Dr. Ira Pastan and Dr. Michael Gottesman — Cancer Immunotoxins and Multidrug Resistance

Tuesday, September 10, 2019

This episode features two legends of biomedical research. In the realm of human health and longevity, cancer’s ability to mutate, grow, and thwart the body’s natural defenses presents one of the greatest scientific challenges of our time. In 2001, Dr. Ira Pastan led the creation of a new type of cancer drug, a recombinant immunotoxin, that promised to directly target and kill cancer cells. After years of research and clinical trials, this first-generation immunotoxin was approved by the FDA in September 2018 for certain adults with hairy cell leukemia, providing a promising new therapy to a group of patients who previously had few other options.

And we have a special guest host for this episode, Dr. Michael Gottesman, who, as the NIH Deputy Director for Intramural Research, leads the thousands of researchers and clinicians working within the IRP each day — while also conducting groundbreaking research in his own laboratory into how cancer cells become resistant to chemotherapy and other anti-cancer drugs. Drs. Gottesman and Pastan are two guiding lights in our quest to overcome the obstacles to effectively treating cancer in order to improve and save potentially millions of lives. As friends and colleagues for many years, they also trained and collaborated with several of the most celebrated IRP researchers who made extraordinary breakthroughs for human health.

Ira Pastan, M.D., is a NIH Distinguished Investigator and leads the Laboratory of Molecular Biology in the Center for Cancer Research (CCR) at the NIH’s National Cancer Institute (NCI). Michael Gottesman, M.D., leads the NCI CCR’s Laboratory of Cell Biology and also serves as the NIH’s Deputy Director for Intramural Research.

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>> So, for many years, we would spend every Thursday afternoon together at a lab meeting, maybe for 15 years.

>> Right.

>> A long time. So, here we are again on a Thursday afternoon.

>> That's true. That's true, but the Thursday afternoon meeting started a little later I think.

>> Yes.

>> And I still have Thursday afternoon meetings. So, right from here, I go to my lab meeting. I didn't realize that was ingrained, so interesting.

>> Yes.

>> Ira, first of all, it's just a pleasure to talk to you about your time at the NIH, and I just wanted to get a sense about the odyssey that you've gone through in getting to the work you're doing now on treating cancer with immunotoxins. And if you look at your own career, obviously, you've made major contributions in multiple areas, microbial physiology, receptor biology, drug resistance in cancer, and, more recently, in cancer therapy. You started out as a clinical endocrinologist and interested in endocrinology.

>> Yes.

>> How did you traverse all those different fields?

>> Like many things in life, a lot of it is serendipity. I was a medical student at Tufts Medical School in my first year and was trying to figure out what I should do that summer after my first year and I had an advisor, Bill VanderLaan. At that time, advisors were proforma. You were given the name of advisor, most people probably never met their advisor. But I thought I'd go ask Bill VanderLaan for some advice. So, I made an appointment and I went to see him and told him I was looking for something medically related to do in the summer, maybe work in a hospital, moving around carts, I really didn't know. They did not have a formal program for medical students then in the first year. And he said, let me think, which meant, I don't know who you are, and I don't know your capabilities. So, he looked up my grades and he saw I had good grades, so he said, well, why don't you come work with me? I have a spot in the laboratory of a senior investigator, Dr. Astwood. Ted Astwood, who is now dead, was a famous endocrinologist, discovered antithyroid drugs, and was editor of Endocrinology for many years and so on. And so, I said, okay, that's what I'll do. So, the first summer, I went and worked for Bill in this lab. My project was actually a project he had worked on as a medical student with Hastings at Harvard that he couldn't solve. He was trying to figure out when iodide negatively charged goes into the thyroid, does chloride negatively charged come out or does something with a positive charge go in with it? Turns out, it was later shown by Jan Wolff that potassium goes in with it. But that was my project. It was exciting to be in the lab, but I was totally unsupervised, and that worried me. So, I'm a little bit hands-on with people sometimes, younger people, because I appreciate how they may need some help. And then Bill left, and Astwood allowed me to stay on as a student. In summers, he supported me I think with money he got from NIH for the second animal keeper, which he didn't have or something, and I worked in his lab on problems. I continued to work on the same project, but it required going to a slaughterhouse in Charlestown to get thyroids to bring back to the lab and study. And in the middle of the summer, the slaughterhouse went on strike and I had no project. And in the lab, the one thing we had, that most people did not have, was radioactive iodide. It was just newly available for research, so I began to think of things I could do with radioactive iodide. Astwood was working on ACTH and other things, he just let me work alone. So, I began to work with radioactive iodide. So, I did two experiments. One, I was looking at iodide transport in the placenta. And that is this famous story about the hurricane. I was doing an experiment in guinea pigs, and there was a bad storm that turned out to be a hurricane, and I had to finish my experiment, so I was on the T, and there I went to the lab, and I was the only one there. And I can't remember what I did, but I did something went home. But based on that, I got a reputation of really being serious about research. That project didn't turn into anything publishable, but a second project did in which I looked at iodide transport in the small intestine. And then I finished medical school, then I went to New Haven. I went to New Haven partly because Dr. Peters, who had written a textbook in physiological medicine, Peters and Van Slyke, on measuring things in the blood because as you remember then we couldn't measure much in the blood, we had just a few techniques. He was there, and I wanted to work with him. And I went to Yale to work with Peters. Unfortunately, Peters died before I got to Yale, but I did work in the endocrine group there. And two years later, I was off to NIH as part of the program of what we euphemistically call ‘yellow berets,’ a program that medical physicians could come to work at this new research institution, NIH, instead of going into the army, although I did have an opportunity to go work at Walter Reed.

>> Did you imagine that would be a permanent move or that you would just be spending a couple of years of the training there?

>> I imagined I'd come here for two years, and Linda wanted to go back to Boston, maybe New York. I wasn't clear how the system worked and if I finished my residency training what I would do. I just came here thinking, well, two years, see what happens. And I fell in love with the institution, and the culture, and the opportunity to do research. So, I joined a group led by Ed Rall, your predecessor. It was a thyroid group, fairly newly assembled, with people from around the country, maybe six or seven people. And each person had a thyroid project. Rall and Robbins looked at thyroid hormone in the blood, Jan Wolff was looking at iodide transport, which I had worked on in medical school. Harold Edelhoch was working thyroglobulin structure, and so on. And I looked around for a project, an original project. And the only project I could think of was how thyroid stimulating hormone regulated the thyroid; nobody was working on that. And around the corner, there was a protein chemist named Bob Bates, and he had purified, a partially purified, thyroid stimulating hormone, which he did give me, so there I was. I had a hormone that regulated thyroid function, and I began to work on that with a senior person named Jim Field. Jim was interested in glucose metabolism and the hexose monophosphate pathway, and I began to look at whether thyroid stimulating hormone, when added to the thyroid slices, at that time mostly from dogs, that I got from Gene Braunwald's lab. Braunwald was doing a lot of cardio — physiology of the heart, and they didn't need the thyroid. And when they were finished with their dog, I could have the thyroid. So a lot of the early work I did was with dog thyroid. And we found that thyroid stimulating hormone activated the hexose monophosphate pathway, but the most striking thing was it happened really fast. You can almost extrapolate back to time zero. You were putting on the peptide hormone, this big protein was getting to the cell, and you were getting this huge response. So, I realized, you know, that it might be pretty close to the initiating event. At that time, no one knew whether -- there were no receptors identified for peptide hormones. People speculated they might get into the cell to work or something, but we made that observation. I then took out two years and decided I needed to know biochemistry, and I worked with Earl Stadtman for two years. And I must say in those two years, I kind of learned how to do research, how to formulate a question, how to critically evaluate it, how to gather arguments against, which, you know, to test it and so on. And then I came back as a full time person in the Clinical Endocrinology Branch and began to work on thyroid stimulating hormone. And around that time, Jesse Roth arrived. He had worked with Saul Berson on iodinated hormones and could measure — could iodinate and insulin ACTH and measure their binding to antibodies. And we adapted that methodology to measure binding to the cells. So, I began to work with Jesse on polypeptide hormones binding to cells to see if we can understand the first step in hormone action. I also, at the same time, I was interested in thyroid stimulating hormone. Earl Sutherland made his discoveries of cyclic AMP and glucagon catecholamines activated adenylate cyclase. And I said, well, probably TSH is activating adenylate cyclase in the thyroid, and that is it’s transmitting the signal from the outside of the cell and crossing into the inside cell.

>>But there were no cell surface receptors…

>>None identified. It was going to bind and activate adenylate cyclase, and so we could show there was binding, the binding was saturable, competitive, and so on, but we had not identified a receptor. The first receptor was identified by Stanley Cohen, which was the EGF receptor. So, one aspect of it was interested in hormone binding, and then that led to a lot of work Jesse did and others did on receptors in disease and so on. For me, the other aspect of it was that cyclic AMP we showed was the second measure in the thyroid, and then I wanted to know how it worked. And by then, there were a lot of people in the field working on it, Fisher and Krebs and others. And I thought if I worked on the thyroid, which is small and hard to work with, I would never solve the problem. So, there is a saying that is attributed to Kornberg, which is, “True for E. coli, is true for the elephant,” or the other way around?

>> Monod, I think.

>> It came from Monod?

>> Jacques Monod.

>> So, I said okay if it's true for the thyroid, it should be true for E. coli. At that time, several of us were giving a course on hormone action to research associates, John Potts, and me, and Jerry Aurbach and maybe others. And we invited, as our guest, Earl Sutherland. And so, the students all had to read Sutherland's papers, as we did. And he came, it's a funny story, but I guess we probably don't have time. But he came and gave a class to the students and mentioned, in the class, that E. coli had cyclic AMP. I think he had published a paper in the JBC with Mackmann. And they showed that if you added glucose to E. coli, cyclic AMP levels fell. But when they ran out of glucose, it went up. And somehow, I knew about this thing described by Monod and others as catabolite repression of the glucose effect in E. coli, where if you, Michael knows this, if you let E. coli grow on glucose, they grow fine and use the glucose. If you put them in lactose, they grow fine and use the lactose. If you mix glucose and lactose together, they prefer glucose. And the question is, why is that? And it turned out that glucose lowers cyclic AMP level, and you need cyclic AMP to metabolize lactose, to activate the lac operon. So, I began to work on that. And there was a guy down the hall named Bob Perlman working with Harold Edelhoch, a few years younger than I, but same research. I guess he was a research associate. And Bob and I started to talk about molecular biology and genes and the lac operon and promoters, and all these new things that we're trying to figure out. What is a promoter exactly? Where is it located? How does it work? It wasn't so clear reading the papers of Monod. So we talked and began to work together on this other project. So, one project was receptors, and the receptor project I was joined by Bob Lefkowitz. He was actually working with Jesse and me to work in my lab, and he began to work on ACTH and binding the cells and activation of adenylate cyclase.

>> And of course later won the Nobel Prize.

>> And that was his whole career, was working on hormone receptors, which became his career and Nobel Prize. And Harold Varmus worked with me, and he worked on the cyclic AMP part of it and how it regulated the lac operon in E. coli and so on. So, I had at the same time in the lab two people working on two different major projects who went on to win Nobel Prizes. So that is how I got interested in receptors, and that's how I got interested in gene regulation and E. coli. So, the receptor project, from Jesse, turned into mainly study insulin receptors and disease. For me, I got into the cancer institute and became interested in EGF receptor and its role in cancer. So some of the work I eventually did with Glenn Merlino was looking at amplified EGF receptor and overexpression in cancer cells. That's how that project evolved. And the cyclic AMP and E. coli story, Bob had worked with us, he and I worked closely together. We carried the project forward all the way to identify the binding protein in making mutants that did not respond to cyclic AMP and showing the complex bound to DNA. The one thing we couldn't do is get the structure of the protein. And I actually made, had made a large amount of the protein CRP trying to do crystal structures, but my collaborator didn't get crystals, whereas, as you know, someone at Yale did. So I felt always, should have I paid more attention to that part of the project? Should I have, myself, tried to make crystals?

>> You might have become a structural biologist then.

>> Oh, maybe. It was interesting. X-ray diffraction patterns always confused me, yes. So, that's sort of how I got him started and got into cyclic AMP and E. coli and into receptor biology. And after being in Ed Rall’s group for a few years and making — I think the discovery that had the biggest impact was the role of cyclic immune gene regulation in E. coli, that was really discovering a fundamental mechanism and understanding how it worked. I was there, in not very much space, in a group that had a lot of people who had not been there very long, and it was pretty clear there wasn't much room for me to expand if you looked around. And Mort Lipsett, who was in the Cancer Institute, in the endocrinology group in the Cancer Institute, offered me a chance to move to his department. So, you know, that happened on a tennis court.

>> Yes, the famous tennis court interactions.

>>Yes. He and I played tennis weekly, and I went to look at a job in California, because of this not having much space and looking around. And when I came back from California, Mort said, how did you like it? And I said, well, it looks great, Stanford's great, its resources are great, people are great, but my wife is not going to move to the West Coast because she's an only child here on the East Coast. And he said, well, I have some resources in my department, why don't you join me?

>> This is a phenomenon we now call networking.

>> It was networking, right. So, I moved there, and there were more resources, there was more space. I moved upstairs one floor, two floors. Harold came up with me I remember for a year and then left. And being in the Cancer Institute and being surrounded by cancer, you start thinking about cancer. So, biology in medicine is incredibly interesting and there are so many unknown problems that it was quickly easy to see how receptors, protein hormone receptors could be important in cancer. It was already known that estrogen was important in breast cancer and that testosterone was important in prostate cancer, these protein hormone receptors, it wasn't a big leap to figure out polypeptide hormones also would have an important role.

>> So, you navigated your way from what is now NIDDK to NCI and established a laboratory initially in Building 10.

>> So, I moved in with Mort Lipsett in Building 10 on the 10th floor. And one day, Mort came in and said, we're going to move to the Child Health Institute. Then I said oh, why? And he said, it's the future, and besides, they have a lot more space and resources.

>> Was Art Levine there yet?

>> I think he was not yet there. And so he decided to move, and then Nat Berlin, who was the scientific director of the Cancer Institute called me in and said, Mort is leaving, we're going to have a lot of resources, would you like to start a laboratory, whatever you wanted to call it? So, I said, yes, of course. And by then, you know, we had biochemistry that I had learned working with Earl, and genetics we started to do, and, of course, that is the molecular biology. So, the laboratory became molecular biology. There was already an existing lab that Gordon Tompkins started in the NIDDK with Gary Felsenfeld, Marty Gellert, and others.

>> In which I was a postdoc.

>> Where you were a postdoc. So, I sat down with Max Gottesman, and then I thought, we'll have a laboratory, you know, we’ll have some biochemistry, I know some biochemistry Max knew genetics, and we put it together. And we studied important problems, one of which being gene regulation in E. coli, Max was interested in lambda, and I had some interest in receptors and receptor biology in animal cells, so that's how we began.

>> So, the designation of animals and vegetables started then, or --

>> Yes. So, we had, yeah, some reason. We called it, yeah, animals was clear. We didn't call them bacteria, we called them vegetables, so we began to call each other animals and vegetables.

>> And without crystallography, there were no minerals.

>> Yes. So, as you know, at picnics, we'd have softball game animals versus vegetables. And this, as you know, goes on till today, we still have animals and vegetables.

>> You mentioned that early in your career, you had two outstanding scientists who became Nobel laureates, and subsequently, your lab, the Laboratory of Molecular Biology, has produced just a huge number, an incredible number of people who are in leadership positions at the NIH and outside of the NIH. And I'm wondering, what's the secret, what's the secret sauce? Why is it that your lab has produced so many outstanding scientists?

>> Well, I mean the first thing is clearly the people, Michael. I mean, okay, so I was lucky enough to have very good people who wanted to work with me. I think that that, that's the very first thing. And then you, of course, you have to find a project. And Ken Yamada, who's worked with me, once said to me, Ira, you're fearless. And I guess I am a little fearless. I don't mind going into new areas that I haven't worked in, I enjoy it. And it's uncrowded, which is pleasing and helps your sanity, we don't have too many competitors. But you have to choose something that's interesting and important.

>> I mean, maybe I can weigh in a little bit because I was in your lab. I think it's not only sort of the rigor of the science, which is absolutely understood, but this fearlessness really means that you're willing to follow a problem wherever it leads. So, if you need a bacterial system to study cyclic AMP, you’ll work on bacteria. And I think that's a lesson that many of the people who've been in the lab have learned and it has really served them well, that we're here in science to solve problems, not to beat a dead horse until it's gone, I think that's an important element.

>> I think this decision about whether to continue with a project or give it up or change direction is a very difficult one. And that's why I mentioned not working on the crystal structure of CRP was a decision I made that probably was the wrong decision, should probably have put more effort into that. But other times, you have to say, this isn't working. A lot of ways of saying it. I remember a few years ago, we'd made a knockout mouse, of a gene we thought was important in cancer, and the mouse became obese, really obese. They sit day and night, and they eat and eat and eat and eat. And they are almost as big as a small rat, long tails, and — not just fat. And we figured out, you know, what the gene, like the mouse gene, was in humans and the chromosome it should be, it wasn't yet identified as a gene in humans. And we collaborated, we thought, ah, this is a key to human obesity, right? This is what's driving people to eat. And there are familial obesity, and we sort of checked with the people working on familial, and we found on the same chromosome that our gene mapped on, there was a locus identified in patients, in humans with obesity. And we finally worked it all out, and our gene was nearby but not there. And I remember discussing this with Francis Collins, and he said, yeah, Ira, there's nothing so hard to give up as a good idea. And I think that sums it up. It's very hard to know sometimes when to stop and when to go on. We stopped.

>> Right. So as a result, you’re not working on obesity, you’re working on cancer. We’re all the better for it probably. There was this big shift in your direction around 1990 or so, where you went from really very basic science, understanding the principles underpinning basic biology, to a much more practical application of what you were doing. Do you want to talk a little bit about what led to that change in your direction?

>> Yes. Well, you and I were trained as physicians who went in to do research, but I know we always kept our eye on medicine, right, and read New England Journal or other such things so we’d know — and it was interesting always to us, right? It was interesting to me. So, I think in 1987, when I was studying with Mark Willingham how hormones, peptide hormones and other large molecules got into cells, a postdoc arrived, Dave Fitzgerald. And he said, I work on Pseudomonas toxin, and I'd like to know how it gets into cells. Could I come work in your group and work on this project? And so, David joined our lab. And Mark quickly figured out that it entered through this common pathway of coded pits and endocytic vesicles. But while working with the toxin, it became evident — excuse me — it was a very powerful cell killing agent, extremely powerful. And around that time, people were beginning to use monoclonal antibodies conjugated to drugs and poisons to kill cells, and there was an interest in using it to toxin. So, I said that we should, you know, maybe we'll try. Let's see if we can use Pseudomonas to kill cells. So, the first efforts were just to get some toxin and some antibody and put them together and put them on cells, and it could kill the cells. So, in principle, it could be used as a targeted agent. So we began. The devil was in the details. It took us from 1987 until 2000… this year to get a drug approved to treat cancer based on that principle because, we had to reengineer the toxin, identify the proper antibody, figure out how to express them, many, many barriers, but that was the beauty in that idea. And then you and I were working on protein kinases and got interested in doing something clinical. And I remember we made rounds, right?

>> We did.

>> Seeing cancer patients, trying to figure out, could we do something useful. And that led to studying multidrug resistance. But the day that we decided that is out of my memory, Michael, do you remember?

>> No. I mean, I remember a few people who influenced that. I mean, obviously, my recruitment was enabled by Al Rabson, who was really very supportive of sort of a broad approach to cancer. And Bruce Chabner was constantly telling us that we should be working on drug resistance because nobody understood why cancer cells became drug resistant.

>> Particularly multidrug resistance.

>> Particularly multidrug, and that is the resistance that occurs when you expose a patient or a tumor to a drug, and then the drug — and then the tumor just becomes resistant to everything, not just the drug, but to many of them. And I don't know when this, it may have been, it was very close to the time…

>> Around that time. It was also around that time.

>> Yeah, it was around the same time. It was certainly in the early 1980s.

>> Before that.

>> Yeah. Because I recently found the strategic plan that we wrote about how we were going to solve the problem. So, we had a plan. And it worked. The first thing was to clone the genes.

>> That's right. Clone the genes.

>> So, we had very talented coworkers, Akiyama, who made the first multidrug resistant cell line, KB cell line, and then Kazu Ueda, who did the cloning. And these people were key in our careers. Key in our careers.

>> Absolutely. So, it was the people, it was also the developing technology, because certain things you couldn’t have done 10 years before.

>> Yes. So, technology is incredibly important, and it takes me back to my work on the EGF receptor with Glenn Merlino. So, we knew the EGF receptor was important, but no one had its sequence yet. And we wanted to get its sequence, but there was no one at NIH — no one at NIH who could help us do its sequence. We were just missing that technology at NIH. NIH is different today. There's a huge interest in having modern technology rapidly available, and they are, but they were not then. And we collaborated with someone in Texas actually to try and do the sequence. And, again, we were a little bit behind.

>> Okay, so I wanted to go back to the immunotoxin story, and obviously, it took 30 years to develop it to the point where you finally got a drug approved by the FDA, and hopefully it will be standard of care for patients with hairy cell leukemia. But I think it would be interesting to kind of reflect on the frustrations and the high points of that development during that 30 years. Some of it was scientific, obviously, but some of it was administrative. It's not simply getting an idea.

>> So, the most exciting part, of course, is when a patient responds. So, to us, to me the most dramatic responses were in patients with hairy cell leukemia that Bob Kreitman treated. We made this drug to kill cancer cells that expressed a particular protein on their surface, CD22. So B cell malignancies generally express CD22. And for some reason, hairy cell leukemia has a lot, and Bob recognized that. And, so, when we were able finally to make a clinical batch of drug, not the drug that was approved, but its predecessor called BL22, B cell leukemia CD22 drug BL22. And Bob began to treat patients. He’d call up, and he said, Ira, the leukemic cells are almost all gone, and it's only been one day. So it killed cells really fast. I must say that was pretty amazing.

>> Yeah.

>> Yeah. It didn't mean the patients were cured or anything, but still, it was a very striking effect in a patient without any bad side effects.

>> So, one of the things I was thinking about was, how do you — I've never — I wish I had had that experience in my work, but I haven't. And how do you react to that? Is the response scientific, which is, okay, this is fine, but we need to do the following controls, we need more statistics and so on? Or is the emotion of the moment, my God, we've maybe cured a cancer, is that the predominant feeling?

>> Oh, yeah, I think it's, my God, we've done something really important, yeah, and exciting. Sure, of course: helped. So, you and I work in cancer research and cancer therapy related things, and you start to work on a drug, and you know it's all incremental. We're just going to help some patients, a lot of patients in some diseases, even the major discoveries today, checkpoint inhibitors. You know, a lot of melanoma patients, some lung cancer patients, but a lot — yeah, almost no pancreatic cancers. So even the big discoveries were incremental, very incremental, but they're still pretty exciting, yes. So, I had our up days, and also, we have a house in Nantucket where we go in the summer, and I also remember being there and being called up by Kreitman or others saying we were having problems. We had a patient who had went into kidney failure. That's a downer. But none of the patients died on the trials. There were side effects we got to understand and manage.

>> Yeah.

>> I'll tell you an anecdote about the kidney failure. One of the side effects of immunotoxins is the patients retain fluid, they gain weight, and they get swelling sometimes. And in order to prevent that, we thought, oh, well, we'll restrict fluid and then they won't gain so much fluid. And that made them worse. My son, Stephen, is a nephrologist, and I asked him about this. And I remember he said this to me, he said, Dad, the kidney is smarter than any doctor, just give them fluids. And in fact, that's how we manage them now. We assure they're very well hydrated, and this side effect is really pretty minimal. So, it's a matter — that is clinical research, right?

>> Right.

>> A problem that got solved.

>> So, you recall that there was a documentary about the NIH called First in Human. And it went into some detail about the anxiety that both the patients and the physicians feel the very first time somebody is exposed to a new therapy. And, I wonder, were you anxious about the possibility of more serious side effects when you first began treating patients?

>> Oh, yes. The first patient we treated was a patient of Tom Waldmann's with acute T cell leukemia, with an immunotoxin directed at CD25 that we made in our lab, that Dave Fitzgerald made in our cold room, can you imagine then? And we gave it to a patient, and the patient developed liver damage, but survived, bad disease, but survived. But, oh sure, I'm always worried about side effects. If you asked me about the first child we treated at St. Jude's with acute lymphoblastic leukemia, who had a very good response. We had treated a lot of adults by then, so when we treated the children, Alan Wayne, who was running those clinical trials, assured me. He said, Ira, generally, kids tolerate bad drugs better than adults. So, I wasn't so —we were concerned, and we actually went down and visited. Alan I flew down a couple days after the child started to visit the child, just to be sure we were there. I do remember that.

>> I wonder what you project is the future of immunotoxin therapy. Obviously, in theory, you could treat many different tumors with immunotoxins. What do you think are the best prospects for the future?

>> Right now, we're working on a drug to treat multiple myeloma. Multiple myeloma is a B cell malignancy, like hairy cell leukemia. So it should respond like it. The cells are, the cell lines are very readily killed in culture. Patient cells we've evaluated from about eight patients are sensitive, including from drug resistant patients. You know, the attraction of immunotoxins is that even if you have multidrug-resistance you’re still sensitive to the toxin because it kills cells by totally a novel different mechanism. And it works quite well in bone marrow models, giving in one model complete remissions that are durable. So, for me, that B cell target is the next target, and that's about 30 — I think 30,000 new cases a year. It's not uncommon, it's pretty common. Solid tumor therapy is more difficult for two reasons. One is, you have to penetrate into the solid tumor mass, and tumors are designed not to let proteins get in very well. And secondly, our toxins is a foreign protein and produces antidrug antibodies. It doesn't happen so much in patients with hematological malignancies where the bone marrow is not functioning very well, but it's a serious problem in solid tumor patients. So, we've been working over the years to either reengineer the toxin to make it not seen by the immune system or by using new kinds of drugs that suppress antibody responses. And there's a lot of interest now in drug combinations to prevent antibody responses. For example, I had dinner with Phil Gordon two nights ago. Phil Gordon worked with Jesse and me and then began work in insulin and some receptor, and he has a stable of patients they identified 30 years ago with antibodies to the insulin receptor and are insulin resistant. And he just published a paper showing that the right combination of immunosuppressive drugs puts those patients into complete remission. So, I think we’re trying to go in that direction.

>> It’s good to hear that Phil is still busy.

>> And he’s fine, yeah. He developed a drug for lipodystrophy.

>> So, you sort of avoided talking about the bureaucracy of getting things done. I remember in discussions with you along the course of trying to get partners, corporate partners, for some of the studies, and trying to get approval from the FDA, you were pretty frustrated. Were there lessons that you learned, other than patience, that —

>> Patience was a large part of it. So, I was very lucky to have bosses who were supportive and sympathetic, particularly Al Rabson, who we all admired, and who when we began to make immunotoxins, the first site visit we had, someone on the committee who was an expert in cancer treatment said it will never work and it's too expensive. That's the kiss of death, right? But Al said, keep working on it. And of course, you know, I've heard Vince Devita say that, if you have a good idea of doing something to treat cancer, come see me. I'll give you a lab and set you up, because, the fact is, there are very few good ideas, despite many, many, many people working in the field.

>> Yeah. And not a lot of good original ideas. A lot of people working in the same areas.

>> So, Al said, keep working on it. But I think a lot of it, we were kind of naive, we thought we could couple the toxin to a protein. But to have a drug, it has to be a stable thing in a bottle on a shelf, you know, the drug company can pull off and sell. And that is more difficult to get to.

>> So, recently, I sent a memo out to people at the NIH, and I asked them whether they had ideas for translating their basic science work into clinical work, and we had a series of focus groups, 30 or 40 people were interested in this. And the one thing that they said to me is they have no idea how to go from the laboratory to having a corporate partner who will develop a drug that will be useful in treating...

>> So, finding, for us and for our group, initially, we made everything ourselves. First, we did chemical conjugations, and then we learned how to use molecular biology to express immunotoxin in E. coli. And that was because of our department, molecular biology. Sankar Adhya knew someone who developed the first vectors, the first PET vectors. But they weren’t commercially available, and we got a vector that we could use to make proteins in E. coli. That was an experimental thing, but our department had access to it. So, we technically were dependent on that. I had a very brilliant postdoc, Vijay Chowdhury, who read a paper in Science on single chain antibody fragments, and he thought he could put them, attach them to the toxin, which he did. They were unstable sometimes, so B.K. Lee, a protein chemist, in my lab — who I met on the tennis court — designed a disulfide bond that you could put inside and stabilize it. That is now commonly used to stabilize single-chain antibody fragments (Fvs). So it took protein engineering and expression, learning how to make the proteins. We made small amounts in our lab, and then at Frederick they'd set up a new group to help make proteins, so they helped us, but I think it was a learning process, finally. And then they set up a group that, Toby Hecht was one of the people out there who helped us a lot, get organized, and get our proteins made, and vialed, and tested, shown to be safe in monkeys, sterile, stable, so we could get into patients. There were a lot of steps that a pharmaceutical company could do. So, if they wanted to do it, they would do it, but without a company. So, later on, we were lucky enough to have companies work with us and do a lot of this. So, without AstraZeneca, MedImmune, you know, this drug would never have happened.

>> Right. So, you've alluded a few times to the NIH intramural environment as being conducive to the research you wanted to do. What are the features that you think are most important at the NIH that allowed you to be successful in your research? And were there things that actually turned out to be impediments that you would rather not see. And I'm speaking as someone who maybe is in a position to make things better in the intramural program.

>> Oh, I think by far the most important was the stability of funding, if you could convince your review committees or whatever that you were in the right track. Without stability of funding, we never could have done it. It's possible if I were at a university, we could have set up a company to do it. Some people have set up companies and been very successful. That was a possibility. But it took a long time, and a long time is not something that the grant system deals with very well, so they would have said no eventually I'm sure. The other administrative things that are frustrating, I guess I'm kind of used to them now, Michael.

>> Yeah.

>> But it has so many advantages. You have wonderful colleagues, you know, science all around you.

>> I mean you've mentioned all the different interactions that you've had — collaborative interactions — a lot of people at NIH to go to if you have questions or just incidental sort of serendipitous discussions. Marty Rodbell used to talk about the slow elevators in Building 10, where he would initiate a discussion about something. They were so slow that by the end of it they had a collaboration going.

>> Well, Marty was a great chatter.>> It served him well.

>> It served him very well, yes.

>> Okay, let me change gears a little bit and remind people that your wife, Linda Pastan, is a very accomplished and highly respected poet. What is it about your life together that has contributed to your science? Do you see poetry in science, or is there some other way in which — other than not allowing you to leave NIH and go to California — that Linda has contributed to your work?

>> Well, I have my day job and my night job. So, of course — so we have friends, we have family, we have the world of poetry, and we have the world of science, and they overlap some. But a lot of, you know, life might be, you know, yesterday, Jane Shore, a poet, came to visit Linda when I was working. And so, yeah, so there's that mixture, but I can't see how poetry has affected my work experimentally. I think science is sort of a metaphor in some of Linda’s poems. But yeah, I think it's just my life generally is interesting, more interesting. But it did affect it in one way. So, when I was a young scientist, just beginning to do my research, my boss, Jack Robbins, said, this year, Ira, you can have a research associate, and you can interview research associates. So, I began to interview associates. And I interviewed Harold Varmus, and I interviewed Mike Brown, and Lefkowitz, who ended up working with Jesse but I interviewed him, and a few others. And each was better than the other, you know? So, then I had to decide among these who I should offer a position to. And it turned out that Harold had gone to Amherst, been an English major, had been editor of the school paper, took a year out to get a master's degree in English before he went back to medical school. And I said, here is an interesting person that Linda could talk to, in addition to his other skills, so I think it had a large part of me choosing him over the others. So, that's important, I would say.

>> Yes. Yes.

>> That's serendipity.

>> Yeah. I mean, I know Linda reasonably well, and I think there's a sort of wisdom in how she approaches life that probably has influenced you — a balance, yeah.

>> A balance is certainly true.

>> Yeah.

>> But you have a scientific marriage, Michael.

>> Yes, I do.

>> You seemed to have managed very well.

>> Well, yes. So, I think, I mean, Susan and I talk a lot about science, but I think having also a complementary marriage is a good thing as well.

>> So, it can work both ways.

>> So, these are sort of broader questions and maybe harder to answer. And one of the questions I have for you is, what do you think is the most important thing that you've done in your career, scientifically?

>> So, that's like asking me which of my children I prefer?

>> I’m not going to ask you that.

>> So, at the time — so I would say, discovering a novel mechanism of gene regulation in bacteria when I was pretty young was very exciting, you know. And the person I worked with, Bob Perlman, who I love dearly, and we had a wonderful relationship, it was very exciting. It happened in a finite period of time, because, as you know in bacteria, you could do an experiment every single day.

>> Right.

>> Not every month or every… So, Bob and I would talk on the phone every night almost, almost every night about that day's experiment. So, it had the excitement and the rapid movement and pretty big impact. So, I can't say that's the most exciting. But at the time, you know, it happened so quickly, it was like a volcano. The other things have been more like climbing Everest — you get to the top finally, like a drug, and you say, ahh, great, we're here.

>> So, we've kind of gone over your career, all of which has been at the NIH, basically, other than the training period. Is there anything about your life at NIH or your scientific career that you would do differently if you could do it over again?

>> No, there are little decisions that I mentioned that I might have navigated a little differently, but I've been lucky to work with a lot of talented people, and nice people — talented and nice people. And, so, I grew up in Winthrop, Massachusetts. My mother went to high school, my father dropped out of school very young, his father had died, and he was having trouble in school, and he was in business, but he had a lot of difficulties. So, I didn't have many expectations of what I might turn out to be. So, I look back, I say, gee, I've done a lot better than I thought I might. Yeah, so I tend to be a glass half-full person, and, you know, things are not perfect, but they’re quite good.

>> Again, another broad question, which has to do with your view of the current area of cancer research. What is happening now that you think is most exciting, other than the possibility of treating more patients with immunotoxins?

>> Yeah. So, when I began to think about antibodies, I remember going to look at a job at a pharmaceutical company, it was Lederle, I don’t remember, because they were near New York City. And I said, if I could move to New York City and be paid a lot of money and have a chauffeur and go to the theater, it might be a nice life, who knows? So, I went to look at this job. And when I finished the day looking around, they said, if you came here Dr. Pastan, what would you do? They were working on cytotoxic drugs. And I said, I think I'd probably work on antibodies. And they said, thank you, Dr. Pastan, we'll be in touch. And of course, I never heard from them. So, antibodies were a big effect, and there were some spectacular successes, like Rituxan and so on. And then things were pretty quiet I think until checkpoint inhibitors. And checkpoint inhibitors have, you know, as a big class of drugs, you know, had a huge impact. And maybe more if we could figure out how to make the environment of tumors more receptive to them. But to me, you know, they really — you could see the number of people with melanoma, 50% or 80% of them. I mean, Jimmy Carter is alive. He had a tumor, melanoma in his brain, he's alive, isn't that amazing?

>> Yeah. It’s amazing.

>> That's totally amazing, never would have happened. So, that, at the moment, seems to be the biggest impact. Engineered therapies, CAR-T cells, they have applications, they're great, but for relatively small numbers of people so far. But check point inhibitors, an off-the-shelf reagent, that drug companies want is amazing.

>> So, the Nobel Prize this year just went for checkpoint inhibitors. One of the recipients was Honjo.

>> So, Honjo was here as a postdoc.

>> Yeah, I was going to ask if you knew him when he was here.

>> I did, because I had a postdoc, Nakanishi, from Kyoto.

>> Right. Who wrote a letter of reference for him when he came back as a Fogarty Scholar. It’s interesting.

>> So, they were friends. So, Honjo worked with Phil Leder. And Nakanishi worked in our lab. And, so, that's how I knew him, and then I met him when I went to Japan, occasionally. So, I knew of him. I didn't know in detail what he had done. I knew he was an outstanding immunologist, but I think, like many others, I did not understand what regulated T cells to be active or inactive until it's practical applications appeared, yes.

>> All right. One final question, maybe the most difficult. If we were to create a museum exhibition about your life and work, what would you want to see in that exhibition?

>> Oh, I think I'd like to have my, all my colleagues, trainees, their pictures, and maybe they could say something, or write a paragraph or something. I think that's … So, I worked with Earl Stadtman, and there's a picture of Earl with a Warburg apparatus.

>> Yes.

>> You know that picture, you know what a Warburg apparatus is. So, it's a big tank of water to keep the water temperature constant, and in the tank, there are some little vessels, sealed vessels. And if you run it by a chemical reaction, they give off gas, and there's a manometer, and you could measure the change in gas pressure and measure the rate of the reaction. So, we had one of those machines in Earl's lab when I was a fellow. And there were six stations, so you could do six measurements at once, like six test tubes, not very many. And I remember saying to Earl, Earl, if you have only six manometers to measure, you know, how do you do many experiments if you have to do duplicates or whatever? And he said to me, Ira, you don't need to do duplicates if you're careful enough.

[ Laughter ]

>> That was the pre-statistics age.

>> And I think that's the main instrument that they have to show with Earl.