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Meet a Nobel Laureate
Gertrude Elion Interview (page: 6 / 7)
Nobel Prize in Medicine
I wanted to focus on your revolutionary development of acyclovir, which has been called your crowning achievement. What was so dramatic about this discovery?
Gertrude Elion: Up until the late 1960s, early '70s, antivirals were a field that drug companies didn't get into. A few compounds had been found that inhibited the growth of viruses, and they were inevitably toxic to the cells. It became a no-no. "Stay away from viruses."
Then in the late '60s, a compound that had some antiviral activity was isolated from a natural product. I think it was from a sponge. It was toxic to normal cells but the therapeutic index was a little bit better than what had been found before. It was a purine, and I had been working all my life on purines. People hadn't been working with purines as antivirals. They had been looking at pyrimidines and those were pretty toxic. Why not go back and see if some of our purines aren't antiviral? It had an unnatural sugar on it. So we began to make these modified sugars, and we found things that were just as good, or better, than this thing that was found in a sponge.
In the meantime, Dr. Schaeffer came to work for us in 1970. He had been playing around with the sugar molecule on these bases. Instead of the whole ring system, he'd made just a piece of the sugar. He saw that you don't need the entire sugar to bind to the enzyme he was working with. The enzyme will recognize even this one piece. That sounded like a good idea to exploit, so we put his false sugar on the purines we were working with. We tested it on herpes virus and, lo and behold, this compound had high activity. Amazingly, they were very non-toxic. We didn't even have the virus growing in our laboratory, so we would send these compounds over to our laboratory in England, and every time something was really active, we'd get back a telegram with the results. We were in a state of absolute frenzy, because these things were so much more active than we had expected, and so much less toxic.
Why is that the case? We put all our efforts into finding out what was going on in a virus-infected cell. Then we began to find that these non-toxic compounds were actually being activated by the virus itself. The virus was converting it to the toxic compound. It took three more steps to get to the really active antiviral compound.
The revolution came partly from having made the compound, but even more from having shown why it was so active and so non-toxic. It was just a big explosion after that. Now people look at all the viruses to see what specific enzymes they have. It's true with HIV, its true for the Epstein-Barr virus. There are so many viruses, and they each have different enzymes. Even herpes type I and II are different. It turns out they are very close as far as acyclovir is concerned, but not so far as all the other compounds are concerned.
Do you remember a particular afternoon when you got the high active results?
Gertrude Elion: In order to find out what was different about the drug in a virus-infected cell compared with a normal cell, we made a compound with radioactive carbon in it. We incubated the compound with the virus-infected cell for seven hours, and did the same to normal cells in which the virus would ordinarily be found. We made an extract of these cells, put it on a high pressure liquid chromatographic column, which would separate out the various components in the extract. And there, lo and behold, were four radioactive peaks in the virus-infected cell, and only one in the uninfected cell. That was the day when you knew where to look.
How did you feel?
Gertrude Elion: We felt it couldn't be true. Everybody was very excited. I had the most wonderful group of young people working together on this. If ever there was a team effort, that was the one. Everybody in the lab would come and say, "What can we do? What part of the action can we have? " It was really tremendous.
What was the time frame between that day and acyclovir being sold in the drug stores as Zovirax?
Gertrude Elion: It was only about eight years, which is very short for a drug these days.
Did you realize the far reaching implications of that discovery?
Gertrude Elion: Probably not. We were too busy. The fact that it had an activity was known in '73, the discovery of the mechanism, was in about '74. The fact of why it had the activity took maybe six months to a year. But... Well, I think we realized the far-reaching consequences for that compound, but I don't think we appreciated immediately for a lot of other viruses.
What was connection between your research with viruses and the first successful treatment of AIDS?
Gertrude Elion: I retired as department head in '83. I think the first successful treatment against AIDS came along about two years later. The same group of people that had worked on acyclovir worked on the AIDS drugs. Viral research was now a major effort for the company. At that particular time, we didn't even have the AIDS virus in the laboratory. We had to build a special lab, because it's such a dangerous virus to work with. But we had continued to make of the same sort of compounds these with strange sugars. We tested it on a number of viruses and we sent it out to NIH (National Institute of Health). We said, "Would you test compound S and compound T on the AIDS virus?" without telling them what they were. Lo and behold, this one was very active. From the time that activity was discovered to the time we really had an AIDS drug was very short, about two years. It was done by people that were trained to do viral research, and they did the right things. But I don't think I should get credit for anything to do with the AIDS drug.
Except that they couldn't have done it without your research.
Gertrude Elion: That's true, but they knew what to look for, and they know how to look. All science is a continuation of science that went before.
In your field there's one great stumbling block, and that's curing viruses. Any hope in that direction?
Gertrude Elion: There are some viruses, probably, that one can cure. But mostly, if you think about viral diseases, the big success has been with vaccination. It was true with polio, it was true with smallpox, it was true of measles. When you can get a good vaccine, and prevent the disease, that's the best thing to do. The next best thing is to prevent the virus from becoming latent. The reason it's so hard to cure virus diseases is that you may stop it from multiplying, but it doesn't necessarily go away. It stays dormant in some cell types, depending on the virus, and comes back. The patient gets elderly, or sick from some other disease, or the patient gets into an emotional state, and suddenly this virus reappears. It's true with the AIDS virus. It actually integrates into the normal DNA of the cell. Until it comes out and tries to reproduce itself, it just sits there, and there is not much you can do about it.
So if you could prevent it from getting there, if you could prevent it from integrating, if you could kill off every cell in which it was integrated, maybe you could cure it.
Is that possible?
Gertrude Elion: Nothing is impossible.
What of your many accomplishments are you most proud of?
Gertrude Elion: I think I'm most proud of the fact that so many of the drugs have really been useful in saving lives. I've run into people whose lives have been saved, and the kind of satisfaction that you get from having someone come up and say, "My child had acute leukemia and your drug saved him." Or, "My little girl had herpes encephalitis, and she is now cured, she is back at school. She is doing very well. People told me that she might be mentally affected, but she is not." I run into people who have had kidney transplants for 20 years who are still taking the drug. And I don't think that anything else that happens to you can match that type of satisfaction.
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This page last revised on Nov 08, 2007 11:40 EST
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