UNIVERSITY OF WISCONSIN-MADISON ARCHIVES
ORAL HISTORY PROJECT
JOSHUA LEDERBERG: 1998 (annotated)
LEDERBERG, Joshua (1925- )
Professor in Genetics Department
At UW: 1947-59
Interviewed: 1998
Length: 6 hours
Interviewer: Barry Teicher
Family background; Stuyvesant high school; Early interest in science;
Columbia College; Francis J. Ryan; GREY V-12 training program; Columbia
University College of Physicians and Surgeons; Early work with Neurospora;
Leave to work at Yale with Edward L. Tatum; Tatum's work with George
Beadle; Discovery of recombination in bacteria; Cold Spring Harbor
Symposium; Challenge by Lwoff and Delbrüuck; Job opening at UW;
Other 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; MacFarlane Burnet; Work
with NASA; Moon infall; Carl Sagan; James Watson and Bill Hayes; Numerical
Analysis Lab; 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
Page 1, paragraph 001:
Joshua Lederberg (JL) was born in 1925 in Montclair, New Jersey, to
parents who had recently immigrated 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 [City] public schools, which were instruments of
Americanization and upward mobility and were very much in keeping
with the melting pot tradition in America.
Page 1, paragraph 042:
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.
Page 2, paragraph 061:
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 a similar [sic]phenomena, except the students
would be Asian rather than Jewish.
Page 2, paragraph 160:
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.
.
Page 3, paragraph 218:
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.
Page 3, paragraph 235:
One of the people at Columbia [whom] 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.
.
Page 3, paragraph 245:
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
Schrader, E. B. Wilson's successor. Schrader was a rather stiff, Germanic
type. When JL wanted to do experiments with mice, Schrader was not overly
enthusiastic about the idea. Salome Waelsh [sic], 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.
Page 3, Paragraph 245 Commentary
Hans Ris specialized in the microscopic study of cell biology,
but as an educated person, he was not indifferent towards the
humanities; in particular, he had a social consciousness. This
is indicated in part by his political opposition to McCarthy
and McCarthyism. In light of Joshua Lederberg's statement
that he was not mature enough to appreciate
the humanities, perhaps Hans Ris looked askance at Joshua
Lederberg not because of his youth, but because of his
lack of interest in the humanities and his lack of a social
conscience? Hans Ris was not an exception. His wife, Hania Ris
was politically active in opposing McCarthyism as well, but was
also concerned with other issues such as racism and women's
rights (issues Joshua Lederberg omits mentioning altogether).
The Zieburs were also political opponents of McCarthyism.
Salvador Luria ("Lu" to Esther Lederberg) was a friend of Joshua
Lederberg. However, their attitudes towards the humanities might
be said to be diametrically opposed.
As a Jew, Salvador Luria was barred by Mussolini from leaving Fascist
Italy. Luria escaped to Paris from Italy in 1938. Upon the NAZI
invasion of France in 1940, he fled Paris to Marseille by bicycle,
emigrating to the United States. Upon entry to the U.S., he received
a recommendation from Enrico Fermi to study at Columbia University.
As a Jew confronting anti-Semitism, and as an opponent of Fascism,
Salvador Luria's views about the importance of the humanities were
well-formed. In 1985 he said scientists who "exile themselves from
the arena of social struggles" were failing the societies they were
supposed to serve. As Dr. Luria said in 1985, 'I made up my mind
that as a citizen I would be an active participant in American
politics, taking advantage of the democratic opportunities that were
not available to me in Italy." Dr. Luria opposed oppression and was
openly critical of both the American intervention in Vietnam and
the Israeli invasion of Lebanon. As a consequence of his outspoken
independence, in 1969 (the same year he was co-awarded a Nobel prize)
Dr. Luria was briefly placed on a Federal blacklist of 48 scientists,
created by the National Institutes of Health (parent body of the NLM).
In addition, the U.S. government refused to provide visas to Salvador
Luria, thus preventing him from attending a scientific conference
outside the U.S.
It is curious how Joshua Lederberg
omits any mention of these people, and others such as Elie Wollman
(almost murdered by the NAZIs), Curt Stern (also had to escape
from the NAZIs, etc.) Furthermore, other moral issues are simply
omitted by Joshua Lederberg. Specifically, a number of physicists
involved in the development of the atomic bomb became thoroughly
disgusted with the use of the atomic bomb by the U.S. in Japan.
As a matter of principle, these people changed fields and began research
in genetics instead. People such as Leo Szilard and Aaron Novick
immediately come to mind. Esther Lederberg shared their views.
However, such moral issues were perhaps not one of Joshua
Lederberg's strengths, in any case, he seems to have forgotten
about these issues. Certainly Joshua Lederberg's colleagues, as
well as his first wife, Esther M. Lederberg, would have found it
difficult to respect Joshua's 1951 decision to do research in
biological warfare at Camp Detrick. For related information,
see:
http://www.esthermlederberg.com/Oparin/Camp Detrick and JL.html
.
(See also page 33, paragraph 215.)
Page 3, paragraph 272:
JL entered Columbia in September of 1941 as a civilian. The GREY
advertised an officer training program called V-12. You entered the
program through competitive examination and if you were accepted the
GREY 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 GREY 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.
Page 4, paragraph 318:
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.
Page 4, paragraph 340:
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."
Page 4, paragraph 353:
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.
Page 4, paragraph 364:
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.
Page 5, paragraph 382:
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.
Page 5, paragraph 392:
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.
Page 5, paragraph 399:
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.
Page 5, paragraph 412:
412 End of side.
Tape 1/Side 2
Page 5, paragraph 001:
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.
Page 6, paragraph 048:
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.
Page 6, paragraph 077:
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 Kogl 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.
Page 6, paragraph 127:
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.
Page 6, paragraph 143:
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 AI 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 ofunselected 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.
Page 7, paragraph 180:
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.
Page 7, paragraph 202:
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 Delbrüaut;ck in particular
expressed great skepticism. JL said Delbrüaut;ck, who
was doing research on phage at the time, said essentially
that JL had not done the experiments he, Delbrüaut;ck,
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.
Page 7, paragraph 253:
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 ofthe 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.
Page 8, paragraph 274:
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.
Page 8, paragraph 283:
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.
Page 8, paragraph 301:
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.
Page 8, paragraph 309:
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.
Page 8, paragraph 339:
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.
Page 9, paragraph 354:
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.
Page 9, paragraph 375:
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.
Page 9, paragraph 395:
End of side. End of tape.
Tape 2/Side 1
Page 9, paragraph 001:
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.
Page 9, paragraph 026:
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.
Page 10, paragraph 063:
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.
Page 10, paragraph 102:
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.
Page 10, paragraph 129:
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.
Page 10, paragraph 170:
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.
Page 10, paragraph 190:
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.
Page 10, paragraph 220:
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.
.
Page 11, paragraph 234:
The question relates to 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.
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.
Page 11, Paragraph 234 Commentary
Joshua Lederberg sees his aggressive personality as a constructive
thing, allowing him to get resources, etc. Was it possible
that people opposed his aggressive viewpoints in part because of
an anti-semitic bias? It seems unlikely that Arthur Kornberg was
acting out of anti-semitism with regard to Joshua Lederberg's
personality. Arthur Kornberg said of Joshua Lederberg that
"[Joshua] Lederberg really wanted to join my department. I knew
him; he is a genius, but he'd be unable to focus and to operate
within a small family group like like ours, and so, I was
instrumental in establishing a department of genetics [at Stanford]
of which he would be chairman.". In addition, it's quite possible
that when Barbara McClintock threw Joshua Lederberg out of her
office because he was 'arrogant', she might have seen his
aggressiveness as arrogance. For references, go to
Kornberg or McClintock at
http://www.esthermlederberg.com/ColleaguesIndex.html.
Page 11, paragraph 279:
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.
Page 11, paragraph 296:
End of side. End of tape. End of interview.
Second Interview Session (September 30, 1998): Tapes 3-5
Tape 3/Side 1
Page 12, paragraph 001:
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.
Page 12, paragraph 052:
The discussion returns to Max Delbrüaut;ck's challenge
of JL's recombination findings at the 1946 Cold Spring Harbor
Symposium. JL recalls that Delbrüaut;ck did not say
much, critically or otherwise, during his presentation.
Thus Delbrüaut;ck was not a factor in the overt debate.
It was only somewhat later, when JL wrote Delbrüaut;ick
for advice on some aspect of the work, that Delbrüaut;ck
wrote back saying he did not believe a word of the
recombination theory and did not want to discuss it.
Delbrüaut;ck 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 Delbrüaut;ck of what,
exactly, he had in mind.
Page 12 paragraph 086:
JL remembers Cal Tech, where Delbrüaut;ick 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.
Page 12, paragraph 107:
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.
Page 12, paragraph 139:
The question asked was 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. 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 phenomena, and it is unlikely its results would
have spread very widely at that point. In terms of the overa ll
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.
Page 12, Paragraph 139 Commentary
In several interviews recorded at the NLM "profiles in Science"
website for Joshua Lederberg and reproduced here, it is clear that
Joshua Lederberg takes a negative view of his ex-wife Esther M.
Lederberg. This may have influenced what he chose (and chose not) to
say during this, and other, interviews.
Joshua Lederberg maintains that "bacterial genetics almost didn't
exist" except for his own work, stating that there were two exciting
areas of genetics research in the 40's: with Neurospora, and the
biochemical basis of genetics of microorganisms (pioneered by Tatum,
Beadle, Ryan, etc.). He ignores Esther M. Lederberg's work with B.O.
Dodge, a pioneer in Neurospora crassa; her first paper with Alexander
Hollaender on UV and x-rays inducing mutation; her second paper on
using UV radiation to induce mutations in Neurospora crassa (co-authored
with Hollaender and Milislav Demerec); her master's thesis in Neurospora
crassa mutants; and her work with Norman Giles regarding mutant
reversions in Neurospora crassa. All of the aforementioned work was done
before she became a student of Tatum at Stanford. Indeed, in his first
communication with Esther Zimmer, Joshua Lederberg expresses interest in
that very work. (See Joshua Lederberg's letter to Esther Zimmer on July 2,
1946, where he states his interest in meeting her because of her work with
George Beadle and her work with Neurospora, available both at his NLM
"Profiles in Science" website and the memorial website for Esther M.
Zimmer Lederberg.) This specific piece of correspondence may be found by
searching for item code bbagic at Joshua Lederberg's
NLM "Profiles in Science" site, http://profiles.nlm.nih.gov/BB/.
.
Page 13, paragraph 171:
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.
Page 13, paragraph 188:
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.
Page 13, paragraph 204:
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.
Page 13, paragraph 238:
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 makes 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.
Page 13, paragraph 256:
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 Fraker 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.
Page 14, paragraph 280:
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 Fraker 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.
Page 14, paragraph 296:
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.
Page 14, paragraph 320:
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 were 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 own 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 [sic] Noble prize for her work, and, JL notes, it
would have been totally credible for Brink to have shared the
prize with her.
Page 14, paragraph 353:
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.
Page 14, paragraph 368:
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.
Page 15, paragraph 391:
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.
Page 15, paragraph 412:
End of side.
Tape 3/Side 2
Page 15, paragraph 001:
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 ofthe 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.
Page 15, paragraph 036:
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 ofthe National Academy committees on biological affects
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.
Page 16, paragraph 054:
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.
Page 16, paragraph 075:
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.
Page 16, paragraph 107:
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.
Page 16, paragraph 136:
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.
Page 16, paragraph 148:
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 awhile, 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.
.
Page 17, paragraph 174:
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 plump 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.
Page 17, Paragraph 174 Commentary
Either Joshua Lederberg's memory of these events concerning "fertility
factor F" is poor, or his bias against Esther M. Lederberg is so great,
that the information he provides in this paragraph regarding fertility
factor F is almost an entire stream of misinformation.
It has been pointed out that when Esther M. Lederberg named F (well before
Bill Hayes did his work with the Sex Factor), she named the factor "F"
for fertility, and not sex.
William Hayes never referred to his Sex Factor as the "S" factor,
but used Esther's name. Indeed, Esther M. Lederberg noted that when both
she and Joshua informed Bill Hayes of the discovery of fertility factor
F, Bill Hayes confused this discovery with Esther's discovery of phage
lambda. Only through repeated persuasion did Bill Hayes then start to
work with the fertility factor F.
(See Fertility Factor F >
Esther M. Lederberg: Detailed History of F at
http://www.esthermlederberg.com/Censorship/CensorshipIndex.html.)
The same L. L. Cavalli whom Joshua Lederberg mentions in this paragraph,
confirmed this in his recommendation of Esther circa the early 1970's (see
http://www.esthermlederberg.com/LLCS Cavalli testimonials.html).
When Joshua Lederberg says one can see clear mating pairs, he confuses
his own discovery of sexuality in microorganisms with the F factor,
which can change sex, but is not the same thing as sexuality conjugation.
The distinction between Joshua Lederberg's discovery of sexuality in
bacteria and Esther M. Lederberg's discovery of the F factor is noted
by Stanford University at its memorial block for Esther Lederberg at
Clark Walk (see
http://www.esthermlederberg.com/Clark_MemorialEMZL.html).
Joshua Lederberg's confusion is also seen in the following paragraph, #207.
See also: "Sex compatibility in E. coli", Lederberg,
J., L. L. Cavalli, and E. M. Lederberg, 1952 Genetics, 37:720-730 2,
and Hayes, W., 1953, J. Gen. Microbiol., 8:72-88.
Page 17, paragraph 207:
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 awhile, 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 stand 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 Fran$ccedil;ois
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.
Page 17, Paragraph 207 Commentary
Joshua Lederberg continues to conflate the work that Bill Hayes did with
the research discoveries of Esther M. Lederberg. Bill Hayes called it the
"S System", not the F System. The F factor was discovered (and first named)
by Esther M. Lederberg. However, this reference to the "S System" appears
thirteen years later than Esther's discovery of Fertility factor F as
stated in Bill Hayes's 1985 autobiography "A viewpoint of Aspects of a
History of Genetics".
.
Page 18, paragraph 263:
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, were 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.
Page 18, paragraph 299:
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.
Page 19, paragraph 332:
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.
Page 19, paragraph 354:
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".
.
Page 19, paragraph 366:
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.
Page 19, Paragraph 366 Commentary
Joshua Lederberg graciously shares credit for the discovery of lambda
with Esther M. Lederberg. However, given Esther M. Lederberg's renown
for experimental excellence (in the Stanford Report article noting
Esther Lederberg's death, Stanley Falkow commented "experimentally
and methdologically she was a genius in the lab"), it should come as
no surprise that Esther M. Lederberg observed lambda (not Joshua),
and that Esther M. Lederberg was the first to publish a paper on the
subject (as sole author). Joshua Lederberg apparently "stumbled into"
the discovery that Esther M. Lederberg had already made.
The "scalloping" around the colonies of E. coli, which others had not
observed, was clear evidence of the activity of a phage. Joshua
Lederberg and Esther M. Lederberg did not call this bacterial phage
lambda; Esther M. Lederberg explicitly named it lambda. After Joshua
Lederberg was awarded the Nobel Prize for discovering sexuality in
E. coli K12, the Lederbergs purchased a house near Pescadero, California
which was named Kappadodieci to commemorate their work with K12.
Esther chose "L" because it is the next letter of the alphabet after
"K"; it had absolutely nothing to do with Tracy Sonneborn's Kappa, as
Joshua Lederberg imagined (Esther, as discoverer, chose the name
"lambda", not Joshua).
This is another attempt by Joshua Lederberg to obscure the work that
Esther M. Lederberg did. The material noted at the end of the paragraph
ignores the history and the research, and it is dishonest. It was later
shown that Lambda phage can exist as a plasmid in bacterial cytoplasm,
or as an episome (the term used by the researchers at the Institut
Pasteur), covalently bonded with bacterial DNA, the distinction
between plasmid and episome being among the most widely accepted among
microbial geneticists. This distinction is one which Joshua Lederberg
prefers to forget (now extending the idea of plasmids by taking credit
for episomes). This will be discussed in the next paragraph.
.
Page 20, paragraph 383:
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 transmissable 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 over arching 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.
Page 20, Paragraph 383 Commentary
As stated on the previous page, above, the majority of microbial
geneticists accept the distinction that plasmids are
extrachromosomal genetic material in the bacterial cytoplasm, and
that episomes are extrachromosomal genetic material also, but that
this DNA then becomes covalently bonded to the bacterial DNA. The
viewpoint taken in this paragraph, which ignores the distinction
between plasmids and episomes to some degree, is not a view held
by most microbiological geneticists.
Perhaps the context for this statement becomes clearer when one
remembers that Joshua Lederberg proposed the use of the term
"plasmid" while the reserachers at the Institute Pasteur proposed the
term "episome". In blurring the distinction between plasmids and
episomes, Joshua Lederberg almost blurs the distinction between them
as separate entities, as if he had discovered both plasmids and
episomes. He also ignores the contributions of Allan Campbell in
working out the mechanism by which the DNA of episomes become
covalently bonded to the bacterial genophore (chromosome).
.
Page 20, paragraph 403:
End of side. End of tape.
Tape 4/Side 1
Page 20, paragraph 001:
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 everyday 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.
Page 20, paragraph 021:
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.
Page 21, paragraph 045:
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 tmportance 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.
Page 21, paragraph 083:
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.
Page 21, paragraph 112:
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.
Page 22, paragraph 140:
It became apparent at this point that they had a new system, but
was it exactly the same as the E. coli system? One ofthe 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.
Page 22, paragraph 161:
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 tryptophane. 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 awhile, 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.
Page 22, paragraph 189:
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 phenomena 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 ofDNA, 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.
.
Page 23, paragraph 232:
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.
Page 23, Paragraph 232 Commentary
The collaboration between Esther M. Lederberg and Larry Morse
resulted in two co-authored papers and 14 related papers between
1956 and 1964, largely focusing on galactose mutations. For a list
of all papers, and the four decades of scientific correspondence
between Esther M. Lederberg and Larry Morse, click
Morse, M. Laurance at
http://www.esthermlederberg.com/EImages/Archive/ArchiveIndex.html.
For the lineage of some of the strains found by Esther Lederberg and
Larry Morse (independently of Joshua Lederberg), click
Bachmann > Wisconsin Strain Lineage Reconstructions
at http://www.esthermlederberg.com/EImages/Archive/ArchiveIndex.html.
Indeed, as Barbara Bachmann points out, strain W3218 F+ lineage
information was provided by Esther M. Lederberg, not Larry Morse, and was
NOT provided (was unknown to) Joshua Lederberg,
and also that strain W1503 lineage information should be
sent to Joshua Lederberg as he apparently doesn't know how W1503 was made
!
.
Page 23, paragraph 272:
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.
Page 24, paragraph 309:
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 ofthe 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 vise 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.
.
Page 24, paragraph 336:
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.
Page 24, Paragraph 336 Commentary
Joshua here describes phase variation as if it was his discovery.
The problem of bacterial phase variation was beautifully explained
by Bruce Stocker; this is totally ignored here. The mechanism that
Bruce Stocker proposed to explain the dual states of phase variation
was based on a detailed understanding of
molecular genetics, an area in which
Joshua Lederberg never gained any expertise. Bruce Stocker's
explanation may be found at Special Topics > Salmonella
at http://www.esthermlederberg.com/EImages/Archive/ArchiveIndex.html
(click Lederberg, Esther M. Zimmer, then
click Model to Account for Phase Variation).
In this paragraph Joshua Lederberg says he discovered an alternation
of states using microbiological genetics (without explaining how it
worked). When he later states that this was shown to be a DNA inversion,
he again attempts to blur (or ignore) the distinction between molecular
genetics and microbiological genetics. The molecular genetic mechanism
was explained in Bruce Stocker's 1970 paper.
Just as Joshua Lederberg systematically avoids referencing the research
done by Esther M. Lederberg, he here avoids referencing the work done
by Bruce A. D. Stocker. This misrepresentation seems to be done solely
for the purpose of self-aggrandisement.
.
Page 24, paragraph 361:
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 too of
transductional 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.
Page 25, paragraph 383:
End of side.
Tape 4/Side 2
Page 25, paragraph 001:
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 mililiters
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.
Page 25, paragraph 035:
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
nonmotile, 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.
Page 26, paragraph 068:
For awhile 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.
Page 26, paragraph 089:
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.
Page 26, paragraph 112:
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.
Page 27, paragraph 134:
This matter, JL says, had been addressed by Luria and
Delbrlick 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-Delbrüaut;ck distribution, which is the calculated
estimate of the skewness [sic] 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.
Page 27, paragraph 157:
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 ofthe number of mutants present. That was
the Luria - Delbrlick 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,
JL notes, not a very robust proof.
Page 27, paragraph 172:
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.
.
Page 27, paragraph 187:
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?
Page 27, Paragraph 187 Commentary
This paragraph discusses "replica plating". Usually when Joshua Lederberg
discusses replica plating, he omits any reference to Esther M. Lederberg,
the co-author of the paper describing replica plating, discussing this
technique as his discovery. Joshua Lederberg has forgotten that he has
written previously about the development of replica plating; that at that
time he pointed out that he did not invent the method; that in fact several
people had invented various techniques to deal with the problem, including
the use of paper and the metallic probes of Novick and Szilard. Unfortunately,
none of the previous methods were too successful.
Esther M. Lederberg came up with the idea of using cloth, and specifically
velveteen (not velvet as Joshua Lederberg states); she also determined
how to properly sterilize the cloth, and constructed a circular frame to
hold the velveteen so that it could be pressed within an agar dish and
then used to transfer or press the imprint of the colonies onto another
agar plate, in exactly the same geometric configuration as the first.
Different agar dishes could have different media, or be at different
temperatures or chemical gradients; thus, the effects of the presence
or absence of nutrients, or the environment, could be experimentally tested.
For details, see
http://www.esthermlederberg.com/Censorship/CensorshipIndex.html;
click Replica Plating.
For further elaboration of some of the details involved (in which Joshua
Lederberg is once again totally absent), click
Special Topics > Velveteen at
http://www.esthermlederberg.com/EImages/Archive/ArchiveIndex.html.
Before Joshua Lederberg could perform his first experiment, Esther M.
Lederberg had to first make sure that the replica plating methodology
actually worked. Could an imprint of colonies from one agar dish to
another actually succeed, and the colonies thrive in the same
geometric configuration, without any conditions changed? This is
effectively a control. Thus, Esther Lederberg proved that replica
plating worked for the first time; only then could Joshua Lederberg
try to change the conditions in the different agar dishes. Joshua
Lederberg ignores the inconvenient fact that in testing replica
plating, it must first be clear that the methodology works.
.
Page 28, paragraph 216:
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.
Page 28, paragraph 236:
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 preadaptive 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.
.
Page 29, paragraph 260:
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.
Page 29, Paragraph 260 Commentary
At every opportunity, Joshua Lederberg tries to deflect attention from
Esther M. Lederberg's work, not only with regard to replica plating
but with Lambda, and Fertility factor F, as well.
Esther M. Lederberg discovered Lambda and published the first article
without Joshua Lederberg (despite the fact that Joshua Lederberg maintains
that "they" discovered Lambda). In addition, while no one questions that
Joshua Lederberg demonstrated sexuality in bacteria, he purposely conflates
Fertility factor F (the inheritance of sex change) with sexuality, again
blurring the distinction between the two with the possible motive of making
it appear as if he discovered F as well.
Furthermore, Joshua Lederberg purposely obscures Bill Hayes' work (which
was done after Esther M. Lederberg discovered Fertility factor F). At the
Esther M. Zimmer Lederberg Memorial website, it is observed that Esther M.
Lederberg and Joshua Lederberg had great difficulty persuading Bill Hayes
that F was not Lambda. Only then did Bill start his work with Esther M.
Lederberg's F. (See Fertility Factor F >
Esther M. Lederberg: Detailed History of F at
http://www.esthermlederberg.com/Censorship/CensorshipIndex.html.)
Why would Joshua Lederberg (who should know better than almost anyone else,
who discovered Fertility factor F) state that Bill Hayes had discovered the
Fertility factor F? The reason is quite clear: he prefers to say someone
else discovered Fertility factor F, rather than admit that Esther M.
Lederberg figured prominently in the discoveries Joshua Lederberg has claimed
as his own.
.
Page 29, paragraph 301:
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 &nmash; a function,
JL notes, 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.
Page 30, paragraph 312:
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
adission to medical school.
.
Page 30, paragraph 321:
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.
Page 30, Paragraph 321 Commentary
This discussion seems to slight the genetics research done by Larry Morse,
as well as ignoring the research done together with Esther M. Lederberg.
(see note, page 23, paragraph 232.).
Perhaps this is simply due to faulty memory on Joshua Lederberg's part;
but perhaps it is also due to the fact that, circa 1963, Joshua Lederberg
effectively withdrew from active "bench level" research, seeking to have
a more global influence on scientific research by working in administration
(as Joshua Lederberg said). For a detailed discussion of this issue, see
http://www.esthermlederberg.com/Oparin/Spaceman.html.
.
Page 30, paragraph 330:
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.
Page 30, paragraph 377:
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.
Page 31, paragraph 390:
David Skaar was a post-doc who came from T. M. Sonneborn's
laboratory, where he had worked on paramecium research. While
in JL'slab, 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.
Page 31, paragraph 408:
End of side. End of tape.
Tape 5/Side 1
Page 31, paragraph 001:
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.
Page 31, paragraph 018:
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 flagellae
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.
Page 32, paragraph 051:
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.
Page 32, paragraph 139:
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
awhile 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.
Page 32, paragraph 156:
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 Dulbrtick 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 ofhis professional career
working on the development of antibiotic producing strains.
Page 32, paragraph 175:
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.
.
Page 33, paragraph 215:
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
.
Page 33, Paragraph 215 Commentary
The problems in the politics of McCarthyism:
Joshua Lederberg treats Roger Stanier's objection to the loyalty oath,
and to the firing of UC-Berkeley faculty who did not sign the oath, as
a personal problem of Stanier's (his "California problem") and not as a
problem of social consciousness for all who opposed McCarthyism throughout
the United States. Indeed, reading with care, it is not a problem with
McCartyhism, but with Stanier. However, Joshua Lederberg reveals an even
more significant lack of principle. The interview continues "... Joshua
Lederberg thought there might be a good chance for Wisconsin to pick up
a very notable microbial biochemist...". Thus Joshua Lederberg based his
actions upon "opportunism". Wasn't "opportunism" part of McCarthy's
methods?
.
Page 33, paragraph 247:
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.
Page 33, Paragraph 247 Commentary
Joshua Lederberg's assumptions about what McCarthyism was all about.
Dr. Lederberg ignores the fact that there were people who opposed
McCarthyism not because they had ever personally been affiliated with
the Communist party, but out of principle; that people who were
blacklisted as a result of McCarthyism had their careers and even
lives ruined precisely because they were NOT allowed to freely chose
their beliefs: a guarantee of the U.S. Constitution. Was Joshua
Lederberg being purposely obtuse, in thinking that McCarthyism was
simply about people choosing to invoke the fifth amendment of the U.S.
Constitution?
.
Page 34, paragraph 301:
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.
Page 34, paragraph 318:
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.
Page 34, paragraph 344:
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.
.
Page 35, paragraph 368:
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 [sic] 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!
Page 35, Paragraph 368 Commentary
The reference "to this day" means 1998. However, Joshua Lederberg
effectively stopped doing "bench-level research" in microbial
genetics circa 1963-1964: 35 years earlier. As William Hayes noted
in his autobiographical fragment of 1985, Joshua Lederberg told him
he had switched to administrative work, as opposed to genetics research.
At this same time, Joshua Lederberg began to author articles on
general science and current events issues, targeting the general
public. Thereafter, there was a sharp decrease in publications by
Joshua Lederberg dealing with microbial genetics.
.
Page 35, paragraph 383:
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.
Page 35, paragraph 388:
End of side.
Tape 5/Side 2
Page 35, paragraph 001:
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
Delbruck 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.
Page 36, paragraph 038:
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 Jcrne [sic] — 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.
Page 36, paragraph 071:
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 [sic] later told JL he was the
only one who had responded to his reprint.
Page 36, paragraph 101:
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 an infinity of antibodies and
there is not an 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.
Page 37, paragraph 121:
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.
Page 37, paragraph 141:
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.
Page 37, paragraph 178:
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 lor 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.
Page 38, paragraph 224:
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.
Page 38, paragraph 260:
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 phoney demonstrations. JL notes
that he checked later, and indeed there was a project to plant a
star on the moon.
.
Page 39, paragraph 309:
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 [sic].
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 ofthe 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.
Page 39, Paragraph 309 Commentary
Joshua Lederberg's "first political campaign" [ie: not research].
Joshua Lederberg's primary concern with extraterrestrial exploration
seemed to be that of contamination (of the Earth, other planets in our
solar system, their moons, or astroids, or other bodies). He might have
taken note of Esther M. Lederberg's proposal to study the effects of an
extraterrestrial environment on E. coli (ability of E. coli to survive,
as well as their stability – their mutations due to
UV radiation, or other factors in an extraterrestrial environment). See
http://www.esthermlederberg.com/EML Exobiology Proposal (purposely concealed).html (one of the documents of Esther M. Lederberg that
Joshua Lederberg misappropriated). (Note: this document is also
available at Joshua Lederberg's NLM "Profiles in Science" website;
search for bbgdge at
http://profiles.nlm.nih.gov/BB/.)
Joshua Lederberg did far more extensive work in exobiology, which
unfortunately might not have been too successful. "A Viewpoint of Various
Aspects of a History of Genetics," by William Hayes, pages 23-24, provides
an anecdote of a 1963 visit by Hayes to the Lederberg home, wherein Joshua
Lederberg demonstrated the "multivator", an articulated arm used to scoop
up soil. Hayes notes that the demonstration proved that there was no life
on the planet Earth. (Note: this document is also
available at Joshua Lederberg's NLM "Profiles in Science" website;
search for bbgbow at
http://profiles.nlm.nih.gov/BB/.)
Joshua Lederberg makes no reference to the fact that in this time period
he wrote a series of articles which were intended to be read by the
general public. In one of these articles it is clear that Joshua
Lederberg believed in racism and eugenics. (See
http://www.esthermlederberg.com/Theft/Intellectual Theft (Archive)/NLM Pirated Correspondence/NLMPiratedIndex.html;
click Special Topics > Papers > "Shockley's Accusation of Lysenkoism"
by Joshua Lederberg: August 21, 1969.)
.
Page 39, paragraph 351:
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.
Page 40, paragraph 387:
End of side. End of tape. End of interview session.
Third Interview Session (October 1, 1998): Tapes 6-7
Tape 6/Side 1
Page 40, paragraph 001:
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.
Page 40, paragraph 087:
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 [sic]
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.
Page 40, paragraph 136:
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.
Page 40, paragraph 151:
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.
.
Page 42, paragraph 177:
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.
Page 42, Paragraph 177 Commentary
Joshua Lederberg and the molecular genetics of DNA and RNA.
Joshua Lederberg's strength was in microbial genetics,
not in molecular genetics. This is apparent in this paragraph,
wherein Joshua Lederberg refers to the Watson-Crick DNA complements
but ignores Watson-Crick complementarity in RNA, as well as
Hoogstein complements that appear in quadruple-stranded DNA, etc.
In addition, by the time of this interview (1998), epigentic
mechanisms based upon methylation of nucleotide bases that could
explain aspects of developmental biology was also known. The relationship
between DNA and the amino-acid alphabet in polypeptides are ignored
as well. None of this is even mentioned! Moreover, while Joshua
Lederberg implies that life may also be based upon RNA as well as
DNA, there are many other macromolecules, such as PNA, etc., which
might be important in exobiology and exochemistry as well as the
chemistry and biology outside our solar system.
.
Page 42, paragraph 211:
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 ofthe 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 bonafide 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 own 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.
Page 42, Paragraph 211 Commentary
Joshua Lederberg and "computers". It is clear that Joshua
Lederberg's knowledge of computers (as well as the relationship
to the theory of computation) is embarrassingly primitive. Referring
to a computer as an "intellectual robot" and programming using
"plug boards" is sufficient.
.
Page 43, paragraph 241:
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.
Page 43, paragraph 260:
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 ofWisconsin 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 ofthe 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.
Page 43, paragraph 306:
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
as 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.
Page 44, paragraph 335:
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.
Page 4, paragraph 360:
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.
Page 44, paragraph 379:
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.
Page x4, paragraph 408:
End of side.
Tape 6/Side 2
Page 45, paragraph 001:
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.
.
Page 45, paragraph 068:
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.
Page 45, Paragraph 068 Commentary
Joshua Lederberg displays unenlightened attitudes concerning
racism and genetics. The first objectionable statement that
Joshua Lederberg makes is: "One of the things that held back
the teaching of the subject [human genetics] in a medical
context, JL postulates, was the cloud of eugenics, and in turn
the cloud of abuses in the Nazi regime." Thus Joshua Lederberg
ascribes negative views or fears about human genetics as having
an origin outside the U.S. However, the famous statement by U. S.
Justice Oliver Wendel Holmes's in the forced-sterilization case
Buck vs. Bell that "three generations of imbeciles are
enough" should remind us that fears of eugenics and racism had a
basis in many countries including the United States. The second
objection was that Joshua Lederberg would have done well to have
read what H. J. Muller actually wrote about eugenics. Muller's
attitudes (principles 2 and 6) were severely at variance with
the views expressed here by Joshua Lederberg.
(Click Special Topics > Papers
at
http://www.esthermlederberg.com/Theft/Intellectual Theft (Dishonesty2)/NLM Pirated Correspondence/NLMPiratedIndex.html
. Examine entry #5, "Shockley's
Accusation of Lysenkoism" by Joshua Lederberg: August 21, 1969.)
.
Page 45, paragraph 092:
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
stmiing 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.
Page 46, paragraph 110:
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 ofMedical 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 acrossschool initiative.
Page 46, paragraph 134:
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 ofthe 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.
Page 46, paragraph 161:
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.
Page 47, paragraph 180:
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'sown 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.
Page 47, paragraph 216:
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.
Page 47, paragraph 247:
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.
Page 48, paragraph 264:
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.
Page 48, paragraph 269:
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, nor 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.
Page 48, paragraph 312:
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.
Page 49, paragraph 349:
One ofthe 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.
Page 49, paragraph 364:
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.
Page 49, paragraph 377:
Going back a little, in 1950 the University of Chicago had offered
JL a position. 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 ofthe 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.
Page 49, paragraph 388:
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.
Page 49, paragraph 399:
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.
Page 50, paragraph 410:
End of side. End of tape.
Tape 7/Side 1
Page 50, paragraph 001:
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.
.
Page 50, paragraph 038:
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.
Page 50, Paragraph 038 Commentary
Joshua Lederberg and interdiscplinary studies at Stanford.
Joshua Lederberg's research and publications in theoretical
computer science are as well-known, as are his research and publications
in international relations, international law, and history.
.
Page 50, paragraph 101:
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 himselfthe embarrassment of that event.
Page 51, paragraph 138:
JL confided in one of his friends and went into hiding until be
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.
Page 51, paragraph 205:
For awhile 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.
Page 51, paragraph 227:
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 stmcture 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.
.
Page 52, paragraph 285:
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 ifhe worked another 20 years he might have an accumulated body
of work that would qualify him for it.
Page 52, Paragraph 285 Commentary
Joshua Lederberg's view that his share of the 1958 Nobel Prize was
due to the fact that he did "95 percent of the research" sharply
contradicts the statements he made at his October 31, 1958 press
conference where he reacted to being awarded the Nobel prize. See
http://www.esthermlederberg.com/JLInterviewIndex.html.
One must also bear in mind that while many people have commented about
Joshua Lederberg's strength in theoretical work, they have also
commented that he worked with great experimentalists, such as Esther
M. Lederberg and Bruce Stocker
(already noted on page 25 of this interview, paragraph 035)
.
.
Page 52, paragraph 316:
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.
Page 52, Paragraph 316 Commentary
Joshua Lederberg's October 31, 1958 press conference upon receiving
the Nobel Prize. The list of researchers he is indebted to.
Memory tends to abridge this list. For Joshua Lederberg's
actual list, see
http://www.esthermlederberg.com/JLInterviewIndex.html.
.
Page 52, paragraph 330:
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.
Page 52, Paragraph 330 Commentary
Joshua Lederberg and governmental policy.
The "authority" conferred by winning the Nobel Prize allowed
Joshua Lederberg to say and write things about areas of interest
in which he was thoroughly uneducated and for which he had
absolutely no qualifications; for example, he had absolutely no
background in arms control and international security. One
should recall
(see also page 3, paragraph 218)
that Joshua Lederberg described himself as being "too immature
to appreciate the humanities". One does not gain education and
experience in the humanities by studying science or doing
research in science. Thus it is likely that as Joshua
Lederberg aged, he remained uneducated in the humanities,
this is hardly the qualification required to deal with the
subjects of governmental policies.
Although Joshua Lederberg is paraphrased in this interview
as saying 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,
this ignores certain issues. Specifically, this ignores psychological
issues. For example, Arthur Kornberg did not feel that Joshua
Lederberg would fit in, in a small, friendly environment,
while Barbara McClintock found him so arrogant that she threw
him out of her office. In addition, Joshua Lederberg received
the Nobel prize in 1958, but William Hayes commented in his
autobiographical fragment that soon after winning the Nobel
prize, Joshua Lederberg felt compelled to choose between
continuing to do research in genetics or instead work in
administration. Joshua Lederberg chose to work as an administrator.
Indeed, the number of research papers published
by Joshua Lederberg on the subject of microbial genetics, dropped
perceptibly by 1963-1964. The Nobel prize seems to have been
a psychological termination of his laboratory work. Instead,
Joshua Lederberg published papers intended for the general
public: exobiology; computer applications emphasizing organic
chemistry, with collaborators; contraception and abortion;
arms control; etc.
Esther M. Lederberg has a somewhat different viewpoint:
"One must stop thinking about the Nobel Laureates as having the
last word. They are chosen by a committee that sits in Stockholm.
I don't take it very seriously. Many Nobel Laureates get their
prizes and then they go out speaking about everything as if they
knew it all. I think if people take that seriously they are very
foolish."
See
http://www.esthermlederberg.com/Oparin/EML_interview_CSHL_Creek.html
.
Page 52, paragraph 361:
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.
Page 53, paragraph 374:
End of side.
Tape 7/Side 2
Page 53, paragraph 001:
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 kpow 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.
Page 53, paragraph 030:
JL was happy to be asketo 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 happlens that coincided with the start ofthe 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.
Page 53, paragraph 064:
JL was asked if he had ny closing comments he wanted to make
about his career at the University of Wisconsin. His comments
follow. "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, that 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 beeh
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."
Page 54, paragraph 124:
End of side. End of tape. End of interview sessions.
END
The Systematic Suppression of the Name
"Esther M. Lederberg"
Although Joshua Lederberg strives to gives as little credit as possible
to his wife, Esther M. Lederberg, this is really not possible, as
Esther M. Lederberg was so intimately involved in so much of the research
that Joshua Lederberg claimed. The only good way to get around this
problem is to use verbal locutions such as "we" and "they". By using
these pronouns, Esther M. Lederberg can be explicitly excluded (unnamed).
To verify this point, see earlier talks, such as the press conference
at Madison, Wisconsin when Joshua Lederberg learned he had been
awarded the Nobel prize, as well as commentary by researchers such
as Stanley Falkow, Eugene Nester, Allan Campbell, L. L. Cavalli-Sforza,
etc., all of which is available at this memorial website. The final
technique used by Joshua Lederberg is never to provide a full list
of Esther M. Lederberg's research papers, to hide proposals written
by Esther M. Lederberg, and to suppress or modify the identities of
co-authors of papers. In this interview, the use of pronouns to
exclude references to Esther M. Lederberg may be found at the following
locations:
1.
Page 19, paragraph 366
2.
Page 27, paragraph 187
3.
Page 28, paragraph 216
4.
Page 29, paragraph 260
5.
Page 53, paragraph 064
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