Part 2: A Detailed Look at the Discovery Process
Work on the project had been shelved more or less, when a paper by Byers and Wolfenden sparked the idea that led to the final discovery. Dr. Cushman provides a step-by-step description of the process.
Rosenberg: Dave, when you and Zola and whoever else, expressed interest in this idea, who had to give it the go-ahead?
Cushman: You know, I really don’t know. I think actually probably Zola had enough power to give it the go-ahead at that time. And I would say one thing—one thing that was very exciting to me about this whole era—was that this was kind of a different time, and Squibb Institute at that time really was an institute. It was a drug company, but there was a lot of freedom, and people were given a chance to take a chance on certain things. We weren’t really meddled with in much of any way on this project. I’m not sure what the powers that be thought of it or whether they thought it had great potential. I know that at the time we had drug candidates that everybody thought were really hot that turned out later not to be. But pretty much we were given a free reign on this. And that was one of the great things about it. We had a chance to do real science at an early stage and to work with outside investigators, for which John Vane was very helpful. It was a perfect environment. So I don’t recall ever having any sense that anything more was necessary than Zola Horovitz’s approval, and he was the head of the pharmacology department to which I had just moved.
Rosenberg: How long did you and Miguel and whatever your team was work before you had the notion that you really did have a drug candidate?
Cushman: Well, now Miguel got interested in this project around 1968 when John Vane, again, had told us that there was in this snake venom an active factor, which he thought inhibited the enzyme. So that would be 1968 when Miguel and I really started to collaborate, and that was the beginning of a wonderful working relationship. So from ’68 to about 1970 really was all that was necessary to come up with a candidate. Unfortunately that candidate had some limitations. This was teprotide, which was a nonapeptide, and it was a very potent inhibitor of angiotensin converting enzyme. In fact, it worked in the clinic, and it lowered blood pressure in hypertensive patients, and I’ve been told maybe saved the life of at least one women who had to take it for a long time.
I had been working on the enzyme from late 1967 to late 1968, and we had an assay available, which was very important. And so Miguel and I started to work together. He was isolating peptides, and I has assaying their activity against the enzyme. So from that time, 1968 to about 1970, it was two years and we had developed teprotide, which really proved to most key investigators the utility of inhibitors of the renin-angiotensin system in lowering blood pressure. But it didn’t develop a drug yet, because it wasn’t orally active and there were other problems in developing large peptides for potential drug use. And the idea of making it orally active was probably a pipedream.
Rosenberg: So what did you guys do then?
Cushman: Well, this was the point where actually our immediate supervisors and all that, pretty much suggested that we should work on something else—which we started to do. But we still maintained contact and were still working on different aspects of this project. Fortunately, it didn’t take us long. Well, I would say it was around 1972 when we were discouraged from this project because—well, there were positive clinical results with teprotide—but the lack of interest in pursuing this particular drug into the clinic. So when in March of ’73, fortunately you had one of those little things that wasn’t exactly “eureka,” but I was reading a bunch of cards that we had sent out about possible new drugs and one of them referred to a paper that had been written a little while ago by Byers and Wolfenden on an extremely potent new type of inhibitor of carboxypeptidase A.
That rang a bell right away because we had been thinking for a long time that angiotensin converting enzyme was probably very similar to carboxypeptidase A, maybe related from an evolutionary point of view. So when Byers and Wolfenden described this inhibitor that they had developed, a very simple inhibitor of carboxypeptidase A, we got very excited and started to talk about it. What they had was a compound that was structurally very similar to the terminal amino acid of the substrate for carboxypeptidase A or product, if you will, the amino acid product. (This inhibitor also contained a succinyl carboxyl group.) They weren’t quite sure what to make of that. They called it a biproduct inhibitor, spelled B-I product, whereas they thought it represented in one molecule, interactions with the enzyme that might be characteristic of both of these products. The terminal carboxyl group of one product and the aromatic amino acid being the other product.
So we discussed this and Miguel and I, I think, probably immediately came to the conclusion that that extra carboxyl group that they had, which they said corresponded to the carboxyl terminal group of the other product, probably was binding to the zinc ion at the active site of carboxypeptidase A, which was known to be involved in catalysis and that was a key assumption on our part. We also assumed that our enzymes being similar, but different, having a dipeptide product, maybe we could make a simple molecule that was an analog of a dipeptide, but also had a succinyl group on it to interact with the zinc ion of the enzyme. And that led us to a very simple compound, succinyl proline, which was probably pretty disappointing as an enzyme inhibitor, but of course it didn’t take us long to test this. But it turned out to have some specificity for angiotensin converting enzyme and gave us encouragement.
To get ahead a little bit here, at this point it was just a matter on paper of one, two, three and we had captopril. It didn’t quite happen that fast, but what happened was from our studies with snake venom peptides we knew that probably the best terminal sequence for inhibitors of angiotensin converting enzyme was phenylalanylalanyl proline, so the dipeptide product that we should probably mimic would be alanyl proline. The succinyl proline we made really mimicked glycyl proline, so we made a compound, 2-methyl succinyl proline, that mimics the structure of alanyl proline, probably the best dipeptide for interacting with angiotensin converting enzyme, and still maintaining the zinc binding carboxyl group. And it was even better, and very shortly thereafter, we started looking at the various interactions we’d proposed and found that the only one that wasn’t optimal was the so-called interaction with the zinc by this carboxyl group.
And it wasn’t long before we tried other groups, and sulfhydryl group was tried, and it was suddenly a thousand times more active than its preceding compound. I remember when my assistant Mr. Cheung tested that compound, we looked at the result, and we didn’t believe it at first. We figured something was wrong with the dilutions of the inhibitor, but after repeating it a few times, we knew we had something that was going to be really exciting. It was so potent that it was probably among the most potent enzyme inhibitors known at that time. So we knew we were onto something pretty exciting here.
Part 3: In Praise of Zola Horovitz
Dr. Cushman relates how the head of the pharmacology department may have protected him and Dr. Ondetti from pressures to end the work on what would be the discovery of captopril. Once the discovery was made, it moved quickly into clinical studies.
Rosenberg: Dave, did you really know right away that this was a real breakthrough? When you realized it wasn’t an error in dilution?
Cushman: Yeah, I did. Some things you just know. I’ve had maybe one or two things in my career previous to that where I discovered something important from nature, and yeah, you just feel it right away. In the back of my mind, I knew this compound would have to be orally active also, because even one of the much weaker precursors was already orally active. And this was so potent and, at least from my point of view, the more specific interactions you had with your receptor, in this case the enzyme, the more likely it was to be extremely specific. And that should carry over in the clinic to a great specificity also, which as it turns out it did. So it just seemed to have everything going for it.
Rosenberg: So where are we now in time, Dave?
Cushman: I’m a little weak on that to be honest with you. I think it was 1977.
Rosenberg: Let me take you back just a little bit because I was curious about your statement that somewhere around 1972, you were encouraged to drop this and go do something else. And you know I’d heard that story too. And I’m curious, how insistent were people that you go in a different direction and how resistant did you and Miguel have to be?
Cushman: I don’t know about Miguel. Fortunately, I was pretty naive at the time so I didn’t realize… Apparently they were fairly insistent at certain levels. Fortunately, we had, at least in my case, I had my hero Zola Horovitz, who didn’t really tell me probably all the things that were being pushed on him. But I didn’t really feel too much pressure myself. I was prepared to do some other kinds of work, but it was made very clear that we would continue to do some work on angiotensin converting enzyme also. There were some villains in the case. In fact, Arnold Welch once wrote an article about it some time ago. He didn’t actually mention names, but there were some people who were very negative. It was kind of the old game of “we don’t know what to do with something like this.” There is no way they are ever going to develop a useful drug from this approach. But there were plenty of heroes, too, and there were plenty of people who supported it.
Rosenberg: Did some of the doubters come from the science side as well as the business side?
Cushman: Not too much. I think there were doubters in the world as a whole. But that’s what you’d expect. It’s probably even easier to publish things that are negative than positive sometimes. There were people who at various stages just didn’t believe that the renin-angiotensin system played any role, and I think they probably at some early point weren’t quite sure that even these inhibitors that we were developing were going to prove much. I think it took people awhile to realize that we were onto something real here. Fortunately, we did our job and published plenty on it, so that I think we gave the world a pretty good view of what we had actually done.
Rosenberg: What made you guys willing to go against the advice or maybe even more than advice, the orders to turn your attention somewhere else?
Cushman: I don’t know, we probably didn’t even know about it—I mean in terms of what was happening at a very high level. See, we weren’t that important. That was the good news. I was a fairly new biochemist, and Miguel had been working on peptides for a long time, but neither one of us was an administrator. Well, Miguel was a group leader, but we weren’t middle managers or anything. We weren’t somebody whose time was being looked at that closely. And we had people above us who were probably protecting us from some of the flack that might have been coming down. And we were still working on this part-time. We were doing what was expected of us, which was to start new projects. I was working on prostaglandins and Miguel was working on antibiotics, but at the same time we were still communicating with each other. And we had these assays available, so we still were trying a few things. One of those few things turned out to work beautifully, and wonderfully if you will, and so after that point pretty soon nobody was complaining too much.
Rosenberg: When you had this dramatic result with captopril, how long did it take before you then found the drug in the clinic?
Cushman: I’m sure it was studied within months. There were several people out there who were still very, very interested in this whole thing. John Laragh was one of them. I don’t think John Laragh was actually the first person to test it, but there were some other investigators, one of whose names is evading me right now, who tested it in the clinic and quite soon they started turning out papers on the utility of converting enzyme inhibitors. In Laragh’s case, he was now pushing converting enzyme inhibitors above beta blockers, which he had been pushing as inhibitors of the renin-angiotensin system. So it was very, very quick then. From ’77, when this compound was synthesized, it only took four years to have it actually approved. Unfortunately, it was approved for a somewhat more limited indication than it should have been. So it was really rapid at that point. We’d done our homework ourselves so that by the time we were in the process of synthesizing captopril, we had a lot of background information. So it went pretty smoothly.
Part 4: On Snags In the Clinical Trials and On Dr. Cushman’s Early Education
Side effects from large doses beset some of the clinical trials of captopril at first. Dr. Cushman also recounts his upbringing and education in Indianapolis. He says a high school biology teacher really set him on the path to becoming a scientist.
Rosenberg: Was it completely smooth sailing from the time of synthesis? Or were there some other moments when things seemed very rocky?
Cushman: Well, there were a few, but it’s the usual thing. To be honest, what it came down to is that our medical department, among others, had never had a really big drug before, number one. Not for years anyway. So it was a little bit more difficult for them than it might have been otherwise to hit something with this potential. So they had a few ups and downs in terms of developing it, and there were always a few people—it’s very easy to get scared in a thing like this. I had never been involved in the development of a drug in the clinic myself. So when it turned out that we gave very high doses of the drug, which was quite possible because it’s not toxic, to patients in the Cleveland Clinic, a lot of them got rashes. So all of a sudden the drug had a reputation for causing rashes, which wasn’t so bad.
Then later it started having a reputation for causing changes in white cell counts, which was bad. Most of these were very, very sick patients, and it took quite a while there to rid people of this interpretation that somehow this drug had side effects (that) were unrelated to its action as an angiotensin converting inhibitor. The Merck people jumped all over the idea that it was a sulfhydryl compound, because some sulfhydryl compounds with other groups on them are (metal) chelating agents and can have some fairly profound effects. But captopril was not a chelating agent and doesn’t really have the kind of effects they were trying to make people worry about. I guess, because they were developing ones that didn’t have sulfhydryl compounds.
So there was a lot of static, and just like anything else, if you read the news every day instead of reading it once a month, you get weird interpretations about what’s going on. The same way with drug development. You can get easily scared. But fortunately they got through all that, and it turned out to be a very, very useful drug in the clinic and even more useful for indications that we hadn’t thought of at the time. I think probably heart failure was a really big surprise and possibly one of the most exciting uses of the drug.
Rosenberg: Dave, are you surprised at the, sort of the pathway of utility that captopril has followed going from hypertension to heart failure to post myocardial infarct patients to diabetics? Did you have any inkling of the remarkable breadths of utility clinically that it was going to show?
Cushman: No. I was surprised obviously like everybody else. The only thing—I’m the optimist in the crew, by the way—so I mean I was always, “Oh well, this will work out.” The only thing I believed and still do, from the very start I thought we were working with an agent, angiotensin II, which probably plays key roles in medicine. So I think we were looking for some surprises along the way, but I don’t think any of us even came close to believing it would be as exciting as it was. And for the naysayers in the company, I think the fact that it was making a billion dollars a year at its height was a pretty good path for them.
Rosenberg: I’m sure the doubters decreased in number rapidly when the commercial success became apparent.
Cushman: Yeah. I think there is a principal here, too, that I always believed in, although I was fairly young and naive about pharmacology, but basically that there is nothing better than a really specific, what the British would call a spanner in the works. Being able to mess up a system specifically is one of the best ways to find out what it really does. I think probably captopril has been a good example of that, and there have been some other drugs that have come along in recent years with that kind of specificity that are showing the same thing now.
Rosenberg: Dave, let me turn away a bit from the wonderful story of captopril to get a little bit more information about you and how you found yourselves in a position to do this work. Tell me a little bit about yourself. Where were you born and how did you grow up and what were the things that led you to become a scientist?
Cushman: Okay, I really want to do that. Yeah, I grew up in Indianapolis, Indiana, which is far away from everything cultural. At least at the time it was particularly far from everything cultural. And I was a bright kid, I think, but a very poor student. So I got along on doing very little work until I was in high school. In my sophomore year, I think I got an F in world history. So I started to realize that maybe I wasn’t going to be able to get along without doing any work. And I got very excited by a course taught by my high-school biology teacher. His name was Mr. Philip Fordyce. And he’s the guy that really set me straight in the academic pursuits, because I so wanted to impress him and so enjoyed his course that it sort of made me get more interested in all my courses and become more of a student.
By the time I ‘d finished high school, I had a good enough academic record so I got a scholarship to Wabash College in Crawfordsville, Indiana, which is a very fine liberal arts institution of the type we don’t see that much. It’s all male, which was probably my social undoing. The other influence in my life was that I was poor. I wish I could get that across to my kids. Being poor is a great stimulus for wanting to achieve something. So anyway, I got to Wabash and did very well, you know, graduated magna cum laude and got a National Science Foundation Fellowship to the University of Illinois to study biochemistry, and I was pretty much on my way at that point.
At Illinois, I spent about five years catching up on some of my science I should have learned earlier in my career and studying microbial enzymes. My boss, Dr. Gunsalus at Illinois, sent me to interview at Dupont, I think probably to scare me away from industry. But I was really impressed by them, although they weren’t very impressed by me because I hadn’t really done enough at the time when I interviewed with them. So that got me interested in looking around at industry. I think I still felt that I might end up in academia, but I really wasn’t too interested in going on and getting a post doc, particularly since I would have been working with one of my boss’s friends, probably. I thought if I went to work in industry, I could be independent and maybe make a name for myself. If I wanted to move back into academia later I could, which I never did, of course.
So I went to work after five years of graduate school. I accepted a job at the Squibb Institute for Medical Research, which is now at Bristol-Myers, Pharmaceutical Research Institute, Bristol-Myers Squibb, after a takeover. As I told you before, I was working on enzymes from Australian plants that introduced fluorine atoms into molecules to form fluoroacetic acid, and that just didn’t have enough of the right factors. I learned a lot of good techniques, but it just wasn’t going anywhere, when John Vane came along. Or actually I was switched—our department of biochemistry was done away with. I switched into Zola Horovitz’s pharmacology department. (Horowitz) was the only biochemist in the department, and John Vane came along and suggested this project. So that’s my career in a nutshell.
Part 5: Tribute to John Vane and a Nod to Shakespeare
Dr. Cushman talks about the influence of John Vane and others on his career, then describes some of his interests outside of science. They include Shakespeare and comic books.
Cushman: I had to mention Mr. Fordyce because he was such an influence in my life. You know, you don’t get a chance that often to tell an old teacher what they meant to you.
Rosenberg: Have you communicated with him since you have become rather a celebrity?
Cushman: I knew he was in Florida. I looked up his phone number on the Internet and I called up and said—you know I got an answering machine—I told him if he was indeed Mr. Fordyce, I would enjoy talking to him sometime or he could write me back. I really didn’t get any answer at that time. I think I had the right number. He’s an older man now. It turns out his daughter went to school with me, too, so when our 25th or 30th high school anniversary thing came out, they put out a booklet. So I put some statement in there about how much he had meant to me, and she got a hold of that and told him about it. I’ll definitely send him some information on the Lasker Award. I’ll probably send it to his daughter and have her… he may not be well. I don’t know.
Rosenberg: Dave, did you come from a science family?
Cushman: No, no, I came from a family that had no tradition of even going to college, so to me initially going to college wasn’t even on my horizon. I had loving parents, who didn’t have too many expectations, I guess. They were from the Depression generation. They had raised a lot of kids, and there weren’t a lot of books around. My mother was more interested in reading and education than my father, I think. But you know, it just wasn’t… I kind of had to discover that aspect of life myself.
Rosenberg: You said your parents had raised a number of children. Were you sort of late in the list of kids in your family?
Cushman: I was second. I was the first one to go to college. My sister went to…we had a choice: We lived in a part of Indianapolis where you could go to one of two (high schools). My sister picked Arsenal Technical School, which from the name you can guess probably didn’t turn out a lot of college-bound students. I picked Broad Ripple High School, which at the time was one of the best schools in the town in terms of turning out college-bound people. That was a good choice. I may have made it for the wrong reasons. I probably knew people who were going there and felt it was a little closer, but that’s where I met this biology professor that stimulated my career. It’s one of those things, you know, my kids have the curse of being well-off. So, I can’t pass that on to them.
Rosenberg: I think I have some idea of what you mean there. Dave, I’m curious about your very clear admiration and affection for Mr. Fordyce. What other people in your life would you classify as your heros or role models or people who really influenced what you became?
Cushman: Well, you always run the risk of leaving people out, but I think there were two who just were so profound that they have to top the list. Anybody I leave out, I apologize for. The other one was John Vane. It wasn’t just because John Vane was a good consultant. I always considered John Vane my friend. I even used to kid him I wasn’t going to call him Sir John. But, yeah, I’ve always considered John a friend. He was either a great friend or a perfect consultant in that he was kind of my mentor. And he was not only helpful in suggesting projects and things like that, but discussing ideas with us, over and over again. And actually John introduced me to a lot of people in the field. So I got to the point where I knew more academic people in the field of hypertension than in other drug companies, which was very unusual for a person working at a drug company. Most of these people know all the other drug company workers. I didn’t know all the academic people working in the medical fields, but he did a lot of good things for me. And he doesn’t always feel completely appreciated, although I think winning the Nobel Prize is a pretty good sign of appreciation. But he definitely was essential for my life, along with my high school biology professor.
Rosenberg: Well, those are two singular folks with very different contributions.
Cushman: Yeah, I should also add Zola Horovitz to that list, too. I was very lucky in having a boss…I mean, I never considered Zola a boss. We were colleagues. The best bosses are never bosses. Zola was a terrific influence on me. I think he protected me from a lot of junk I didn’t need to know about and was very, very, very important for the development of this program.
Rosenberg: Dave, let me again take off in a slightly different direction. You and I both know that when people read about scientists, they’re always curious about what kind of folks these are. Are they absolutely singular in their interests? Are they workaholics? Do they care about anything else? How would you characterize yourself as a human being? What other things do you enjoy? What things give you pleasure? How do you spend your time—or how did you spend your time when you were an active scientist, other than when you were working?
Cushman: Well, I’m probably not typical actually of a lot of scientists in that, I guess part of it is, I had what I thought was a very great undergraduate education, a true liberal arts education, which maybe shouldn’t have lasted as long as it did, four years, but nonetheless it stimulated in me an interest in learning of all kinds. So I have a number of really strange and conflicting interests. I enjoy playing golf very much. I’m much, much more interested in history than I ever was when I was in school. And the history, that can be added to by traveling and visiting places, you know. I’m still very active at that.
I’ve gotten, if anything, more interested in languages as I’ve gotten older. Even in retirement, I’ve been taking Italian and German courses. I suspect I’ll continue to take some French and Spanish courses, as well, and maybe eventually put them all together and come up with some ability to speak in some of those languages. I came up late in life with an interest in the opera, so I spend a lot of time going to the operas. I think my initial interest in Italian came from the fact that it seemed like a very easy language for me in these librettos. I still read a lot and try to keep up with some things intellectual. I still read poetry, now and then, catch up on some of Shakespeare’s plays. And of course the other side of me, there is a side, I collect old comic books. So I spend an awful lot of time reading comic books. It may not go along with Shakespeare exactly, but it’s recapturing my youth.
Part 6: Retirement and Why He Took It Early
A number of factors came together to prompt Dr. Cushman to retire from Bristol-Myers Squibb at age 54.
Rosenberg: Are you married, Dave? Do you have a family?
Cushman: Yeah, my wife’s name is Linda. I have a son, Michael, who got married and gave us a grandson a year ago. And my daughter, Laura, is still living with us. She’s doing local archeological work and hasn’t quite made enough money yet to get her own house or hasn’t found a rich man yet.
Rosenberg: How old were you, Dave, when you left Bristol?
Cushman: I was fifty-four. I took early retirement. This is another thing that’s atypical about me.
Rosenberg: Can you give me an idea why you did that?
Cushman: In essence, I’ll be honest with you, I think part of it—I may have high expectations—I think part of it is that as you get older, you don’t always get as much, what’s the word…it’s like there’s a conspiracy to keep you from being creative. I think it happens a lot of times in academic places when people become administrators, rather than scientists. There was not only (that) everything was trying to conspire to get me to do other things other than basic research, which is what I wanted to do, but also the old guy versus the whippersnappers. You sometimes feel that people don’t have as much respect for you as you get older, and some people that have accepted the administrative jobs make it a little more difficult for you to do what you really want to do, even what’s good for the company, I think.
Just all in all, I thought about retiring early several years before I did, fortunately because I was able to financially be able to do it. It’s not a religion with me to work for a living, so I thought I have a lot of interests. And I had a medical problem, too, and I wasn’t sure how long I might be fit. I think probably now, as things stand, I’ll be fit for a very long time. But you know to be able to travel and do things like that, you have to be able to handle it physically and everything else. There were just a lot of things that kind of led me in that direction.
Rosenberg: Well, I’d have to say you’re a very fortunate man. You not only have made a remarkable scientific discovery, but you sound as if other things in life matter a great deal to you, and I guess that is not always the case.
Cushman: No, a lot of people couldn’t stand to be retired. It’s as simple as that. You know, science is a difficult mistress, isn’t it? If you do it right, you spend so much time trying to keep up with the literature and trying to maintain your position in science so that you’re still…in academia it’s probably even worse than in a company…You’re trying to make sure that you still have the resume that indicates that you’re worth hiring if you do want to move somewhere else. You really just have to spend so much time keeping up with what’s going on in the world…It probably interfered with my family life pretty early in my career. To be honest with you, it was kind of a relief to get rid of that. I feel a little guilty now that I don’t know what’s going on, but it is so much of a relief not to have to go read reprints and the like all the time.
Rosenberg: Well, Dave, I think we’ve covered the things that we needed to cover. I want to thank you very much for taking the time to talk to me, and, again, I just want to tell you how pleased I am not only on my own behalf, but on the behalf of lots and lots of other people. It’s a pleasure to hear your story a bit. I’m sorry that you and I didn’t get to know each other better when I came to Bristol-Myers Squibb.
Cushman: I was going to say that to you. There wasn’t much of an interval there when we were working at the same time.
Rosenberg: No, but this gives me a chance to go back a little bit into the lore of that company and maybe some of the very best of it, and I very much appreciate the opportunity to talk with you about it.
Cushman: Well, I certainly appreciated talking to you. I never had a chance before. I enjoyed it a lot.
Rosenberg: Thanks very much.