H. ROBERT HORVITZ: So I
think we'll get started. I want to welcome everybody,
thank everybody for coming. At least today
wasn't snowed out, although Ed said the
traffic coming in was-- ED SCOLNICK: Horrible. H. ROBERT HORVITZ: --not good. ED SCOLNICK: Horrible. H. ROBERT HORVITZ:
So I'm absolutely delighted to introduce
Ed Scolnick today for our conversation
with a scientist. And I would say I'm delighted
for two different reasons. First, these conversations,
they have been great. We have some of our conversants
in the audience today. The precedent sets
a high bar, Ed. And they've been enjoyable. And they have been
very educational in terms of both a
history of biology and really a history
of biologists. They've been very personal. And I basically will
go to every single one I can possibly go to because
I've just really enjoyed them. ED SCOLNICK: No threats. H. ROBERT HORVITZ:
So that's number one about what makes this special. Number two about what
makes this special is Ed because Ed is special. And I actually had the privilege
of introducing Ed once before. It was four years ago. It was for a dean's lecture
that Marc Kastner had set up. And Ed gave the lecture
for this dean's colloquium. And I have the title here,
"The Power of Basic Science Applied to Medical Progress-- Past Examples and the Hope
for Schizophrenia and Bipolar Illness." It was a great lecture. It was science and
personal-based. If you want to watch
it, you can watch it. It's on the MIT
video site, which you get to by just
putting in video.mit.edu. And you can find the lecture. For that lecture,
I was asked to give an extensive 15-minute
introduction. So if you haven't
had enough of me, you can get the
introduction there. And if you want to fast
forward through that to get to the real stuff,
you can do that, too. The simplest thing I
can really say about Ed is that he is literally
a legend in his own time. And he's known through academia. He's known at NIH. He's known in the
pharmaceutical industry. And he's known for a
variety of different things. And when I gave the
previous introduction, I asked a number of
people, who I knew had known Ed for a long time,
what they thought of him? And there was one comment
that was really telling. I asked somebody who used
to work for Ed at Merck what he thought of Ed? And Ed doesn't look too
nervous, and that's OK. [LAUGHTER] The response-- and this
is a verbatim response-- "I am an unabashed
hero worshiper when it comes to Ed Scolnick." That's a real quote. And I think it doesn't
get better than that. I've known Ed now for-- I guess it's about 25 years. I knew Ed before he went to
Merck, when he was a researcher and trained as a physician. He then became a
research biochemist. He worked on the mechanism
of protein synthesis. And then turned
to tumor virology and made an incredible and
very well-known discovery, namely RAS as a viral oncogene. Now, of course, we
know RAS locally from the work of
Bob Weinberg, that showed that what Ed
found in a viral genome also has a counterpart in the
human genome, very important in cancer. And it was actually
at that stage we started talking because
we were working on a RAS gene in C. elegans. And Ed kept calling
me every month saying, what do you know now? [LAUGH] And I kept
saying not all that much more than we knew a month ago. ED SCOLNICK: Yeah. It hits pretty hard. I know that. H. ROBERT HORVITZ: Yeah. No, I remember the calls. [LAUGHTER] Ed then moved to Merck. He had an exceptional
career there. He was president
in Merck Research Labs, 22 years at Merck. And amongst many
other things, he helped develop the
breakthrough therapy that has been used for AIDS. He then made another
transition and came here to the Broad Institute. And at the Broad,
he's become a leader in applying genomics
basically to the field of neuropsychiatry. And he was the
founding director. That means also fundraiser
for the Stanley Center. And has had really
a pivotal impact on our local community here. And I have to say
personally, I've been very delighted to have it
close by since he's come here. I've never failed
to be impressed by Ed, delighted by my
interactions with him. And I have to say that I am
very much looking forward to his remarks. And I will not take
another minute of his time. Ed, welcome. Thank you. ED SCOLNICK: Well, this
is a very different kind of interaction or talk than
I've given in many other venues. And I was told it was supposed
to be a personal history, with enough information that
students could glean something from it besides just
knowing more about me. So I'll try to do that. I grew up actually in Boston,
in Dorchester, was born in 1940. When I grew up in Dorchester,
it was a very nice community, quite safe to roam around
in, and very supportive, but extremely insular. I basically grew up in
something that might be called a ghetto environment. I had almost no
exposure to anything outside my immediate family
and the local schools I went to until it was
time to go to college. I was fortunate
that at the time I went to grammar school
and high school-- and I ended up going
to Boston Latin school at a time when the entrance
exams were not necessary. I went to Boston Latin School. And at that time if
you did reasonably well at Boston Latin School,
you were almost guaranteed that you'd get into Harvard
if you applied to go. And I applied. And I was admitted. I wasn't really sure
what I wanted to do. And I liked science,
thought I would go and be a physician
because the environment-- I grew up in a Jewish
household in the '50s-- really that was kind of the goal
for a nice, young man growing up in that environment. And that was all I had in
mind for my professional life at that point. I would make a couple of
remarks about my first years at Harvard and the
difference at MIT. I had an enormously difficult
social adjustment to Harvard in my first few months. It was such a
different social world. And so diverse compared
to what I grew up in, and socioeconomically
what I grew up in, that I found it extremely,
extremely stressful. And I was always highly
motivated to do well in academic studies. And I decided finally, in around
November of my freshman year, that I had to do
something different or I might really decompensate. And so I looked
around the community for what kind of activities
to get involved with, to try to find a part of this
massive university, a smaller section of it, a
smaller cut of it, where I actually could feel I
belong to something because I never felt like I belonged to
Harvard University, Harvard College. I felt very out of place. And I ended up pledging for
and joining the Harvard radio station, WHRB, which
still is on the FM dial. And that was actually
transformational for my life in college. First, it forced me to
be organized because of the amount of time
spent at the radio station versus having to study. And it did give me a social
focal point for a smaller organization, where I could
feel I belonged to something and was comfortable with
the people that I was with. And I ended up doing
radio broadcasting for new sports
and special events at Harvard, which again was a
transformational event because in learning how to
broadcast on the radio and being taught what you had
to do to communicate with people who were listening
in and who could only hear what you had
to say once, as opposed to reading the newspaper
where you can reread stories, it really helped
my social growth. It helped my communication
skill growth. And I made an enormous number of
terrific friends, some of whom I've stayed in touch with until
a couple of them passed away. And it enabled me
to relax and feel very comfortable in
the university setting. And I decided to major
in biochemical sciences. And the second event at
Harvard, which is very important and has some of you know
a real MIT connection, was Harvard College had a
so-called tutorial system for students. I don't know if
it still has that. And what that meant is
you met on a monthly basis with a professor somewhere
in the Harvard system, who you met with and discussed and
read about topics in science outside what you were
taking in your courses. And I was fortunate to
have Boris Magasanik, who at the time was a professor
in the microbiology department at Harvard Medical School. So he was part of the
Harvard tutorial system. And I was fortunate that
Boris ended up being my tutor. It took me a while
to appreciate Boris. He was so much more
sophisticated than I was. And to appreciate
what he was trying to teach me, which was how to
think in science, as opposed to just memorize. And I met with him regularly. And in my junior year or
just before my junior year in college-- and things
had begun to go pretty well for me-- Boris moved to MIT, in
the biology department. Salvador Luria, who I think
in modern times really built the biology department here,
recruited Boris from Harvard to MIT, to help
build MIT Biology. But Boris stayed as a tutor. And in my junior year,
in the fall, of college-- this would be 1959 and '60,
he said I'm moving at MIT. And you like science-- and
maybe me teaching a course in the spring with Salvador. And you should take the course. So said, how we do that? I'm a Harvard student. And he said, it's easy. You just go to the
registrar's office at Harvard. And you tell him. And there's a few forms. It's very easy. You take the bus down. And that's what happened. And he taught a
course in the spring. And I said, well,
that would be great. I really enjoyed the little bit
I knew about bacterial genetics and what Boris used to
do with me in tutorial. And this is a time in
science, as some of you may know, where it was
really the fomenting time in bacterial genetics
and bacterial physiology. Basically, a lot of
mathematically gifted people, after the war, went
into bacterial genetics, in phage genetics,
because precloning days, there were genetically
manipulable systems, where people could start
to understand cell biology and how cells work, even though
it was mostly E. coli biology. And I thought that was
really, really interesting. I had taken a course at Harvard
either my first or second year-- I think it was my first year-- taught by George Wald. It was a mandatory
general education course. And like all
freshmen at college, particularly people who
came from a pretty insular background, I was
trying to figure out what life was all about. And you'd spend
your late evenings with your roommates discussing
the philosophy of life. And none of that led to
anything particularly profound. And one day came into
George Wallace lecture. And he gave a talk about
DNA, and the double helix, and what was known at the
time, which is 1958 roughly. And I heard that lecture. And Wald, as some of you know,
was a fabulous lecturer, just lucid and excited about science. And I said, oh, my god, that's
how I can learn about life. And literally it was one of
the transformational events in my education. And then Boris had me take this
course with him and Salvador. And that was a second
transformational event because it was completely
different from any course I'd ever had in college
at that point. Because instead of making you
memorize things and certainly integrate them to
a certain degree, it was all experimental biology. They either gave you
experimental results and asked you to interpret
them or they gave you a biological problem,
in bacterial physiology, and said, how would you
design an experiment to try to do this? That was stressful. I had never had to do that. And I really struggled in
the course for a few weeks. And I was fortunate to
sit next to in the course, another person many
of you know, Sam Lapp, who was an MIT student,
incredibly gifted person. I think he ended up
at Children's Hospital as professor, died
prematurely unfortunately. And Sam befriended me
and spent a little time after class explaining
to me what was really going on in the course. And I managed to
pass the course. But I loved the material. I mean, having
heard Wald, and then Boris and Salvador
teach this course on bacterial genetics, all
the classical experiments, and I decided for sure that
I wanted to somehow do work in that area of biology because
you really could potentially understand how cells
worked, how the body worked. And I struggled as to whether
to go to graduate school and get a PhD, which Boris
encouraged incessantly, relentlessly, or to
go to medical school. And I really didn't-- I just didn't have the courage
to go to graduate school. I thought going back
to school was safer. And my parents pushed
me a little bit to do that in addition. So I ended up going
to medical school. And I ended up going to
Harvard Medical School. And having survived an interview
by the Daniel Funkenstein-- I can't remember his first name. There was a
psychiatrist/psychologist who used to interview all the
medical students for Harvard. His name was Funkenstein. And he was
notoriously difficult. And he would put you in
very awkward situations. So I grew up in Dorchester. I went to college at Harvard. I wanted to go to
medical school. I'd never been out of
the city to travel. So I remember, he had the
reputation of nailing down windows and asking
students to open them, and seeing how they work,
kind of that stress. He didn't do that to me. He said, you grew up here. You went to school here. You want to go here. Don't you think
you're pretty narrow? And I said, well,
you missed something. I was born at the Boston
Lying-In Hospital. And I just feel
comfortable in [INAUDIBLE].. So he ended up admitting me. And I found Harvard
Medical School a magnificent
intellectual environment. I loved it. I was happy I'd
made that choice. I really was interested
in science, and biology, and medicine. I had done some research
in my senior year at college with someone
Boris had put me in touch, with Ed Lin, who was
a professor in the-- I think actually in the
physiology department in Harvard Medical School, on a
bacterial, genetics, physiology project. And it had gone all right,
but not it's not swimmingly, I would say. But, again, the atmosphere
I found just wonderful. Ed Lin used to have and
once-a-week evening sessions with medical students who
were working in his lab, where they would bring in
Chinese food, or some pizza, or whatever. And one of those
students would have to get up in front of the group,
in a very informal atmosphere, and talk. And there would be
a couple of hours of questions and dialogue. And again, I just found
the whole atmosphere of doing that enormously
stimulating and tremendous fun. So I really wanted to do that. I wanted to do
research in my life. What I had done in medical
school was only fair, and really not a
great experience. And so I was going along
during my medical school life, not quite sure what
direction to go in. And later in my junior
year, early senior year-- this is in the mid-'60s-- the Vietnam War was
enormously heating up and a miserable situation
as many of you know. And I realized
that the odds were, I was going to get drafted
when I graduated or finished my internship and potentially
get shipped over in something called the Berry Plan, to
take care of soldiers in a war situation. Clearly, I didn't
particularly want to do that. And at the time, when there
was a draft, this was-- yeah, there was still a
mandatory draft-- It was known that if you got
into the so-called public health service and
went to NIH, that would serve as your two
years mandatory draft, different draft requirement. So I went to the dean's office
or Harvard Medical School and said, I'd like to spend
the last six months of my four years here doing
research because I wanted to be able to do enough
to potentially get into I NIH. And they said, sure
you can do that. You clearly have a
good track record. And the only problem is
you haven't had OB/GYN yet. And you're going to have to pass
part 1 of the National Boards when you graduate
medical school. So if you think you can pass
without taking the course, we'll let you do
research for six months. And so I bought a little
book and I read it. And I managed to pass the test. I knew I was never
going to deliver a baby. So [LAUGHTER] I was not
worried about that at all. And I worked for a man
named Dan Dakin, who I think is still
alive and a professor at one of the VA
hospitals, at least that's where he used to be. And at the time it was at
the Beth Israel hospital. We worked on platelet
biochemistry. I was interested in
atherosclerosis at the time. And that went, again,
kind of OK, nothing great. I liked it. I wasn't particularly
good at it. And I had basically
given up the thought that I could do research. But people who had mentored
me Ed Lin, and Dan, and others thought I still had potential. And when I applied to the
National Heart Institute, I was accepted. In the meantime, I
had gotten accepted to be an intern at Mass General
Hospital, which was a shock. I never thought
I'd get in there. It was so different from
what I had grown up with. It was a bastion of white
Anglo-Saxon, protestant medicine and culture, not
anything like my background. But I remember the interview
I had when I was interviewing for the internship. And as I said, I really
loved genetics and biology. And we were a group of
students sitting around, semicircle, being interviewed
by a series of professors in medicine. And the question they
asked the group at one time-- so you're in
a group environment. And you're obviously
trying to show off your-- compared to your colleagues,
who are competing to be interns, be accepted as an intern. And yet you didn't
want to be a jerk and really tried
to be too pushy. So they asked a question
about childhood-- chronic myelogenous leukemia. They asked a question
about CML I think or some leukemia like that. And they asked the group,
well, if you wanted to try to explore the causes
of this, who would you go to and how would you go about it? And I used to follow the
literature a little bit in genetics. And the other students
in the group chimed in. And they talked about a
professor at Children's named Park Gerald, who
was interested in leukemia and genetics. And I just didn't say anything. And then when they
kind of stopped, I said, yeah, well,
that's very good. But there are these two guys at
the University of Pennsylvania, Nowell and Hungerford,
who have described something called the
Philadelphia chromosome and a two-hit theory of cancer. And I went on and on about that. And I was actually
convinced that that's what got me into
the MGH because they could see that I had some
breath to what I knew about. So I was accepted to the MGH. And then accepted in
principle to go the hardest. You learn this in the
beginning about the time when you were beginning
your internship at MGH. And I loved being an intern,
even though it's exhausting, and a first-year resident. I really learned how to be
a careful, scientifically oriented person and scientist
in the first few months I was an intern, for two reasons. One, you're so responsible
for people's lives in a stark way,
that you appreciate the weight of that
responsibility and how much you really have
to be careful and respond. And I happened to be-- I was really lucky. I had an assistant
resident at the time, named Bob Snodgrass, who I'm
told is still alive, somewhere in the Midwest,
practicing medicine, or mid-South. Snodgrass was a great guy,
totally unpretentious, and took care of his patients
like nobody I had ever seen or met at that
point in my life at the MGH. And I realized what he did
was what was necessary. So I became a super-compulsive,
dedicated intern. And it was great. I loved what I was doing. And then toward-- about
halfway through the internship, maybe in the spring
of that year, which would have been 1966-- '65 or '66-- no, no, I'm sorry. I'm off here. Yeah, '6600 you went
to the Heart Institute to interview with lab chiefs,
to do another matching for which lab you'd end up with. And So I went down. And it was a two-day
session, I think. I went around and
met a lot of people. And I wasn't really interested
most of the people I met. I didn't really want
to work with them. There were two people I
was really interested in. At the time there was a
biochemistry laboratory in the Heart Institute. It was overseen by
Earl Stadtman, who was just a giant in
classical biochemistry, many critically important
contributions to cell biology, biochemistry, and
bacterial biochemistry. The regulation of
an enzyme called glutamate synthetase
was probably one of his fines things. And it's just such a
complicated system. And he worked it
all out gorgeously, with a combination of
biochemistry and genetics in bacteria. And one of the people in his
laboratory, who had a section, was Roy Vagelos, who was
studying lipid biochemistry. I met with Dr. Vagelos. And he told me
what he was doing. And I had been interested
in atherosclerosis. And I said, boy, this
is really terrific. I'd like to come work for you. Would you take me into your lab? And he said, I think so. I want to do more
checking on you. But, yeah, potentially
you can count on this. And then I went to-- but he said there's one thing--
and I'll keep you informed. I've been negotiating to
be chairman of biochemistry at Washington University of
St. Lewis, Cori's old position, a giant biochemistry. And if I take it,
don't come here because you won't
have a lab to come to. So I said, OK, let me know. And he did. He subsequently
called me at home, like a night or two later. He said, I've decided to take
the job, don't come here. And then my last interview
in the Heart Institute was with Marshall Nierenberg. As Monty knows, one of
my tremendous heroes. And I think Monty's here. And so I knew what
Marshall had done. I'd seen his paper
on polyphenylalanine. And I understood the
excitement in the genetic code because all of the stuff that
was talked about in the Luria and Magasanik course was
about bacterial genetics. And was the code triplet,
was it four bases, two bases, six bases? How could you figure it out? So I sat down and started
talking to Marshall. And I was mesmerized. I was absolutely mesmerized. It was obvious this was
a very exciting person. The work was spectacular. It was interesting. And we talked for a long
time, more than an hour, just about what he was doing. And I said to
Marshall at the time, and I said I'd really
like to come here, if you would have me. And he said, no, I've
had a lot of MDs come. And you have a good pedigree. And I'd be happy
to have you come. I said, well, Marshall, I
have one question for you. It really bothers me. I'm sorry to ask you this
because you may think it's a ridiculous question? He said, no, no, go ahead. I said what you're
doing is great. This field, I know
from the outside, is fiercely competitive. How do you deal with that? How do you deal
with that I'm not sure I'm psychologically
capable of handling that kind of
competitive pressure. And he smiled. He just sat there. It was beautiful. I can never forget
to smile on his face. And he said, look,
most of science fails. It's 99% perspiration
and 1% inspiration. If you're going to
go into science, you have to pick a problem
that if you do succeed, people will care about. And I said, wow, that's pretty-- pretty amazing. I said that's really true. I said, OK, I'll take a chance. What have I got to lose? I'm coming here for two years. I can go back to medicine
if it doesn't work out. I'd like to come. He said. OK, we'll accept you. Send in your matching list. So I did. I matched with Marshall's lab
and came in the summer of 1967. I had no idea what was
going on in the lab or how to research
when I got there. And I realized that instantly,
absolutely instantly. None of the technologies
that were being used-- I didn't know how any of it. I mean, nothing. And I stumbled around. And Marshall said that he was
going to work in neurobiology. And I ended up working more
directly with Tom Caskey. He was a sort of senior fellow,
senior position in his lab. And at the time the one
important remaining problem in protein synthesis
was the termination of signals in the
biochemistry of determination. And so we worked with Tom. And Tom and Marshall
taught me what I had never been taught in college
or a medical school, that is how to do research,
how to think about it, how to think about
the execution of it, how to think about the
design of experiments. Marshall was a true
genius in more than just the intellectual part of
thinking of projects to work on and how you approached it. He was a genius at teaching
you a system of doing science experimentally. And I've said this to people in
the Stanley Center many times. It guaranteed that
you could never have irreproducible results. And I never had been taught
that by my professors at college or medical school. And if you want on lecture
on that, invite me back and I'll tell you how to do it. [LAUGHTER] But you can ask Monty,
too, because he still uses the same system. And that really transformed
my life in biological science because I realized
all the stupid things I used to do when I did research
in college and medical school and how I was my
own worst enemy. And we struggled
for about a year to try to figure out an approach
to the termination problem. It was known at the time that
of the 64 triplets in the code, there were three that were
unclear of their function, except that they probably
were responsible for protein termination, as the chain
finishing and falling off the ribosome. They were UAA, UAG,
and probably UGA. No tRNAs have been found-- natural tRNAs for UAA and UAG. And the UGA one was not
considered that important at the time. And it was ambiguous. So we worked and worked. And Tom led the group
for several months, trying to figure out
how to approach this. And in about the
middle of the year, a young assistant
professor, someday to be a Nobel Laureate, at
Harvard Medical School, named Mario Capecchi, who
was at Harvard Medical School at the time, published
a paper in PNAS using a phage system, in which he had
ribosomes programmed with a RNA phage-- messenger RNA. It was R17. And when he programmed that
with partially purified factors in just ribosomes. The polypeptide chain
translated on the phage message. It was made and stayed
on the ribosome. When he added some
supernatant factors from the bacterial extract-- he had a sucrose
gradient method, where you would spin down
the ribosome and the assay the stuff that stayed up. You could knock the
chain off the message. And that it was related to
the UAA termination kernel. So there was
something in the S100 that-- it was a very
cumbersome assay. It was a beautiful experiment. It was just gorgeous. It opened up the field. But it was a very cumbersome
system for trying to go further and figure out the really
what was in the S100. Tom Caskey had a brilliant
idea after that came out, in which he picked up on
the triplet-binding assay that Phil Leder developed
in Marshall's lab for codon recognition,
in which he created a dinucleotide codon,
AAG, terminator codon, bound to ribosomes, and with
on-the-complex formylmethionine tRNA. So formylmethionine is
blocked at its end terminus. So it's like a little peptide. And you could make
that complex in vitro. And importantly, you
could freeze the complex. So you could make gobs and
gobs of fMet tRNA bound to the ribosome
with the initiator codon and the terminator codon. And then he worked
out an assay, where if you hydrolyze-- because
Capecchi had shown this worked, the S100, that
hydrolyzed the peptide. You could hydrolyze the peptide. It's simple extraction
procedure because it was hydrophobic at that point. And you had a very rapid assay. It took about 10 minutes
to do the whole experiment. And then process your
samples, put them into this simulation counter. The label was in the methionine. So this was in the late spring
of the first year I was at NIH. And excited, but not
feeling particularly great because nothing-- we hadn't discovered anything. And I was still thinking
I'd go back to medicine. I was going to apply
for fellowships in infectious disease
and hematology because they were kind
of molecular at the time. And I thought that would
be what I would do. Tom went away for a vacation
over Memorial Day weekend in 1967-- '68, '68. And he left myself;
another postdoc named Dick Tomkins; and his
trusty technician, Theresa Caryk, who I met at an honorary
event for Marshall last summer. She's still alive
and looks great. And we were supposed to
fractionate the S100 using the assay and figure out what
the factors were in the S100. So Dick Tomkins ran
some of the assays, I ran some of the assays, and
Theresa around the termination essay because she was
Tom's personal technician. And so we ground up a
kilogram of E. coli. We made the S100. And we worked like
the dickens all day. And we fractionated
everything out on a column. I think it was a
ion exchange column. And we looked at the data
late in the afternoon. And it was very clear we
had all the regular protein synthesis factors. They had come off the column. They had their peaks. And Theresa brings us
the termination data. And there's a big peak of
termination factor coming off the column, much later than
any of the other known factors. So we knew we had
something unique. And the peak goes up. And it's about right
here, coming down. Si Dick had to leave. He had a family at that time-- I mean a child, in
addition to being married. And I said, Theresa,
we can't leave it here. Let's just go out
another 40 tubes, every third or fourth tube. And we'll pool the peak. We'll put it away. We'll come back and study it. I says, OK, I'm going
to be here after 5:00. So sure, no problem. So she runs the assay, which
doesn't take very long, and comes back and
shows me the data. And this was the changing
event scientifically in my life because it produced a dopamine
rush that was like nothing I had ever experienced. And I was addicted forever
to science, totally addicted. It goes up, comes down, flat. Second peak, up and down. Two peaks? Not in Capecchi's
paper, he had no peaks. So I said Theresa, it's late. But do you mind staying because
she had run all the assays. I said, no, I said take
the peak tube from peak 1 and the peak tube peak 2 and
run it against each of the three triplets. So she said, OK, good. She does this. And I'm sitting and waiting. And she comes back. And it is the clearest result
that one could imagine. Pick 1 terminates with
UAA and UAG and not UGA. And peak 2 terminates with
UAA and UGA, and not UAG. And I said, m my god, we've
got termination factors. There's codon recognition here. So we scurry around together. And everything's been
run and duplicated. And there's just no ambiguity. There's no p values. There's nothing. It's just black and white. [LAUGHTER] I didn't need Mark Daily to
calculate like the p factors. So we put all this stuff
away, so we can study it. It's very late on Friday,
maybe 9:30, 10:00 o'clock. We're both very tired. And I-- Marshall is
such a great guy. I call him up at home. And I say Marshall,
I said, got a minute? Yep. Let me tell you
what we just found. And I tell you the result.
The first thing-- this is classic Marshall and Monty. He says what are the controls? [LAUGHTER] And I said, Marshall,
you don't understand. The peak tube is the control. It's inherent in the experiment,
reciprocal experiment. And he says, oh, wow. And then you won't
let me off the phone. And he's got me there
for another half hour. And I actually-- it was a great. I went home. My wife was furious. I was so late. [LAUGHTER] And we played a trick on Tom. We told them nothing worked. And it's Monday morning. We hid all the
notebooks from him. And then it was all great. And at that point, I
decided I wanted to do this. And it was such a
gratifying experience. And I do believe what I said,
there is a dopamine rush. You get such a high out of that
it is almost like an addiction, or if it's not an addiction. And I just wanted to keep
doing that in my life. I had enough confidence
at that point to do it. So Marshall said, well, if
you want to stay in the lab and be a staff person
in the Heart Institute, in Tom's section,
you can do that. And I said, oh,
that would be great. It's terrific. My wife was pregnant
at this point. And we're looking for some
stability in our life. And we decided to stay at
NIH, in Marshall's lab. And then, after about a year
most of the project was over. There was still work to do
in the mammalian system. And another kind of just
an interesting anecdote, when I had been an intern
and resident at the MGH, when I was a first-year resident
in medicine, Joe Goldstein and Mike Brown were interns. And I had very
little interaction with Mike, a little bit. But Joe turned out
to be my intern. The ARs always
taught the interns. So Joe was my intern. It turned out like two or three
times in a year, by chance. So we got to know each other. We're friends. And he called me in the
spring of my second year in Heart Institute. And he said that the lab he
had applied to had-- the person was leaving to go
to some university. He didn't have a lab. Could we help get him
into Marshall's lab? So I went down the hall
and talked to Marshall. And Marshall said,
a good, smart MD. But we have no space. I said, well, we'll
squeeze him into our 200-square-foot module. So we worked together
for a couple of years. And again, remained extremely
close over the years. So I stayed in Marshall's
lab for about another year. The project was kind
of coming to an end. We were doing the same
thing in mammalian cells. And I'd come to realize what
every young person in science I think struggles with
is your own identity. I realized that if I
stayed in Tom's section forever, as much as I liked
him, and liked Marshall, and liked the lab,
I'd never really have my own identity in science. And I didn't like that. I decided I wanted to
have my own identity. So I didn't know
quite what to do. And everybody in science so
I talked to at that point said, well, phage genetics was
the key field for understanding bacterial physiology. And mammalian cell
biology now is starting to think about using
animal viruses in the same way bacterial geneticists used
bacterial viruses because this is precloning days. Remember, they were
littler organisms. And they could be manipulated
a little bit genetically. And so you had the chance-- much more complicated--
to use them to understand mammalian cell biology. So I said-- a lot of smart
people thought this way. It sounded good. And Cold Spring Harbor
had the summer courses, which it still has. And it was teaching a course
that summer in animal virology. So I signed up for the course. And my wife came
during the summer. Our second child was born
at Cold Spring Harbor and that summer was
it was impregnated. And there was some great
people in the course, Ann [INAUDIBLE],, Phil Leder, a
couple of people from overseas. It was a wonderful environment. And the course was taught by-- Phil Marcus. He used to be a
professor at Connecticut, I think in microbiology-- and a couple of other people. And it was fun. I learned how to
culture mammalian cells and learned how to work
with animal viruses. And I decided this is good. I'd like to do this. I wasn't sure whether I'd do
it in a research environment or a medical school environment,
doing some clinical medicine, some research. And I started looking around
for opportunities to do this-- people at the MGH, a
couple people at Stanford. And at the time-- so now it's 1969, 1970-- the country--
Richard Nixon et al. decided to have a war on cancer. And I had learned about tumor
viruses as part of this course. They had had Howard Temin,
one of the fathers of RNA tumor virology, come to the
Cold Spring Harbor course and give a talk on RNA
tumor viruses, mysterious, but clearly important. And there was a good lab
in at NIH at the time because I was still
part of Marshall's lab, studying tumor viruses. It was run by George Todaro,
who had done some very nice cell biology. He and Howard Green developed
contact-inhibited cell lines from mouse embryos. And they were clearly regarded
well and were close by. So I went to
interview with George. And said, I'm interested
in animal virology, tumor virology. I come to your laboratory
and give up my tenured job at the Heart Institute
and be a senior fellow? And he said, yeah, you've
got a great background. We don't have anybody here
with molecular a background. We'd love to have you here. So this is like May or April. So I started trying to
learn a little bit more about tumor viruses. And there was a lecture
given at the National Academy in Washington by
Sol Spiegelman, who was a famous, and very
productive, and creative, and showy bacterial biochemist. I'm not quite sure
what to call him. So I went had to hear his
lecture on the replication of RNA tumor viruses. And I listened to
it, sat in the back, way up in the balcony
in the auditorium. And I heard the lecture. And he talked about
the RNA-dependent RNA polymerase of Rous
sarcoma virus and how that explained everything. And I had been reading. And I said, doesn't
make any sense. Doesn't explain the DNA
requirement for replication. But that's about all I
could say at that point. And at that point,
in July 1 came. I had told Tom and
Marshall what I was doing. And they said,
great, your choice. And I joined George's lab. And I've been there
about a week learning how to do cell culture,
when George wanders into the fellows' office,
were myself, and Stu Aarons, and Wade Parks-- we all shared this big office. And he says, I just got a
call from David Baltimore. And David says he's just
discovered an RNA-dependent DNA polymerase in Rous
sarcoma virus. And he wants to come down to
get some mirroring retrovirus, to be sure that this is general. And he's going to come at
the beginning of the week. So, boy, he's really exciting. And so Dave Baltimore
arrives in our contract lab in Northern Virginia-- we're introduced-- and tells
us about its discovery. We're going around,
touring George's lab. It's a big, big facility. And while we're doing
that, I said Dr. Baltimore, I'm just moved here. And I don't know that
much about the field. But it looks like your
discovery explains all it-- it provides a basis
for the replication. I said, from what I know
it doesn't really explain the cancer part, does it? He said, no, no. It's completely
mysterious still. So when he left, I
went to George Tagao. And I said, George, I want
to study the cancer part because the replication
part is now known. And he said, well, you
can do whatever you want. We need you to help us
set up certain assays so we can look for
human retroviruses. And as long as you do
that, on your own time you can do whatever you want. And I said great, good. So I did it. I helped them set up
their various assays. And then started trying
to figure out how to approach the cancer part. For those of you who
don't know anything about the history of
RNA tumor virology, the major beginnings
of that field really came from the chicken
world, the chicken virus world, Rous sarcoma virus. And they were extremely
fortunate in that they had a single virus, a unit
virus, that both replicated and transformed. You could clone the virus. And inherent in a single
virus were both properties. So they could manipulate
the replication genetically. And they can manipulate
the cancer part, the oncogene transforming part. And Peter Vogt, Duesberg-- and the was another
guy at Berkeley who-- I can't remember his name now-- made the first
temperature sensitive-- Martin, Martin, Martin. What was his first
name, do you remember. Steve Martin, yeah. He made the first
temperature sensitive mutant of Rous sarcoma virus,
showing that transformation was a biochemical
function of some protein. And then Duesberg and Vogt
these magnificent experiments, where they showed that
starting with a virus particle, you could isolate so-called
transformation-defective mutants, which had lost
the oncogenic properties. And Duesberg and Vogt
together fingerprinted these with RNA fingerprinting
and precloning, showed there was some
oligonucleotide spots missing in a transformation-defective
virus. So it was pretty
clear that there was some kind of
oncogenic function coded for by the virus. In the mammalian system,
we weren't so fortunate. All the viruses that
transformed in culture were replication-defective. And Stu Aaronson in George
Todaro's lab, with George, had shown that you could
isolate the oncogenic virus, the transformation-defective
virus, in so-called nonproducer cells. You could get endpoint diluted
foci, where the foci grew up and no virus is coming out. And you could add
replicating murine helper virus, a retrovirus, rescue
it, and transmit the foci. So all the viral
stocks that transformed had two viruses in it,
a replicating component, a transforming component. George's lab was
interested in the genetics and predisposition
to human cancer. And so they were
using by pure chance a virus called the
Kirsten sarcoma virus, to look for a genetically
susceptible human fibroblasts. And the reason they chose
Kirsten virus was you could see the foci
on human fibroblasts better than you
could with a number of other oncogenic
viruses that were available at that time
in the murine system. So naturally I started to
work on Kirsten sarcoma virus. And there was a Kirsten
leukemia virus, basically a replicating helper. So about the only
thing you could do, because it was
too complicated to do fingerprinting, you could
do hybridization experiments back then with the technologies
that were available. And it was clear from
the chicken virus work that there was something
called an oncogene. So we started making stocks of
the pure helper and the mixed virus. There was about a 1 to 1
ratio in the mixed virus. And making cDNA from
one, cDNA from the other, using the endogenous
enzyme of the viral preps. And then cross-absorbing and
looking for what was left. And we did these experiments. And it was very clear that
the sarcoma virus stock had sequences in it that were not-- is this too long? Am I running over? No. Maybe too long. H. ROBERT HORVITZ: [INAUDIBLE]. ED SCOLNICK: Yeah, what time? H. ROBERT HORVITZ: [INAUDIBLE]. AUDIENCE: Noon. ED SCOLNICK: Noon? H. ROBERT HORVITZ: Not
more than five minutes. ED SCOLNICK: Five minutes. OK, we'll end in five minutes. And then you can ask questions. AUDIENCE: This
will be the part 2. ED SCOLNICK: There's
going to be the part 2. So I'll finish the story, which
is worth finishing I think. You'll see. And there is a
lesson in the story, which is why I'm telling it. It was very clear
the sarcoma virus stock had sequences in it that
were not in the leukemia virus stock. Did this experiment
dozens of times, no idea what to do with it at
that point, absolutely no idea. And one morning, in my
home on a Sunday morning, I was literally in
the bathroom reading a textbook, sort of
historical volume, written by Ludwik Gross, one of
the fathers of tumor virology. And he describes all
the tumor viruses that are discovered, DNA and
RNA, talks about his friends in the field. And there's a chapter
on his friend Werner Kirsten, professor
of microbiology at the University of Chicago. And he says, my great
friend Werner Kirsten, with Kirsten/McKinney Labs,
Kirsten sarcoma virus, found that he had to passage
the leukemia virus in mice to keep it leukemogenic. Then one day he
passes it in rats, to see what would happen
after a few passages. He took it back out of the rat. And lo and behold, it
had a new property. It transformed cells in culture. And it caused formalin to
elicit leukemia in the mouse. I read this, and I say, oh,
my god, look what happened. It picked up a rat gene. So we devised the right
experiments, which took months to do at the time. And we found rat sequences
in the Kirsten sarcoma virus and exploited the system
for many years after that. And then I ended up
going to Merck in 1982 because at the time the
Cancer Institute decided-- this is pre-Weinberg transfer
infection experiment, that they really weren't
interested in cancer virology. They weren't-- they emphasized
chemical carcinogenesis. I started reducing
the size of my lab despite its productivity. And I decided, I
don't need this. And when I got an offer to
go to Merck-- and I had known Vagelos. I went to Merck. So if you want to know
about the Merck years, you can invite me back. So I think the
take-home lessons here are there's a lot
of chance things that happen in your life,
circumstances around you. But you have to have a
kind of vision for what you want to do, pick an
important problem, and figure out with the
circumstances in your life that are available to you and
that come up by chance, how you can pursue what your
real emotional goal is. And you should never
give up on that. And I do want to say one other
thing about MIT, which I've said in other environments. I said that, when
I was at Harvard, and even subsequently I used
to go back to Harvard, it was, perhaps not is anymore,
but it certainly was a very different
sociocultural environment than MIT. When I was at Merck and would
come to recruit at either MIT or Harvard, the
people at Harvard always made me
very uncomfortable because despite what I had
done in science before going to Merck, they
clearly looked down at what I was doing at Merck. And I was never made to
feel that way at MIT. Whenever I came to MIT, I
was treated like a scientist and treated with respect. And it is a nonsocial,
hierarchical environment. The coin of the realm is
what you do scientifically, not where you were born,
not who your parents were, not how much money your family
has, not where you came from, the color of your
skin, your blah, blah. And I have always cherished
the place because of that. It's still that way. And you're really lucky
to be students here. So thank you for reminding me. [APPLAUSE] H. ROBERT HORVITZ: I have to say
my expectations have certainly been fulfilled. And I did learn a lot. And I did enjoy a lot. And I'm only sorry that we
have to follow the clock. But I think even
given that, I hope Ed you'd be willing to
take a few questions-- ED SCOLNICK: Of, course. H. ROBERT HORVITZ:
--at this point? ED SCOLNICK: I'm free. H. ROBERT HORVITZ: So questions? I mean like, how about
the rest of your life? [LAUGHTER] OK, questions from the
audience, anything? Anybody would like to
ask or hear more about? Yes, please. AUDIENCE: So what was
the big difference when you went to Merck [INAUDIBLE]? ED SCOLNICK: Well, the
biggest difference-- I didn't exactly know
what I was getting into. And Merck wanted to revitalize
its virology department. And were building a building
and gave me a lot of resources. And I was very unhappy at the
Cancer Institute at the time. So I went. And I trusted Vagelos,
because I'd him years ago. And after a few weeks I
realized what Merck was. It's a big department
of medicine focused on
therapeutics as opposed to just pathophysiology. And I loved that idea. I had a good background in
biochemistry, and microbiology, in medicine. There were lots of
illnesses and projects that I thought we could take on. And unfortunately
at the time, Merck did not have the staff
technical infrastructure, except a little bit
in biochemistry, to do any of them. So it was a big
recruiting process to try to get people with
the right backgrounds and the right fields to come
in and then start projects. That was the biggest transition. Yeah? AUDIENCE: Well, one of
the things that I loved about this talk is that you're
kind of sharing your instincts and your nose to sniff out,
testing new areas to get into. I wondered if you could
just say something about how you landed in brain
science, at the Stanley Center. ED SCOLNICK: Yeah, sure. As many of you know, some
of you in the audience know, for very personal reasons. We have three children. Our second child, a boy, went
to Harvard, extremely gifted, and developed a psychotic
illness after he graduated. And for many years, it's not
clear what his diagnosis was. It became clear in the late '90s
that he had bipolar disorder and not schizophrenia. And for many years,
between 1992 and 1999, 2000, when he became
really, really sick, he became catatonic. And had had a terribly
rocky road in between, even tried to commit
suicide at one point. I learned about the field,
both through his illness and volunteer work
that my wife and I did for NAMI, the National
Alliance of the Mentally Ill-- how bad the field was. And I decided, gee, I'd really
like to do something here. I was quite intimidated. But then I started reading
journals and visiting schools to learn about neuroscience. And ended up-- well,
we don't have the time to go through it all--
but ended up meeting David Altshuler at a meeting. And ended up at the Broad, to
help them build their program. So this is really a
personal mission in a sense. All I knew was that the
genome had been sequenced. I knew enough to know that
the field was hopeless unless we could find the
genes because you couldn't do biochemistry on living brain. And the Broad, Eric, David,
were really good at it. So that's how I came here. And I was very fortunate
that people at McClain, that I had been involved
with because my son had been hospitalized there
for six months, put me in touch initially with
the Stanley Medical Research Institute. And I went to visit
them before I came here. Told them-- they had
had a son with illness. Told them what I wanted to do. And they basically
said, well, we-- and I told them about my son. And they said, look, we
see your track record. You're motivated. We'll give you
some startup money. And that was the beginning
of our interaction with the Stanley Center. There's much more. But I can tell you in
person if you want to know. H. ROBERT HORVITZ:
I think with that, we should thank Ed very much. [APPLAUSE]
