Interview with the 1998 Nobel Laureate in Physiology or Medicine Ferid Murad, at the 57th Meeting of Nobel Laureates in Lindau, Germany, July 2007. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.
Ferid Murad talks about his natural knack for science, why it took 100 years to discover how nitroglycerine works in the body (20:28), how light helped to shine light on nitric oxide (31:59), and why it is difficult for medical students nowadays to receive the research training that he received (49:20).
Ferid Murad, welcome to this interview with Nobelprize.org. Could we begin by you telling us a little about how you became a scientist in the first place?
Ferid Murad: Thank you, I’m pleased to be here. I had a knack as a youngster for mathematics and science, I really enjoyed it, starting in the third and fourth grade. I found that those classes were so much more fun and appealing than some of the other classes, the English classes and the government classes and so forth. Some of the science teachers I had along the way were very encouraging and that helped to have the mentors there at the right time. When I was about 10 years old, I thought I was going to go into medicine. How I decided that I don’t know. My parents had very little education but I’d recognised the importance of education because of them. I thought my first choice would be medicine and my second choice would be teaching, perhaps mathematics or chemistry and my third choice was pharmacia or pharmacology. I’ve found that those goals haven’t changed. I think it’s because I really enjoyed science and mathematics, I had a knack for it and I did very well with it.
The humanities in school were not quite as exciting to me but I did it. I learned how to memorise, I played mathematical games in my mind. I’d walk down the street and memorise licence plate numbers, things like that. I developed lists of random numbers and tried to learn them all and memorise them. It was great preparation for medical school but because of the knack in science, I thought that what I should do is go into medicine. I also, because of teachers, thought teaching was a possibility. One summer, I was interested in butterflies with a friend, I was a youngster and we were catching butterflies. I didn’t want to touch them with my fingers as I mounted them with pins in this cloth or frame that I constructed, so I went to the local pharmacist and asked them if I could have some cyanide, potassium cyanide and hydrochloric acid and he gave it to me, today that wouldn’t happen.
Those were the days.
Ferid Murad: But that got me interested in chemistry and I also was thinking about the possibility of pharmacia or pharmacology and in eight grade we were asked to write a paper, an essay about career choices: What do you want to be when you grow up? My first choice was medicine and my second was teaching, being a professor, and my third choice was a pharmacist or pharmacologist. I’ve become all three of those. I guess I knew what I wanted to do and I had goals and worked very hard for it, but what really influenced the whole process so much was the recognition, the encouragement from so many mentors, high school teachers, college teachers and certainly graduate school and medical school. When I decided, instead of going to medical school, to go into an MD PhD programme which was a brand new, spanking new programme in Cleveland, had just gotten started.
That was the programme that Earl Sutherland began.
Ferid Murad: Earl Sutherland began that programme in Cleveland in 1957, a couple of years after he went there as chairman of the pharmacology department. Earl was an MD who was a clinician in the army and subsequently went back to St Louis and trained with Carl Cori in biochemistry and got interested in glucagon metabolism and phosphorylase and then as a very young man, went to Cleveland as chairman of pharmacology. A couple of years later he hired a young assistant professor, Ted Rall who was a biochemist and Ted looked after his laboratory as Earl did his administrative things, as the departmental chair, but Earl had an incredible vision as a physician and as a scientist, he could put it all together. Ted had the skills of how to do that right experiment and make it work, he had the hands for the laboratory and he insisted on all kinds of controls, so I was fortunate to have worked with both of them.
Earl had this incredible vision about how biology should work or did work, and Ted taught me how to do the experiments so that you would believe your data. Ted would ask for so many controls that, as an MD PhD student I kept flipping back and forth between medical school and graduate school because it was not a federally funded programme at the time, it was all pieced together with some of Earl’s donations from some /- – -/ companies for his interests with glucagon with Lilly, a training grad that he had and his research grads. In order to get my stipend, I had to spend so many months a year in the graduate programme, otherwise I’d have to forfeit my stipend, so I was flipping back and forth between medical school and graduate school and that was exciting and the curriculum was quite unusual. It was the first school, not only to create the MD PhD programme because of Earl, but also to teach in a different fashion with the working systems, it was a very integrated approach to teaching. One lecture would be anatomy and the next would be physiology and the next would be biochemistry and the next would be clinical applications, so you learned how to put it all together very quickly. Having worked with both Earl and Ted, who were quite different and having this curriculum, I just got really turned on and when I decided to go into this programme, instead of going to medical school, my parents were rather disappointed.
I can imagine, because you were taking a step away from a traditional career.
Ferid Murad: My parents wanted me to become a doctor and go home and practice in a small town on the south side of Chicago, Whiting, Indiana, and I didn’t know what to say to them. I looked at them and I said, If I become a doctor and come home and practice, in my entire lifetime maybe I can help 2 or 3,000 people, but if I go into research and if I’m lucky and find something important, I’ll be able to help a lot more. They then understood it and it made sense to them. I really got turned on, both in medicine as well as laboratory, got married, had quite a few children, we had four children when we finished that seven-year programme …
… and you needed a job to pay for them.
Ferid Murad: … and I wasn’t ready for a job, I wanted some more training, so I decided to take an internship of residency and went to Mass General and that’s where I got to meet Mike and Joe and a lot of other wonderful people.
Tell me about the beginning of Mike Brown and Joe Goldstein’s relationship, because you were there at the start.
Joe came from Dallas, he had gone to medical school at South Western and Mike came from Pennsylvania, University of Pennsylvania, and they were both brilliant students. The whole group, there were only 12 interns in their class and I think all of us were the top one or two students in our classes, so we were all very bright people, but only a couple of us had experience in a laboratory. I was one, Tony Gotto was another with a PhD and the rest hadn’t had much experience in a laboratory, but that class turned out a lot of academicians and scientists, a stellar group: Tom Smith who became Head of Cardiology at the Brigham and Ed Scolnick who became President of Research at Merck and myself, it was really quite a group.
Mike and Joe have had this extraordinary relationship of working so closely together for 35 years, did they recognise it immediately when they started?
Ferid Murad: No, I think they became friends initially, like we were all really good friends and colleagues. There wasn’t much free time in this process, we worked 100 hours a week and whenever you had a little bit of free time, we’d go to somebody’s house for a party. We’d steal some lab alcohol and make some punch and that was entertainment for a weekend. I think their relationship grew when they got to NIH. They worked in different laboratories, but I think their relationship was fostered and promoted. Then what happened was that Mike, after NIH, went to Dallas to do a fellowship in gastroenterology with Dan Foster, I believe, and Mike went to Seattle to do a fellowship in genetics.
Yes, Joe went to Dallas and Mike went to Seattle.
Ferid Murad: No, Mike was in Dallas and Joe went to Seattle.
Oh, really, okay.
Ferid Murad: Then Joe was recruited back to Dallas as a young faculty member and that’s when their collaboration began. It was probably, let me guess, I would say the early or mid-1970s, early 1970s probably. They were now both on the faculty, seeing each other and their relationship really took off, with genetic approaches lipid metabolism, that’s how it got fostered.
Yes. One thing that you seem to emphasise when you talk about science is the amount of work that’s required and you just referred to 100 hour weeks. Is that something that came out of your background?
Ferid Murad: My parents worked very hard, my father was an immigrant, he was an Albanian from Macedonia, he came to the US when he was young, 19. My mother he met later, she was American. Both came from very poor backgrounds, little or no education, they ended up in a family restaurant business, putting in long, long hours, 14-, 16-hour days. I grew up in that environment and although they had hadn’t had much education, they really encouraged their three sons and I was the oldest of three, to go on to school. If we were going to have a different lifestyle, we had to get an education and that was apparent and a lot of folks coming into the restaurant, this was a family restaurant where the workers and teachers and bankers were coming in for lunch, many of them became mentors and advisers and they kept encouraging me as well. My parents gave me an awful lot of freedom, they told me how important education was, I recognised how important it was and if I was going to have a lifestyle different than theirs, I had to have an education, but I saw the work ethic that was necessary to accomplish what you wanted to do. I was a bright kid, I had a pretty decent IQ I think, but I’m not brilliant and I made up for it with a lot of extra hard work and I think you can do that, so I’ve always, I think my whole life, worked 70, 80, 90, 100 hours a week. I still work 70, 80 hours a week.
That’s a message worth spreading.
Ferid Murad: You do it if you enjoy it, it’s not painful to do it, it’s fun to do it. It’s fun to go to work and solve problems.
Another thing I think you stressed in some of your writings was the need for competition, the importance of competition.
Ferid Murad: I think competition is important. I competed with my brothers, I competed with classmates in school, it was fun, we had a great time. One of my best friends I met in kindergarten, we’ve known each other ever since, he became an aeronautical engineer, he was on some of the projects with Boeing that built the Stealth Bomber, very talented aeronautical engineer. I went the medicine route but when we see each other, in the past we would compete with chess or we would compete with whatever and we still compete, but it’s fun.
Ferid Murad: I say competition is very healthy, it motivates you, it drives you. It’s got to be friendly competition, it can’t be horribly aggressive competition, but it’s most fun when you win.
Yes, that’s true. I suppose that it’s a fine line to tread between friendly competition and unfriendly competition.
Ferid Murad: Correct.
When you think of mentorship, what characterises a good mentor?
Ferid Murad: It’s like raising a family, you want to encourage your trainees or children, you want to provide everything they need, the resources, the space, the equipment, ideas, but you expect them to contribute as well and what I enjoy is having, not arguments but discussions about my ideas versus theirs. I want them to be open and straightforward and tell me what’s on their mind, tell me when I’m wrong and I’ll do the same with them and that’s an interesting interaction and dialogue. There are lots of educationaI systems that don’t work that way, where the trainees feel suppressed, afraid to test the boss, ask questions and I think that’s wrong, that inhibits creativity, I think.
I suppose classically, medical training fits into that.
Ferid Murad: Exactly.
When you recruit students to work in your lab, what do you look for in them?
Ferid Murad: I have a lot of international students. Of the 130 or so trainees I’ve had, probably ⅔, ¾ are foreign, from all over the world and the others are American, I mix them up. The trainees have backgrounds in genetics, molecular biology, biochemistry, pharmacology, physiology, cell biology and I put them all together and they all teach each other something. They end up collaborating. They all have their separate projects and when they come to start working in the laboratory, I offer my ideas but I want them to meet everybody and come back with some of their own ideas and they will settle in on a project. They each have a project to work on, but all of the projects intermingle and overlap to some extent, resulting in collaborations and assistance from other people in the laboratory, so they’re all learning something. I learn a lot.
How do you organise a lab where people are working on different projects, with different skill sets and yet you need them to interact?
Ferid Murad: We have lots of meetings, lab meetings weekly, where three or four of them will present their work over the last month or so, so over the course of a month, basically everybody has an opportunity to present what they’re doing. It’s an opportunity for others to see what they’re doing, learn about new techniques and ideas, opportunities to collaborate. I’m there to orchestrate, I’m there to provide the resources, test some of the ideas, offer ideas but not inhibit experimentation. I never ever tell a person not to do the experiment, I say if that’s important for you and interesting enough for you, you do it, even if it means doing it on your own time, you do it. I think it’s good and healthy for a trainee to discover something themselves and when they do, they really get into it, they really have ownership of that.
We’re a bit jumping out of temporal sequence, but when you found yourself in industry in the 1980s and 1990s, were you able to apply the same principles to allowing people to do their own experiments?
Ferid Murad: My laboratory, when I went to industry, was different than the other laboratories. It’s only because I went into the industry in a very senior position, with a lot of authority and a lot of resources and they weren’t hiring me to run a laboratory. They were hiring me to be an executive to run RND, but I said, If I’m coming into industry, the only way I will come is with my own laboratory, post-docs and grads, because I want to continue doing my own thing in the midst of all of this. They agreed to that, they didn’t want to lose me as a candidate, but once I got in the system, then they said, You’re really an executive, why are you running this laboratory? I said, I’m running the laboratory because I love it and how can I manage research if I don’t do it myself? You have to be able to do it and you have to be an example. I’ve always thought that, as an administrator – and I’ve become more and more of an administrator over the years – that I have to do better and more research and more funding than anybody else to be a leader. If I can’t do that, I shouldn’t be a leader, so I work very hard at it.
Were you able to have any influence over the way that Abbott [Laboratories], as a whole, did its research?
Ferid Murad: I influenced a lot of projects. I terminated some that I didn’t think were going to be successful. It’s very difficult to do that, you have to do it slowly and it’s not easy and created a lot of new projects. I think I was having a lot of fun at Abbott, learning an awful lot about the pharmaceutical industry, about toxicology and formulation and marketing and acquiring a lot of skills, that I hadn’t had from academics, but what disturbed me was my senior managers. There were about three people above me in the company, were marketing sales types, they were not scientists and their philosophy and notion about science was quite different. They thought that you could open the spicket and turn it off at will, they didn’t realise that you had to have a programme going on for some five or ten or 15 years sometimes before you saw a product come out of it and that you couldn’t just stop it all of a sudden for fear that you’d chase off a lot of talented scientists. I was also concerned that their investments in RND were not sufficient compared to their investments in sales and marketing. The sales marketing budgets were twice the RND budgets and that didn’t make sense to me for a technology-based company.
Is that still the case?
Ferid Murad: Yes, it is, in fact it’s getting worse and I think that’s why the pipeline in large multinationals is drying up.
We’ll return to that theme in a little while. I wanted to focus on the discovery that in particular led to the award of the Nobel Prize, together with Robert Furchgott and Louis Ignarro in 1998. You found that nitroglycerin, which had been around for 100 years and used to relieve chest pain and angina, works by the release of nitric oxide which is an unusual signalling molecule because it’s a gas and the question that seems to be begging is how come nobody had found this for 100 years?
Ferid Murad: If you went looking for a gas or a free radical as a messenger, it would be an impossible project and the way we discovered it was really through the back door, through another avenue. I grew up in Cleveland working with Sutherland and Rall, interested in cyclic AMP. How do hormones regulate cyclic AMP and what are the biological effects of cyclic AMP to regulate glycogen metabolism, fat metabolism etc?
Cyclic AMP being the first second messenger.
Ferid Murad: The first intra-cellular second messenger and then in the mid-1960s, cyclic GMP was discovered by some chemist. I kept an eye on the field because I was intrigued with that notion of another messenger molecule and over the next few years, a couple of messengers started popping up. Calcium came along, prostaglandins were looking promising, diacylglycerol was looking promising, cyclic GMP started looking promising and when I left my training in NIH to go to my first faculty position at Virginia in 1970, I said, I’m going to switch from cyclic AMP to cyclic GMP. As a young faculty member, I saw a lot of activity in the field of cyclic AMP research, a lot of laboratories were now working with this. In 1971, Earl Sutherland got the Nobel Prize for that, so that attracted even more people and I didn’t want to compete with these big factories as a young faculty member. I thought there was a lot of high risk to that and I saw cyclic GMP as a new emerging field where I could take my information and ideas from the cyclic AMP field and work in another direction, so I made the switch to cyclic GMP. I wanted to figure out how hormones and drugs regulated cyclic GMP production and what are some of the biological effects of cyclic GMP, those were unknown at the time.
In our very first experiments we found that tissue extracts contained not just one enzyme to make cyclic GMP but at least a couple, a soluble activity and a particulate activity. With some biochemical studies we thought they were different isoforms, one had cooperativity with substrate, the other did not and I thought, wouldn’t it be interesting, whereas adenoid cyclase at the time appeared to be a single isoform in the membranes. We now know they’re mini-isoforms but in those days we thought there was just one and for guanylate cyclase, it’s cousin, to now have multiple isoforms. I thought wow, this is interesting, they’re different compartments in the cell, perhaps they are different hormones and mechanisms to regulate each of these enzymes. There will be different pools of cyclic GMP in the cell, perhaps with different functions and wouldn’t that be an interesting complicated problem to tackle? We went after it, it turned out hormones wouldn’t activate the enzyme in cell free preparations, which was one of our goals, we wanted to figure out how hormones worked, how did they couple to the cyclase regulation? They didn’t work in cell free systems and because we thought we had different isoforms, I thought maybe different hormones would work on each isoform differently. Ultimately we had to purify those isoforms and clone them and express them but that took a long time, that took 12 years probably, so I took a shortcut and threw in the kitchen sink. I knew that you can’t trust kinetic data in crude preparations room for a lot of artefacts. Our preparations had nucleotidases, phosphatases, phosphodiesterases, competing for substrate, competing for a product that we were measuring, so what we were seeing could have been spooky and erroneous…
Ferid Murad: I took a shortcut and made a cocktail of all sorts of inhibitors like you pull off the shelf, to inhibit nucleotidases, phosphatases, phosphodiesterases, pyrophosphrate, fluoride, azide, hydroxalamine, methylzanthines.
As you say, everything that was on the shelf.
Ferid Murad: Everything I thought would inhibit this pathway and re-examine the kinetics and accidentally found that some of these compounds activated the enzyme. Azide, hydroxalamine and sodium nitrate and that was an important lead. As a student, I recognised the importance of fluoride activation about doing cyclase. We had another small molecule in the cyclic AMP system, that turned out to be very valuable in understanding the role of adenoid cyclase regulation and the role of G proteins.
So you were pre-warned to look for small molecule activation.
Ferid Murad: Yes, there was a precedent for it and now we stumbled into another class of small molecules that did it with guanylate cyclase and I said, Maybe these will be hormone surrogates that are bypassing the system. Obviously the hormone receptor binding at the cell surface is not communicating to the cyclase. In a cell free preparation we’re missing something but these are activating, maybe they’ll help us figure out what we’re missing and that’s what led us in the nitric oxide, we took these compounds and we put them in the tissues and they raised cyclic GMP levels in lots of tissues, including smooth muscle. I thought cyclic GMP in smooth muscle would cause contraction. As a student I knew that cyclic AMP caused relaxation, I thought they would antagonise each other.
Ferid Murad: That’s not what we saw, they caused relaxation and once we saw that we said, What do other smooth muscle relaxants do? What does nitroglycerin do and what does nitroprusside do? We put them in and sure enough, they elevated cyclic GMP levels and I don’t mean intact cells but in broken cells. Now we ended up with a family of molecules that were capable of increasing cyclic GMP levels in intact cell cultures and slices and tissues, as well as activating the soluble isoform of guanylate cyclase. Then it became a mystery story for a couple of years. What is this intermediate, they’re all pro drugs and an important lead for us was the discovery that some tissues did not respond to azide. That’s because they possessed inhibitors and we purified those inhibitors and they were haemoglobin and myoglobin, so we knew that haem proteins could somehow interfere with the activation. We had a long list of we call nitro vasodilators, they were all nitrogen containing, some were nitrose, nitrosos, hydrazines, whatever. We said, Could the intermediate by nitric oxide? because in the literature, we found papers with a very high affinity of nitric oxide for the haem prosthetic group of these proteins …
Okay, so it was binding nitric oxide.
Ferid Murad: … and we said, Let’s see if it’s nitric oxide, and sure enough it was. That’s how we found it. It was accidental, some biochemical you know, rationalisation, serendipity, it happened that we had to have smooth muscle in the lab at the time.
Yes, many things coming together and above all, a preparedness to look at the data in a particular way.
Ferid Murad: We were approaching it from a very biochemical direction but I thought in a very meaningful, logical, sequential fashion. The big mystery is, how do we jump from all these nitro vasodilators, which we thought were pro drugs to the activator of G cyclase. We stumbled with it for a couple of years and then finally we realised there could be nitric oxide and made it and sure enough it worked.
Have you pondered whether there were people out there in previous decades who were close to the possibility of solving this problem?
Ferid Murad: Yes, there some other laboratories, one that I remember quite well. A fellow up in Minnesota, Nelson Goldberg who was also interested in cyclic GMP, trying to figure out what regulated this production, what were some of its functions? He was working with lymphocytes and a lot of other systems. Nelson was really a very aggressive, hustling, clever scientist, however Nelson, although he was a good friend, we were fierce competitors and a lot of stuff that he did I didn’t believe. I could never tell whether Nelson did the experiment once or a dozen times and Nelson had the preconceived notion of this is what cyclic GMP should do, it should antagonise cyclic AMP. He came up with yin yang hypothesis, one goes up, one goes down, this was all nonsense in my opinion, because we couldn’t see any of that sort of stuff, but what it did for us is motivated us to work harder. We were trying to be number one and Nelson was very close, he could have, had he not forced his data to his preconceived notion of how things worked, he probably could have found before us, but he was forcing all the data to fit what he believed should be and I think that’s always a bit mistake in science. Instead of really saying, this didn’t work the way I thought it would work, maybe something else is going on. That’s what Ted Rall taught me to do. Earl Sutherland taught me to be as imaginative and free associating as you can be, just pluck it out of here and there and try to figure out how to put them together, his mind was incredible. Ted taught you how to pigeonhole all of it into a spot and do the experiment in such a way that it was either right or wrong. So it was fun to have had that experience working with both of them.
Yes, you got the air and the land right there.
Ferid Murad: Yes, when we did an experiment and I got a result, I knew I could believe it and if it didn’t fit my ideas, I said, Something else is going on, let’s go think about this now.
Following up on the story, you then had Furchgott discover quite rapidly that there was this thing, EDRF, Endothelium-derived relaxing factor, and that that was the mechanism of action of certain drugs action on the smooth muscles surrounding blood vessels, but it took another six years or so for the connection between nitric oxide and EDRF to be made. Lookingback, it seems perhaps to students …
Ferid Murad: For some people it took six years.
Oh right, oh okay.
Ferid Murad: I’ll tell you this story.
Yes, please tell me the story because it seems, looking back, that it might have been an obvious …
Ferid Murad: Robert Furchgott was a vascular biologist, pharmacologist for many, many years. I met him as a student in Cleveland when I was a graduate student. Earl Sutherland would bring dignitaries through for seminars and I got to meet Furchgott very early on, in the days where he was looking at receptor theory and receptor abundance and excess receptors in vascular preparations. It had been known for a long, long time that some agents, acetylcholine, histamine, others would lower blood pressure in animals or man, they were hypertensive vasodilators, but they would never work in the laboratory and that’s because the integrity of the endothelium was destroyed in the process of making those preparations. One day, Bob gave an experimental protocol to his technician and instead of making strips where they would take a muscle and open it up and put it on their finger and clean off the tissue and mount it on the hooks, in the process what you’re doing is touching the endothelium and destroying it. His technician took a short cut and just like the salami, whacked off rings and hung them up and now they caused relaxation. It was a different preparation with the endothelium intact and Bob is so meticulous and clever that he realised the difference. He said, My goodness, now we have the endothelium and here we didn’t.
Now the other tip-off: one day their chambers were near a window and they had a shade and somehow they put up the shade or put it down, one or the other, and they noticed that when they opened the shade, the muscles relaxed, when they closed the shade, they contracted – he had light induced relaxation. When we found nitric oxide activation of guanylate cyclase, I was very excited to find a free radical activating enzyme, that was a precedent and it had never been shown before. I thought perhaps other free radicals might regulate other enzymes and I knew that there was a lot of free radical chemistry and photo chemistry, so we’d drink cocktails with riboflavin and other goodies in our preps and would shine light on them and try to activate the enzyme. On one occasion we were successful, but we could never repeat it, but when it worked once, I knew it had to work, but we couldn’t repeat it, something was different the next time we did it. Again, it reflects Ted Rall’s assistance in how to design an experiment, if you’ve got your data, you can believe it, but if you can’t reproduce it, it doesn’t mean it doesn’t work, it means you’re doing it differently, but we could never get it to work. When Furchgott found this factor coming out of endothelial cells that caused relaxation of smooth muscle, he came through Charlottesville to give a seminar, all excited about these endothelial dependant vasodilators and EDRF. This was in the spring of 1980, before his Nature paper. After his seminar, I buttonholed him and took him off to my office and I said, Bob, EDRF with a short half-life of several seconds is a reactive species, it’s probably a free radical or some other reactive molecule and I think it’s going to work through cyclic GMP and it might be something like nitric oxide or a complex, let’s collaborate and figure this out. We agreed to do that. It turned out that in that trip to Charlottesville, his wife fell, broke her hip, turned out she had metastatic breast cancer in her hip, they returned to New York and he was so distracted with her breast cancer. Shortly after that I started looking at Stanford, we moved the lab out to California, so we never collaborated, I wish we had.
Yes, that’s a missed opportunity.
Ferid Murad: Yes, we lost about a year or so because we hadn’t collaborated because of his experience and hers, but then we got out to Stanford, I moved in the summer of 1981, about a year after his visit. Michael Peach, a pharmacologist from Virginia and a colleague and a vascular biologist, interested in prostaglandins but also following the EDRF story, came to visit and consult for syntax across the street from the VA where my office and labs were. He came over one afternoon, we were chatting and he said, What are you doing with EDRF? and I said, Mike, we’re waiting for samples from Furchgott, we’re going to collaborate and see if it works with cyclic G, I think it will, but we never gotten any samples from him, as far as I know. I said, Let me call the post-doc in who was going to do the experiment. I called in Robert Rappaport who was with me at the time and I said, Robert, have you ever gotten samples from Furchgott’s lab? He said, No, and then he smiled. I said, Robert, what’s going on? Sheepish smile. He said, I’ve been stashing samples away that I’ve been doing in the Revco. I said, Robert, this is an example of a trainee who’s inquisitive enough to take the time to do it, but he’s afraid to tell the boss, but he’s doing the right thing. How can you ever inhibit that sort of activity, behaviour? You don’t want to do that. I said, You better go back to the lab and get all those azides and sure enough it worked and we then showed that EDRF worked through cyclic GMP. That was a nice follow-on story to Bob’s work. Shortly thereafter, he and Ignarro and even Muncada started saying the EDRF might be nitric oxide and I said, No it’s not. I said, Maybe you’re making nitric oxide but what is in that interstitial space regulating the smooth muscle, has got to be something else.
Why did you think it had to be something else?
Ferid Murad: Because NO’s a free radical and is going to collide with all sorts of stuff and it won’t survive, it has a short half life, a few seconds. To this day, I believe that the enzyme, nitric oxide synthase makes NO, no doubt about that, we’ve purified most of them, it doesn’t have others, but I think that Furchgott’s EDRF is a family of molecules. NO is a candidate, nitrosothiols, nitrosamines, nitros of fatty acids. All of those are EDRFs, as defined by Furchgott.
How generally accepted would that view be now?
Ferid Murad: Nobody wants to accept it. I’ve been saying that since about 1988 or 1989.
I remember in the late 1980s, people sitting around in the coffee room in the pharmacology department in Oxford, disbelieving the possibility that EDRF could be NO.
Ferid Murad: The enzyme makes NO, NO certainly gets through the lipid bile air. It can go one or 200 extra from studies now with electrodes and other methodologies, but I think it’s a family of molecules and all of those are capable of delivering NO as NO donors to activate G cyclase.
Is the hypothesis testable, is there any way that you could actually …?
Ferid Murad: I don’t think so with current technology. I think the concentrations of EDRFs in that interstitial space are so low that we just don’t have methods to identify them and isolate them and mass spec them or whatever we’re going to have to do. I think that they could well be several or a family of molecules, all of which are capable of relaxing smooth muscle. If you look at Furchgott’s definition, which is sort of a loose definition, all it is, is a substance with a short half-life that relaxes smooth muscle. That can be a lot of things. The enzyme no doubt makes NO, NO comes out, that’s been measured with electrodes and with theoretical calculations, distances of 100 to 200 microns are possible, so for small vessels there may be enough, for big vessels, I’m not sure it gets that far, but how do you determine what it is, it’s going to take some new approaches.
Apart from the basic interest of knowing that EDRF would be a family rather than a single entity, are there practical applications?
Ferid Murad: I don’t know. That’s something that’s been pointed out to me, does it really matter? If NO is made and NO activates the enzyme and is responsible, does it matter what’s in between? Probably not, but as a scientist you like to know.
Yes, it’d be nice to know.
Ferid Murad: I think if you knew some of the substances that were in between, perhaps the chemists and the pharmacologists could in the future design molecules to either protect or scavenge them in some way and that might lead to a new approach for drug development.
It would seem to offer the possibility of more cell activity.
Ferid Murad: Maybe.
You did find yourself in industry for a few years and then you returned to Houston, to the lab. Did the sojourning industry change your approach to the way you ran your lab, did experiments?
Ferid Murad: My laboratory in industry was an academic laboratory, it was no different than what it was at Virginia and Stanford. We turned out to be a resource for reagents for other laboratories. Other laboratories were becoming interested in cyclic G, in phosphodiesterases in other words. We had reagents, antibodies, whatever, that we were supplying other laboratories. But we were sort of an island in the midst of the company really and I think the laboratory was viewed differently by other scientists and perhaps favoured by me, which I’d hope was not the case, that we had more freedom, our own grant money and post-docs, things that other people in the company didn’t have. It made for a little discomfort in the company. There was pressure on me to give it up, I refused to do that. The reason I gave it up is because I was concerned about some of the decisions being made by senior management. We had some problems where drugs should have been pulled from the market and weren’t. We had situations where they would not pursue directions for research that I thought were important. One of the examples, in Virginia I collaborated – about the time we discovered NO actually – with an Infectious disease faculty member, Dick /- – -/ who was interested in third world diarrhoeal disease, particularly Bangladesh at the time, he had been in the Public Health Service for a while. He had a strain of E-coli that produced a heat stable endotoxin that caused diarrhoea. He had worked previously at Hopkins showing with Bucky /- – -/, the /- – -/ toxin increased cyclic AMP production toxin and he thought that perhaps this toxin would do the same, increase cyclic AMP and cause diarrhoea. I said Ok, we’ll help you work out the mechanism, but I want to look at cyclic G also.
Sure enough, this toxin activated the particular isoform guanylate cyclase and it was a new novel pathway for diarrhoea. It turns out both cyclic AMP and GMP activated the inappropriate kinase in the intestinal mucosal epithelial cells. Those kinases which you’re going to hear from Edmond Fischer this week, phosphorylate, the cystic fibrosis transmembrane conductance channel, the chloride channel. When it’s phosphorylated, chlorine comes out the cell as does sodium, water and that’s the mechanism of diarrhoea. I’ve always wanted to find a compound that would block that pathway and I wanted to work on it at Abbott, because it was such a simple, straightforward problem and we had the resources to find it pretty quickly, I think, but I wasn’t permitted to work on. I didn’t understand why and one day my president said, It’s a third world disease, we’re not interested in third world disease, there’s no profit.
Given the current antagonism towards the pharmaceutical Industry that this is a generic problem for them, one would have thought that such PR exercises at the very least would be …
Ferid Murad: If it were Merck, with Roy Vagelos, he would probably have said, Go chase it, Ferid, but Abbott and others wouldn’t have done that. What has happened is, I left Abbott for a variety of reasons. I learned as much as I could about the industry, I was a little concerned about how things were going, a little bit concerned about the lack of freedom to work on things that I thought were important. We had compounds that could have been very effective in a lot of infectious diseases in AIDS patients, they didn’t want to chase it. Ultimately they did but they wouldn’t listen to me. I was the senior scientific officer, I felt it strange that they wouldn’t listen. I said, Okay, time to go back to academics and I went to Houston, I looked at some other opportunities and chose Houston, but now we have found such a compound and I’m really excited about it. I’ve screened the library, we have a hit, a lead, we’ve got a compound that not only blocks guanylate cyclase activation by E-coli heat stable enterotoxin, but it blocks G cyclase activation by guanylin in intestinal peptide. It blocks /- – -/ toxin activation by adenoid cyclase, it blocks /- – -/ and epinephrine activation of adenoid cyclase, it blocks atriopeptin activation of guanylate cyclic. This is a marvellous compound, I think it’s going to be universally effective in all the diarrhoeal diseases.
Where is it now, the compound?
Ferid Murad: Right now we’ve patented it, we’re trying to do some initial chemistry to make some analogues. We know it works in vivo, in animal models, it does block diarrhoea due to toxin, it blocks anthrax, it really is marvellous. Now the problem is to move it forward into toxicology, medicinal chemistry, analogues, formulation and then the clinic and that’s tough to do in academics.
Yes, you need a trustworthy partner in industry.
Ferid Murad: I can do it, if I had the resources and money, I could do it because I’d have the experience, I know how to do it. It’s easier to do in industry, where the resources exist and the money exists, but I’ll find it and one way or another I’ll find it. I’m really anxious to get this into some clinical trials.
It matters but it’s tough.
Ferid Murad: I know. I figure it’s going to take me five or six million dollars to get it into clinical trials and at that point we’ll stir up some interest. I think it may also work in inflammatory bowel disease and that’s where the interest will come. If we can get it to work in inflammatory bowel disease, the big companies will be interested and hopefully they’ll give it away to WHO for third world diarrhoea or something.
Yes, otherwise one goes the route of finding Gate’s money or something.
Ferid Murad: I’d try all the avenues I can at the moment. I’ve told people I’m going to sell my house if I have to.
I wish you a lot of a luck with that. That’s a tremendous project. I think to finish, I’d like to just discuss a little bit more about what it is that you think is most important for medical students now to understand. You yourself had training and very novel training in the 1950s based on basic research and medical training combined and of course MD PhD programmes are very popular now, but the majority of medical students don’t go through this.
Ferid Murad: I think there are in the US, I believe, out of the 126 medical schools, probably about 30 or 40, maybe a little more with MD PhD programmes and typically they only have a handful of students, although some programmes like Washington University and a few others are much larger, but typically less than 5 or 10% of the class is MD PhDs. They’re always very good students. The programme is designed to, in my opinion, train academics to come back and do research, either in a clinical department or a basic science department, one or the other. If you look at the spread, people have done both, people have gone into clinical departments to research or basic science departments to research. Some of us have done clinical training, ended up in clinical departments and then switched to basic science departments, as I have. Others have not done clinical training and gone into basic science departments. I don’t think it matters. I think the programme is designed to train academics to come back and teach and do research. The difficulty that we’re having, certainly in the US and I’m sure it’s true here in Europe as well, is that for the clinical faculty member to do research today is becoming extremely difficult because of managed healthcare. You have to spend so much of your time seeing as many patients as possible to satisfy the budgets and financial justification of the programmes, that there’s no time left for research. For many, many years, I have always believed that you have to emphasise one or the other, it’s wonderful if you can do everything, I wish I could, I tried for some time, but after a period I had to decide whether I was going in for science clinical medicine and teaching or research. I chose the research track, but I always tried to do research in a clinical department, so I could impact and influence the clinical faculty and collaborate with them.
Today, it’s very, very hard to do both. You can only be an expert if you spend most of your time doing one thing, whether it’s research or patient care. If you’re doing patient care and it’s part-time, you’re not going to be the pro, an expert, you’re not going to get the referrals from your colleagues. They’re going to send them to the person who’s doing it full-time. If you’re not doing research full-time, you’re not going to get the grants. Now it doesn’t mean 100% of the time but certainly more than 50 or 60 or 70%. You’ve got to choose, it doesn’t mean that you can’t be concerned about the other and participate to some extent, but to be the triple threat and be the perfect teacher and clinician and scientist, that’s not feasible these days. It’s going to be frustrating for students, more so than it was for me, to make those choices. I took it all, I absorbed it all because I enjoyed it all, but at some point I realised I’ve got to emphasise one thing or the other. I think it’s going to be a little harder for people to make those choices. Educational costs are escalating through the roof, people can’t take the long training programmes that I went through. I trained for 12 years after college, let me think, is that right? Yes, 12 years. It’s hard to do and I did it with a family, with five kids, it was very hard to do.
You’d have to go into practice after that these days, just to pay for it.
Ferid Murad: Exactly, well that’s what’s happened. I have a son-in-law who’s a cardiologist and another son-in-law who’s a neuroscientist, one’s a PhD. and one’s an MD. The MD has done a lot of research, cancer research, cardiovascular research, he’s probably spent about four or five years in the laboratory. He got himself an American heart fellowship and the whole bit. He grew up in California, he wanted to go back to California. To afford housing in California and pay off all of his debts, he had to go into practice, so now he’s a cardiologist in California to pay all of his past loans and move into a house. He’d loved being an academic but I don’t think he can afford to do it, which is sad.
Yes, so now it’s a case of do one thing and do it well.
Ferid Murad: Yes.
On that note, I guess we should stop. Thank you very much indeed for taking the time to talk to us.
Ferid Murad: I think the important message for young people … When I was a student, I absorbed everything, I never cut a single class in my career because I thought everything was important. I couldn’t determine what was important and what wasn’t, therefore I learned it all. In our faculty we’d say, half of what I’m going to tell you is true and real and the other half is not, but I can’t tell you which half, so I would learn it all. Today that’s different and I think that education is so costly that you can’t afford not to take advantage of it, the opportunity and what you’re learning may not be applicable later on, but it prepares you to learn it later and you’ve got to do what you enjoy doing. It doesn’t matter what you do, as long as you enjoy it and do it very, very well, the best you can be.
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