Albert Lasker
Clinical Medical Research Award

An Interview with Miguel Ondetti
Interviewed by Leon Rosenberg

Leon Rosenberg, Professor, Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs, Princeton University, interviews Miguel Ondetti, who shares the 1999 Albert Lasker Clinical Medical Research Award with David Cushman. Dr. Ondetti, now retired, was senior vice-president for cardiovascular metabolic diseases at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, NJ. Dr. Rosenberg is also president and chief executive officer of the Funding First initiative of the Mary Woodard Charitable Trust, August 1999.

Part 1: Education In Argentina and Early Influences
Dr. Ondetti talks about his education at the University of Argentina, his mentor at the Squibb Institute in Buenos Aires, and his decision to come to the United States.

Rosenberg: Miguel, I'm delighted to have a chance to talk with you, first to congratulate you one more time on your being the recipient of this year's Lasker Award for Clinical Research. As somebody who had reason to be associated with you at Bristol-Meyer Squibb, it is a particular pleasure to have a chance to interview you and to find out a bit about how this work came about. So let me ask you first...tell me where you were born...a bit about your early years. I know you were not born in the United States, but I'm curious as to your beginnings.

Ondetti: Yes, I was born in Buenos Aires, Argentina, and I received my education in Buenos Aires at the School of Science of the University of Buenos Aires. I came to Squibb because I was the recipient of a scholarship for training in scientific research to work with Dr. Deulofeu, who was then the head of chemistry at the Squibb Institute for Medical Research.

Rosenberg: Now, Miguel, this was not the Squibb Institute here? This was the Squibb Institute in Buenos Aires?

Ondetti: Yes, but it was really a branch of the Squibb Institute here that had been built in the early '50s by the Squibb Company in Argentina.

Rosenberg: Was Dr. Deulofeu a senior person in the Squibb Institute in Argentina?

Ondetti: Yes. When I came to the institute, the head of the institute was Dr. Sordelli, who was a very well-known microbiologist. He was world-renowned in microbiology. He was the head of the institute and Dr. Deulofeu was the head of the chemistry part of it. I was working on a project proposed by Dr. Deulofeu on the chemistry of carbohydrates that was eventually part of my doctoral thesis.

Rosenberg: Would you say that Dr. Deulofeu was an important mentor for you in your early scientific years.

Ondetti: Oh, very much so. He had been my professor of organic chemistry at the University and for me was a representation of what research was or was meant to be in chemistry. He was the dean of chemistry in Argentina and recognized by a very large, long series of collaborators. So for me to work with him was not only a great learning experience, but really what encouraged me to continue in research.

Rosenberg: Miguel, how old were you when you first met Dr. Deulofeu and how long were you associated with him actively in research?

Ondetti: As I said, I met him first as a student in the University in 1953. But I started collaborating with him in 1956 until I came here in 1960.

Rosenberg: So you worked closely with him for four years.

Ondetti: Exactly.

Rosenberg: And maybe you'd like to tell us about the circumstances that led you to come to the U.S.

Ondetti: After I finished my doctoral thesis work with the scholarship from Squibb, I was offered a position as a full member of the scientific staff. So I joined them in 1957, and I was working on the isolation of natural product, alkaloid, from South American plants for three years. And in March of 1960, Dr. Deulofeu's secretary called me to his office and said that Dr. Langlyke, who was then the head of the Squibb Institute here in the U.S., and he normally, routinely every year paid a visit to the Squibb Institute branch in Buenos Aires, that he wanted to talk to me. And when I went to the office, Dr. Langlyke right away off the bat asked me whether I wanted to work in the United States.

Then I asked him for how long and he said for as long as I wanted to work. That he was offering me actually a position, a permanent position of the Squibb Institute and that I had two days to think about it and give him an answer because he was leaving for the States in two days. So I discussed it very thoroughly with my wife, who was ready to open her office as a dentist, and we decided that we were going to take the chance, because we could always come back—and that was 39 years ago. We never did. So we're still here. So that's how I came to work at the Squibb Institute in the United States.

Rosenberg: Have you ever regretted, Miguel, that decision?

Ondetti: Well, no. Regretted, no. I have thought that there would have been a number of other things that I could have done if I had gone back and joined the handful of people who had been my classmates, that they are now in good positions, in very high positions at the University. But I didn't, by the same token that I never regretted that I went to Squibb, an industrial lab, and I never left. I felt that I had found my niche in which I could work in collaboration, not only with chemists, but we also with biologists. That was very important to me.

Rosenberg: Do you think you would have discovered captopril if you had not come to the United States?

Ondetti: No. I guess the answer is almost certain.

Rosenberg: Why?

Ondetti: Well, because there were a number of circumstances that had to sort of come together. And even though I was always interested in chemistry that was connected with biology, it is more difficult to have that connection when you are working in a completely academic chemistry department. It's much more feasible when you work in a pharmaceutical company. And I think that's one of the key important points of my career.

Part 2: Initial Work on Peptide Synthesis at Squibb in the United States Proves Useful as Interest Turns Toward the Renin-Angiotensin System
Earlier tedious work in peptide synthesis proves an advantage when Dr. Ondetti joins John Vane and David Cushman in a search for converting enzyme inhibitor. That work produces teprotide, a compound that attracts interest from clinical investigators. The company, however, decides not to put any more effort into the angiotensin converting enzyme.

Rosenberg: So now let's pick up again on your adventure after you came to the U.S. How did your work begin here and how did it come toward the renin-angiotensin system?

Ondetti: Well, when I came here, the head of chemistry at Squibb was Dr. Gus (Joseph) Fried who had made a very important name in the chemistry of steroids. And honestly I was hoping that I was going to be allowed to work on the chemistry of steroids, but he told me that they had decided that I was going to join the team of peptide synthesis that was headed by Dr. Bodanszky, who had been working with DuVigneau, and he was hired to really initiate the project on peptide synthesis. I was a little bit disappointed at the beginning because peptide synthesis for a chemist sounds, and is considered by many, kind of repetitious.

But I was very soon taken over by the tremendous value of peptides in biology, by the large variety of biological functions that are controlled by peptide. And I began working with him interestingly enough, just a coincidence...he asked me to synthesize bradykinin because the structure had been discovered, proposed first wrongly. And he had made the wrong structure. So he asked me to re-synthesize. We had what we believed to be, correctly so, the right structure. And that was my first peptide. And it had a tremendous impact on me.

When I took 3 milligrams, or something like that, 3 or 5 milligrams, that I had managed to purify and asked Dr. Rubin, who was going to be my collaborator for many, many years, if it was enough to test. He said if it is bradykinin, it should be enough. Then he called me afterward and told me that to get the compound within the range of the contractile activity of the muscle, it had to be diluted with a liter of water, taken and diluted again with a liter of water and taken again and diluted some more.... I think he said the compound is active at the level of less than a nanogram. At that time I wasn't very sure what a nanogram was, but I was impressed by how peptides could be kind of boring for a chemist but very important for tissues.

So I worked on peptide synthesis for the best part of the '60s. Dr. Bodanszky had left to join Case Western Reserve University, and I was the leader of the group. We were working on gastrointestinal hormones and synthesized secretin and then cholecystokinin. And we managed to convince the management to put on the market one of them, cholecystokinin, as a diagnostic agent. But the interest in gastrointestinal hormones was sort of tapering off, and the head of the institute—that was Arnold Welch, who came from the Department of Pharmacology at Yale—decided that the emphasis should be on cardiovascular research. It was at that time that, through the interaction between the new consultant Dr. John Vane and Dave Cushman, that they had decided to initiate a search for converting enzyme inhibitors. And I was sort of enlisted to the do the chemistry of that area, and this is how I got involved in the renin-angiotensin system.

Rosenberg: What was the first thing that you did once you were encouraged to join that effort?

Ondetti: See for me it was like a return to a natural product chemistry because we had to purchase the venom of a Brazilian snake, a pit viper that is called the Bothrops jararaca. A Brazilian pharmacologist in Dr. Vane's lab had shown that the crude extract from this venom was able to block the conversion of angiotensin I to angiotensin II. And he had shown before that this crude extract of the venom was able to also potentiate the effect of bradykinin. That 's the reason why they originally called it BPF (bradykinin potentiating factor). Now at that time it was not known that those activities were the consequence of the action of the same enzyme. So I was asked to purchase venom from the Institute Butantan in Sao Paulo and fractionate it and isolate the compounds that were responsible for the activity. And that was the task of my chemistry group.

Rosenberg: Do you think that the potency of the venom was directly related to this action on bradykinin and on the converting enzyme?

Ondetti: I really don't know and I don't know if anybody knows that for sure now. But the venom kills by producing a very drastic drop in blood pressure and all the consequences that lead to shock...and so they may play a role. I don't know if there are also other high molecular weight compounds that have an effect but they probably do play a role.

Rosenberg: So how did the work evolve, Miguel, once you had isolated these substances from the venom? They turned out to be peptides, is that right?

Ondetti: I guess even before we started, we knew that they were going to be peptides. We didn't know that there were a large number of them. So we had to isolate several components and separate them and determine the structure and then synthesize them. And then that was one of the advantages of our previous experience with peptides because if we had any doubts on the structure, we made them and thus proved if the structure was correct or not. They were in length between 9 and 12 amino acids. So when we selected the one that we thought was the most active and that was a nonapeptide, we synthesized a large amount, sufficient for initiating all the toxicology to obtain the IND.

That compound was introduced in clinical testing in I think it was '71 or '72 with the name of teprotide. I guess because it has four residues of proline. And the studies were very interesting, even though it was an injectable drug and could only be used either subcutaneously or IV. But we had a lot of interest on the part of the clinical research community because it was a new tool to investigate the function of the renin-angiotensin system. So there was a lot of interest and a number of very important clinical investigators were conscripted to do clinical research. On the other hand, we in the lab were involved in trying to simplify the structure, because we knew that with that large size it was impossible to get oral absorption, and also in obtaining compounds that would not be degraded by digestive enzymes. We did a number of synthetic modifications, but we were not successful.

Rosenberg: And so what happened to teprotide?

Ondetti: It was maintained as a sort of a research tool, and the company was willing to provide the compound to clinical investigators but officially it was declared not a development candidate. As a matter of fact, the company decided not to put any more effort into the angiotensin converting enzyme, and some of the clinical studies which were done, were done by investigators who were interested enough to have their own financing.

Rosenberg: Who were some of those clinical investigators? Do you know?

Ondetti: Yes. John Laragh was one of them and his group that at that time—I'm not so sure where they were—still associated with him. It was Harry Gavras, who then moved to Boston. And then there was a group in France that was headed by Menard and Corvol that did a lot of very interesting work. And then the group at the Cleveland Clinic also did a significant amount of work.

Rosenberg: Was that Irving Page?

Ondetti: No, not Page himself. Irving kept in touch with the development, but he wasn't doing the clinical studies then. I don't remember exactly the name.

Part 3: Paper by Wolfenden Jump Starts Dormant Research on Angiotensin Converting Enzyme
When Dr. Cushman see a paper on the inhibitors of carboxypeptidase, he and Dr. Ondetti see new possibilities for their ACE research. Captopril is synthesized in October 1975.

Rosenberg: So in 1971 or 1972, the company decided to de-emphasize, in fact to discontinue, work on the converting enzyme. How did you feel about that and what did you then pursue?

Ondetti: Well, it was a disappointment, not necessarily for the work of converting enzyme, because we knew the direction in which we were going wasn't productive. I mean we had done it. But the company made a more radical change. They decided to actually terminate all the work on peptides. They felt, like many other companies had felt on and off, that peptides are very unlikely to become drugs in the way that people were interested—with the oral absorption. So they felt that they had to put more importance on other projects, and they asked me to be the head of the antibiotic research in chemistry.

It was not a happy occasion, and I did consider whether I should sever my association with Squibb or to continue. I had sort of developed a name in peptide synthesis through my work. But I found the work on antibiotics challenging enough, and I had a certain degree of freedom to do some projects on my own with my assistant Emily, so I took on antibiotic research with great zest, waiting for the time that things would change. And they did change.

Rosenberg: Now how did that change come about, Miguel? When and how?

Ondetti: I think it was in March 1974 that I received a brief note from Zola Horovitz's desk in which he attached a comment from Dave Cushman saying how interesting was this paper by Wolfenden on the inhibitors of carboxypeptidase. And Zola wanted to know whether we could get the compound to test whether it would be an inhibitor of a converting enzyme.

Rosenberg: Now why was there a thought that something that was an inhibitor of carboxypeptidase might be an inhibitor of ACE (angiotensin converting emzyme)? After all, inhibitors usually are very specific, and enzymes have great specificity.

Ondetti: I think the idea came about because during the time that I was doing the isolation of the peptides from the venom, we were also working in collaboration with David to know more about the converting enzyme. Dave had isolated and purified it from the lungs, and he had looked at the properties of the enzyme. His feeling was that it was a zinc metalloprotease like carboxypeptidase. But converting enzyme somehow had evolved to be able to cut two amino acids from the carboxyl end of the chain. While carboxypeptidase, as you know, cleaves only one amino acid, and carboxypeptidase has a great specificity for aromatic amino acids, while converting enzyme has not very strong specificity.

But we had found that, interestingly enough it did prefer compounds that had C terminal amino acid proline. So when Dave saw that paper, it wasn't that he believed that the compound was going to be an inhibitor of angiotensin converting enzyme, but he thought that, well, this enzyme was closely related to a converting enzyme and since enzymes do belong in families and have similar mechanisms, maybe one could use the same rationale.

So I never really made any attempt to get the compound that Wolfenden had—it was benzyl succinic acid. As a matter of fact, I don't think we ever tested it. We knew that it couldn't be. But we got together, and we discussed what did it mean, this observation, for our studies on angiotensin converting enzyme. And then we decided to get going on it. So March 1974 was really the beginning of our going back to the project.

Rosenberg: How easy was it for you to get approval to return to this area? Did you have to seek permission or did you guys just make up your mind you were going to do it?

Ondetti: No, we didn't officially seek permission or approval of the project as such—for a number of reasons. One of them was that we had a certain degree of flexibility in terms of work that we could do that we didn't have to actually report every single compound that we made. And second, I guess, in the back of our mind we knew that Zola was going to support it. And Zola was the head of all the biology. He was an associate director for the Institute in charge of all the biology and there was Pat Diassi, who was the head of the chemistry as an associate director. But as I told you, I was told to assume that my assistant Emily could be working on any project that I chose.

We told them it was an exciting idea, and it was something that we discussed the generalities of the hypothetical active side of the enzyme and said, "Listen, make the simplest compound to prove if we are in the right direction." And Emily made that first compound before she left on vacation in April, and that was succinyl proline. Dave Cushman found it was active, but very poorly active. But what was more important is that Bernie Rubin had been involved with us in the ACE program and had developed a combined assay using guinea pig ileum using angiotensin I and bradykinin. He said this compound behaves like a specific inhibitor, even though it was like a thousand times less active teprotide. So we said, (laughter) "We're back."

Rosenberg: Where did you go from there?

Ondetti: Well, then when Emily came back, we just started modifying this basic structure. But we had the idea from the very beginning that the important portion of the molecule was the carboxyl that was acting as a ligand for the zinc in the enzyme. So we started to try different groups that might also act as ligands, and that's how we ended up with the sulfhydryl group. And that's what led to the synthesis of captopril, and that was done in October 1975 for the first time.

Rosenberg: So that was really only a year and half from the time of the Wolfenden paper?

Ondetti: From the time that we decided to go back, it was a year and a half.

Rosenberg: Which was really very fast.

Ondetti: It was very fast by the standard for other areas, and I guess it was because we had an outline of the path that it was very straightforward. We didn't try to make a large number of synthetic compounds. We just were thinking about what this hypothetical side was telling us. Interestingly enough, if you look back now after many years, most of the ACE inhibitors that have been developed have maintained the structure or the underpinnings of our SAR (structure activity relationships) from the very beginning.

Rosenberg: Miguel, from the time that you tried succinyl proline, approximately how many compounds did you test before you got to captopril?

Ondetti: I think once we did a count...less than 100. It is interesting that before we dropped the angiotensin converting enzyme program, we had searched from all the files of the Squibb 2,000 compounds and tested them and practically all of them were inactive. So it was a big difference. I mean when you were on the right track and you knew what you were trying to get, that you could plan better.If you looked at the comparative activity of succinyl proline and captopril, it's like four orders of magnitude that was achieved in 100 compounds or thereabout.

Rosenberg: That's a remarkable....

Ondetti: It was a fairly direct approach (laughs).

Rosenberg: I think that's an understatement. You're being a bit modest. Four orders of magnitude in less than 100 compounds means that you guys knew very much what you were looking for.

Part 4: Two Key Experiments Demonstrate Captopril's Effectiveness; Clinical Studies Follow Post Haste
Its orally active nature and potency on spontaneously hypertensive rats indicate captopril's promise. Squibb puts full support into clinical trials.

Rosenberg: Now once you found captopril, did you think captopril was in fact a drug right from the beginning?

Ondetti: I guess we didn't quite believe it until we had seen two key experiments. First of all, it was that you could achieve inhibition of the angiotensin converting enzyme orally with a milligram and that was unheard of and very striking. And the second thing is that, you know—and I think it still is being used—at that time the key screen for antihypertensive agents were the spontaneously hypertensive rats. When we found that captopril was very potent on the SHR, we knew that we had a very potent drug.

As a matter of fact we sort of argued, sort of haphazardly, with management that we should be sure that we looked for other compounds to be sure that we had the best compound, but nobody wanted to listen. They said, "This is it. This is our candidate and now we have to make so many kilograms to do toxicology and we're going to Phase I." The first Phase I studies were done in Switzerland in December 1976 (by Hans Brunner). We made a compound for the first time in '75. To have a compound clear all the development in a year, that means it was a lot of push.

Rosenberg: So what that really does mean is that once captopril was discovered, it must have attracted a great deal of support very quickly from management all the way up to get that kind of priority. Who was the CEO of Squibb then?

Ondetti: This is a very interesting story. We didn't have a president of the Institute. The Institute had no president. Zola and Diassi as associate directors were running the institute and only I think very close to the middle of '77, I'm sorry, the middle of '76 or by the end of '76, was when Dr. Mackaness was brought in.

Rosenberg: What did George think about all this?

Ondetti: Oh, George was very excited, as you can imagine...

Rosenberg: Right away?

Ondetti: Oh, yeah. Before Dr. Mackaness came we had a sort of a quote unquote interventor. Somebody who came and sort of looked over...and it was Henry Harris from Oxford. He was called in by the management, Larry Marks, who was then the quote unquote chairman of the Institute. He was called in to pass judgment and to work at the Squibb Institute. I believe they must have offered a position to him, but Henry was not interested in leaving Oxford. And I think he was the one who proposed Dr. Mackaness because George had worked at Oxford in the time of the penicillin.

Rosenberg: Miguel, it would seem to me that the kind of push that was made would have had to have the support, not only from people in science, but it would have had to have support from the people on the business side. In retrospect, who were the critical business folks who climbed on the bandwagon?

Ondetti: I think that the critical person in management at that time was Larry Marks, who had come from the legal side of the company, but I'm not exactly sure what his position was. But I think they had a certain amount of concern, because nobody had a drug of this type. And even though the animal studies were very clear, indicating that they had an antihypertensive action, there were no precedents for it. And the only other drug that had been in the clinic as a blocker of the renin-angiotensin system was a peptide that was an angiotensin II antagonist. It was called saralisin, and it hadn't done very well because it was a peptide and second, because it had some agonistic activity.

So there was some hesitation, but I guess it also played a role, the fact that there was no other compound that was so quote unquote hot at that time at Squibb. Everybody felt that, well, there was a risk--and there was a risk because we did a number of things that were not probably correct because we were the first ones to do it. There was in everybody the idea that this was a completely new type of drug, and I believe that was one of the main roles.

Part 5: Trouble and Triumph
Serious side effects in clinical studies threaten the captopril project. General use studies finally show it to be as safe or safer than other drugs for hypertension.

Ondetti: There was a time in the history of the development of captopril when I believe, even though I didn't participate in that meeting, that the decision was pending to discontinue clinical research on captopril because we had run into a number of problems.

Rosenberg: This was while it was in the clinic?

Ondetti: That's right.

Rosenberg: What were the things that were encountered?

Ondetti: Well, as I think I mentioned, is that we didn't know that blocking the renin-angiotensin system would not necessarily affect blood pressure in all hypertensive patients, but only on those in which the tone was an important factor and where volume was not. And it took us a very long and difficult time to learn that lesson and to learn that we had to use a diuretic combination. And people, to counteract this lack of response on patients, kept increasing the dose until the doses that were used were ten times what it is now assumed to be a super effective dose. The people at the Cleveland Clinic reached more than a gram per day, and then, as you can expect, everything started happening.

Rosenberg: What were the things that happened to those patients? Do you remember some of them?

Ondetti: Well, one of the first things is that a very large number of patients at those doses developed rashes, and they had to be taken off, and that in some patients renal failure set in. But particularly, there was another lesson that we had to learn very carefully. When we got into the angiotensin system, it was believed that the only applicability of this system was for people who had renovascular hypertension. We later learned that those patients are the most delicate in the sense that they had to be treated very carefully because the renin-angiotensin system is the only one that maintains the renal function, and if you remove it, these people will go into renal failure. So you had to be giving very low doses and very carefully monitored and they didn't do it. So some of these patients were precipitated into renal failure.

Rosenberg: Was that the most dangerous moment in the clinical development—the work from Cleveland?

Ondetti: Well, then we ran into trouble in a number of other places. There was a point in which there was a very critical discussion (about) whether we should discontinue.

Rosenberg: Do you know who was involved with that discussion?

Ondetti: Well, I know that George was very strongly in favor. George Mackaness. I really don't know who the people were who were very concerned about the eventual responsibilities of the company, and they wanted to call it off. I think eventually Dick Furlaud as the final arbiter prevailed and said we would have to proceed with great caution. And as you know, the first time that finally captopril was approved, it was approved with severe restrictions.

Rosenberg: That would have been in 1981?

Ondetti: Yes, but it was very fast, comparatively speaking, because they filed the NDA in '77 or '78, but it was only approved for patients in which all other medications had failed. Then what really turned the situation right around was what we called the GUS study, the general use study, that was undertaken, I think it was by John Alexander and people at the Veteran's Administration in which it was given to a very large variety of hypertensive patients in low doses. And that proved that captopril was as safe or safer than any other drug. But there were very difficult times.

As a matter of fact, I remember one of the Merrill Lynch stock analysts had coined the name or the phrase, "the saga of captopril," because everybody was excited by the way we had come out with a compound. And to think that everything was going to end up in nothing, made people very, very unhappy. So it was a tremendous turnaround when we finally got the release. And then interestingly enough, we have very few problems with congestive heart failure because it proved from the beginning that it was very beneficial and people used very small doses. So it was a tremendous feeling of excitement and sometimes very severe depression (laughs).

Rosenberg: Miguel, it's a wonderful story. It is a saga because it has moments of great exuberance and then moments of feeling despondent. There's excitement all the way through it.

Ondetti: A lot of drama.

Rosenberg: So Miguel, talking about some of the drama and some of the lessons to be learned....As I listen to you talk, it seems to me that one can point to a number of serendipitous events where if things had not been done, captopril probably wouldn't have been discovered. Let me just tell you what some of those look like to me, and I would be interested in your thoughts. First, of course, if you hadn't worked with Dr. Deulofeu, the likelihood is that you would not have been invited to come to the United States.

Ondetti: Yes. Almost certainly that's the case.

Rosenberg: Second, if you had not been asked to go to work on peptides, even if you didn't like it, you would not have learned the tools of the trade which would have enabled you to recognize how to synthesize peptides and how peptides might be degraded. Do you think that's right?

Ondetti: Oh, yeah, that is quite correct. I think that if I would have had my choice of working in steroids, I would probably never have been asked to collaborate on converting enzyme.

Rosenberg: So a third point is that when John Vane was able to excite Dave Cushman about the snake venom, Dave obviously needed a collaborator where the biology and the chemistry could be coupled and the two of you guys had to be willing to work together for this to proceed. Isn't that right?

Ondetti: Yeah, that is true. Dave had come to the Institute like a year before, and I knew that he was working on some type of enzymes that were fluorinating compounds, but we never had a chance to interact. But we were asked, I guess by the powers that be, I guess Dr. Smith and Welch and Zola had decided that we had to work together and it came out very naturally. We had different backgrounds, but we were sort of attuned to each other's research needs. He was a biochemist, and I was a chemist, so from the very beginning we had a very close collaboration and not only among ourselves, but also with the rest of the pharmacology department. Because Zola had sort of taken over Dave's lab that was in the department of biochemistry, but he had asked David to move to pharmacology, and David was happy to oblige. So we had this collaboration with pharmacology with the isolated smooth muscle testing and the biochemistry and the chemistry. I think that was critical.

Rosenberg: And I guess you know, one can say that the environment in the company at that time was also very important. You have mentioned Zola Horovitz a number of times. Zola had to be supportive. At moments I'm sure he had to run interference for this activity. So he had to believe in the importance of the science, even when it was completely unproven in terms of concept because, as you pointed out, there was no precedent for this sort of work. So it seems to be there are a number of moments and a number of critical people, and it makes for a great story, as well as a great discovery.

Ondetti: Yeah, I think many times we don't realize how important is the particular environment, not necessarily only in terms of having people of the right intellectual capability, but people who are fired by something that is different, something that is new, something that gives you the possibility of making a contribution, a research contribution. And that is very critical in a pharmaceutical endeavor. Zola came to the company, actually, to do research because he was supposed to be having a lab on CNS research and slowly, because of his personality, he was drawn into more of a managerial function because he could get along with people. He was always very keen in supporting people who had projects that had a great basic research impact.

Rosenberg: So Zola understood that at the end of the day, the quality of the people determines the direction and the success of the company.

Ondetti: It is not necessarily only that you pick a project because it has at the end a dollar sign in terms of drugs that are known, but whether you are going to make a significant basic contribution. And he understood that. He was always supporting that. And he has, of course, a personality (that makes him) able to convince other people. He would always listen to them, and that was a great asset for us.

Rosenberg: Well, I guess what we all have to hope is that companies like Bristol-Meyers Squibb will continue to have an environment where outstanding science will be valued, even if it isn't clear at the outset—because it never is clear at the outset if you're really doing something original—where things will go.

Ondetti: Yes.

Rosenberg: Well, thank you, Miguel, very much.

Ondetti: Thank you very much.