Oral History: Dr. Allen Spiegel, NIDDK Director Emeritus


[music] SPIEGEL: I arrived in Boston at the age of
three, in 1949. I’m going to use the word “allegedly”
here because we want real facts as opposed to alternative ones. So a lot of what I’m going to say about
this early history is based on what you receive from your parents. My parents both from Lodz, the second largest
city in Poland and both Auschwitz survivors, so not only Holocaust, but concentration camp
survivors, sent there from that ghetto, which was the longest standing ghetto and not liquidated
until September 27, 1944. They pretty much, alone among their respective
families, managed to survive. He was liberated by the Americans because
he was on the death march from Auschwitz to Buchenwald. She was liberated by the Soviets because she
was quickly sent from Auschwitz to a camp in Czechoslovakia. They managed to reconnect in Lodz. He quickly presciently realized this was not
where they wanted to remain, and managed to get back to the American sector [in Germany]. I was born then in May of ‘46, allegedly
the first child born in this displaced person’s camp in Landsberg, Germany. So we did come to America in ‘49, although
disembarking in Boston, took the train down to New York and lived in Manhattan in an area
that’s now been rebranded as Hamilton Heights, 155th and Broadway. He was a tailor and worked in the garment
district. We came under what’s called the Truman Quota,
so that’s relevant to current immigration issues. It was the Johnson-Reed Act in 1927 that precluded
most people from Eastern Europe, Southern Europe, certainly Asians, from coming to the
United States, and that didn’t really change. The Truman Quota just said they would let
a few refugees in. One of the other amusing stories which I doubt
is true, but your mother says this is what happened, Eleanor Roosevelt used to come and
meet and greet these ships bringing refugees and she would give every young child coming
off the boat a dollar. But when she saw me, she gave me an extra
dollar because my mother said she recognized I was so special. So there you go. Only a mother can tell you that kind of story. Early days living in Manhattan and going to
initially public school, my mother had come from an observant family, whereas my father,
absolutely not. That becomes relevant later when I talk about
college applications, another current topic. They didn’t have the $500,000 to get me
into Harvard. But the upshot is she insisted that I go to
a Jewish parochial school, a Yeshiva, and it was a progressive co-ed one in Washington
Heights. She had to work as a cleaning lady to be able
to pay for the tuition. But then, in a recurrent motif, I quickly
got a scholarship and she was relieved of that responsibility. A signal event was moving from Manhattan to
Brooklyn, and that’s significant in several respects. When I told this story at a dinner party for
some Einstein donors they all burst out laughing. Shouldn’t it be the other way around, because
that’s usually the upward mobility. But it’s astonishing. When I came to New York City in 2006 to become
Dean at Einstein, the rebranding and the emergence of Brooklyn as not just hip, but a whole brand,
is just astonishing. It wasn’t back then. In any event, he [my father] was able to get
enough resources to purchase a cleaning and tailoring store. And so we lived in Brooklyn for those years
and I continued to attend a Yeshiva high school. [music] SPIEGEL: The Sputnik satellite, which was
put up by the Soviets, the space race, the Cold War, created kind of a wave of consternation,
almost paranoia in the U.S., which is a little hard to imagine now, despite all the things
that continue to go on. One of the beneficial effects, though, is
that it spurred more efforts to get students interested in science in specific ways. And for me, that manifested as a National
Science Foundation program for high school juniors. And that summer, the summer of, it would be,
‘62, I participated in that program with my first laboratory experience. I wouldn’t glorify it with the term “research,”
but that was at the Albert Einstein College of Medicine, which was then all of seven years
old. And I would be taking the subway from Brooklyn
to the Bronx to do research, working on effect of barbiturates on enzymes in rat testes. But it was a rewarding and interesting experience,
and it was really my first taste of research and that kind of stuck. But going forward to college admissions thing,
again, given my folks with their limited background and resources, it was the opposite of the
situations we see now with, you know, helicopter parents pushing and driving, etc. I applied to a small range of schools, Cornell
and Columbia, because those were within New York State, and there was something called
a Regents Scholarship, which would be relevant. But I also applied to Harvard and Dartmouth. Don’t ask me why Dartmouth. That was nuts. But the upshot is I got into all those places
except Harvard. And I do want to bring back this theme with
the Harvard interview. So this is now the fall of ‘62. This is now into my senior year in high school
and it’s in the Graybar Building on Lexington and 42nd in Manhattan. It’s an alumni interview. I didn’t have the resources to go up to
Cambridge. The attorney who was giving the interview
says, “You’re going to this Yeshiva, so you’re obviously going to need kosher food. Kosher food costs more at Harvard, but your
father is a tailor. You’re going to need a scholarship.” He goes on and on in this vein. Nowadays you would sue probably or get out
on social media and he’d be shamed or trolled, or whatever. But I didn’t want to give him the satisfaction
to know that because of my dad, he and I were going to the Chinese restaurant eating pork
spareribs all the time. So whatever, but the upshot is I didn’t
get into Harvard. So what. I did go to Columbia and that was really an
outstanding education and a really rewarding experience. And at Columbia, I had further opportunities
to do research. One deviation was working in what used to
be called the Catskills, which are now a shadow of their former selves. I was working as a bus boy at a place called
Kutsher’s Country Club. And that was a very well paying position [for
a college student]. So that was the summer after my freshman year. After my sophomore year I had the opportunity
through a classmate to work in Germany at a Max Planck Institute. The Max Planck Institutes were renamed after
the denazification. This was in Frankfurt, Germany in an institute
for biophysics. You may ask, why would you be going back to
Germany? There were several reasons, and not Poland,
specifically Germany. It was a very interesting experience. I did get to do and participate in some interesting
research and certainly the personal experiences—I remember vividly in the street, hopefully
this isn’t politically incorrect but, an attractive young woman wearing some outlandish outfit
and my eyes look at her, another middle age German gentleman’s eyes look at her and
then our eyes lock together. And he says to me, “Ach ja, was diese Frauen
machen,” [translated to] “Oh what these women won’t get up to.” Then we then just started a conversation and
immediately he didn’t perceive— I don’t want to give myself too much credit. I had taken two years of German actually at
Columbia. In the DP camp, my parents of course spoke
Yiddish, which is middle-high German, so it kind of helps a little bit. But I was not by any means fluent going into
that class. But I became much more conversant. And he didn’t immediately perceive that
I was a non-native speaker. But then I divulged being American and his
first words were, “I fought on the Eastern Front.” This is in the ‘60s. It’s relatively early on. But he then- I won’t go into great detail
here but long story short, the residue of anti-Semitism and Nazi influence, if you think
about it, it wasn’t really until sometime into the ‘60s that, even in the U.S., there
was more of this kind of recognition of the Holocaust, not that people weren’t aware
in Germany. As is evident from everything I’m saying,
this is obviously a dominant theme in my psyche and even to some extent in my career. That summer of research ended and then continued
in several other forms. I actually worked, not at Columbia, but in
a lab at NYU Medical School after my junior year at Columbia, again summer program, and
that’s really very germane. I worked with a man, now deceased, named Mark
Bitensky. He had been at NIH in this institute as a
research associate. Remember, we’re talking about the years
of the doctor draft, the derisively termed “Yellow Berets,” there was not a yet a
Vietnam War in his era. He worked with Gordon Tompkins and Lemone
Yielding. This was the laboratory of molecular biology. It still exists and is arguably one of the
premier labs at NIDDK. He got me really turned on to research. I worked with him for two additional summers,
after senior year at college, and then even after my first year in medical school, and
got completely hooked on a molecule called cyclic AMP, the second messenger of hormone
action. I want to just telescope ahead here because
it’s relevant to the NIDDK and indeed the NIH intramural program, and to my own career. He was working on mechanism of hormone action
and he was really one of the few at the time who was working on it. An investigator named Earl Sutherland, who
shared the Nobel Prize in 1971, purportedly, this is before my time, came to NIH to give
a seminar in 1968. He had discovered cyclic AMP back in ‘55. Very, few people totally appreciated the significance
of his work and also technically it was very difficult to perform the biochemical assay
to measure the substance. There were many labs in NIH and I can rattle
them off, not just in NIDDK, working on the mechanism of their particular hormone of interest. My to-be mentor, Gerry Aurbach was working
on parathyroid hormone, Orloff and Handler of the Heart Institute were working on antidiuretic
hormone. Marty Rodbell and others were working on glucagon
and catecholamines, Jesse Roth working on insulin, that’s a separate theme. They hear the seminar from Sutherland and
suddenly the proverbial or clichéd lightbulb turns on in everyone’s head. They realize everyone had thought that their
hormone works in a unique way. Because in fact, the dominant feature of these
particular hormones is the great specificity in the target cells that they act on, which
we now know is due to the receptors, and the physiologic effects they elicit. For parathyroid hormone, specific effects
on phosphate handling in the kidney, specific effects on calcium phosphate handling in bone. But it turned out they all realized that every
one of these hormones, not insulin, but the ones they were working on, had cyclic AMP
as the common second messenger, the common intermediate step in action. As I would later describe in some of my own
work, the specificity is at the front end and the back end, the specificity for the
hormone is in its unique interaction with the cell surface receptor. These are cell membrane receptors. Then you get cyclic AMP. It activates a so-called cyclic AMP dependent
protein kinase A. That phosphorylates specifically intracellular proteins changing their biochemical
action, and it’s the specific substrates expressed in those cells that determine the
physiologic effects. This was the thing that they needed to comprehend
and they all then started publishing papers, as did Aurbach, on the role of cyclic AMP
role in their respective hormone’s action. This was all started by the work with Bitensky
and it was then carried on in medical school. I’m going to weave a number of themes here
together. We’re now talking the fall of ‘66. INTERVIEWER: Were you in pre-med in Columbia? SPIEGEL: Yes. So I’ll backtrack for a moment. I was in pre-med in high school and the reason
for that is this is really a unique high school. I say now defunct, but really a series of
brilliant kids, mathematically, many many outstanding individuals, one of whom by the
way, Joel Moss who was a classmate, I believe is still working in the Heart Lung Institute. He is the head of the pulmonary branch. He went on to get an MD-PhD at NYU. That’s the quality of some of the people
in the class. That said, our mindset was very clear. Many of us were pre-med, determined even at
that stage, and we insisted that the school provide Latin as a course. Why? Because of the misconception that you needed
to write prescriptions in Latin. How crazy is that? That was the mindset. But that worked out well because I managed
to read at least Caesar’s Gallic Wars and got to early Cicero, so there are beneficial
effects. INTERVIEWER: Did you ever consider going into
a PhD program rather than to medical school? SPIEGEL: It’s a very relevant question. I didn’t and I’ll be very candid. I was very conscious, and again, I’m emphasizing
this immigrant theme and of course the sparse resources, so yes, I went to Columbia essentially,
virtually on full scholarship, along with a 20-hour a week job, right through the four
years, prize room in the dormitory in my senior year, which meant I couldn’t live in an
apartment. The fact is that I didn’t- I wanted to be
able to hedge my bets. When now as a former dean of a medical school,
I stepped down in July of ‘18, but it’s relevant today. You basically see students now getting out
with so much debt, although some schools have managed with philanthropic contributions to
be debt-free, but [as an M.D.] you were always guaranteed of at least some reasonable income,
and that was true then. I recall that PhD programs, and specifically
MD-PhD programs, were just in their bare bare beginnings, so that would have been for me
a viable option. That would have been the preferred option
actually is MD-PhD, but I did not go that route. In fact, just jumping ahead, my Harvard Medical
School class, two individuals in that class who were in the M.D. program went later and
got Ph.Ds., so they were not MD-PhDs. One of them, by the way, Bill Wickner, is
the brother of Reed Wickner, who I believe is still a distinguished scientist whom I
promoted to lab chief when I was the intramural director. That’s just showing you how embryonic the
MD-PhD program was back then. The real reason was hedging my bets. I figured, look, this way I can always go
into clinical practice. The other relevance is, sadly, this is why
physicians with M.D.s only who go into research, unless they do like the Master’s in clinical
research, which is a good program, they’re often not successful in terms of pursuing
a research career and getting NIH funding. And often they’re forced by deans to do
more clinical work, so it’s kind of a Catch-22. But for me, I knew that I wanted research
as an important part of my career. It’s not that I didn’t relish patient
interaction. And because of the exposure to research that
I had, cyclic AMP and the mechanism of hormone action, and also the desire to be involved
in clinical medicine, I picked endocrinology as a specialty very early on, and that certainly
made sense in terms of the research. The other thing, which is not intuitively
obvious now, back then in late ‘60s, early ‘70s, endocrinology was arguably one of
the only internal medicine specialties that was really biochemically science-based. Immunology basically was in its very early
stages. Neuroscience was just being founded. Cardiology was “plumbing.” I’m being a little derisive. Endocrinology really made sense. Too much of a hormone, too little of a hormone,
the hormones were synthesized; gratifyingly, you could replace the hormone if it was missing. So that was a very appealing specialty. That’s where- you could almost say it was
tunnel vision. Harking back to the fall of ‘66 and the
medical school applications, so I applied to Harvard Medical School among just a few
others and what a difference. I get in in November, in the first wave of
admissions. And I’m going to relate this to the Einstein
situation. The Albert Einstein College of Medicine was
founded in 1955. It was founded as part of Yeshiva University
because of the virulent discrimination against Jews to go to medical school. Very very few were accepted to a very very
limited range of medical schools. A visionary president of Yeshiva University
decided this is a way to rectify it, went down to Princeton to the Institute for Advanced
Study to interview and request Albert Einstein, would he be willing to lend his name, and
he said, “I’m a physicist, not a physician. Why would you name a medical school after
me?” He said, “Okay, we’ll name it the Joe
Blow School of Medicine.” He said, “Who’s Joe Blow?” “That’s why we want to name it the Albert
Einstein College of Medicine.” At least that’s the anecdote. That’s indeed what happened. Einstein is everywhere on campus. There’s no copyright on his name or appearance. There are other entities around the world
even with the Einstein name. I was consulting on a scientific advisory
board last fall for the Albert Einstein Jewish Hospital in Sao Paulo, Brazil. And so you can pick up that name if you want
to lend some panache to it, scientifically, humanistically. So the upshot is the anti-Semitism though
in that period of time and the discrimination hadn’t disappeared totally, but it was really
dissipating. And another manifestation of that is Mt. Sinai. Mt. Sinai is a hospital in Manhattan that
goes back to the mid-19th century, [founded by] the German Jews who were among the first
waves of Jewish immigration. The hospital had a very distinguished record,
but no medical school. Why would they bother? In 1969, 14 years after Einstein, they founded
what is now the Icahn School of Medicine. The reason for that is obvious but the reason
is the few Jews who got into medical school had very few choices of residency. They [Mt. Sinai] had their pick. As the anti-Semitism started dissipating,
they realized they were going to have to be competitive and they grew their own pipeline. This is some of the sociology of what was
going on. At Harvard Medical School my research theme
continued. I was very fortunate to work in the laboratory
of the person who was the Chair of Medicine, a man named Alex Leaf, very very distinguished
and interesting individual. He was working on antidiuretic hormone and
he was one of the first M.D.s in the National Academy of Sciences. So again, you had elective time, you had summer
time, so there were times to weave in, and continuing the same theme of mechanism of
hormone action and indeed cyclic AMP. What’s relevant here in terms of my NIH
career, it’s pretty much a given that if I can get in I’ll go to the NIH. And the reason I say that is this is the era
of the doctor draft. So graduating in ‘71, as I did, that turned
out to be the last year of the doctor draft, but I was still at risk. People interested in research tried to get
to the NIH. People interested in epidemiology would try
to go to the CDC. Being in the public health service fulfilled
that requirement of military service, it was the Commissioned Corps of the public health
service. Fortunately, I was able to get in there. There’s a huge hole in the ground now, on
Woodmont Avenue at Wisconsin Avenue where there used to be a motel, and that’s the
motel where I stayed, taking the Greyhound Bus from Boston, overnight, into D.C., coming
up from New York Avenue to that motel, for two days of interviews. Again I didn’t want to take any chances. I had arguably over two dozen interviews in
many labs in many institutes, and I was fortunate to get my first choice with Gerry Aurbach
in what was then NIAMDD, the names have changed over the years, in the metabolic disease branch. Aurbach was a phenomenal mentor. He died tragically in ‘93 at UVA [in Charlottesville,
VA]. He was arguably the only graduate of UVA Medical
School to get into the National Academy of Sciences. INTERVIEWER: There is a connection with Aurbach. Your first paper I understand was in endocrinology
and was- SPIEGEL: Yes. He was either an associate editor or he was
on the Editorial Board of Endocrinology. That paper on glucagon structure function
and activation of cyclic AMP formation in the liver was with Mark Bitensky. That paper was written based on work done
those summers after college and first year of medical school, and was accepted. Yes so that is my first publication, you’re
right. The other twist here is at the Mass General,
which I went to for internship and residency, they thought they were the center of the universe,
medically, and didn’t realize there were other places like Hopkins and even Einstein,
Montefiore, etc. Jacobi. There was the Ether Dome, the Charles Bulfinch
Building built in the early 19th century where ether was first used in maybe 1854 or so for
a procedure. So that Ether Dome still exists and that would
be where endocrine rounds were given and the speaker, one year I was there as a student,
was Jesse Roth, who was then not a branch chief, but he was at the NIH in a section
within the clinical endocrine branch. Later to be split off as the diabetes branch. He’s such a charismatic figure and I was
so taken. And I went up to Jesse hoping to be able to
work in his lab. And the way things worked, his lab only had
associates every other year and it was not my year. Now I don’t want to denigrate Jesse, but
it is a great great twist of fate that I did not get into the lab. There are terrific people who came out of
that lab and we should mention them: Ron Kahn, who I just saw at the diabetes meetings a
few weeks ago. Ron was in NIDDK in the diabetes branch for
about 10 to 11 years, with Jesse, doing really the pioneering work on the insulin receptor. The insulin receptor is a tyrosine kinase. So this is different from the G protein coupled
receptors that go into the cyclic AMP pathway, but again an important mechanism of hormone
action. Jeff Flier stepped down just a few years ago
as the Dean of Harvard Medical School. He came out of the diabetes branch, did very
important work on some of these extreme forms of insulin resistance, which then Simeon Taylor
carried on, Phil Gorden and others continued to work on. So there’s a rich history there. So I’m not saying one couldn’t do well
in Jesse’s lab. But he was very controlling figure let’s just
say. So it’s not coincidental that Ron left. He went up to Boston and Jeff Flier followed
him there. That was the opposite of Aurbach. He really was “sink or swim.” He gave you guidance and support. He really was a remarkable figure and a remarkable
scientist. [music] SPIEGEL: You don’t get instant feedback. But literally- I literally washed up in the
Greyhound Bus station washroom on New York Avenu as I said, came straight up to campus. It’s a good question; there was no metro. How would I have gotten up here? I certainly couldn’t have afforded a taxi. There must have been some way that I got up
here and went through the first day of interviews. There were all sorts of people who were quite
good. It wasn’t random. I was picking people in areas that were of
interest. But there were quite a number of different
institutes. Aurbach again is a very mild mannered, kind
of laid back guy. It wasn’t a given, but I had a good feeling
about that. Nonetheless, I did repair to that motel, spent
that night there, and the next day took the Greyhound back. This was really during the course of my residency
basically. You apply early on as a medical student, but
you actually have to go through the interview process at a later stage. But I was very gratified to get word that
I managed to get into the Aurbach lab and again met a series of distinguished individuals. A person who followed me by a year was Ed
Brown. Ed Brown left after about four or five years
and he went to the Brigham [Hospital in Boston] where, in ‘93, he made the seminal discovery
of what’s called the calcium sensing receptor in parathyroid cells, which is really a very
important discovery and very relevant to the work initially started in the Aurbach lab. So let me bring this back to some kind of
coherence. I’ve described the medical school phase and
some of the research there, applications to the NIH and matching, internship and one year
of residency, you were allowed to short track at Mass General. And again that was a very demanding and rewarding
experience. At the same time, I was quite clear, I was
eager to get on with subspecialty training. And here’s where again a number of happy
circumstances came together. At the Mass General, the head of the endocrine
unit was a man named John Potts- Potts still alive and well well advanced into his 80s. He had worked with Aurbach when he had been
at the NIH, in the Heart Lung Institute, on the sequence of parathyroid hormone. And that structure determination is important
right through to clinical medicine. One of the treatments of osteoporosis is a
synthetic version of parathyroid hormone that builds back bone. So that’s an example of how important Aurbach’s
pioneering discoveries were. The idea was that I would do my two years
in the Aurbach lab, come back to Mass General and do an endocrine fellowship, and we’d
see what would happen from there. Well none of that happened because just then
an inter-institute endocrine training program was created at NIH and I was one of the inaugural
fellows in that program. So I was able to do my internal medicine boards
in 1974, and then my endocrine and metabolism boards in 1975. And again that was a very gratifying experience. I want to just step back here also. I told you the anecdote with Earl Sutherland
and the various NIH intramural scientists. If we now just look at the collection of endocrinologists
and endocrine researchers in NIDDK, also the Child Health Institute, Griff Ross, Mort Lipsett,
not alive, someone who is still alive, Lynn Loriaux, who came out of that ilk, they focused
primarily on steroid hormone pathways and just extraordinary clinician scientists. Within NIDDK, Saul Rosen, Bruce Weintraub,
Jesse Roth, Phil Gorden, Gerry Aurbach and his associates, Rodbell was a pure PhD, but
relevant here, so he was not part of the clinical group, but he was relevant in the sense that
he working as I said on mechanism of hormone action. And I’ll weave his discoveries that were important
to me personally. You cannot- one is tempted to say these were
the days of the giants, but they really were. To sit in the eighth floor solarium [in the
old Building 10] and have clinical rounds with these individuals was unbelievable. It was really the top of the top. The Ether Dome in Mass General had some heavyweights,
and Hopkins, John Eager Howard, etc, but this was really supreme. Furthermore, the opportunities, because of
the clinical center and the nature of the patients— within short order we saw three
patients with a very unusual kind of pineal tumor, so called suprasellar germinomas, and
that led to a paper with Phil Gorden and others. Because we learned- and I was a Clinical Associate
taking care of a young 14-year-old girl who was admitted to the Child Health Institute
with primary amenorrhea. She never had her periods. And as I took her history it became clear
that she also had something called diabetes insipidus, inability to concentrate her urine,
so she was constantly drinking and peeing. And to me that spelled more than just primary
amenorrhea. Indeed she had what we call panhypopituitarism
as well as diabetes insipidus. This spells some trouble up above the optic
chiasm where the pituitary is. It turned out to be one of these tumors. And by that time we recognized it sufficiently
to know it’s exquisitely radio-sensitive. She had one of the first what we now call
CT scans. They were called EMI scans, which is really
the company that was also the Beatles’ publisher, Eastern Music Instruments. The EMI scan, Hounsfield shared the Nobel
Prize for discovery of things related to CT scanning. So that showed calcification. Then she was radiated and she was saved, and
in fact, had children later. Her parents, mother crocheted a little blanket
for our newborn as a gift of thanks. So the few- again I never portray myself as
a clinician. In fact, my typical statement which actually
is a bastardized version from something I heard from Ira Pastan, who is still working
at the Cancer Institute, although started at NIDDK. The clinicians think I’m a biochemist, biochemists
think I’m a clinician, my mother hopes I’m a doctor. That was the schizophrenia of trying to be
a physician scientist, even albeit, not an MD-PhD. The upshot of that is being in the inter-institute
endocrine training program. And the other thing in retrospect- the doctor
draft ending in ‘71, basically I think the powers that be at NIH recognized that this
endless stream of people coming, giving them you know Brown and Goldstein, Bob Lefkowitz
who I ended up collaborating with extensively when he was at Duke, although he had been
with Jesse Roth in the diabetes branch, Stanley Prusiner, many of them Nobel Laurates who
came out of this program, that was going to end. Ultimately I was offered a permanent position,
essentially in 1975. And so I told John Potts, sorry, I’m not
coming back to Boston. By that time my wife had a position at the
World Bank. She’s a librarian. She actually worked at the main library at
Copley Square [in Boston]. It was then by the way that I got my first
medical school loans. We got married at the end of my second year
at Harvard Medical School. I had been on full scholarship throughout
and the loans are just a minute fraction of the kinds of [current medical student] loans,
even with the changing dollar. They figured since she’s working, so the
classic story. She came down with me to DC to NIH to work
at the Georgetown University Library and then was able to get a position at the World Bank,
and worked at the World Bank even two and a half years into my being Dean at Einstein. It’s part of the reason we kept the house
in Bethesda. In any event, they recognized that they needed
to hold onto talent. Now there was a little bit of momentum that
continued- Ed Brown didn’t have to come. But he did come the year after. So we scraped together the bonus that was
given to people in the Commissioned Corps, for the first time in ‘75, purchased a small
Cape Cod on Radnor Road in Bethesda, about a mile and a half from the NIH campus, and
that’s where we lived for quite a number of years. So that was really the beginning of a 33-year
career at NIH and NIDDK in different positions. And within the first few years, given Aurbach’s
mentorship, I was able to establish my own research program. The initial papers really hinged on discoveries
of Rodbell. I’ve alluded to him. Rodbell had been working as I mentioned on
mechanism of hormone action, cyclic AMP formation, once they got wind of the Sutherland discovery. But he made a crucial crucial discovery, which
is that most people who are doing the assay for cyclic AMP, the substrate- I’m going to
use some of these technical words- is ATP. The ATP they would purchase from Sigma Chemical
Company was contaminated with the related purine nucleotide GTP, several orders of magnitude
lower in concentration. But it turned out, Rodbell, he was a really
sophisticated biochemist, they purified the ATP. They added the hormone in the usual way, no
cyclic AMP whatsoever. What’s going on here? They then recognized that they needed to add
something back and that something was GTP. And again I’ll telescope all of this, but
through pure biochemistry enzymology kinetics they realized that- there’s a diagram for
a symposium, just to fast forward- he [Rodbell] won the Nobel Prize in 1994 I believe it was,
shared the Prize with Al Gilman, who sadly died of pancreatic cancer just a few years
ago. He had been many things. He had been the Dean at UT Southwestern. He was the first to purify the first G protein,
the one that is involved with stimulation of cyclic AMP. He took the Rodbell kinetic discovery and
manifested it in real physical terms as a purified protein. This was all critical work which just opened
up enormous fields, which are still ongoing. Lefkowitz eventually shared the Nobel Prize
in Chemistry with his former post-doc, Brian Kobilka at Stanford, for determining the three-dimensional
structure of G protein-coupled receptors (GPCR). So in essence, the paradigm is the hormone
binds to a seven-membrane spanning cell surface receptor, a GPCR, or heptahelical receptor. That couples to a so-called heterotrimeric,
three different subunits, G protein. They’re a family of different G proteins,
which in turn lead to different kinds of second messengers, not just cyclic AMP, and in turn
different physiologic effects. My early work involved some of the basic studies,
picking up on some of the Rodbell things, on the G proteins and working with systems
that Aurbach had pioneered in. But my own interests were to try to combine
this basic biochemistry with clinical endocrinology. And one of the key discoveries related to
a disease that goes back to one of the pioneers of endocrinology at Mass General in the Ether
Dome, Fuller Albright. So Albright’s hereditary osteodystrophy
and, he gave it a terrible name, pseudohypoparathyroidism. So this terrible name, it’s like they’re
deficient in parathyroid hormone, but they’re not, they’re resistant to it. Back in the ‘40s, he recognized, without
benefit of radioimmunoassay or ways of measuring the hormone, that they weren’t deficient,
that they were resistant. He was an extraordinary pioneer. This was really an opportunity for me to jump
in here. And just again telescoping a lot of different
detail. It was widely viewed that that disease was
a defect in the parathyroid hormone receptor, that that’s where the specificity is. But I’m reading literature and I see there
are reports of patients with the disease who have hypogonadism, hypothyroidism. And I’m saying to myself, “Wait a minute,
this can’t be the parathyroid hormone receptor.” It goes back to what I was saying earlier. It’s something common to these different
hormones that act through G proteins. Hence, the speculation, the hypothesis was,
maybe it’s a genetic defect, a loss of function of the G protein involved in stimulation of
cyclic AMP. And that’s exactly what it turned out to
be. [music] So we’re in the midst of roughly the late
‘70s to early ‘80s, and I’m at this stage close to splitting off from the Aurbach
lab. The then scientific director determines that
I’ll have a branch of my own, the molecular pathophysiology branch, still with cordial
relations with Gerry Aurbach, but fellows of my own, and the work is candidly going
well. We’re doing basic work on G proteins. We were able to make some of the first antibodies
to G protein subunits. There are three subunits: alpha, beta and
gamma. And again one of these interesting twists,
that goes back to work related to what my early mentor Mark Bitensky was doing, not
when I was in the lab but he carried on his career. He was working on the mechanism of what’s
called phototransduction, how the retina perceives light in the rods and cones. There’s a whole field working on this, completely
divorced from our field, which is working on mechanism of hormone action. But what begins to emerge is that these are
exactly parallel systems in terms of evolution, that the receptor, rhodopsin, for light perception
in rods is a G protein coupled receptor. Now Lefkowitz picks up on that and runs with
it. We picked up on the fact that the G protein
that’s specific to the rods, it’s got the trivial name transducin, is a three subunit
G protein just like the ones that are much more rare that we’re dealing with, rare
and hard to purify. Gilman gets the Nobel Prize for purifying
the Gs one. I would send my technician to Catonsville,
to the slaughterhouse where he would get cow eyes. We would wash out the retinas and it was a
trivially easy purification to get pure transducin and we made antibodies to it, and then were
able to show that these antibodies cross-react that’s the term with the subunits of the hormone
related G proteins. That was an important advance and it helped
advance the field in general. At one point I had a technician doing nothing
but sending out dry ice packages all over the world to people we shared [them with]. Somewhat embarrassingly, NIH determined we
should patent these antibodies, which was a strange thing to do, but it was basically
so that other companies could pick up and use these as research reagents, so that was
done. Believe me, no mega royalties there, but nonetheless
it was a good thing to do. So a variety of strains of work in the lab
relating to basic aspects of G proteins, some terrific fellows, a few of whom are still
here at NIH. I’ve mentioned William Simonds, Lee Weinstein,
who’s the head of the branch that I had headed, that Aurbach had headed. He’s here as a branch chief. There are individuals like Sunita Agarwal
who had worked in the lab on a project I’ll get to, and Michael Collins who works in the
Dental Institute, who also picked up on projects that we had picked up on and was in the inter-institute
endocrine training program. So all this time the training program is going
on and I’m able to be an attending for the patient service and pursue this research. In roughly 1990, the then scientific director
Jesse Roth leaves to go to Hopkins and there is a search and a determination by Phil Gorden,
who is the Institute Director, for a new intramural director, and candidly, in those years it
was virtually impossible to recruit someone from the outside. People on the outside had better than government
salaries, even research space for a laboratory, which typically the scientific director still
had, was problematic. And so it was invariably not only an internal
candidate, it wasn’t even someone from a different institute. So it does show you times have changed somewhat. This has waxed and waned [at NIH] but that
was certainly true then. I’m going to name names. There were certainly two outstanding individuals
who I hope and believe are still alive and well. Gary Felsenfeld is one. He was one of the co-chiefs of the Laboratory
of Molecular Biology. William Eaton, Bill Eaton, Chief of the Laboratory
of Chemical Physics. These are individuals who really should have
assumed that role to be the scientific director. And there are various versions of the story,
either they didn’t want it or the community was polarized, half saying “if he gets it. I’m…” The bottom line is that Phil Gorden approaches
me and says, will you take this position. Now I’m about 44 at this stage roughly and
here I will say two things. I’ll make the arrogant statement, which
is not intended that way. I knew, this was 1990, there would be a Nobel
Prize for G proteins and I would not win it [laughs], so perhaps I could contribute in
other ways. At the same time, going back- I’ll relate
an anecdote- to my internship interview at the Mass General, there were two committees
that interviewed the candidates, one headed by Alex Leaf and the other headed by the Vice
Chair of Medicine, a man named Dan Federman. Necessarily, I was interviewed by the Federman
committee because I had been in Leaf’s lab, so that was a conflict of interest. And at one point Federman says to me, “Do
you see yourself becoming Chair of Medicine one day?” And my response was, “Why? That would be a waste of time.” So I was immediately completely insensitive
to the fact this was an insult to him; that it implied that you know I have more important
things to do in terms of my research, etc. Of course the irony is I didn’t become a
chair of medicine, but look at the administrative things I took on. So I really didn’t want this position, but
ultimately I allowed my arm to be twisted. So I served as the intramural so-called scientific
director from fall of ‘90 through the fall of 1999. INTERVIEWER: And you came from the metabolic
diseases branch? SPIEGEL: Yes. These names were renamed. As I may have mentioned, Aurbach was tragically
killed in Charlottesville in ‘93 and at that point the branches were kind of condensed. There was no need for me to have a separate
branch. Also another figure to mention is Steve Marx. Steve Marx, I’m four years younger than
he is, and had been in the Aurbach lab some years before. He was at the Mass General for senior residency
and came back to the Aurbach lab. So he was in the lab about the time I was. He’s significant in a number of respects. I didn’t go into this but he excelled as a
physician scientist clinical investigator in the rarified context of the NIH. What I mean by rarified, on the one hand you
can work on rare diseases, on the other hand common diseases like primary hyperparathyroidism,
excessive activity of the parathyroid glands. This is a program which arguably represents
the best that the clinical center can do. It’s a credit to Aurbach who founded this
program. What it consisted of is being the magnet,
the mecca, for patients with primary hyperparathyroidism, the treatment for which is generally surgical. It’s removal of the offending gland or glands. And if the surgery failed either right off
the bat, calcium stayed high or recurred, these patients were very difficult to then
treat because there would be scarring in the neck. Where was the offending gland, what’s going
on? And so this is germane because we had this
bias of referral and we being the metabolic disease branch, a pioneering radiologist who
pioneered in the localization of the abnormal glands, the late John Doppman in the clinical
center, and then a succession of outstanding surgeons in the surgery branch of the NCI. Many of these surgeons have gone on to major
careers at other academic institutions right through to this day. So that kind of multidisciplinary collaboration
was benefiting the patients, benefiting the research. This is how Aurbach determined the sequence
of parathyroid hormone, human parathyroid hormone. But also this is where Steve Marx excelled. He began to recognize that many of the patients
that we were seeing had hereditary forms of hyperparathyroidism. And that’s significant because they are
very difficult to cure because instead of one single sporadic abnormal gland that had
become an adenoma, so called, they had hyperplasia. All four glands had a germ line defect, which
led to this hyperplasia. A disease he didn’t put on the map but really
described in its full flower is so-called familial hypocalciuric, hypercalcemia, FHH. And again the way these things all come together,
that turned out to be due to a loss of function mutation in the calcium sensing receptor,
which Ed Brown then discovered in ‘93. A lot of the work on FHH was done here by
our group in the clinical center. [music] SPIEGEL: On the one had the research that
I’m describing is ongoing. One of the non-conflicts of interest, but
clear benefits of being the intramural scientific director is not only can you, but you’re
expected to, continue research. So I’ll come back to that later. The issue really was- first I want to credit
two individuals, early on, a man named Ed Steers. Ed had been the Deputy Scientific Director
to Jesse Roth. He was a PhD who had worked with Chris Anfinsen,
in a famous lab, but had soured on research and had real administrative skill. And he’s the first example, which was replicated
a few times in my administrative career, of having an individual who was trusted by the
community, who had institutional memory and who I believe or deluded myself into thinking
wasn’t upstaged by my coming in and being their boss. So Ed and I had a terrific relationship. He was also a Lincoln buff, an expert. Until he retired, he was a crucial companion
to me in running the intramural program. The features of the intramural program that
were crystal clear is just the quality of the science and how outstanding it was. Now in my neck of the woods up in Manhattan
a key institution is Rockefeller University, replete with members of the National Academy,
a scattering of Nobel laureates, etc. But the NIDDK intramural program really was
right at that level. Anfinsen had won a Nobel Prize. Baruch Blumberg who had worked there had eventually
won the Nobel Prize, although he was at Fox Chase, Marty Rodbell, many National Academy
members and both in terms of basic molecular biology, chromatin structure, DNA recombination,
Marty Gellert, the three-dimensional structure of proteins, both by x-ray crystallography,
David Davies, and NMR— Ad Bax, Marius Clore, absolutely outstanding science. And some of the clinical branches were quite
good also. I alluded to our own branch, the diabetes
branch had a rich history, and so the program, even preserving its quality, but the challenges
were clear. We had the election of Bill Clinton and Al
Gore reinventing government. So we think sometimes, without getting into
political things, about Republicans cutting things back, we had to eliminate a whole series
of so-called FTEs, and that led to some interesting dancing to be able to accommodate that. There were always budget constraints. The issue of recruiting new individuals, particularly
the difficulty of recruiting physician scientists was quite challenging. And Jesse, for example, recruited away a man
named Alan Shuldiner from the diabetes branch. Alan Shuldiner is now Vice President for Genetics
at a company called Regeneron up in New York, a very successful company. He had been at the University of Maryland,
splitting away from Jesse, a theme that continues. But we managed to retain people like Mark
Reitman who, although had a brief period at Merck, did come back to NIDDK. The challenge of recruiting PhD scientists
however, was not as great a challenge again because salaries are lower, because the intramural
program was a terrific place to work, and we were able to recruit some outstanding individuals. The challenge of the Phoenix branch, with
the Pima Indians, the Arizona Republic was publishing articles about [the Pimas being]
“poked, prodded, what good are you doing.” So that was something that we were very cognizant
of. I remember going to Phoenix one July in 105-degree
weather to see what could be done in terms of certain things that needed to be rectified. Nonetheless, I don’t want to over-dramatize
the challenges, it was an enormous privilege and opportunity. And I discovered pretty early on that I had
arguably some knack for administration and leadership positions. And I would say the key thing is to realize
that it’s not about you, it’s really about everybody else that you’re serving. If you keep that in mind I think you can be
successful. [music] SPIEGEL: Phil was a source of wise counsel. He had been the Clinical Director coming out
of the diabetes branch then he became the Institute Director. I think that began in ‘86 if I’m not mistaken
and as you undoubtedly know he was the Institute Director until ‘99. We’ve enjoyed a close relationship over
the years. He and Vivian his spouse, we’re still friendly
with and get together on numerous occasions. There could have been some awkwardness in
my ending up replacing him and the circumstances, but he’s the kind of individual and I hope
I am too that that was far from the case. Back to intramural director, one of the challenges
was how best to reconfigure my own lab. We have the Board of Scientific Counselors
that would reviews all of the intramural labs on an ongoing basis and I used that opportunity,
and Phil was relevant to this, to begin to provide more independence for some of the
people like Bill Simonds, like Lee Weinstein, I’ve alluded to, so that their own careers
would be fostered. Again, you don’t have to stay [at NIH]. I had a fellow MD-PhD named Andy Schenker,
and I’ll give some illustrations to his work in a moment, who went off, first to academia
then industry and that’s a good thing, too. But there was a downsizing of the lab, but
to good effect. So I want to come back to the research theme
briefly touch on a few things during the scientific director phase because they were quite rewarding. One was work published in the New England
Journal with Andy Schenker as the first author with Lee Weinstein involved. This was really the flip side of the pseudo-hypoparathyroidism
study. It also shows the strength of the clinical
center and the intramural program. In the Child Health Institute in the Endocrine
Branch they were studying girls and boys with precocious puberty, the opposite of that in
the amenorrhea situation. There are many potential causes. But one cause is another Albright disease,
and that’s called the McCune-Albright Syndrome, a very perplexing disease. They had these cafe au lait so-called pigmented
spots. They can have bone lesions called fibrous
dysplasia, and they can have all kinds of endocrine over-activity, precocious puberty,
but also hyperthyroidism, growth hormone hyper secretion. And here, too, I speculated, and there was
some other work that was relevant to this, that an activating mutation in the same GS
G protein that stimulates cyclic AMP could lead to this phenotype, so called, but not
a germline activating mutation. Because the reasoning was if you inherit this
and it’s in every cell that may not be compatible with normal embryonic development. But if instead it occurs post-fertilization,
post-zygotic, you can get what’s called a mosaic and that term is now much more appreciated
than it was before. And indeed, this was the first example of
a G protein disease that was due to this kind of mutation in a mosaic distribution. That’s why the skin lesions would be on
one part of the body, the fibrous dysplasia. This was important. There are other examples. There is another G protein, which is mutated
and causes uveal melanoma. This is the disease that Oliver Sacks died
from actually, metastatic to the liver. There are other syndromes you’ll see sometimes
kids with this huge hemangioma, Sturge-Weber Syndrome etc. That’s a mosaic activating G-11 mutation. This was very important work. It actually spun off into the Dental Institute
with Mike Collins and Pam Robey working on the bone disease. And he’s really picked that up and run with
it and is doing a lot of terrific work in that area. So that was one example of a project. The other one comes back to Steve Marx. We, in addition to the FHH, we had many families
with other forms of inherited hyperparathyroidism. One of them, so called familial isolated hyperparathyroidism,
that was the only genetic component, has only in the last few years had a mutation described
by Sunita Agarwal, it’s a so called transcription factor, GCM-2, which is unusual because it’s
an activating transcription factor and it’s inherited and causes these parathyroid tumors. The main one of interest to us was multiple
endocrine neoplasia type 1. There is a type 2; we weren’t dealing with
that. This is anterior pituitary, pancreatic islet
and parathyroid tumors. That’s the dominant phenotype. And we had many many families with these. Steve Marx was doing the clinical characterization. And a paper in the New England Journal by
Eitan Friedman, an Israeli fellow working with me at that time, was able to show that
a locus on the long arm of chromosome 11, 11q13, where a lab in Sweden at the Karolinska
Institute had described a putative tumor suppressor gene as lost. So this is the so-called Knudson two-hit hypothesis. It’s true of retinoblastoma, it’s true
of other tumor suppressor genes. You inherit one bad copy. Now in the BRCA1 and 2 example, those tumor
suppressors, that’s it. You just inherit that one bad copy and you’re
off getting breast and/or ovarian cancer. In this case, you inherit one bad copy, it’s
in every cell, and then you lose somatically the second good copy in some cell like a parathyroid
cell or islet cell, and then you get an endocrine tumor. That led to a hunt for what this gene was. We only knew the chromosomal localizations. This is called positional cloning and there
was a big European consortium that formed to try to find this gene. And at this point, Bernadine Healy fired Jim
Watson, or they parted ways. She was the NIH Director, he was the head
of the Genome Center. She recruited Francis Collins from Michigan,
and this is circa ‘93. So I’m still Scientific Director. So Francis’s terms of coming to the NIH
was he had to have an intramural program. The Genome Center did not have an intramural
program. She gave him Building 49 where he recruited
an intramural program. And Francis was known as one of the masters
of positional cloning. I met with him early on. I said, “You know we can do this together. We’ve got all this patient material, you
know how to do the positional cloning.” We quickly scoped out that the European Consortium
hadn’t made much progress. And the usual story was this would take a
graduate student two weeks now, but it took four years until ‘97. This was a gratifying, multi-disciplinary
NIH intramural collaboration with Cancer Institute, our branch, the Genome, NCBI for Informatics. So we found this tumor suppressor gene [the
MEN1 gene]. We called it Menin and that led not yet to
cures for the disease, but it certainly led to possibilities of early diagnosis. You have a 50-50 chance of inheriting it from
an affected parent. So if you are negative you don’t have to
be screened [clinically monitored] all the time. It’s had beneficial effects, plus it turns
out to be a fascinating protein with very unusual biology and not in the cell membrane,
in the nucleus. So I knew this is not an area of our own great
expertise. We would have these weekly data meetings. He [Collins] made a terrific comment, at an
early meeting, we saw the protein and it didn’t look like anything else in the database. It was not part of a gene family. He said “at least it’s not in the middle
of a pathway that David Baltimore is studying,” and that had a certain significance. So the upshot is two different groups, one
at Stanford, one at Dana-Farber later managed to scoop us and find out what this gene really
does. It’s involved in chromatin regulation, so-called
epigenetics. And Sunita Agarwal announced- Steve Marx moved
on and is semi-retired, but she continues intensively working on it, particularly on
the pancreatic islet and is making some progress as are other labs around the world. One other example, Bill Simonds was involved
with a different group at the Genome Center. He had another one of these diseases we were
seeing called hyperparathyroidism jaw tumor syndrome, and they found that gene, another
tumor suppressor gene. What you get from this is the richness of
the research that can be done, the collaborations across different institutes in the intramural
program, the clinical center as such a major resource. And I think that’s the present challenge,
to really take full advantage of the clinical center as a resource. I’ve consulted on that in a variety of ways
over the years. [music] Fast forward to the spring of ‘99, and it
becomes apparent that Harold Varmus, the then NIH Director is determined to appoint a new
NIDDK Director. There is a search and I’m the only internal
candidate, and at this point I’m thinking to myself I’ve been at the NIH a long time,
and candidly, I had looked over the years at very few positions. I had looked at other positions from time
to time, but it was very rare. And again not out of spite or whatever, but
I thought probably if I’m not selected this is a time to move on. Harold calls me into his office, and I’m going
to say this flat out, in June of ‘99, and I was about to go off to an international
meeting on the different inherited endocrine neoplasias, and Harold says, “Allen, because
I think so much of you I want to let you know that I’m going to give the job to Person
X, who was one of the other three choices.” “Harold, thank you very much.” Fast forward to September of that year when
he called and said, “I would like you to take the position.” At this stage I was already- this was not
like the scientific director position- I was heavily involved in the institute and in an
administrative responsibility. I was under no illusion; this was going to
be very different, a different kind of challenge, but I hoped that I would rise to that. So I accepted it with equanimity and took
over just a few months before Varmus left to go to head Memorial Sloan Kettering in
NYC. I find it amusing that when I came to Einstein
in the summer of ‘06 as Dean, Harold invited me to tour Memorial and have lunch, maybe
making up for the short time we had spent together. But he and I are very friendly. We see each other at the New York Genome Center. In any event, now- the challenges of taking
over as NIDDK Director were really considerable. First, I’m not a diabetologist. I’m an endocrinologist in the calcium field. But it isn’t just a question of a diabetologist. What about digestive diseases, what about
kidney diseases, even some hematologic diseases, kidney, urolog, hematology… urology! Here too I want to credit individuals who
were so helpful to me. I will say that I replaced- so there are three
divisions that are very important: diabetes endocrine metabolism division, digestive disease
nutrition division, and kidney, urology, hematology, the latter headed by Josie Briggs, outstanding
nephrologist and it was a pleasure and always interesting working with her, very stimulating,
and she’s gone on to different things. She was at Hughes for a period of time. She then was the head of the NCAAM, as it
was at that time. She’s now semi-retired, or editing a Kidney
Journal. In digestive disease and nutrition, it was
Jay Hoofnagle, a major figure in clinical hepatology and clinical trials. As he stepped back, Steve James was recruited. In diabetes and endocrine metabolism I’m
going to be fairly graphic. I’ll try to be measured in my words. There was a very unfortunate episode which
really had an impact on the Institute and on that division and its division director,
and it was one of the most important clinical trials, the DPP, Diabetes Prevention Program. There had been multiple arms to that trial,
a control arm (usual care), this is prevention of type 2 diabetes in roughly 3,400 individuals
at high-risk because they had impaired glucose tolerance but not frank diabetes. One arm was a lifestyle intensive intervention,
another was Metformin. But another was the first of the thiazolidinedione
drugs, Troglitazone, and that drug turned out to have idiosyncratic liver toxicity,
leading to deaths and need for liver transplantation, and it involved at least a couple of people
in the trial arm. It turns out the then division director was
getting honoraria for speakers engagements from the company that made Troglitazone. A Pulitzer Prize winning reporter, David Wilman
from the L.A. Times, won the Pulitzer Prize for his reporting around what happened with
this drug, primarily involving the FDA, the drug company, an academic investigator at
UCSD, but also touching on our division director. And this is one of the really difficult and
challenging things about administration always. I always say I don’t relish wielding power
for power’s sake or saying you’re fired etc., although I don’t shrink, it’s not
a question of personal confrontation, it’s recognizing that there is hopefully some higher
good, there’s integrity and you have to take responsibility. And I said to this individual, “This is
injurious to the Institute, it’s injurious to you.” And so he left. He went to the west coast to a glucose monitoring
company. And I appointed an internal candidate, Judy
Fradkin, who has just retired, just stepped down, really outstanding individual. And I had great confidence that she would
lead that very important division with its clinical trials and basic research. She herself, she’d come as a clinical associate
to what was the clinical endocrine branch working in thyroid. She would attend at Bethesda Naval when it
was Bethesda Naval (now Walter Reed Medical Center). I really respected her judgment and her wisdom,
and that turned out to be well served. These individuals, Barbara Merchant, who had
been my administrative director in the intramural program, eventually became the executive officer,
replacing Earl Laurence. I had Griff Rodgers (current Director of NIDDK)
as my selection to be Deputy Director. And that was a gratifying opportunity to work
with him. I think my trust in him has been well vindicated,
all of these individuals. This period of time, from ‘99 to March of
2006, there are many important highlights. I have already alluded to the DPP. This was arguably one of the most important
clinical trials. There were many important clinical trials
in kidney, the ASK study and hemo, and many others in digestive disease and nutrition. It’s a measure of the progress that’s
made and there really is progress made. The HALT-C trial was a trial administered
by Jay Hoofnagle, multiple centers around the country for treatment of hepatitis C with
Ribavirin and Interferon gamma, and both miserable drugs, both only partially effective in treating
the disease, and look how far we’ve come, but that was the best we had to offer at that
stage. And now you can cure this disease in a matter
of weeks and it’s arguably cost effective. But in the diabetes arena, the DPP was really
so important for multiple reasons. In August of 2001, the Data Safety Monitoring
Board made the determination that the trial should be ended early and the rationale was
that it turned out that the lifestyle intervention unequivocally was effective. The Troglitazone had been stopped and those
patients were just followed. And this has really flowered. There has been an ongoing outcome study of
DPP. In fact, the book is right here, “The Prevention
Outcome Study: Celebrating 20 Years.” There are Medicare approved prevention programs
at Ys around the country and churches, and other places. And one can make a strong case that this is
cost effective. Sadly, as I now know, in my new guise, I’m
taking on additional responsibility at things like the Research Foundation of the American
Diabetes Association (ADA) and that was part of the reason I was just at the meetings. Even though we’ve made tremendous progress
in both Type 1 and Type 2 diabetes, a lot of it through work supported by the Institute,
we still don’t have a cure for Type 1, we still don’t know what the actual environmental
trigger is for Type 1, or triggers. In the case of Type 2, we’re still fighting
this extraordinary tide of the obesity epidemic, which then turns into a Type 2 epidemic, and
the huge disparities involved. But the DPP has made a measurable difference
and there are other examples there. So that trial was ended early and then has
led to the follow-ons that I described. In the case of Type 1, when I came in as the
Institute Director there had been special legislation outside of the NIH budget for
$30 million of so called Type 1 money that the Institute administered. We had the opportunity through the advocacy
of the Juvenile Diabetes Research Foundation and the ADA to increase that amount, and we
seized that, and it was up to $150 million a year. And that still survives amazingly enough to
this day, and that gave us the opportunity with Judy and others in the community to all
sorts of new initiatives that we couldn’t do otherwise— TEDDY, for example, the environmental
determinants of diabetes in the young. If you think about it, we know that there
are genetic determinants, and we know what several of them are, of Type 1 diabetes. But monozygotic twins are still discordant
in a significant percentage. So we know that there’s some environmental
trigger or triggers, and if we could just know what that is, there might be a way of
avoiding it or if it’s a virus, vaccinating against it. And that’s what TEDDY is trying to do. They’ve made significant progress. There have just been reports, first from Australia,
now from the U.S. There’s a Rotavirus vaccine and it appears
that kids who have been vaccinated with the Rotavirus vaccine have a much lower incidence
of Type 1 diabetes. It’s an enteric virus. These have long been suspected to be a possible
trigger. And as far as a cure for Type 1, this brings
me into another major theme of my period as the NIDDK Director. There are always things coming out of left
field that you didn’t seek or couldn’t prepare for, and that’s the human embryonic
stem cell controversy. At one level it seems so old hat because we
have to work of Yamanaka and others, induced pluripotent stem cells, etc. But this was a huge issue at the time. An investigator named Jamie Thompson at the
University of Wisconsin first showed in human cells that they could derive from embryos,
inner cell mass, the human embryonic pluripotent stem cells. It was said there were a hundred thousand
frozen embryos from IVF, why not take advantage of that and do the research, which excited
lots of people. This was one of the few examples where the
huge bipartisan support for NIH, in Congress, which continues to this day as measured by
the increases in the budget, notwithstanding anything the administration proposes, which
we can’t take for granted and has been enormously helpful. But this was one issue which split along the
usual lines. Little did people know, people seemed to be
quite oblivious of the fact that even though, as we’ll get to, federal funding for derivation
of human embryonic stem cells lines was forbidden, the so-called Dickey-Wicker Amendment, Jay
Dickey, Arkansas, Roger Wicker, Mississippi, then in the House, now I think still in the
Senate. Fetal tissue research was going on and was
funded- for Parkinson’s, for other kinds of diseases, and it’s only now that that’s
surfaced again as an issue. It’s been banned in the intramural program
and they stopped a contract at UCSF. The way this transpired, Varmus was very supportive
of funding human embryonic stem cell research, but he left to Memorial. You had Ruth Kirschstein as the Acting NIH
Director, she had been Deputy, and you had this controversy, which was front page at
the New York Times, day after day etc. There were two areas that were front and center,
spinal cord injury and Parkinson’s disease, hence NINDS. At the time, Gerry Fischbach was the Director
of NINDS. And Type 1 diabetes. I made the mistake at my first Senate hearing
for the appropriations- so we always testify at appropriations hearings and this would
have been April of 2000 Senator Tom Harkin, poses questions planted by the JDRF among
others, about how can we do pancreatic islet transplantation. Because in Edmonton, Alberta, Canada they
developed a new protocol for islet transplantation, which they get from cadaveric pancreases and
it seemed to work. There would never be enough pancreases to
be able to fulfill the need, hence the need to turn human embryonic stem cells into pancreatic
islet beta cells. So I answered those questions and apparently
the audition worked because I ended up testifying before Specter and Harkin, usually along with
Fischbach on probably half a dozen occasions, either at standalone meetings- sometimes with
Christopher Reeve as a witness and others. I remember Senator Sam Brownback who was a
senator then before his somewhat questionable period as Governor of Kansas etc. These are very challenging hearings because
you’re part of the administration Executive Branch, but you have people like Senator Specter
telling you in no uncertain terms that human embryonic stem cells may be a “veritable
fountain of youth.” And I would tell his chief aide, “Tell him
to lose that language.” [laughs] That is not necessarily helpful. But this culminated in an appearance, August
9, 2001, in the Oval Office, one of a series of meetings that President George W Bush 43,
had for “advice” about what NIH should do about funding human embryonic stem cell
research. So it was I, the then-Head of the Office of
Science Policy, Lana Skirboll, and a true stem cell researcher from the Intramural neurology
Program, Ron McKay, who was working on creating dopamine secreting cells for Parkinson’s
disease. I was there really at the request of the JDRF
to talk about the pancreatic islet situation. And in retrospect, this was clearly a charade. I believe that they had made their decision
and they were using us partially as “cover.” In addition to the President there was Karl
Rove, remember him, and Andrew Card, the Chief of Staff. And I felt gratified, when after showing my
printed Powerpoints to the President, he said, “Now I can see why these JDRF folks are
so cranked up about this.” So I felt I had somehow gotten the message
through. But then a voice over my shoulder, Karl Rove
says, “What about porcine islets?” I’m a little taken aback and I’m going
to talk about porcine endogenous retro viruses. Before I can say anything, the President turns
to Rove and says, “Porcine, back in Texas, you would have said pig.” What was amazing is that he knew what the
porcine means. And you know most, shall I say, elected officials
have the gift of making you feel that they’re very nice people, and he certainly did. He’s modest, self-deprecating. When he got the NIH stem cell primer, he said,
“This is perfect for me, you know, a C student.” It was a 45-minute meeting, but as I say in
retrospect, as the meeting closes, he escorts us out and says to the Vice President with
whom he is about to have lunch, “Dick, come and meet these nice folks from the NIH.” These things are emblazoned in your mind. It’s hard to forget. But about a week later, August 9, so that
was August 2, at 9 p.m., from Crawford, Texas, he gives a speech saying that they will allow
funding of the existing stem cell lines, but not of any new or derivation of any lines. Then he has a press conference on the porch
of the ranch, apparently, on August 10th, and the reporters say, “Are there enough
lines to do research on?” And he says, “Sure there are.” He says, “The NIH walked into the Oval Office
and looked me in the eye,” so he anthropomorphized us, and says, “Yes there were.” That continued apace in the various hearings. So where are we now? Sad to say even with the California Institute
for Regenerative Medicine, which was a $3 billion proposition 71 bond initiative, which
was largely funded because of the concerns about NIH limitations on research and certainly
funded major programs, including in industry on creating pancreatic islet beta cells, and
there are clinical trials, it’s still not ready for prime time. Doug Melton at Harvard University, Cambridge,
not the medical school, and this is public knowledge, who has two kids with Type 1 diabetes,
he’s a premier developmental biologist, has devoted his lab to try to make beta cells,
has spun off a company, Semma Therapeutics, which appears to be making progress. So there is progress, but not yet a cure. Even if you can get authentic glucose responsive
beta cells to transplant you will need to find some way to prevent the autoimmune process
from destroying those, micro encapsulation, etc. The Edmonton Protocol which led to that first
Senate hearing, sadly it turned out that after a few years those islets which we typically
injected to embed in the liver, petered out for any number of reasons, including the immunosuppressive
medications. Just as an aside, I should come back to this. During the intramural director phase, I learned
of two individuals at Bethesda Naval, as it was at that time, doing their payback to the
military for their medical school training. Allan Kirk, a surgeon, scientist, MD-PhD,
and David Harlan, a diabetologist, I was able to recruit those two individuals and establish
a transplant branch at NIDDK. Varmus was pleased because we opened up a
“mothballed” ward in the clinical center at the old Building 10, and that really went
well for some time. Kirk was doing kidney transplants using immune
tolerance protocols, the Holy Grail, so that you don’t need immunosuppressant medication. He’s gone on to be Chair of Surgery at Duke,
currently. Harlan is currently at the Diabetes Center
at UMass. During that period of time they did six islet
transplants and they were successful in the short term. We had visiting congressional delegations. One of the women [islet recipients] was brought
forward and to my consternation she started lifting her sweater. She was wearing a t-shirt with islets on it,
saying, “Kiss my islets.” It was interesting. [music] This period of time, toward the end of it,
I felt for a variety of reasons that I should really move on. It was going to be 33 years in ‘06 at the
NIH. There was a peculiar reason, again I’m letting
it all hang out- that same David Wilman guy from the L.A. Times, he reemerged to do an
exposé in- I’m thinking roughly 2003, thereabouts, when Elias Zerhouni is the NIH director and
gets blindsided by this, about conflicts of interest in the intramural program. Some were truly atrocious examples in the
Mental Health Institute, one or two others. Again I’m not saying we’re holier than
thou, nothing involving NIDDK at all. But you know, you would from time to time
encounter people, and this is so counter-productive, who if you work for the NIH, from the federal
government think you’re a federal bureaucrat. First of all, what’s wrong with being a
federal bureaucrat? Look what’s happening at the Department
of Agriculture now? Beyond that, you know Senator Specter, at
the end of a hearing he would always say, “Rush back to your labs at NIH and continue
the important work you’re doing.” So he had real respect. The upshot is on top of it, accused of being
venal and these things, and again that didn’t sit well with me. Be it as it may, I did start looking at some
positions. One dumb maneuver was to look at the Presidency
of the University of Medicine and Dentistry in New Jersey, which I did make the mistake
of going for a second visit. There was a Newark Star Ledger piece, which
fortunately didn’t mention my name, but said the choice came down to two people, some
guy who they eventually picked who was in New Jersey or the Director of NIDDK. The place was rife with corruption, top to
bottom. Several people were indicted, imprisoned for
Medicare fraud, etc. And fortunately they’ve completely restructured
that place, made it part of Rutgers, as they should do. Long story short, the position at Einstein
came open and I was encouraged by several people to look at that position as Dean, one
of whom was an alumnus of our liver disease section, Allan Wolkoff, who’s still at Einstein. Another is a fellow named Rossetti, who was
the head of the Diabetes Center, who I would encounter at diabetes meetings. There was the nostalgia of having worked in
the Einstein lab. Sentimentality only goes so far. The campus is in the Bronx. It’s separate from the rest of the university. Outstanding in terms of research; it had been
remarkably- even after its founding in ‘55, within a few years. We just celebrated another prize for a long
time Einstein faculty member, Susan Horowitz, who was the person responsible largely for
bringing Taxol as a chemotherapeutic based on her basic studies of mechanism of action,
for breast and ovarian cancer. So phenomenal science there, but clearly it
had fallen down over the years. My predecessor was one of the giant founders
of neuroscience, Dom Purpura had been the Dean for 22 years, arguably too long for anyone,
but he had done remarkable things. I saw an opportunity and did seize that opportunity. You’re pretty much a lame duck at NIH once
you declare you’re applying for an extramural position. So by March of ‘06, even though I didn’t
take over officially until June 1st, I took the shuttle up on a Sunday night and my wife
was still at the World Bank. For the first four months I lived in our student
housing on campus. We have three high rises. In a way it’s a manipulative thing to do. It has a certain cosmetic appearance, but
why should we spend extra money for a hotel room or an apartment, and this was right on
campus. At this point I’m going to defer to you
and see what else needs to be said. Let me just say that was itself a very challenging
period. The financial crisis turned out to have a
huge impact on Einstein in particular and other factors that one couldn’t imagine. At the same time, extremely rewarding and
I initially intended that this might be a ten-year thing. By then I’d be the ripe age of 70. But for a variety of reasons, we, by the fall
of 2015, completely reconfigured the medical school so that the fiscal and legal obligation
for the school went from Yeshiva University to Montefiore Health System, which is not
only our affiliate, but our major affiliate. I fostered from the get-go a much stronger
relationship with them realizing that was going to be central to our success and that
has culminated in May 24th, the commencement, for the first time, we granted our own degrees. I managed to get with a lot of help through
all the various accreditation, things necessary for us to get independent degree granting. We are structurally a medical school like
Sinai, that is a medical school not part of a university, but within a health system,
and that’s turned out to be, hopefully will be successful in the years to come, and my
successor who took over in July of ‘18. So in ‘17, I said I want a year and then
I’ll step down. Gordon Tomaselli is an Einstein alumnus, Class
of ‘82, was the Chief of the Cardiology Division at Hopkins, outstanding individual. I have every reason to believe he’ll be
successful. I wish him every success. What I’ve done is stepped into a part time
position on the Einstein faculty with an office way away from the Dean’s floor, where I
can serve as a mentor for MD-PhD students and still teach in some of our courses, which
I had done to a degree. I’ve never been the clinician, but I do
come to some of our endocrine clinics in Montefiore and even Jacobi. Then I can spend part of my time at the NIH
as a special volunteer, and then other pro bono things like the American Diabetes Association. So that’s the story. [music] SPIEGEL: I’m guilty on multiple occasions,
both in terms of swimming, to the extent that I was an inveterate lap swimmer for a period
of time, playing tennis. I don’t take lessons. I have atrocious form and just do it to the
best of my ability, which means you may be successful to a degree. Eitan Friedman, whom I mentioned in the study
in the New England Journal and MEN-1, was an Olympic caliber swimmer in Israel, and
tried once to show me what to do. I said, “Eitan, I’m just trying to get
exercise.” Then I got to meet Gary Hall, Jr., who turned
out to have Type 1 diabetes at the age of 25, but nonetheless managed to win the 50-meter
sprint in Sydney, in the Olympics. I met him at an ADA dinner, and I remember
I said to him, “I’m an addicted lap swimmer, but I don’t do flip turns.” And he says, “Flip turns are over-rated.” Only then did I realize in the 50-meter sprint
you don’t do any turn, you just go. I’ve arguably made the mistake of not reading
managementese books. Barbara Merchant did buy me a book once, Who
Moved My Cheese? So out of respect to her, I read it. I’ve relied first on my own personal sense
of integrity. I am a terrible liar. On the other hand, I think I can be persuasive,
but only if I have true conviction in what I’m saying. I think Griff told me this, Billy Tauzin,
who was a representative from Louisiana and then became head of the Pharma Association;
he talked about how you can be successful in Louisiana politics. It’s all about sincerity. If you can fake that you’ve got it made. I can’t. For me, certain intrinsic things, a sense
of mission, and I’ll come back now in a hopefully not maudlin way, to my background. You had a sense that if your parents are alive
and they’re here, you have some reasons to be dedicated. I always get somewhat emotional at this part
because you just can’t take that for granted. So hopefully you can contribute and be useful
in some way. At the same time trying to be a judge of other
individuals who are relying on other people, best and brightest, that is managementese,
surrounding yourself with them, giving them responsibility but holding them accountable. Running NIDDK as the Director, I didn’t
sufficiently go into this. I focused on the trials, I focused on some
staff, I focused on embryonic stem cells, but this was an enormous learning experience
for me. First of all, it went from intensively reading
literature in a very, very focused area to being spread over this huge landscape, diabetes,
digestive, kidney, urology, hematology, etc., and I took that very seriously. You can’t be the master of all those areas. Learning about epidemiology and public health,
being the Chair of something bureaucratic sounding, the Diabetes Mellitus Interagency
Coordinating Committee, the various federal agencies, private sector, Kaiser Health, VA,
etc. that were involved there. The Diabetes Education Program, Josie had
us start a National Kidney Disease Education program. It was a huge growth experience for me and
that was very broadening. That’s one point. Another point, and this is going to seem very
strange, Einstein, before our being part of Montefiore, and the significance there is
if you’re a research intensive medical school, that’s always a money losing proposition. Bob Alpern was the Dean at UT Southwestern
then just recently stepped down as the Dean at Yale, a distinguished nephrologist, he
was on my National Advisory Council. He would complain in open session, “For
every dollar you, NIH, give me, it costs me…,”despite the indirects. I was very glib, “so don’t take it.” That’s still a right answer because if you’re
a research intensive medical school that’s your mission. So how do you make up those deficits? Cross coverage from clinical revenue. You need to be part of a clinical enterprise
and if you’re fortunate, philanthropy. Medical school tuition, that doesn’t do
it. That sits on its own bottom. It typically doesn’t lose money, but it
sits on its own bottom. As far as philanthropy is concerned, that
was crucial for Einstein. I had done my due diligence. We had a significant endowment before the
fiscal meltdown and that gives you from the endowment payout, in our case, arguably with
a billion at a five percent level. You can do the math. The upshot is you need heavy duty philanthropy. As the NIDDK Director, one of the things that
I was doing was giving talks at various places like Mary Tyler Moore’s apartment when she
lived on 5th Avenue, helped her promote the stem cell theme. The home of Edsel Ford in Michigan, because
of the ADA, the Modells, who were involved in the Crohn’s Colitis Foundation of “Gotta
Go to Mo’s.” So here you are interacting with these folks
who are of substantial means and you’re there as the NIDDK Director there being part
of advocacy groups. That gave me the sense, and this comes back
to the “sincerity” piece that I would be able to raise money and interact with these
folks since if I have the conviction of what I’m asking for. We were able over a ten-year period, and there
were definite hiccups here having to do with the fiscal meltdown, to raise about $500 million
and some very substantial gifts from some mega-wealthy donors. Others, we had a faculty member at Einstein
who was the most modest individual, taught the anatomy course, lived in the Bronx, had
no family, and sadly when he died, I remember visiting him in the hospice setting, he left
$8 million for scholarships to the medical students. That was, on the one hand, in some ways, guided
by some experience I had as an institute director, but taking it to a different level and dealing
with a board. Here dealing with an actual Advisory Council,
it’s a kind of board that you’re accountable. The Board at Einstein is a different kind
of board, made up of often super wealthy individuals, mostly men, but not exclusively. The chairperson of our board for seven years
in my tenure was a woman named Ruth Gottesman, a doctorate from Columbia Teacher’s College,
one of the most remarkable individuals. I was fortunate to have lunch with her this
past Saturday. We’re still quite friendly. She was actually on the Einstein faculty with
founding the Center for Adult Literacy as part of one of the programs that we have. She’s an individual of exceptional wealth,
but an exceptionally kind and motivated individual. I took a leaf out of her book. She would take the express bus from the Upper
East Side to the Bronx. I was always embarrassed when I came as Dean,
having my own car and driver. I soon realized that was necessary. I wasn’t used to that. Richard Hodes and I would take the Metro down
to the Senate hearings. Now I take the express bus most of the time,
even though I have parking space. There was a lot in this experience broadening
my overall, and now when you’re a Dean it’s things like HIV, which I wasn’t responsible
for, suddenly responsible for everything. Very necessarily superficial, but I think
it was very formative, very helpful. [music]

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