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Meet a Nobel Laureate
Gertrude Elion Interview (page: 5 / 7)
Nobel Prize in Medicine
What was the influence on your work of the findings of James Watson?
Gertrude Elion: It was a very important finding for us because we were involved in nucleic acids. There weren't many people interested in nucleic acids. There weren't many people who believed that was the way to find drugs. But when we found out the structure, and we began to understand what kind of bases could be incorporated, and which ones couldn't, and where they could be incorporated, it put a whole new dimension on it. So it had a very significant effect. Up until then, we weren't quite sure what the effect of incorporating an abnormal base would be. We didn't know there was such a thing as a double helix. We didn't appreciate that we could get something in there that could distort that helix and make it non-functional. It was a wonderful piece of discovery for us, right at the most appropriate time.
So, in a sense, it speeded things along.
Gertrude Elion: Oh, yes. And again, it explained a lot of unknowns. It explained things, it gave us clues on which way to turn and what kinds of compounds to make next.
Were colleagues of yours in the field skeptical at the new approach that you and Dr. Hitchings were taking?
Gertrude Elion: Yes, I think they were. They thought we were just playing. When the first successful drug came, people sort of raised their eyebrows, and said, "Wait a minute, maybe there is something to this." Of course, it also came at the right time. It came in the early '50s, when a lot of these enzymes were being discovered. The double helix was in '53. They got the Nobel Prize for it, so the timing was perfect. Everybody began to think maybe this is the way to go. From a time when everyone interested in nucleic acids could probably sit around one table in a lunch room, it got to the point where a conference on nucleic acids was oversubscribed, and you couldn't let everybody come who wanted to come.
Were you affected by other people's skepticism?
Gertrude Elion: Not really. My feeling was "Maybe you are right, maybe we are right, we'll see."
This partnership that you had for many decades is quite an extraordinary one. How did you and Dr. Hitchings complement each other? Was it immediate?
Gertrude Elion: No, I don't think it was immediate. It was a boss/assistant relationship for the first couple of years. He is always willing to let people do the maximum that they are capable of doing. That's not true with a lot of people. I would read a lot, I would question why, I would have my own ideas, and he would encourage me to do that. Little by little, I began to have my own thoughts about what to make, and I began to get assistants to help me. I was working in the purines, someone else was working in the pyrimidines, and gradually these two began to branch out into different diseases. I was following one line, someone else was following another, and Dr. Hitchings was the overall coordinator. Each branch got bigger and took on more and more people. Suddenly had a department of 20, and 25, and 50, all responsible to me. It just happened gradually, as the need arose. "He never said, "OK, you've gone as far as you can go." That's why I stayed, and that's why I prospered. I felt it was up to me to do the best I could, and not to be hampered in any way, to be encouraged along the way.
Some people are threatened by a young upstart...
Gertrude Elion: That's correct. He was very unusual.
Obviously, this grew into more of a partnership.
Gertrude Elion: As time went on, he became more and more the administrator and the coordinator, and we were the soldiers in the field doing the actual work, the actual synthetic, biochemical work, and reporting to him. I think I had a little more patience to do the nitty-gritty kinds of things in the laboratory, but he had more insight, more appreciation of what these things all meant. We would have long talks about it. At the end of a long talk, you wouldn't really remember who said what and whose idea it was to do the next thing, which was great. You could never say, "You told me to do this," or "I was the one who thought of it." It was very much a meeting of the minds.
That's quite admirable for that period, for a man to treat a woman as an equal.
Gertrude Elion: Yes, it is.
Could you tell us how you figured out the difference between normal cell, cancer cells and bacteria?
Gertrude Elion: It was experimental testing. What you had to do once you found a lead compound was to put it into a whole animal and say, "OK, this tumor is not growing. What about the animal's bone marrow? What about the animal's intestinal mucosa?" These are natural, normal tissues that divide rapidly. So if you're only hitting a rapidly dividing tissue, you may end up with toxicity. You can't determine the toxicity ahead of time, until you begin to compare what it does on the tumor versus what it does on the rest of the animal. You find, in cancer therapy mainly, that there isn't a large difference. In other words, you will eventually reach a level which will be toxic to the host. You're sort of walking on a tightrope, trying to find out just how much is necessary before you run into toxicity, or you try to find a compound that may have a better therapeutic index.
It's not as true in antivirals, because the virus metabolism is very different from the host. It was possible to get big differences between the normal cell and the affected cell. You could find things that were very safe, that really inhibited bacteria, because they have a different metabolic route for getting there. You could do that with malaria. The malaria parasite has a different mechanism of making its nucleic acid from the normal, but until you tested it in an animal, you really couldn't be sure. I'm not very patient with animal rights activists these days, because they seem to think that you can predict toxicity on a computer, but you don't have a liver in a computer, or a kidney, or bone marrow. Until you have it tested in an animal, you really don't know what you have.
As I understand you, this is why people have strong reactions to chemotherapy. This stuff does affect normal cells.
Gertrude Elion: It does. Most of the anti-cancer drugs we have today are really not that selective. That's been their problem. Nowadays, I think, we are beginning to understand a little bit more about the cancer cell. What is different about it? Maybe we will eventually have compounds that will be more specific and more selective. The outlook is really good in that direction, but it may take a long time.
It seems that you and Dr. Hitchings were going in a completely new direction with your research. How were you looked upon in the field?
Gertrude Elion: The field was new. People hadn't thought of anti-metabolites, which is the name it finally got. Except for two people, Woods and Fildes, who had postulated that the reason sulfonamides affected bacteria was that these sulfonamides look very much like a natural nutrient that bacteria needed. This interfered with their getting it, and it was structurally quite similar, and people were willing to believe that was possible. But then Dr. Hitchings said, "If it happens with one nutrient, why not with nucleic acid derivatives?" In his doctorate he had worked on the purine and pyrimidine bases. "Why don't we try this anti-metabolite approach to the nucleic acids?" People thought that was a real wild dream. "Just because you work with sulfonamides and bacteria, now you are talking about the structure of a living cell. Obviously, you are not going to find something that will work on one kind of cell and not on others. So all you are going to end up is making a lot of poisons." So we were off in our little ivory tower and nobody bothered us, and nobody paid much attention. It took the first active compound for people to say, "Maybe that's not such a stupid idea after all."
People were still skeptical until it showed activity in man. You could report that these worked in bacteria, and nobody paid much attention to that, because often the bacteria weren't even the real pathogenic bacteria that cause disease. It was just a bacteria that grew in milk, and who cares if you can inhibit that? I don't think we really cared whether they believed us or not. We knew it was working, and we knew we were on the right track. It got to be almost a joke in the lab. "Now we have all the cures, we have to find the right diseases for them!" We were obviously interfering with nucleic acid in some of these. The anti-malarial compound and the pyrimidine series came at just about the same time as the anti-leukemic drug in the purine series. So we had both arms showing activity in two entirely different types. Then people began to say... " Here's two different kinds of drugs coming out of this work. Maybe it's not so silly after all." That was nice, although it made for more competition of course.
And then people jumped on the bandwagon?
Gertrude Elion: They jumped very quickly on the bandwagon. It was obvious that there were a lot of changes that could be made that we hadn't tried yet. We just kept plugging away. We knew that we didn't have enough chemists to compete with Merck, or Ciba-Geigy. So we just went on with our business as best we could. I didn't worry about it.
What was the general philosophy at Burroughs Wellcome? What were they trying to do as a company?
Gertrude Elion: Burroughs Wellcome is a very unusual company. It was founded as a foundation, and all of the money that was made by the company went to the foundation and then to the trust that distributed it in philanthropy. So there were no stockholders. It was the vision of Henry Wellcome that this would be a research organization, and it would make its money by selling pharmaceuticals, and that money would go back into research. Our research lab grew very rapidly as we began to be successful. The money did go back to research. Some of it went to our research, some of it went to other people's research, via the Wellcome Trust. It's a little different now, because the trust has sold a quarter of the stock into the open market and there are stockholders, but the trust still owns 75 percent of it, and the mission is still to have new drugs, not repetitions of things that are already in existence, but to open new fields. That was what we tried to do. We weren't trying to imitate anybody. We weren't trying to make another diuretic, another analgesic, things that are already doing pretty well. Not to say that we don't have such drugs, we do: over-the-counter antihistamines and things of that sort. But on the whole, the idea was to do research, find new avenues to conquer, new mountains to climb.
It's extraordinary that you stayed at the same company all these years. You obviously found a comfortable home.
Gertrude Elion: I wouldn't say it was comfortable, but it was challenging. It was a place where you could do good work. People wouldn't be looking over your shoulder saying, "What have you done for me lately?" For example, we ended up in the field of gout, which nobody had any intention of getting into, until we discovered that one of the ways that 6-mecaptopurine was destroyed was through an enzyme in the body that oxidized it. We set out to prevent the oxidation. We did, and we ended up with a compound that prevented the formation of uric acid. That became a very big item for the company because there were many people with gout, and it was very good treatment. As long as we continued to come up with novel things, nobody said, "Why haven't you done this, or why haven't you made that?" Which is a very enlightened research management. Considering the size of the company, which was much smaller than most of the big ones, we probably wouldn't have done as well if we hadn't been allowed to go into new fields.
You repaid them by being very faithful.
Gertrude Elion: I originally set out thinking, "I'm going to stay here as long as I continue to learn." Here I am, 46 years later and I'm still learning.
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This page last revised on Nov 08, 2007 11:40 EDT
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