NOBEL

LAUREATES

Harold Varmus, MD

and J. Michael Bishop, MD

rs. Harold ~ar~~s and
J. ~ichael Bishop are two of our
institution ',c brightest stars. Zbe. c
have worked closely together for the
past two decades, sharing a
devotion to teaching and research o
Happily, they now share the Nobel
Pnke for medicine.

By wa-y of introduction, the11 have
supplied us with the. following
biographical material.
J. Michael Bishop, MD was born
and raised in irrrul Perms-vlvania.
He attended Get(ysbtrrg College,
graduating as valedictorian. He
earned an MD at E-iaward liir?iuersity
and ohtained his first research
experience by taking the unorthodox
approach of ignoring the formal
Ji,ui-th,year c~~~~ci~i~~~~. Iro~~ical~,
his interest in research wasprst
awakened by the hope of becoming a
teacher. The example of his most
respected faculty soon taught 3ishop
that teaching and scholarly inves-
tigation are compnnion and

                   insepa ra ble uocations. I~~~epe~~~en t
by MD '75 and reading had piqued his interest in
Robert Scbindler, MD '67      the burgeoning field of molecular

biology. Casting about for new
departures in thispeld, he chose the
zise of animal viruses to study genetic
processes in higher organisms.

Tu90 years of training in internal
medicine at Massachusetts General
Hospital left Bishop  certain qf his
future in clinical medicine, so he
entered enthusiastically into the
unique Research Associates Program
at the ikational Institutes of Health.
He then joined the fact@ at the
~Tni~~em-ity of California and began
his work on Kicil tumor viruses,
which has since remained an
unforgiving preoccupation.

Harold Varmus, MD was born on
the south shore of Long Island. He
attended public schools in Freepoa,
New York, before entering Amherst
College in the fall of 1957, intending
toprepare for medical school. The
intensity a~~dplea~ure of academic
l<fe challenged Varmus 'presumptions
about his future as a physician, and
his course of study d~~tedfrom
science to philosoph-y a~~~~fi~~all11 to
English Literature. Following gmd-
uation from Amhem-t, a \.Voodrow

G

Wilson fellowsha$ enabled him to
pursue his interest in literary
scholarship by beginning graduate
studies at Haruard University.
Within a year, he again felt the lure
of medicine and entered Columbia
College of Physicians and Surgeons.
In preparation for a career in
academic medicine, he worked as a
medical house oflicer at Columhia-
Presbyterian Hospital from 1966 to
1968, and then joined Ira Pastan's
laborato ry at the National Institutes
of Health as a clinical associate. He
joined J. Michael Bishop, MD as a
postdoctoral fellow at UCSF in 1970,
was appointed lecturer shortly
thereafter, and in 1972 became a
regular member of the faculty in the
Department of Microbiology and
Immunology.

This past January, Drs. Robert
Schindler and Michael Drake
interviewed Drs. Bishop and Varmus
in the Ernest Jawetz Library,
Department of Microbiology at the
University of California San
Francisco. Excerpts from that
interview follow.

I'm interested in what brought
each of you to UCSF. Mike, you
arrived first. I understand that
Leon Levintow, chairman of
Microbiology and Immunology,
was involved in your coming
here. How did that happen?
Dr. Bishop: When I went to the NIH
looking for a postdoctoral slot, Leon
was one of the staff who interviewed

me. I was particularly interested in
animal viruses, and he was the
person from that orbit who
interviewed me and subsequently
offered me postdoctoral training. He
was my postdoctoral supervisor. He
skipped town after a year to come
here, and I spent a year at NIH
working more or less on my own,
corresponding with him. Later,
Ernest Jawetz offered me a job here.
I went off to Germany to think about
it and eventually decided to take this
job. When I arrived here my lab was
essentially joined to Leon's.  When I
wasn't at the bench, we spent a great
deal of the working day talking
about everything. The
administration didn't know who I
was or anything about me, and I
think Leon had a great deal to do

with convincing them when I was
young and unknown that I was
worth supporting. Also, he was very
encouraging about the idea of
joining up with Warren Levinson to
study retroviruses.

Warren and I essentially pow-
wowed together, each of us making
our own contribution, and my
responsibility was to get the
molecular biology going any way we
could. Leon really fostered that
collaboration and fostered my
interest in RNA tumor viruses.

Harold, what attracted you to
the group?
Dr. Varmus: I came on rather
different terms.  I had been at the
NIH, learning to do science after
clinical training, and had learned
enough to know that I was attracted
to the tools of molecular biology.  As
a result of some courses taken at the
NIH, I became very interested in
tumor viruses and was looking
around for a place to learn the lore
as a postdoctoral fellow.  At that
point, I had never heard of Bishop
or Levintow or Levinson. The
people I'd heard of were people like
Harry Rubin at UC Berkeley and
Renato Dulbecco at Cal Tech.  Rubin
asked me to come chat with him and

he mc.ntioned that there was a group
just st;irting to work on tumor viruses
at the L:niversity of California San
Francisco. I knew about Moffitt
Hospital. as a place where one could
go without suffering ;I loss of
reputation as a clinician, but I didn't
know anything about the science
that was being done here.  The truth

There's been a
"sea change"
... It's been amazing

was there wasn't an awful lot to talk
about at that point. Anyway, I came
over one day to meet Leon and Mike
and was told they were having lunch
in the Golden Gate Room, which
seemed to me to be a wonderful
place to be having lunch - until I
had a look at it!  That led to
conversations with Mike and Leon.
Mike obviously had a lot of energy
and Leon had a fatherly attitude and
a strong history in biochemistry.

Mike, when did you make the
decision that you wanted to be a
laboratory scientist as opposed to
a clinician?

7

Dr. Bishop: I had no idea what I
wanted to do when I entered
medical school.  I wasn't even sure I
wanted to be a doctor.  But I was
interested in human biology and
medical school was the obvious
place to study that. I received my
degree in chemistry, but I took the
minimum to get the major.  It was
not a real chemistry major. I spent
most of my time dallying with other
things. Academic things, you name
it, I tried it!

Harold, you majored in the hu-
manities, right?
Dr. Varmus: I did.  But I had a
certain amount of science to take.
At Amherst in those days there was
quite a large segment of required
core curriculum.  I had assumed that
I'd be like my father, a doctor, and
take a pre-medical course.  But I
hadn't been there long before I
started dabbling in lots of things -
philosophy, physics, and other
things - pretty superficially in the
first couple of years.  But then I de-
veloped a true love of literature and
majored in it. I went to graduate
school for a year before realizing
that I liked science too much and

was too interested in contemporary
things to spend my life studying 17th
century prose.

Mike, what impressed you about
Harold in the beginning?
Dr. Bishop: To a nominal supervisor,
the quality most important is inde-
pendence. Harold was independent
from the moment he arrived.  We
kicked around ideas about what he
might do.  He chose what he wanted
to do and ran with it.  I don't think
we ever really had a supervisory
relationship. We very quickly fell
into a co-equal relationship.  Most of
our collaboration consisted of advis-
ing others together. That was very
intensive. We met regularly with all
the students and postdocs who were
under our joint supervision and
would discuss what they were going
to do. It was never really a mentor
kind of relationship.

Dr. Varmus: I don't think we should
undervalue that because certainly at
the very beginning I needed advice
about working with the system.

Dr. Bishop: Yes, but that was avail-
able in the lab.

King Carl Gustaf of Swedenpresenting the Nobel Prize to
J. Michael Bishop, MD

Dr. Varmus: Sure it was, but there
were moments of advice that I can
still recall. I suppose that the advice
I got could have come from a lot of
sources, but because I value Mike's
judgement, the advice that came
from him I took more seriously.

Harold, when you came here
what drew you to Mike, was there
something about his science?
Was there something about the
questions he was asking?
Dr. Varmus: I think it had more to do
with commonality of language. I
had been shopping very briefly in
the tumor virus field.  I had done a
fair amount of reading at NIH, and I
was finding people still mired in the
old school of phenomonology,
attempting to put a virus into an
animal to see what kind of tumor the
animal gets.  I wasn't interested in
that. I had grown up in the previous
couple of years in an atmosphere
where the questions were being
asked at a more molecular level.  I
hadn't been here more than 5
minutes before Mike and I were
talking about making specific
hybridization probes. We were on
the same wavelength in a way that
hadn't been the case with other
people I had been speaking with
about postdoctoral work.

When did you realize that you
had made a discovery? That you
had proved a theory?
Dr. Bishop: The work in the first
paper made it reasonably clear.
From that moment on we could
argue that if what we had found in
the cell was indeed a reasonable fac-
simile of the oncogene in the virus,
most likely the gene had moved
from the cell to the virus rather than
vice versa. This was the first pur-
chase on anything resembling a pre-
cancer gene, if you will, in cells.  It
was a way station and I'm sure we
thought we discovered something
important, in the sense that the
simple hybridization curves weren't
lying. Exactly what it meant and how
the rest of it would work out keeps
you going.

Dr. Varmus: We knew, obviously,
that it was important. It was a long

8

time before I realized how important
everyone else thought it was.

Dr. Bishop: Right, for me, too.
People within the field, of course,
recognized it. You could tell from
the flood of people beginning to do
the same kind of experiments, that's
a sure sign that you're on to some-
thing.  Bees know where nectar is.

I'm interested in something Mike
said earlier. You were talking
about UCSF as a place for science
and how it was in the late 1960s
when you arrived. How has the
milieu changed in the last 20
years? How would you compare
it then with now?
Dr. Bishop: To use a phrase, there's
been a "sea change".  Where did that
term come from?

Dr. Varmus: From "The Tempest."

Dr. Bishop: There's been a sea
change, it's amazing.  When I came
here there were about three people
on campus who were in any way,
shape, or form on my wavelength
scientifically. Herb Boyer was here,
and he and I spent many nights
together in the cold room.  He
taught me how to run columns and I
kept his morale up. I didn't teach
him anything! There was Warren
Levinson, there was Leon Levintow,
and there were one or two folks in
the biochemistry department who
have long since departed, who at
least had an inkling of where I was
trying to take animal virus problems.
There were one or two folks around
who weren't molecularly oriented.
The biochemistry department had
been decimated by a seven-year
vacancy in the chair.  There was

I nothing going on.

Getting Bill Rutter to be chairman
of biochemistry was the first
important step. On the other hand, I
still look back with some nostalgia at
the fact that I was completely on my
own and free to think about
whatever I wanted and to find my
own pace.  I didn't have all these
incredibly accomplished peers in my
immediate presence to cause me
anxiety. I had my own standards.
So I've nostalgic recollections of that,

King Curl Gustaf ofSu1edenpresenting the Nobel Prize to
Harold E. Varmus, MD

but I would still say that if you had a
choice you should choose an
environment that's rich rather than
one that's poor, as this one was
when 1 came here.

Dr. Varmus: Things had obviously
improved quite a bit, even between
Mike's arrival and mine three years
later, because Bill Rutter and Gordon
Tompkins had both added a
tremendous amount to the
atmosphere. Gordon, although not
chairman of the department, was
incredibly influential at attracting
young scientists, many of whom are
still here, like Keith Yamamoto.
Even though the faculty definitely
was stronger by 1980 or so,
something happened around 1980
that made this place much more
popular.  Part of that was increased
attention to our graduate programs
and to the MD-PhD program.  So
that at this point, a day like today,
for example, is filled with a morning
meeting with graduate students, MD-
PhD students, PIBS Journal Club in
the afternoon, and seminars.  I don't
know how we got any bench work
done in the 1970s.

Do you feel pressure living as a
role model now for young
scientists coming in or doesn't it
ever come up?
Dr. Varmus: I feel a little more
cautious about making a joke
because I don't want to be taken as
treating someone lightly.  I am aware
of the possibility that they would
take my comments with undue
seriousness.

How about you Mike?
Dr. Bishop: I would agree with
Harold. You're always a role model
from the first time you stand up in
front of a classroom.  We haven't
been in this exalted state very long.
Maybe we're going to learn
something we don't know yet!

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