it. The net result was that at every cell division this non-reproducing 	gene would continue to function, confer motility on its cell, but the other daughter 	not receiving it would very soon lose motility and remain stationary and form a 	colony around the place where it was initiated.

01:31:50	No question: For a while JL was pretty skeptical about this very simple minded 	but, as we now know, correct interpretation. Both he and Stocker embarked on a 	substantial and laborious series of studies in which they followed the fate of 	motility cell by cell directly under the microscope. That meant finding a motile 	initial out of a large pot of cells exposed to the transducing phage, which was not 	as hard as it sounds. What Stocker and JL did was pick up this really fast moving 	cell and put it into a fresh droplet of medium, waiting until that cell divided, 	taking the two progeny cells, watching to see if they were motile, then watching 	to see what their progeny were like. JL has charts where this goes on for twenty 	or thirty generations. JL notes that if he had allowed twenty to thirty generations 	of growth exponentially, it would occupy the universe. What they did was take 	one cell, the one that was still motile, and see if it retained motility. When a cell 	was no longer motile, it was essentially discarded.

01:33:03	No question: Stocker turned out to be substantially correct. There was a little 	residual motility—sometimes a daughter would be feebly motile. They thought it 	was because it still had flagella, although it could not make new ones, and that 	might even be passed on for one more generation. These very quickly petered out 	and after two or three generations the non-motile progeny, the ones that by 	hypothesis were not carrying the non-reproducing gene, would become non-	motile. It was an outstanding example of where you could see gene function 	expressed visibly under the microscope on a single cell. This is a kind of model, 	JL notes, for asymmetric cell division, and in a paper he wrote he explored several 	examples where differentiation takes this course—where one product of cell 	division remains a stem cell and the other product becomes a differentiated cell.  	He gives an example of this. What this did was open up a general framework of 	looking at what JL calls linear versus exponential inheritance.

01:34:26	No question: JL turns to another theme which has less to do with the use of the 	recombinational methodology but addresses questions that had come up in the 	course of broader considerations of bacterial genetics. One of these has to do 	with the actual origin of drug resistant and phage resistant mutants. These are 	adaptive mutations, in the sense that once they happen in particular environments 	they are very good for the survival of the cells that are carrying them. That is 	particularly important for drug resistance. You put a culture of E. coli in the 	presence of streptomycin, for example, and those organisms are pretty unhappy 	about having to live through it. But if one of them should become a resistant 	mutant and survive, then they can be inured to that environmental hazard. But the 	question that had been kicking around in microbiology for many years was: how 	can you know whether these mutations would be happening anyhow—or is it 	possible that they are actually induced by this environmental change? Speaking 	loosely that is sometimes called a Lamarckian interpretation, where you think that 	the environment is causing the mutation rather than just selecting for it.

01:35:50	No question: This matter, JL says, had been addressed by Luria and Delbrück 	back in 1943 with a statistical distribution of the number of mutants in parallel 	cultures derived from small inocula, which turned out to be highly skewed—the 	so called "jackpot phenomenon"—and has been and remains a strong argument 	for the prior occurrence of these mutations. The skewness is easily interpreted in 	terms of spontaneous occurrence.  Thinking very simply, if you have a small 	inoculum, there are so few cells that the odds of a mutation occurring in the first 	direction are very low. But that is where you have a jackpot, because if by any 	chance that rare event does take place, then you have all the rest of the growth 	time, and all the rest of the growth from that inoculum, to expand that clone, and 	you will then get a very, very large clone. As the culture grows towards saturation 	then there are many, many more cells, and the likelihood of at least one of them 	being a mutant is greatly increased—but it will not have very many progeny as a 	result. What you get, then, is what has been called the Luria-Delbrück 	distribution, which is the calculated estimate of the skewness of the number of 	mutants in a series of parallel cultures. It is hard to get a robust statistical test for 	exact compliance with the distribution just because it is so skewed, but there are a 	lot of experimental data that are in accord with it.

01:37:26	No question: The alternative hypothesis is that the environment is inducing the 	mutation. Unless there are uncontrolled extraneous variables, and one really does 	have to worry about that, you should then get essentially a mean tendency, a 	Gaussian distribution of the number of mutants actually induced. If each culture 	resembles the next one then they should have the same statistical expectation of 	the number of mutants present. That was the Luria-Delbrück test. It was not a 	constructive test, however, in that it did not directly prove the prior occurrence.  	Rather it just said whatever the mechanism that results in the production of 	mutants, it is going to give you a skewed distribution. It is not a very robust proof.

01:38:22	No question: It occurred to JL at some point that there might be another way to 	approach that problem. It was one that also would address a technical problem JL 	was having about how to deal with manipulations that went past picking one 	colony at a time. If you wanted to test a colony for its growth factor 	requirements, which is one of the most usual things, or to see if it is sensitive to a 	phage or to an antibiotic, the usual procedure is to take a colony, make a loop-full 	of suspended cells with it, and then put it onto a new plate to see how it grows 	under the particular conditions of that plate. There had been some effort to try 	and get around this. Novick and Szilard had invented a little device which had a 	lot of steel hairs on it that would act as an inoculating needle, so in a sense you 	would have an inoculum from an entire plateful at once, that you could then put 	on a fresh medium—and that way you could get a hundred colonies transferred all 	at one time. It was pretty cumbersome, however, and does not work as well as it 	might, because the needles have to be lined up just right.

01:39:40	No question: It occurred to JL one day that a proxy for that machine would be velvet, so you have cloth with all the bristles on it, and you would have a hundred points to the inch instead of one or two. This could be used for the purpose of testing large numbers of colonies from one to another.  They called this replica plating. Today it is one of the classical methods in microbiology. Velvet, JL notes, was used because it is the only fabric that has a pile where you have bristles sticking out but space in between that could absorb extraneous moisture or pick up little bits of the colony growth. He later learned that people like Nick Visconti had been trying similar experiments using filter paper, and it just did not work.  You need the bristle structure of the velvet or velveteen to make it work. Bob Burris sent JL what he thinks might be some of the very first samples of velvet which they used for these experiments, and “it worked like a charm.” Besides being a technical help in handling a lot of cultures, it then occurred to JL that they could solve the problem of prior occurrence of the mutants in the following way.  Suppose, JL notes, that he grows a plateful of bacteria from a small inoculum. It starts out with a few thousand cells, and by the time the plate is covered there may be a billion cells. If this is streptomycin resistant there are likely to be two or three clones of streptomycin resistant cells buried somewhere in the plate. Classically the only way to find them would be to pour streptomycin on the plate and see what would grow up; but that would nix the question you were asking, which was: Was the streptomycin inducing the mutant? How can you tell whether the mutant was there before you add the streptomycin?

01:41:49	No question: JL’s first test was to take a replica plate, make three copies, and add 	streptomycin to each of them.  If the clone came up in the same place, then the 	only reasonable explanation was that it was already there on the source original 	plate. That worked. Then it occurred to him that you could go even further and 	they could actually isolate the mutant.  What they did was in addition to making a 	copy of the streptomycin plate, they made a copy to a plate without streptomycin.  	They knew where the clone was hiding, from the copy with the streptomycin.  So 	they put the plates in register, carefully marked what the geography was, and 	picked out the growth in the area of the non-streptomycin plate, matching the 	place where the colony grew on the streptomycin plate.  It was not too difficult to 	pick out a volume of growth which was about 1 percent of the total growth on the 	plate. It is hard to get better than that, but a one in a hundred resolution you could 	do. By theory if you did that you would enrich the frequency of resistance 	mutants by a factor of a hundred—because JL would have gotten all of the 	resistant clone that was left, and he would have excluded 99 percent of the 	sensitive cells which he wasn’t picking. That was testable and that worked.

01:43:18	No question: That being the case, what JL could then do was to dilute that culture 	that he knew had a hundred times higher frequency of streptomycin resistance for 	another plating down to the point where there were only one or two streptomycin 	resistant clones.  He found out where they were, and enriched them by another 	hundred fold. You do this three or four times and you get a pure culture of 	streptomycin resistant organisms, and yet the culture had never been exposed to 	streptomycin—it was only the sibling plate that had done so. They called this sib 	selection, to match what goes on in other areas of genetics. So here were several 	things wrapped up at once. It was a very simple experiment with very simple 	material which solved a lot of technical problems, and also went very deeply into 	the issue of the pre-adaptive occurrence of the mutations. There has been some 	flurry about this recently, and of course this works for a very narrowly constrained 	set of occurrences—that is to say mutations that result in resistance or an 	environmental change which is very abrupt, which is all or none in its killing, like 	phage resistance or streptomycin resistance.  It does not prove that every other 	adaptive mutation is also pre-occurrent, pre-adaptive, and some people have had 	the idea that if you take bugs that cannot use lactose, leave them starving but alive 	in the presence of lactose, that under those conditions you nudge them to want to 	become lactose positive—they’re still alive so their wants might be satisfied, and 	that you might under those conditions have a new form of environmentally 	induced mutation. There has been a huge fuss about that for the last several years, 	and JL would be the first to admit his replica plating experiment does not really 	bear on those conclusions, but in the end that has turned out to be so full of 	artifacts that very few people will still concur.

01:45:22	No question: Several people have asked JL about his wife Esther’s role in this 	particular experiment. Esther, who was a superb experimentalist, was a co-author 	on the paper relating to replica plating. Esther received a Ph.D. from the 	University of Wisconsin. For her dissertation topic she took on something close 	to R. A. Brink’s interest, which was, might there be genes affecting mutability in 	E. coli?  The system she looked at was reversions from lac - to lac +, which are 	easily detected because if you grow your E. coli on an indicator medium with 	lactose as the principal but not the only carbon source, the lac - cells that you start 	with make reasonably constrained colonies, but lac + mutants, that can use a 	sugar, grow much better and emerge as papillae, literal button-like outgrowths in 	the colony.  You can actually more or less readily count them colony by colony.  	So strains of different mutability would have different numbers of papillae per 	colony. She tried finding genetic factors that would influence mutability.  In the 	end, she did not find such factors partly, JL thinks, because they were all imbued 	with looking at this from the reverse end and they were, in effect, looking for 	genes that would reduce mutability. So it’s rather unlikely that they would get, by 	further mutation, strains that would be more faithful—less mutable than the wild 	type—but they did not know any of that at the time.  That whole framework of 	thinking about mutation did not then exist.  So Esther actually did find things that 	had different papillation numbers, but they ended up being either second 	mutations at the lac locus, which would then take a double mutant, which doesn’t 	happen, to make a papillae, or other modifiers of lactose metabolism that so 	slowed them up that they did not emerge very well. So it ended up giving a 	negative answer, but it was just ahead of its time. The same system has been used 	subsequently to identify factors that will in fact enhance mutability, but she did 	not encounter that.

01:48:52	No question: To meet all the formalities, Esther was registered as a student. Brink was listed as her supervisor, but she did her research with JL in his laboratory. After receiving her Ph. D., Esther remained in JL’s lab as a research associate through the remainder of their stay in Madison.  Esther served more or less as JL’s “chief operating officer” and attended to many of the details in the lab—a function she performed extremely well. JL’s lab, which was small, was usually staffed with a research assistant, a couple of lab technicians, and two to three graduate students—somewhere in the vicinity of six to eight people.

01:49:47	Question: Let's talk about your graduate students. Answer: The discussion turns to 	some of JL’s graduate students. Norton Zinder was JL’s first graduate student and 	was, by all accounts, outstanding. JL found his graduate students basically 	through word of mouth.  In Norton Zinder’s case, he had worked a little with 	Francis Ryan. Zinder turned to JL when he was denied admission to medical 	school.

01:50:43	Question: Another graduate student was Morse? Answer: Larry Morse also served 	as a graduate student under JL.  Morse, who had been working at Oak Ridge, 	sought out JL. Morse did his work on galactose transduction, and subsequently 	took a job at the University of Colorado-Denver.  He ended up being a dean for 	research and retired a few years ago.  He has continued working on other 	galactose metabolizing systems, which is more physiological than genetic work.

01:51:30	Question: S.G. Bradley? Answer: S. G. Bradley was another of JL’s graduate 	students.  Bradley worked on looking at recombination in still another microbial 	group called Streptomyces. Streptomyces were important in many ways, but 	especially because they were the source for new antibiotics—starting with 	Streptomycin and moving on to numerous others.  Thus learning about their 	genetics would be of practical importance.  The gist of Bradley’s dissertation was 	proving heterokaryosis, which JL discusses.  In the course of the work, JL and 	Bradley began suspecting that there was some gene silencing going on, in that 	there were genes being carried along that were not being expressed over many 	generations.  This phenomenon has been noted by others in other Streptomyces, 	and also in other gram positive organisms where cell fusion has taken place and 	you have mixtures of nuclei in one cell.  Even today this is not very well 	understood.  It is one of the reasons JL wants to get back to cell fusion in E. coli, 	where if these phenomena occurred we would be in much better shape doing a 	detailed genetic analysis of it.  JL notes that we are still at a very early stage, 	comparably speaking, in that we do not know as much about how to handle the 	genetics of Streptomyces or of other gram positives compared to E. coli.  Bradley 	continued his research at, JL believes, Old Dominion in Virginia, and also has 	become a dean.  He is at present CEO of a biotech institute in Baltimore.  

01:55:38	Question: How do you decide what graduate students are going to work on? 	Answer: Concerning what research a graduate student of JL works on when he 	begins his training, JL notes that if a graduate student approached him with a 	carefully crafted proposal, such as JL presented to Ed Tatum, JL would be most 	eager to at least negotiate the nature of the research with the student.  This has 	basically never happened.  Generally, graduate students need a basic introduction 	to the area of research. What JL has typically done is present the student with a 	problem that had been bothering JL or his lab for some time.  The student is then 	assigned to work on that problem until he finds something he finds compelling, or 	until he becomes sophisticated enough to present an alternative research proposal.  	Almost without exception the first happens.  Then the student has something he 	has discovered and can make his own. This is exactly what happened with Norton 	Zinder. It is a developmental process for the graduate student, in that they start 	out with an opportunity to learn the field, learn the methodology and get some 	actual experience doing research under fairly close supervision.  Then they 	become more and more independent as they begin to grab hold of a problem they 	can make their own.  This is what JL strives for.  He wants that student to know 	that he knows more about the problem he is studying than any other person in the 	world.

01:57:26	Question: P.D. Skaar? Answer: David Skaar was a post-doc who came from T. M. 	Sonneborn’s laboratory, where he had worked on paramecium research. While in 	JL’s lab, he found an accessory mutability factor in E. coli. This was a mutation 	that enhanced mutability. Skaar also found that if you cultivate E. coli in the soft 	agar and you push it for maximum motility, it drops the F factor on the way. Thus 	it becomes a very handy way of getting F minus variants. The process is not fully 	understood, and JL discusses why this might occur. Skaar did some work, also on 	the F factor, that one could treat cells with periodate, which is an oxidizing agent 	that goes after polysaccharide.

01:59:13	End of side.  End of tape.

Tape 5/Side 1

01:59:14	JL continues his discussion of David Skaar’s research.  One of Skaar’s findings 	was that one could inactivate the F+ phenotype—that is, the ability to conjugate 	with F- cells in E. coli by treating them with periodate.  What Skaar’s research 	suggested was that there was a carbohydrate marker that is necessary for that 	interaction. The chemistry of that interaction, JL notes, has not really been 	followed up in detail and is worth doing. Skaar then went out to Wyoming, but JL 	has lost touch with him since that time.

01:59:59	Question: Aleck Bernstein? Answer: Aleck Bernstein was a post doc who came to 	JL's lab with some experience in Salmonella serotyping. He did not stay long, but 	during his stay he assisted in work on serotypic variation in Salmonella. He also 	found something quite curious. As JL noted earlier, there are two phases of 	flagella—the group and the specific kinds. Bernstein found that quite consistently 	the one we call group makes its cells agglutinable with acridine dyes, and vice 	versa. There is some general chemical difference in the structure of the flagellar 	protein at one end of the locus. There has been a lot more work done on the 	chemistry of flagella since then, but JL is not aware if anyone has noticed this 	particular observation. While in Madison Bernstein met Helen Byers, another 	graduate student in JL's laboratory, and they married. Bernstein found a job at the 	University of Wisconsin-Milwaukee, or perhaps Marquette, and remained there 	for a number of years.

02:01:41	Question: Let's turn to Bob Wright. Answer: Bob Wright was a post doc who 	came to JL's lab after he had a visit from Professor Sydney Rubbo, who was head 	of the Bacteriology Department at the University of Melbourne.  This would be 	around 1954. Rubbo had approached JL because he wanted a sabbatical 	experience.  He was a very progressive minded but old line microbiologist who 	wanted to learn microbial genetics.  Getting back to Bob Wright, he was in JL's 	lab as a graduate student, having been highly recommended by Sydney Rubbo.  	Wright was a very bright young man deeply committed to science.  Rubbo was 	interested in yeast and Wright had a similar interest.  The problem Wright 	addressed was very early work on what would now be called cytoplasmic hybrids	—cybrids—in yeast.  There is a stage in yeast conjugation when two cells have 	formed a conjugation tube and they mix cytoplasm, but where the cells are still 	very much intact and can be separated.  This is a way of getting a clone of one 	haploid strain of yeast that has been contaminated with the cytoplasm of a 	completely different strain.  You can put genetic markers in the nucleus and you 	have no trouble at all making sure what happened.  JL briefly discusses some 	other work on petite variants that Wright engaged in.  He goes on to note that 	Wright did crosses where he showed that the inheritance of the normal versus 	petite variant did not segregate along with the chromosomes, but that did not 	prove it was in the cytoplasm.  If you contaminated the cytoplasm of one yeast 	clone with the cytoplasm of another, then you restored the normal mitochondrial 	phenotype. This was pretty much the nature of Wright's work in JL's lab. JL goes 	on to note that Wright was visiting a friend in the winter of 1956 and was 	involved in a serious automobile accident that left him significantly impaired. He 	returned to Australia and later committed suicide.

02:06:55	Question: Two other people I'd like to discuss, one is Boris Rotman? Answer: The 	discussion turns to another of JL's graduate students, Boris Rotman. Rotman was 	a Chilean who JL thinks might have originally been in chemistry at Wisconsin.  	He worked with Henry Lardy for a while at the Enzyme Institute, where he did 	some brilliant work on measuring enzyme production in single bacterial cells. He 	turned up again at Stanford, where he was an early member of the Syntex Institute 	for Molecular Biology. He ended up as a professor at Brown University, which is 	where he has been ever since.

02:08:04	Question: And Tom Nelson? Answer: Tom Nelson, who was very much interested 	in kinetics, was a post doc who had completed his doctoral degree under Francis 	Ryan.  Nelson wanted to do what Dulbrück was chiding JL for not doing, which 	was to study the kinetic aspects of the yield of recombinance as a function of the 	concentration of the parental cells, and so forth. The way they went about it, there 	were no surprises. Nelson first got a job at the University of Wisconsin-	Milwaukee, then at Eli Lilly & Company, where he spent most of his professional 	career working on the development of antibiotic producing strains.

02:09:23	Question: Could you talk about your leave to visit Berkeley? Answer: The 	discussion turns to the two leaves JL took while on the Wisconsin faculty.  The 	first leave was in 1950 to go to Berkeley for the summer.  Roger Stanier had been 	the moving figure relating to this.  JL had never been to California before, which 	had become a vital place in microbiology.  In retrospect JL thinks that perhaps 	they were trying JL out for a possible future move.  JL enjoyed the summer, and 	California, very much. He and Esther lived in the hills and it planted a seed in his 	mind regarding moving there someday.  JL got two research programs underway 	that summer. One was with Roger Stanier and it showed that ultraviolet light 	prevented enzyme induction and stopped it dead in its tracks, yet allowed the 	expression of the set of enzymes he was interested in, which was oxidative 	metabolism of organic molecule substrates.  That made it much easier to do 	kinetics of the rate of development of new enzymes. The second line of work he 	engaged in was with maltose metabolism, which was discussed earlier.  JL notes 	that his summer in California coincided with the beginnings of the Korean War 	and occurred at the height of McCartyism, so a lot was going on at the time.

02:12:20	Question: Could you tell how it came about that you suggested the hiring of 	Stanier? Answer: When JL returned from Berkeley, he suggested to the UW 	administration that it might be interested in hiring Stanier.  This came about 	because in California at the time there had been a lot of reaction about the 	imposition of the loyalty oath.  The oath itself, as JL recalls, was not so awful.  	What was bad, however, was who it was demanded of. The implication was that 	if you were a faculty member of the university, you had to redouble your proof 	that you were loyal to the United States. There were some number of faculty who 	simply refused to do it. Stanier signed the oath, but said he would resign if other 	members of the faculty were fired without there being a proper tenure proceeding 	for it.  Other members were fired, and Stanier submitted his resignation to be 	effective at the end of 1950.  Thus JL thought there might be a good chance for 	Wisconsin to pick up a very notable microbial biochemist.  JL believes the 	problem was resolved by Stanier solving his California problem.

02:14:51	Question: Did you have any problems with McCarthyism? Answer: In terms of 	McCarthyism and the University of Wisconsin, JL notes that Joe McCarthy was 	very shrewd, in that he was very careful about Wisconsin.  When he did start 	picking on Wisconsin is when he started getting into serious trouble. There were, 	JL recalls, any number of petitions and campaigns and JL stood up for civil 	liberties, but he took a somewhat maverick position on this matter, in that he 	thought it was anybody's constitutional privilege to invoke the Fifth Amendment 	and he did not think it was such a good idea to hide evidence of past relationships 	with the party.  JL believes that if everybody had banded together and 	acknowledged their membership, McCarthy would have been laughed out of 	court.  That never happened, and JL thinks one of the reasons it did not was 	because the far left did not want it to happen, and the reason they did not was 	because they liked nothing better than to keep McCarthyism an issue and 	something to be feared.  During this period the far left and the far right, JL notes, 	fed off each other.  The faculty was critical all along, and JL is sure he signed any 	number of petitions regarding McCarthyism.  Still, JL had some reservations in 	that he thought Communism was a threat.  JL says he was too young to become 	involved in any far left affiliation, but his instincts were against communism as he 	did not like authoritarian regimes of any stripe.

02:19:10	No question: JL returns to a discussion of his research, focusing on protoplasts, L 	forms, and penicillin.  Penicillin, he notes, has had a checkered history in the past 	he has been describing.  It enters this narrative in a couple of ways, most 	importantly because of the penicillin method for isolating auxotrophs.  This was 	founded on the empirical observation that non-growing cells were barely affected 	by penicillin, whereas growing cells were rapidly killed—in fact, they literally 	dissolve if you try growing them in the presence of this antibiotic.  Penicillin has 	historically probably been the most important antibiotic we have ever had, so 	trying to understand its mode of action was an interesting challenge.  This also 	comes up in rather fitful efforts to get at the genetics of penicillin resistance.  In 	gram negative bacteria it is rather more complicated; in gram positives you can 	get sharp increases of resistance fairly readily with mutational changes.  With 	gram negatives, like E. coli, there are plasmids that carry penicillinase genes, 	which are genes for an enzyme that will destroy penicillin.  You do not get these 	by mutation, rather you get these by infection or contamination from plasmid 	particles.  These are the general reasons to be interested in penicillin.

02:20:54	No question: JL had been reading some papers by Weibull in which he talked about being able to sustain protoplasts in Bacillus subtilis, a gram positive, which had been produced with lysozyme, if you keep them in high osmotic media—that is media with two moleasucrose, or other high solute concentrations. In effect, this balances out the osmotic pressure of the inside of the bacteria, and when its wall has been dissolved it does not pop and lyse. It occurred to JL that the previous observations that penicillin only attacked growing cells and that you got lysis as a result could be tied together if penicillin attacked the wall. This would be of little damage if the cell was static, but a broken wall would be disastrous if the cell was growing and expanding against it. One Saturday afternoon JL thought he would try an analogue of Weibull’s experiment of Bacillus subtilis with E. coli, but more importantly instead of using an enzyme lysozyme, whose action we do know is directed at the cell wall, he would use penicillin instead—	and use this as a test as to whether the cell wall is the target. The experiment worked within the first hour. JL went into a much more systematic study of it, 	published a brief note in the proceedings—that this was an argument that the cell wall growth was the target of penicillin—and this coincided with a couple of other people’s work, especially Jack Strominger’s.

02:23:17	No question: Looking at these globular forms, they seemed to reproduce pretty 	much by budding—certainly not by the usual form of fission. These were little 	balloons that would grow and grow, and every now and then there might be an 	out-pouching of another little balloon. They could be quite large, in that they 	could be 20-30 microns in diameter, which is immense compared to E. coli. Then 	it struck JL that these were the L forms that others had been talking about—and 	from there everything just seemed to all come together.  These bizarre L-forms 	were wall defective mutants or wall defective because of external agents, which 	might be lysozyme.  Phage secrete lysozyme and bacteria have their own wall 	lytic enzymes, so they might be generated under those conditions, or, as JL then 	found, also by having mutations that are on the pathway of wall synthesis—and a 	particular one that requires a wall component called diaminopimelic acid.  These 	mutants would lyse if you tried growing them without diaminopimelic acid, but 	again if you put them in hypertonic medium—high sucrose medium—they would 	form these little globules and sustain themselves like the protoplasts or L-forms 	that JL was getting with penicillin.  Everything all came together.  So these were 	not life cycles or gametes or whatever.  They were soft forms that had defective 	walls.  JL notes he was called up short on one point, in that when others did more 	detailed chemical studies on what JL called protoplasts, they found they really did 	have almost everything that is present in normal walls.  They were not devoid of 	walls; they had greatly weakened walls.  So they said let's not call these 	protoplasts.  JL agreed, and they called them spheroplasts.  Since then they have 	been used for various purposes, but mostly to understand what happens in natural 	history.

02:25:38	No question: There are still some strange things about L-forms. You can sometimes find streptococcal infections in joints where the penicillin being administered is not effectively curing the patient and there seems little doubt that the so-called L-form type of growth is what is responsible. Since they do not have enough of a wall to matter, they are not inhibited by penicillin. JL notes one does not always need hypertonic media to preserve them, in that other medium constituents might do it. This line of research helped clear up a mystery that had been befogging bacteriology for a long time. There is still a lot we do not know about them. To this day JL is trying to use them to make cells fuse. He conducted these experiments in 1956, '57 and '58 with Jackie St. Clair serving as his technical assistant. He has recently come back to this problem and says there must be a way to make this work!

02:27:10	No question: Spheroplasts are sometimes more amenable to transformation with 	DNA, so there have been some genetic uses of this category of things, but they 	end up mostly clearing up a curiosity that had been misinterpreted by others and 	put away.

02:27:30	End of side.

Tape 5/Side 2

02:27:30	No question: There are two science related issues that were initialized during JL's 	career at Wisconsin. The first has to do with the mechanism of antibody 	formation and JL's Fulbright trip to Melbourne, Australia. This took place in 	August through early November, 1957. JL and his wife, Esther, were both fellows 	of the Fulbright Foundation. Sydney Rubbo from Melbourne had orchestrated the 	arrangement. When it came to a choice of where to work, JL thought he could 	learn the most by going into MacFarlane Burnet's laboratory. Burnet had been a 	renowned early worker in bacteriaphage. He tends to be overlooked because of 	Luria and Delbrück but he really did provide, after D’herelle, some of the most 	important foundations for quantitative studies with bacteriaphage. But he then 	moved in somewhat similar fashion into the influenza virus, and he had recently 	discovered a recombinational mechanism in the flu virus that intrigued JL. For 	his part, JL wanted to learn more about it and learn how to handle flu, and perhaps 	pick up some work along those lines when he returned to Madison, particularly if 	Wisconsin was going to be branching out in other directions with a new 	department. That was JL's premise for going down there.

02:29:18	No question: When JL reached Melbourne, he learned that Burnet was at the tail 	end of his work on flu. Burnet put JL into a lab and he went through the basic 	exercises of how one handles flu, how one does a recombination experiment, and 	a few genetic systems that JL might be able to carry on further—methods of 	selection for influenza variants, for example. But the fact is Burnet was turning 	his attention to antibody formation, and had just reformulated a proposal that had 	been floated by Niels Jerne—we are talking about Burnet, a future Nobel prize 	winner and Jerne, another future Nobel winner—so this was leading edge stuff.  	That had reopened the question, very closely related to what JL had been talking 	about earlier in connection with induced resistance in bacteria: How does an 	antigen induce the formation of a new antibody? The prevalent theory, which had 	been crystallized most sharply by Linus Pauling, is what JL later called an 	instructionlist model, which is shorthand for saying that the antigen instructs the 	on-coming would be antibody molecule what shape to adopt.

02:31:04	No question: The alternative in principle could be, just as with bacterial variants, 	that maybe antibody forming cells beforehand are diversifying all over the place, 	and maybe the only role of the antigen is then to select out what diversity nature 	had already provided. Oddly enough, in 1954 or 1955, JL had put that hypothesis 	next to his discussion of enzyme induction, but said no, it isn't going to work for 	antibody formation because there are too many kinds of antibodies.  For selection 	to be feasible, you have to have no more kinds of antibodies than there are kinds 	of cells to start with. JL was led to believe that there was an infinity—that for any 	antigen you care to mention you could always find an antibody. JL says he had 	not really thought through the numbers on this point. So he walked right up to 	this wonderful new theory, then turned his back on it. It was Burnet who walked 	up to it again and did not turn his back on it. The provocation meanwhile was 	Niels Jerne, who had floated a paper on a selective theory, but it "was wacky" 	because his unit of selection was a globulin molecule. He said nature provides a 	wide diversity of globulin molecules. Prefigured beforehand the antigen reacts 	with this immunoglobulin, and then somehow this reproduces itself. JL could not 	swallow the "somehow," and he wrote to him and told him so. Gerne later told JL 	he was the only one who had responded to his reprint.

02:32:48	No question: It all hinged, basically, on how many kinds of antibodies there are.  	So JL walked into Burnet's office and Burnet told him about his idea and asked 	for JL’s opinion. JL said he thought about it and decided it was not going to work, 	because there is infinity of antibodies and there is not infinity of cells. At that 	point Burnet backed up a bit and said Jerne could not be right, because it has to be 	a self-reproducing unit. The only one they were certain of was the intact cell.  	Perhaps there were a lot of diversified plasmids, and perhaps every cell has a few 	thousand of those that would multiply the opportunities, and then the antigen 	might select one plasmid for further replication—that in principle might work—	but there was no particular evidence for it at the time. But JL does not think 	Burnet was on to that. His intuition was the cell, and when JL challenged this, 	Burnet said, in effect, “Says who?” about how many antibodies. To which JL, 	upon reflection, responded by saying that Burnet was, indeed, right.

02:34:06	No question: JL said as he stopped to think about it, he was not sure that it had 	been proven that there were more than about a thousand antibodies all together.  	To prove it, you would have to have a panel of 1,000 antigens and 1,000 	antibodies, and show that each one reacted specifically only with the other one.  	The fact that you get specific anti-flu when you inoculate with flu, and specific 	anti-strep when you inoculate with strep, does not prove a point, because until you 	have tested it one of these anti-streps might be the same as one of those anti-flu.  	But that thought had not been given in the whole history of immunology. JL thus 	became an enthusiastic supporter, and the job he did was translate this very good 	biological intuition, put it into molecular genetic lingo, and retranslate it into 	terms of what DNA sequences are, what protein sequences are, what the 	diversification could consist of—and produce what you might call a much sharper 	version of Burnet’s theory.

02:35:23	No question: In the meantime a man called Talmadge, from the University of 	Colorado, was coming up with some similar notions as well.  Thus JL notes that 	he does not claim primary authorship on clonal selection, having looked at it and 	turned his back on it.  However he had given it enough thought, conscious and 	unconscious, that he very quickly came to a much more precise formulation.  JL 	believes that has been generally recognized.  He wrote a paper for Science 	Magazine on genes and antibodies in which he put together a version of the theory 	of antibody formation that had all the necessary ingredients laid out and allowed 	the different points he laid out to be supported or attacked one at a time.  What 	misled JL was his belief in Occam’s razor, which is the philosophical principal 	that you do not multiply entities without cause.  JL tried making an economical 	theory of antibody formation using no more different cell types than the data 	absolutely demanded, and of course they did not have the data then, but the 	number of cell types is what nature says, not what a philosophical simplicity 	would say.  JL says he now realizes that there are some aspects of evolutionary 	diversification that defy Occam’s razor, that nature sometimes multiplies entities 	without obvious reason.

02:37:30	No question: JL notes that he did one little bit of experimental work while he was 	in Australia with Gus Nossal, who was a young post-doc Burnet had assigned JL 	to work with.  JL says he brought the Salmonella motility lore along with him, in 	this case turning it around and using the bacteria of known composition to 	diagnose what kind of antibody a single plasma cell was making.  One of the 	postulates of the clonal selection theory would be that the antibody present in the 	serum is the aggregate of what all of the immune cells are pouring into it—but 	that a single host cell is only making one kind of antibody.  Another cell might be 	making a different antibody, JL notes, so in the serum is the mixture, but cell by 	cell they ought to be segregated out.  They tested this hypothesis in rats by taking 	two different Salmonella strains, immunizing rats against them, taking out plasma 	cells from those immunized rats, putting them into little droplets of fluid, and then 	injecting into those same droplets either Salmonella 1or Salmonella 2.  Most of 	the cells did not react to either, which was no surprise.  The ones that did react, 	either reacted with 1 or with 2—but not with both. That was support for the 	clonal selection story. It did not really prove it, because they were not clones of 	cells—they did not know how to do that in those days—instead they were only 	looking at cells as they finally arrived at the end of their differentiation. The work 	only started while JL was there. Gus Nossal finished it up. They exchanged a lot 	of notes and papers, finally publishing it as a note in Nature. This was JL's one 	and only published report in experimental immunology. Nossal followed up on 	the work and indeed built his career on it. Nossal succeeded Burnet as director of 	the Institute, but not until after JL had tried to recruit him at Stanford. What 	happened was Nossal had come to Stanford for a year or two, but Burnet lured 	him back by promising him the directorship when he retired. Now retired, Nossal 	ranks as Australia's outstanding biomedical scientist. He currently serves as 	president of the Australian Academy of Sciences, which he is trying to build into 	an important policy forming organization.

02:40:49	Question: Could you talk about how you became interested in moon dust? 	Answer: Another interest of JL's has to do with NASA.  This includes the space 	program, the search for life on other planets, and the like. This came about as 	another outcome both of how history was unfolding, and of JL's trip to Australia	—or rather his trip home from Australia.  On October 6, 1957, while JL was still 	in Melbourne, the Soviet Union launched Sputnik.  It created a sensation in 	Australia, because due to the orbiting pattern of Sputnik people living in Australia 	were able to view it on its first night.  It was right there, so there was a lot of talk 	about its implications.  A month later, on his way home, JL stopped in Calcutta 	where he had been invited by J. B. S. Haldane to spend a week.  Haldane, who 	had helped JL develop the background for the statistical analysis of JL's data on 	linkage mapping, was at the Indian Statistical Institute. JL knew he was a 		confirmed communist, even though he had broken with the party over Lysenko.  	JL could believe he was a radical alternativist. Haldane had left England earlier in 	1957 under the slogan that he wanted to leave a country under American 	occupation, but the real fact of the matter is the professorial appointment he had 	been hoping to get did not materialize, and he had alternative arrangements in 	India.

02:44:26	No question: JL and his wife Esther were met at the airport in Calcutta and 	brought into town. There were several parades in progress, because it was the 	night of an eclipse. They soon arrived at a palace, the Indian Statistical Institute, 	which was where Haldane was living. As they prepared for dinner, Haldane 	remarked that this was the 40th anniversary of the October Revolution. At dinner 	Haldane was gloating about the Soviet success with Sputnik, and he commented 	that maybe even more spectacular things would happen later that evening. He 	then remarked, in jest, "what if they planted a red star on the moon?"  The 	discussion then turned to whether or not you would be able to see a thermonuclear 	device if it was exploded on the moon, and they determined that indeed you 	would be able to.  At a point in the conversation they both began wondering what 	the world was coming to, in that this competition between the superpowers might 	end up in a destructive exhibition just to show who is first.  It left JL with a 	determination to try and see what was happening when it came to putting science 	in the space program. He realized that the reaction to Sputnik ought to be to 	produce good, solid science, and not just phony demonstrations. JL notes that he 	checked later, and indeed there was a project to plant a star on the moon.

02:48:24	No question: JL started a science policy campaign, which was his first political 	campaign.  He wrote a couple of memoranda pointing out the opportunities that 	space exploration held for biological inquiry, and deploring the possibility that 	there would be missions planned either for the moon or the planets without 	thought to contamination—be it radioactive, physical, chemical, or biological—	and that some scientific study committees should be formed to explore those 	possibilities and recommend a sensible program to the president. This caught on 	and got to Detlef Bronk, who was the head of the National Academy of Sciences 	and later president of Rockefeller University. It got to Fred Seitz, who was 	chairman of the policy committee at the National Academy and was Bronk’s 	successor as president of Rockefeller University. Both Bronk and Seitz dealt with 	it very seriously. JL notes that in 1957 he had just been elected a member of the 	National Academy, which gave him the standing to raise this kind of issue. The 	committees were set up and JL was asked to join some of them. JL promoted 	planetary quarantine as the first step. This became institutionalized, and JL was 	subsequently challenged to do something constructive as well as critical. Thus he 	was basically offered a chance to enter into preparing experimental missions for 	NASA, which occurred later during his transition from Wisconsin to Stanford, 	and it helped him set up a very significant instrumentation laboratory at Stanford 	with NASA funding.  For twenty years JL was closely tied into it, and ended up 	being on the Viking Lander bio-instrument team.  JL saw his job as trying to see 	that sensible experiments were being designed and planned with sensible 	objectives.  At one point he wrote a letter to Vice-President Johnson, who was 	then chairing the National Space Council, relating to our sending a manned 	mission to the moon. JL noted that we should show how much smarter we were, 	both policy wise and technically wise, by sending automated devices to Mars.  	The drumbeats, however, were to send man into space, which, of course, is what 	ended up happening.

02:52:19	Question: So why moon dust? Answer: In terms of his interest in, and article 	concerning, moondust, JL notes that it seemed likely the moon would be a much 	earlier target—which indeed it was.  JL was invited to attend a symposium 	organized by AAAS early in 1958, where he met Dr. Dean Cowie, who was a 	biophysicist at the Carnegie Institution.  They discussed what one might find on 	the moon.  JL was not as concerned about contaminating the moon, which he 	viewed as self-sterilizing, as he was Mars.  He thought the moon might have 	preserved primitive infall—that is everything that comes in as meteorites and 	comets and gets burned up in the earth’s atmosphere.  JL says that neither he nor 	Cowie were thinking too clearly about what would happen next, which was that 	somehow this would end up on the moon intact.  The flaw is that the moon has 	been reworked by successive collisions—by new craters, new meteors—so its 	surface is much more weathered by meteoritic impact than is the earth’s, which is 	weathered by the atmosphere but has not had as much damage done to it by infall.  	There were people besides JL who were calculating that there might be a very fine 	dust on the surface of the moon that was as much as a kilometer deep, and that 	there was a danger that any vessel landing on the moon would go “clunk” and be 	smothered through this very loose alluvium.  Some of the premises were right, 	and the innovation as it relates to life is that maybe life did not begin on earth, in 	the sense that organic matter is being manufactured throughout the universe on a 	very large scale, and the precursors for the origin of life might in fact be in the 	comets and meteorites and things of that sort.  That is what JL was discussing in 	his article about moondust, or meteoritic in fall.  It is worth looking into, but you 	are not going to see much organic matter at this stage because of succeeding 	impacts volatilizing most of what was there before. There may be some, he notes, 	but there may be even less than is on the earth.  This is the beginning of the story 	which took place while JL was at Wisconsin.

02:55:52	End of side.  End of tape.  End of interview session.

Third Interview Session (October 1, 1998): Tapes 6-7

Tape 6/Side 1

00:00:00	Question: Let's begin today by talking a little bit about Carl Sagan and your 	relationship with him. Answer: The session begins with a discussion of JL’s 	relationship in Madison with Carl Sagan.  JL believes he met Carl Sagan through 	Lynn Sagan, who was a graduate student in the Zoology Department working 	with Walter Plaut on her dissertation.  At some point JL met Carl Sagan socially, 	probably in 1957. When the time came for JL to put together a committee to start 	exploring the issues of planetary quarantine and the establishment of a biological 	basis for investigations using spacecraft, it occurred to him that despite his youth 	there were few astronomers who could speak biology as well as Sagan.  JL 	essentially introduced Sagan, who was doing his doctoral work with Kuiper at the 	University of Chicago, to NASA.  JL describes Sagan as bright, articulate, eager 	and energetic, as someone capable of imaginative and critical judgments.  Sagan 	proved helpful in getting JL’s committee underway and provided authentic 	astronomical verisimilitude to the other kinds of things they were arguing about.  	There were not that many astronomers interested in planetary astronomy in those 	days, being drawn instead to the study of stars and galaxies and the like. Besides, 	there was not much information available at the time about planets. More was 	known, relatively speaking, about the composition of the sun and stars. JL 	continued seeing a good deal of Sagan after his move to Stanford in February of 	1959. During all of 1958 JL was very busy with the academy-based committees 	on space travel, with Carl Sagan playing an active role as well.

00:04:27	Question: Watson did some bacterial research, are you familiar with that? 	Answer: The discussion moves to James Watson, the co-discoverer of the 	structure of DNA with Francis Crick.  During JL’s years in Madison, Watson 	occasionally attended meetings of the so called Midwest phage group Leo Szilard 	had organized.  The group had two purposes: one was Szilard’s own education; 	and the other was a means of getting together people who were at the cutting edge 	of this work, who those days were mostly in the Midwest.  The group included 	Luria, Sonneborn, Spiegelman, Novick and Szilard in Chicago, Benzer at Purdue, 	and the Madison group.  Various group members met from time to time in 	Chicago or Madison or some other city in the Midwest.  Watson showed up at a 	couple of these meetings as one of Lurie’s graduate students. JL describes Watson 	as a very “lanky fellow”—then even more than now.  He had just changed his 	interest.  As an undergraduate at the University of Chicago, JL believes him as an 	avid bird watcher primarily interested in birds.  His work with Luria altered his 	direction, pointing him toward canonical phage work.  After completing his 	degree, Watson at some point tied up with Bill Hayes and did a paper on mapping 	genes in E. coli.  Since JL had reported on this at the Cold Spring Harbor 	Symposium of 1951, a crisis had developed in trying to understand the 	chromosome structure in E. coli.  There was no question about linkage—up to a 	certain point you could draw a linear map, after which it collapsed.  Using the 	methods of analysis available at the time, the only way JL could formally 	represent the data was for the map to branch, because there were two or three 	different things that appeared to be linked to some common point, but were not 	closely linked to one another.  These just did not fit linear mapping at all.  Some 	people thought JL was proposing a branched chromosome, which was not correct.

00:07:30	No question: Watson and Hayes did their own analysis using mostly existing data.  	They came out with an alternative theory stating there were three separate 	chromosomes in E. coli.  JL did not think that was justified.  He had data 	suggesting there was linkage between markers they had put on separate 	chromosomes—even if he could not put them on a linear map.  That was a 	passing item, soon superseded by the work of Jacob and Wollman, showing what 	was wrong was not the question of linearity in the chromosome, but the fact that 	you were not getting the entire genome into a fusion cell “all in one go,”and 	different fragments of varying size were entering.

00:08:27	No question: JL had no idea Watson was going to work on the structure of DNA.  	He did not think Watson himself knew he was going to work on the structure of 	DNA.  Watson’s original fellowship abroad was to work with Herman Kalckar in 	Copenhagen, but as Watson has described, Kalckar was preoccupied with his 	courtship of Barbara Wright. Watson describes how he then moved to Cambridge 	and the rest, as they say, is history. As far as the chemistry of DNA, the previous 	node of studies on that point appears in the 1951 Cold Spring Harbor Symposium.  	At that Symposium there were extensive allusions to the work of Gulland, 	Chargaff, and others.  None of those people were doing x-ray structures, as far as 	JL can recall.  They were doing analytical work to try and get a little more detail 	on the precise space composition—and especially from the work of Chargaff it 	eventually became evident that there was not an exact one to one to one ratio of 	the four nucleotides, and that deviations from that meant that there was a rather 	more complex structure than the tetranucleotide that Phebus Levine had been 	arguing for.

00:10:13	No question: These were very active years, but JL was not connected to Watson in 	the years he was abroad and he does not recall precisely when he heard of the 	structure, although he believes there was some inkling of it in the days 	immediately preceding its publication in Nature.  JL was not aware of the race at 	the time, nor was he aware of who was in it.  He thinks it uncanny how 	thoroughly and how profoundly Watson and Crick not only did the structure, but 	how they understood how to couple the physical structure that they elucidated 	with what this meant for the biological mechanism of replication.  That, JL 	believes, is the really brilliant part of their paper—a totally accurate forecast of 	how complementarity of DNA sequences was going to work out for the 	mechanism of information transfer of replication. The only thing they got wrong, 	according to JL, was they thought that somehow DNA all by itself would have 	this self-replicating capability.  It was Arthur Kornberg’s lot to have the 	inspiration to study the enzymatic machinery by which DNA was replicated. 	There is no mention of such enzymatic machinery in the Watson-Crick paper. But 	in a way maybe the nucleotide chemists have had the last laugh because it now 	turns out that if not DNA, RNA has enzymatic activity as well as its informational 	one. This has not been demonstrated for DNA, but it was not such a bizarre 	thought after all to think that it might have both catalytic activity and be the 	information store. Again, it has not been substantiated yet for DNA, but it has for 	RNA.

00:12:50	Question: When did you start working with computers? Did you use the Numeric 	Analysis Lab? Answer: The discussion turns to computers.  JL notes that his first 	introduction to computers was in 1941, when there was a card sequence 	controlled calculator installed in the American Institute Science Laboratory at 310 	5th Avenue, in the shadow of the Empire State Building. This laboratory was the 	forerunner of what later became the Westinghouse Science Talent Search, but in 	1941 it was the program that provided facilities to high school students who 	wanted to do bona fide research at a time when high school labs were less 	equipped to do that than at they are at present. By examination, JL won what 	might be called a scholarship permitting him to work at this laboratory. While his 	project was in cyto-chemistry—the chemical identification of cellular 	constituents by specific staining reactions under the microscope—there were 	some other students who were starting to experiment with these various machines.  	These were not very elaborate computers.  They were relay driven and involved 	punch cards.  Basically the only memory they had were the intermediate cards, so 	if you wanted to calculate a square root, for example, you could put in a number, 	program it to do that, and probably burn up several cards to get the results.  But it 	was the first intellectual robot JL had ever seen.  He was quite intrigued by its 	analogy to living organisms, and he from that moment on followed the 	development of computers, though mostly from afar and from the press.

00:15:06	No question: When JL came to Wisconsin, he found there was a Numerical 	Analysis Laboratory, which was run by Fred Grunenberger.  JL did not have any 	immediate use for the lab, but be thought he should familiarize himself with 	robots at that stage of their development.  This took place around 1952.  He took 	Grunenberger's course, and it was there he learned about plug board 	programming. JL understood the importance of what he was learning, but was not 	doing the kind of statistical work that Jim Crow and others were doing, so 	computers had no practical use for him at the time.  In addition, the machines of 	the time were pretty rigid and did not yet have compilers, programming 	languages, and the like.  It was not until he arrived at Stanford and took a 	FORTRAN course that he began working more seriously with computers.

00:16:48	Question: You also had some course responsibilities, could you talk about those? 	Answer: The discussion moves from JL's research at Wisconsin to his teaching. It 	was expected of JL, and he says he would have been disappointed if it had not 	been, that he give a course on the genetics of microorganisms.  JL suspects it was 	among the early courses of its kind in the country.  The course was cross-listed 	with microbiology and was offered as an advanced undergraduate course.  For a 	textbook JL used a compilation of papers of recent work, which he reprinted and 	bound into a red covered book, which was put together by the University of 	Wisconsin Press. Using that kind of material was in itself an innovation, but in a 	rapidly developing field there was not time to wait for the publication of a 	textbook. The technique proved successful, and the use of the red book was 	emulated by others on campus. JL briefly discusses some of the topics covered in 	class. Until the mid-1950s, one could in a single course teach everything that had 	been published in the field. JL notes that he almost certainly gave at least an 	annual lecture in the standard genetics course, and from time to time he lectured 	in other courses, such as microbiology.

00:20:33	Question: Talk about the early development of what became the Department of 	Medical Genetics. Answer: The discussion turns to the early development of what 	eventually was to become the Department of Medical Genetics.  JL begins by 	noting that his own work was in the genetics of microorganisms, and while he 	was very much concerned about the further reaches of genetics and its 	implications for medicine, that was not going to be a first order of consequence in 	his own investigations. Nevertheless, he was strongly committed to medicine and 	medically oriented research. He had gone past the midway mark in his studies as	a medical student, and had faced a difficult dilemma in deciding whether to 	continue working for his M.D.  It would have very much been JL's preference to 	have continued his research work in a more medical environment.  Still, his 	research with Ryan at Columbia had not been in a medical environment, nor had 	his work at Yale—although he had been a frequent visitor to the medical library 	and knew several people in the medical school.  At the time, there was not that	much interest in genetics by medical schools generally.  There was nothing going 	on at Columbia at the time, for example; nor can he think of any genetics at Yale 	at that point in time.  But there were matters of locating genetic factors in the 	human, of genetic counseling, of tracing pedigrees, and the like.  The field was 	burgeoning.

00:23:05	No question: An important factor was that JL got to know Jim Neel rather well.  	Neel had gotten his Ph.D. with Curt Stern at Rochester, had been a visitor at 	Columbia, then had made the very bold decision that he was going to go into 	human genetics and get an M.D.  JL remembers others thinking Neel crazy 	because what could you do in human genetics?  But Neel persevered and he 	proved—famously—that he was right.  He worked out the genetics of sickle cell 	disease, noting that it was a classic recessive mutation.  That was part of the 	background in JL's thinking about how one instills more genetics into medical 	research and into medical education.  In spite of what R. A. Brink said in a letter 	to JL in 1946, that there was no obstacle to genetics becoming a factor in medical 	research, neither was there much enthusiasm concerning it.  Van Potter and a few 	others around the McArdle Cancer Lab would have certainly listened to these 	matters. JL had posited a genetic somatic mutation theory for the origin of cancer 	while he was a medical student in 1946, and they could have—may have had—	several conversations around that.  But nothing was happening in that area, and 	besides JL was extremely busy with his own research.

00:25:29	No question: The possibility of going further in that direction appeared with John 	Z. Bowers' arrival as dean of the Medical School in 1955.  It so happened JL had 	met Bowers at a dinner in Curt Stern's home in Berkeley in 1950, during his 	summer teaching sabbatical. Stern had left Rochester and accepted a position as a 	professor of biology and genetics at Berkeley.  Stern would have known Bowers 	from Bowers's connection with the Atomic Energy Commission (AEC).  For a 	few years prior to 1950, Bowers had served as director of the Division of Biology 	and Medicine at the AEC.  In that position he oversaw research on the effects of 	atomic radiation in animals, and also the program investigating the consequences 	of Hiroshima at the Atomic Bomb Casualty Commission.  JL had known Stern 	since he was a medical student at Columbia in the 1940s. 

00:27:15	No question: Bowers was about to assume his position as dean of the medical 	school at the University of Utah when JL met him that night at Curt Stern's house.  	JL challenged him at the dinner table about what he was going to do about 	genetics in his new role, and he received an encouraging response.  JL does not 	recall having any further contact with Bowers before his arrival at Wisconsin, nor 	did JL play any role in his selection as dean.  As soon as JL heard he was coming, 	he contacted him immediately and repeated the challenge he had made at dinner 	that night five years earlier.  When asked by JL to do something combining 	medical school and genetics into a program at UW, Bowers said: "Let's try it."  	Bowers asked JL to put together a proposal, which he did.  Eventually this led to 	forming a program which provided the opportunity to teach genetics in the 	medical curriculum.  The program needed to start there because up to that point 	no genetics was being taught in the medical school—which was typical of the 	times.  They may have had a course in embryology and human development as a 	subsidiary to the gross anatomy course, and within that framework there may be 	two or three lectures on Mendelian genetics or something to that effect, but one 	must remember that there was not that much to teach in that area.

00:29:59	End of side.

Tape 6/Side 2

00:29:59	No question: The discussion moves to Curt Stern's book, The Principles of 	Human Genetics.  Although 99 percent of Stern's research was in Drosophila 	genetics, he was the next generation after Muller, Morgan and Sturtevant.  Stern 	had a deep interest in human genetics.  He taught it not in the medical school, but 	as a course in the biology curriculum at Berkeley.  His book was basically the 	only text available.  The history of the teaching of genetics in medical schools, JL 	notes, has yet to be written.  It did exist as a subsidiary topic, and JL thinks the 	first major teaching program—and he does not think it was elevated to the 	departmental level—was initiated by Jim Neel when he went to the University of 	Michigan.  But even there it had a secondary role in the teaching of medical 	students.  The typical pattern, JL recalls from his own experience as a student, 	was that a few lectures in the genetics of Mendelian ratios and the like were given 	as part of an embryology course.  Then there would have been examples like hair 	color and a few of the classical recessive mutations. One of the first of those to be 	understood was sickle cell disease, a hemoglobin disorder, and the genetics of that 	was only first worked out by Jim Neel, as mentioned earlier.  This research and 	some of the research in the area which follows on its heels, and which JL 	describes briefly, constitutes what might be called the beginning of molecular 	genetics—that is to say of the understanding of a disease syndrome of genetic 	origin in molecular terms.

00:33:21	No question: Thus the field was just beginning at a research level, but it was 	taught only incidentally in the schools.  Still, there were questions of radiation 	injury and of chemical mutagenesis that one needed to be concerned about.  One 	of the things that held back the teaching of the subject in a medical context, JL 	postulates, was the cloud of eugenics, and in turn the cloud of abuses in the Nazi 	regime.  At the time, there was a debate going on, with Muller being one of the 	centerpieces, about the extent to which one should encourage selectivity in human 	reproduction in ways analogous to how we breed race horses or better strains of 	corn and the like. There were obviously so many ethical no-nos in that general 	arena that one could see how it might be regarded as a very touchy subject. At 	any rate JL does not recall ever being required to lecture to the medical students at 	Wisconsin.

00:34:44	No question: What JL did was propose the establishment of what was first a 	program and then a department of medical genetics in order to instill better 	appreciation of the numerous developments occurring in the field, such as the 	discovery of the structure of DNA, which JL and others could readily see was 	going to overtake many aspects of research in medicine, as it was already 	beginning to in agriculture.  Newton Morton was hired to staff the early medical 	genetics program.  Morton, a former graduate student of Jim Crow’s, was very 	skilled in population genetics and provided a good starting point for a human 	genetics program.  JL notes that had it been up to him, he would have brought in 	someone with a microbiological background, while still others might have 	preferred a more molecular orientation.

00:35:50	No question: Naming the new program brought about some interesting questions.  	Since there already was a genetics department, it would have been confusing to 	have a separate department of genetics in the Medical School.  The department 	was thus named the Department of Medical Genetics, which brought about some 	misgivings on JL’s part, because he viewed it as a basic science department 	housed in a medical school. It was a convenience to put “medical” in the title, but 	JL was concerned that it might be too confining a term—because it would not 	have left a place for JL, for example, or for the more molecular aspects of it.  JL 	objected to the term “human genetics” for the same reason, in that this was just a 	part of the field. What eventually happened, of course, was that the two programs 	joined together in an across-school initiative.

00:37:20	No question: When he was first starting the programs, Bowers faced a lot of 	conservatism from the people in the Medical School.  He did not exactly 	encounter a lot of enthusiasm on the Ag side, either.  There were several turf 	issues and a lot of split votes on many of the committees, although there was a 	slow approval of these concepts as it worked its way through the Medical School 	and the rest of the University administration.  Relating to financial support, there 	was reasonable promise of substantial support from the Rockefeller Foundation, 	however there was no assurance that the Foundation’s funding would extend 	beyond five years.  The question Bowers and the others faced time and again was 	even if they got funding for five years, what funding guarantee did they have after 	that point?  JL believes that if the top levels of administration had shown more 	foresight about where the program was going, and how indispensable it was going 	to be, they would have understood that this was something that would have to be 	furthered.  It was pretty slow going, JL notes, to get that degree of formal 	approval, even with the promise of short term funding from outside sources.

00:39:12	No question: This more or less dragged on through 1956-57.  John Bowers 	showed a lot of dynamism—perhaps even too much.  Maybe, JL notes, he tried 	pushing things through faster than the medical community was ready to accept.  	JL had some friends in the medical community, people like Phil Cohen and Van 	Potter, who were certainly enthusiastic about it.  The microbiologists were, JL 	thinks, mostly uncomprehending.  Paul Clark probably had some positive vision 	in this direction, but he had long since retired as chairman.

00:40:29	No question: In the meantime other things were happening in JL’s life.  He had 	ambitions and aspirations that he is sure were connected with some degree of 	exasperation that things did not happen promptly and enthusiastically—that it 	took all the push Bowers and JL could offer to move them at all.  As far as other 	members of the Ag Genetics Department were concerned, JL is sure Jim Crow 	was very enthusiastic. Brink and Irwin, however, may have been a little perturbed 	that JL was so distracted by organizational issues.  They may have felt, and quite 	rightly, that this was going to compete in time and energy with JL’s own basic 	research.  He thinks that in their hearts they might have preferred he stick to pure 	lab work, but they also understood the realities of what was happening to genetics 	in the wider world.  Though Brink and Irwin supported JL, they did not provide 	aggressive support, perhaps because they foresaw there would be many problems 	in getting it to happen.  There was less than enthusiasm on the part of other 	members of the Ag Genetics Department.  They were not going to get in the way, 	but they were not going to push it, either.  This is reflected in many of the split 	votes in the various committees.  JL thinks there was less than great vision, even 	at the funding level, in relation to starting and supporting the program.

00:43:11	Question: You were looking to hire other people in the department of genetics? 	Answer: Along these lines, there had been discussions about hiring people for the 	newly formed department.  After Newton Morton, JL looked to Kimball Atwood, 	who, at the time, was doing some very interesting studies in mutagenesis in the 	human using red cell phenotypes as a measure. Atwood found ways in which one 	could measure the frequency of odd ball erythrocytes that had a different 	antigenic composition from the main population, and he attempted to validate that 	as a measure of mutations occurring during production of red cells.  Atwood 	published a number of papers on that, and JL thinks his work in this area has been 	regarded as a very useful tool.  He would then want to correlate it with exposure 	to radiation, exposure to chemicals, and so on.  He had a solid base for that 	research and he was someone JL had a close personal history with, in fact Atwood 	and JL had roomed together in New York City when they had both been medical 	students, Atwood at NYU and JL at Columbia.  At some point Atwood married 	and his wife moved in with them, since housing was extremely difficult to find at 	the time.  JL notes that “there is nothing lonelier than being the third man in an 	arrangement like that.”  He subsequently found separate quarters a few months 	later.

00:45:44	No question: Atwood had done brilliant work in a number of areas and JL was 	eager to have him as a member of the department.  He was not notable for 	answering his mail in a timely fashion, however, or being particularly prompt.  	This came to the floor at Wisconsin as well in relation to the launching of the new 	department.  Bowers and JL agreed to organize a symposium that might help 	define the field of genetics in a medical context.  Again, JL notes, it seems absurd 	that one would have to do this, but the field of medical genetics simply did not 	exist at that time.  The symposium was scheduled for April 7-10, 1958.  Several 	notables in the field were scheduled to appear, including Atwood.  Atwood 	appeared and gave a paper but never turned in a manuscript, thus the publication 	relating to the symposium does not refer to Atwood.

00:47:03	No question: Prior to the symposium, there had been considerable discussion 	about Atwood’s possible appointment to the department.  There had been a 	decision to postpone a decision until after the symposium, in order to see what 	kind of impression Atwood made.  Other events overtook the process before that 	materialized, however.  In other words JL made the decision to leave Wisconsin, 	putting the question of any other appointments on hold.

00:47:56	No question: In December of 1956, Tatum announced he was leaving Stanford 	and taking a position at Rockefeller University.  JL was visiting in California at 	the time and had some discussions with Stanford officials about the possibility of 	his being considered to succeed Tatum.  JL very promptly made an inquiry as to 	what his connection to the medical school might be, and received a pretty 	negative reply.  There were plans afoot to establish a new school on the main 	campus, moving the Stanford medical school, which was associated with a 	hospital in San Francisco, to the Palo Alto campus. JL would have been delighted 	to hear that the new medical school was going to embrace genetics, but he did not.  	The dean of the medical school, however, gave him no encouragement, saying 	only that he would be happy to have JL teach some courses if he was established 	in the biology department.  That pretty much discouraged JL from considering 	Stanford.  It must be remembered that Stanford was not that great a power base at 	that time in science or biology. Tatum was no longer there, Beadle had left, and 	JL did not know what else was going on in biology to make it attractive. Berkeley 	seemed a much more exciting place. As soon as word got to Berkeley that JL had 	been talking with Stanford, he started hearing from them about whether he might 	consider a Berkeley appointment. Early in 1957, JL started conversations with 	the genetics department at Berkeley, which was housed in the School of 	Humanities and Science. During that same time, the UC-Davis campus was being 	organized and consideration was given to locating the genetics department there.  	That did not appeal to JL, or to a number of the existing members of the 	department.  It had to do at least in part with ag school connections.  At any rate, 	matters moved forward regarding a position at Berkeley, and while Berkeley did 	not have a medical school it did have a school of public health, which was loosely 	affiliated with the medical school in San Francisco.  There was also a rich 	intellectual environment at Berkeley, even without a medical school.

00:51:22	No question: In the summer of 1957, JL was on sabbatical for several months in 	Melbourne.  In late 1957 he picked up the threads again, and Berkeley began to 	look more and more attractive.  There were several issues about laboratory space, 	but they were satisfactorily resolved.  There was also a question raised about a 	position for his wife Esther relating to nepotism which appeared to be on its way 	to getting resolved.   He also liked the idea of being near San Francisco and 	sharing in the intellectual life of Berkeley, besides which he was exasperated that 	things were not moving that well in Madison.  However his Berkeley hopes were 	dashed rather suddenly when, in spite of having been approved at every stage of 	the game on the Berkeley campus, JL received an astonished letter from Jenkins, 	the head of the genetics department, saying that the president of the California 	system had vetoed JL’s hiring.  No explanation was given regarding the action.  	Meanwhile more had been happening at Stanford, in that the acting dean from 	before had been replaced by Bob Alway, who had been head of pediatrics. Alway 	was to oversee the building of the medical school and its move from San 	Francisco.  Not only was Alway sympathetic to the idea of genetics in medicine, 	but Stanford was just about to recruit Arthur Kornberg, and then they began 	thinking of a package deal: if Kornberg was recruited, would JL come?  JL says 	he did not need a lot of arm twisting on that score.

00:54:50	No question: One of the things JL sorely lacked at Wisconsin was a base of 	interest, knowledge, and on-going programs in nucleic acid chemistry, and 	Kornberg represented the top of the pack.  JL had met him a few times before and 	they got along extremely well.  Still, JL felt committed to Berkeley and did not 	feel he could explore the Stanford option much further.  It was at that point in 	time that the president of the University of California System vetoed JL’s hiring, 	thus freeing him of that commitment.  Within two months, JL had a firm “yes” 	from Stanford.  JL then wrote President Elvehjem a letter indicating his 	intentions.

00:56:12	Question: Did UW know that this was going on at the time, did they try to get you 	to stay? Answer: Relating to the UW, JL did not keep his intentions secret but 	neither did he push matters very hard, choosing not to get into “a bargaining 	game.”  He did not have a firm promise from UW regarding the additional 	positions he was asking for.  Along that line, he was not able to make an offer to 	Atwood.  JL is sure that if he had really wanted to stay at Wisconsin he could 	have pushed that process along, but he was not about to play any games. Once he 	decided his preferences, he presented his conclusions.

00:57:22	Question: Going back a little, in 1950 the University of Chicago had offered you 	a position? Answer:  At the time he had close relations with Novick and Szilard, 	who were building up a biophysics unit at the University of Chicago.  They 	inquired about JL’s interest and, while there were many aspects of the University 	of Chicago that were very appealing, JL and his wife had been in Madison only a 	few years where they had been treated warmly and well, and he just did not see 	moving at that point in his career.

00:58:37	Question: I know that Wistar Institute in Philadelphia made you an offer as 	well, was that a little after Chicago? Answer: In approximately 1955 there were 	movements made in two different places to hire JL.  He gave some lectures in 	Denver and Ted Puck started a move to see about a genetics program in their 	medical school.  What was appealing was that Puck was one of the founders of 	somatic cell genetics, which is where you put human cells into tissue culture and 	do genetic experiments with those cultures.

00:59:41	No question: The issue of facilities was an important consideration in helping 	drive JL to explore other job opportunities.  They were very primitive when JL 	arrived at UW and remained so, though there was a renovation.  In the same vein, 	Hillary Koprovsky was reorganizing the Wistar Institute at the University of 	Pennsylvania and made a similar bid for JL’s services around that period of time.  	The offer was generous in terms of facilities. JL notes he could see things moving 	in other institutions, whereas at UW things appeared to be stuck.  Nevertheless it 	was Stanford that came out on top in the end.

01:00:43	End of side.  End of tape.

Tape 7/Side 1

01:00:43	No question: Stanford came out on top because it had everything going for it.  It 	demonstrated a real understanding of the program JL wanted to develop, it had a 	very progressive attitude, it had an attitude about medical education which was 	very research oriented, and at the same time there were interdisciplinary 	connections with the rest of the school.  This combination that the climate draws 	the people draws the money was evident in the rebuilding of the science base at 	Stanford.  It was the beginning of Silicon Valley and, not too many years after 	that, biotechnology alley, in terms of being at the very focus of exciting 	developments in every field.

01:02:28	Question: Did things work out as you had hoped at Stanford? Answer: What 	followed during his years at Stanford exceeded JL’s expectations, especially the 	interdisciplinary base.  He had a chance to work in everything from computer 	science to international security and arms control. His main disappointment about 	Stanford, oddly enough, was in the medical school.  While it built an 	extraordinary basic science division, with people like Arthur Kornberg, the 	interdigitation of the basic science with the clinical programs was more 	disappointing.  JL notes part of the reason may have been that at Stanford the 	sheer financial flow and power of the clinical programs ended up dominating the 	direction of the school.  While there was certainly a high quality of research in 	those programs, it did not really match the full aspirations of what had been 	looked for earlier in the ideals of the school.  This is a problem that will beset 	many academic medical centers in that as the funding base for the continued 	operation of the school chases the patients, chases the dollars, and provides a 	political base for the continued development of the organization, the basic 	sciences, in its connection with the clinical programs, tends to lose out.  JL notes 	that still there is little reason to complain, since the basic science component 	benefitted from what by contemporary standards will seem like unlimited 	amounts of federal funding, this being the burgeoning years of the NIH. That part 	JL had no complaints about.  It was the integration of it with clinical activity that 	fell behind, or at least did not meet JL's expectations.  

01:06:04	Question: Could you talk about the May-October 1959 period? Answer: In May, 	1958, JL had the Berkeley job pulled out from under him.  On July 19, 1958, he 	wrote President Elvehjem that he was leaving UW for a job at Stanford.  A few 	months later, in October, 1958, JL was notified he had won the Nobel prize. What 	followed was an extremely busy time, one that found JL and his wife busy selling 	their house, making living arrangements at Stanford, and preparing goodbyes for 	their friends in Madison.  So it came as quite a shock when he received a 	telephone call from a reporter asking about his reactions to having won the Nobel 	Prize. At first JL thought it a joke, since he had no expectation he was even being 	considered for the prize.  It ended up being a standoff with the reporter.  JL was 	concerned that this could generate a difficult situation, because if the rumor 	spread any further, and if he met his friends, who would be effusive in their 	congratulations, how was he going to deal with them the next day when they 	discovered it was a joke?  JL wanted to spare them and himself the 	embarrassment of that event.

01:08:24	No question: JL confided in one of his friends and went into hiding until he had a 	clear understanding of what was actually happening.  The situation quickly 	became embarrassing and awkward.  First of all it was painful severing the bonds 	he had established in Madison.  People like Brink, Irwin and Crow, much to JL's 	relief, took the news of his leaving with more grace than he had expected.  Then 	to have the Nobel prize come in just at that point was bitter-sweet, in that while 	winning the prize has many benefits for the host institution, announcing one's 	departure at the moment one secures the prize magnifies the rebuff.  JL even 	seriously considered not accepting the prize.  He expressed concerns to friends 	about whether all the fuss over the prize was helpful to science and whether it 	elicited inappropriate competitiveness in some areas. There was also the problem 	that so much scientific work was interconnected that one was bound to leave out 	people when one makes an award.  Although ambivalent about accepting the 	award, he understood there were virtues as well.  At an even deeper level turning 	it down would have been a slap in the face of Ed Tatum. Besides, if he had turned 	it down it would have ended in even more notoriety—which is exactly what he 	was trying to avoid.  So JL decided to accept the award.  Winning it when he did 	made things bitter-sweet at UW, but it also left Stanford in an awkward position, 	for he was winning the prize for work he had done elsewhere.

01:13:03	No question: For a while his wife Esther was so busy preparing for the move that 	she seriously considered not making the trip to Sweden for the awarding of the 	prize.  JL found an acceptable route to deferring for six months the lecture he was 	required to give in Sweden.  This gave him time to settle in at Stanford and have 	time to prepare the lecture.

01:14:38	Question: What was the celebration itself like? Answer: Once in Sweden, there 	was an entire week of festivities.  The whole country is involved in Nobel week, 	which is a week of celebration.  There were banquets and affairs of one sort or 	other almost continuously. All of the other Nobelists gave their talks that week, 	so JL attended several of these presentations.  Besides the academic meetings 	there was the formal ceremony, which was held in the beautiful structure of the 	town hall.  At the formal presentation, the king of Sweden presented the awards.  	There was a certain amount of socialization among the laureates, and JL was 	happy to meet the Russian physicist Igor Tamm, who was outspoken and who, 	because of his age, told JL he was not worried about being punished for being 	outspoken. This was also the year Boris Pasternak won the prize but was not 	allowed to attend.

01:19:24	No question: Beadle and Tatum were JL's co-laureates.  The prize for medicine 	and physiology was divided into two parts, with JL receiving one part and Beadle 	and Tatum sharing the other part.  The Beadle-Tatum award was for their joint 	work on Neurospora, and while Tatum had been JL's collaborator this was an 	acknowledgment of the fact that the work had really been done at JL's own 	initiative and that he had done 95 percent of the laboratory work.  JL was very 	proud and honored to be in their company.  Those were people who had preceded 	him by ten or fifteen years in their own scientific development, and JL had "stood 	on their shoulders" for the work he had done.  JL had never doubted that they 	would eventually receive the Nobel Prize, but he never thought that issue would 	come around to him—especially since he was only 33 at the time.  He thought he 	had been a good enough scientist and if he worked another 20 years he might 	have an accumulated body of work that would qualify him for it.

01:22:07	Question: Who was Phil Edwards? Answer: In his Madison press conference 	following his winning the award, JL made a point of naming several people who 	had been instrumental to his winning the award.  The names he mentioned were: 	Bradley, Cavalli, Phil Edwards, Morse, Stocker, Wright, Zinder and Iino.  All 	except Phil Edwards have been discussed earlier in this interview.  Phil Edwards 	was the leader of the Center for Disease Control in Atlanta which provided the 	raw material with which JL had done his studies on the immunogenetics of 	Salmonella.  JL had visited him for a couple of weeks in 1953.

01:23:25	Question: How helpful was the Nobel Prize to you in your subsequent career? 	Answer: In terms of the effect the Nobel Prize had on his career, JL said he did 	not need it, since his career was going fine.  It probably added a little bit to 	prestige, and it probably did not hurt Stanford in raising funds to support the work 	he was engaged in.  JL notes it probably gave him a standing outside of the 	immediate scientific area he would not have had otherwise.  There is a certain 	certification of authority that goes along with the prize.  When a Nobel winner 	talks about scientific topics in public—sometimes quite inappropriately—it is 	credited with likely being true.  The Nobel Prize probably drew attention to JL in 	policy quarters so that he would be consulted or drawn upon in ways he might not 	otherwise have been.  There is also a certain responsibility associated with 	winning such an award that one must not abuse.  JL notes he does not think the 	Nobel Prize does much for individual scientists in that if it goes to the right 	people they don't need it, and if it goes to the wrong people, it is inappropriate.

01:26:13	No question: The cash, JL notes, has gotten to be a significant factor.  At present, 	the prize is worth over a million dollars.  JL’s share of the prize in 1958 was 	$21,000.  One other factor about winning the prize is he is forever introduced as 	“Joshua Lederberg, the Nobel prize winner.” This is an impediment he constantly 	has to work around. He sees it as a source of distancing from people, as being 	dehumanizing.

01:27:28	End of side.

Tape 7/Side 2

01:27:29	Question: Could you discuss your continued relation with those in Madison? 	Answer: The discussion turns to JL’s return trips to Madison after having departed 	for Stanford.  Harry Waisman was a renowned figure in the history of medical 	pediatrics at Wisconsin whom JL had gotten to know pretty well.  Waisman was 	interested in genetic disease and he played an important role in the development 	of PKU screening for newborns in Wisconsin, and a number of related matters.  	JL consulted with him, and they may have been fellow members of a president’s 	panel on mental retardation that President Kennedy’s family had initiated early in 	his administration.

01:28:49	No question: JL was happy to be asked to receive an honorary degree in 1967. On 	his trip to Madison to receive the degree, JL relates how he and his luggage 	became separated because the travel agency had neglected to inform him that he 	would be departing from a different terminal in Rome.  As a result JL’s bags went 	on to the next destination, which was Tel Aviv, and JL did not.  It just so happens 	that coincided with the start of the Six Day War, and the flight JL missed was the 	last commercial flight into Israel.  He ended up heading back to the states sans 	luggage, but managed to buy a new suit of clothes before arriving in Madison to 	accept his honorary degree.

01:30:32	Question: Do you have any closing comments you wanted to make about your 	career at the University of Wisconsin?  Answer: “It was a wonderful experience 	for me. It was a different world. The University’s roots had been in agriculture as 	a life style—a closeness to the earth—a very important set of values that are 	connected with that, which I was glad to have an opportunity to experience.  It 	was also a wonderful liberal tradition, a very tolerant one, which Wisconsin had 	been famous for. And of course there was a severe blot on it with the Joe 	McCarthy days, but I think totally repudiated by the state as well. The University 	was the jewel of the state, was regarded as such.  The legislature was proud of it	—and it’s always been amazing that the state of Wisconsin, which I think ranks 	twenty-fourth in income ... has still had one of the highest ranking of the public 	institutions of learning in the country.  And I think that tradition has been 	maintained.  The quality of friendships that we had, not only the very close and 	very intimate ones but almost everybody else—I’d feel that whenever I come 	back to Madison that you can count on an amiability and a friendliness and a 	courtesy that’s really very, very hard to find anywhere else in the country at this 	time.  Now you know Madison has become heavily urbanized since fifty years 	ago, and become probably more like the rest of the country in many regards, but I 	think it still has an edge on these kinds of qualities.  It’s a somewhat quieter life 	then, say, New York or San Francisco, but it still has no lack of cultural amenities	—you just don’t have twenty or thirty to choose and pick amongst, if you’re 	talking about theater or music. But what there is, is very good and you don’t have 	to work hard to have the advantage of it.  The climate we’ll leave to another 	situation. But it’s the people that really are so wonderful. It’s the people who are 	drawn there, the people that stay there, the people whose own ethos is conditioned 	by the environment that they find, and who in turn condition that environment 	themselves. So I have just an enormous fondness and admiration for every level 	of life there. I certainly learned a lot, grew a lot—in the human as well as the 	professional side of my life—and it would have been very sad indeed if I had 	never been there.”

01:34:11	End of side.  End of tape.  End of interview sessions.

END of Oral History #529