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If you like Gertrude Elion's story, you might also like:
Elizabeth Blackburn,
Linda Buck,
Sylvia Earle,
Judah Folkman,
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Gertrude Elion's recommended reading: The Microbe Hunters

Teachers can find prepared lesson plans featuring Gertrude Elion in the Achievement Curriculum section:
Meet a Nobel Laureate

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Gertrude Elion
 
Gertrude Elion
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Gertrude Elion Interview (page: 4 / 7)

Nobel Prize in Medicine

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  Gertrude Elion

The Nobel Prize rewarded not only your invention of specific drugs, but the way that you revolutionized the way that drugs are developed, in general. When did it occur to you that you could design drugs, rather than follow the traditional trial and error approach?

Gertrude Elion: I don't think I can take credit for that. It started out in almost a naive way. I was only following what Dr. Hitchings had decided was the way to go. He didn't know any more than I did whether it was going to succeed at the time. We knew something about the nucleic acids which make up the nucleus of the cell. We knew it was very important for cells to have this in order to divide. We didn't know much about the structure -- it was prior to the Watson hypothesis of the double helix -- but we did know that there were four bases that were essential for nucleic acid. So the thought was, "What would happen if we made artificial bases? Things that look very close to the regular ones, but couldn't really be utilized by the cells." That was the approach. We didn't understand all the pathways, how these compounds could be used, or what would happen if they got into the nucleic acid. So, the idea was not that we knew exactly what to make, only that we would make things so close to the original that it would fool some enzymes, some cells into taking them up. We used to call it a rubber donut. It looked like the real thing, but it wouldn't work, and that's what we found.

Gertrude Elion Interview Photo
Then we had to find specifically in what kinds of cells these compounds would work. Some of them worked in bacteria, some of them worked in malaria, some of them worked in cancer cells, some of them worked in viruses. It wasn't predictable in the beginning, so we looked as widely as we could. As soon as we got a lead, we could make compounds similar to that, find the best one, and so on. In a sense it was trial and error, but something Dr. Hitchings used to call "enlightened empiricism." In other words, you knew the kind of thing you were looking for, and you were making that kind of compound, but you couldn't predict which one would work for what. In a sense, I think of it now as invention of new compounds and then discovering what they were good for, because it wasn't really a single process. We didn't know ahead of time which one would work for what. Perhaps that's why we went into so many fields.

Can you explain, in lay person's terms, how that approach differed from the traditional approach?

Gertrude Elion: The traditional approach was to take something that worked and to make some changes in it, and see if you could get another compound that worked as well. Or to take things off the shelf and try them. Things that had never been looked at before, even natural products, or just chemicals. Well, we didn't do that. I mean, we made specific kinds of chemicals with very specific ideas in mind.

We had a bacteria in the laboratory that we used to say was our little black box, because it knew how to grow with very simple bases that were nucleic acids. If we gave that bacterium the wrong compound, it didn't grow. So the bacteria knows that it's close but not the right thing. Then you have a lead to follow. You might have put in a sulfur instead of an oxygen. That's what we did with a very simple base that turned out to be an anti-leukemic drug. The bacterium, which is a milk bacterium, Lactobacillus casei, knew that compound wasn't the right one. It tried to use it, and then it was inhibited, it couldn't grow. So we said, "OK, that will inhibit growth. Let's try a mouse tumor. Let's see if that will be inhibited." And sure enough, it was. "Well, how about a mouse leukemia?" Yes, it inhibited that. "Well, how about a human leukemia?" So, it was a step-wise thing from a simple organism that recognized that this was not the right base, to go on from there.

What people in general were doing in pharmaceutical companies was saying, "I want to develop a diuretic. I'm going to test everyone of these compounds as a diuretic." Even though you don't know what the mechanism is. We learned a lot about biochemistry with these compounds. We learned some of the pathways that existed but which we hadn't clearly identified before. So the compounds themselves ended up being tools for discovery as well as ends in themselves. One of the most important things about discovering new drugs is to let the drug lead you to the answer that nature is trying to hide from you. We were able to deduce that certain enzymes existed, even if we didn't have a name for them. Then these enzymes were discovered, and it was this wonderful feeling of "There it is!" We knew it was there, now it has a name.

It sounds to me like your approach was to respect and to analyze the bacteria itself, rather than just throw things at it blindly.

Gertrude Elion Interview Photo
Gertrude Elion: That's right. We could say, "OK, the bacteria is inhibited. Why? Let's give it the natural base that it needs. Will that reverse the inhibition? And the answer was yes, it would. Therefore, those two are on the same pathway, and we have hit the pathway we are looking for." You could organize your tests in such a way that you could actually determine what would reverse the inhibition, and that would give you a clue as to where it was working. This is what made it so exciting. There was so much to learn. In the 1950s, when all these things began to come together -- we learned how the nucleic acids are synthesized, what the structure looks like, what the enzymes were -- we already had all these things to plug into it. We had known that they existed, but we didn't know what to call them.

Did you have any inkling of the far-reaching effects of these ideas in the medical world?

Gertrude Elion: Not until they happened. Many of them happened maybe because the time was right, the instrumentation changed, we could determine things we couldn't have determined in the 1940s. We were able to do things much faster because of mechanization of spectrophotometers, radioactive precursors, being able to have scintillation counters. The revolution in instrumentation that happened after the war was so phenomenal. Looking back on it now, I realize experiments that took five years could have been done in five days.

When did you first begin to realize the great implications? It's staggering to see how many different diseases you were able to have a powerful effect on. Was it immediately clear that this had reverberations in many different diseases, or was it sort of one at a time?

Gertrude Elion: It was sort of one at a time, but some of it was really serendipity. It was luck. For example, 6-mecaptopurine was the first real hit in acute leukemia of children from our laboratory. Not the first compound, but the second compound that had been discovered to have activity. The children weren't cured, so we knew we were on the right track, but we weren't there yet. We knew we were close, because children went into remission for six months or a year, then relapsed. We began to say, "What happens to the drug in the body? Is there something we can do to make it better?" We studied the metabolism of the drug, and we found out that a lot of it was destroyed in the body. So we said, "Let's try to design a compound that will release this in the leukemic cell, and not harm the other cells. Maybe then it won't be destroyed as readily." I spent several years making derivatives. One of these derivatives was as good, but not better, in leukemia.


Just at that time, we got interested in immunology. And we got interested because somebody who had written to us for 6-mecaptopurine looked at it in the immune response in a rabbit, and let us know that it inhibited the immune response. So he came and saw us, and said, "You know, you have some compounds that could be very interesting in immune response." We listened, and said, "OK. We will set up a screen that will try to determine whether some of these anti-leukemic compounds have activity on the immune response." And lo and behold, this one compound that I had made which was equivalent in leukemia, was better on the immune response. Then along comes a young surgeon who had read the paper about the rabbit antibody response. And he says, "You know, I tried 6-mecaptopurine on kidney transplants in dogs, and it really prevented the rejection for quite a long time. Do you have anything that might be better?" Well, we don't know, but here, take this compound. It looks better in mice. So he goes off on a fellowship to the Peter Bent Brigham Hospital in Boston, tries it, and finds it definitely is better. And the next thing you know, it's preventing rejection of kidney transplants in man.


Now, I didn't start to make a compound that would do that. But if you listen, and keep your mind open, this is what can happen. This was the story of our lives. Because then we were off in the field of kidney transplantation, autoimmune disease, and so on.

It sounds like a scientist has to be able to get along well with colleagues and have a spirit of team playing. Otherwise you are stuck in your own laboratory with no input.

Gertrude Elion: Absolutely. It's a team effort all the way through. There are so many aspects of drug development, finding out what are the side effects are, finding out the best way to give it, finding out any number of things. One person can't do that. You could, I suppose, if you spent a lifetime on every drug. I've always compared it, in a way, to an orchestra. Everybody plays his own instrument very well, but it isn't until you put them all together that you have anything that sounds like music.

It also sounds like you have to be brave enough to spread the word about what you are doing, and not be too possessive of it.

Gertrude Elion: That's true. I think we publish very widely. There are short periods where you can't do that, especially working in a pharmaceutical company, where you have to protect your work with patents for the sake of the company. You have to keep it under wraps for a year or two, particularly if you know you have something very novel and very hot. Then you know that other companies, with three times the staff, will jump into the field almost immediately. That happened to us with the antiviral drug, acyclovir. Nobody was working on antivirals until the first big success, and then everybody was working on antivirals. As soon as we had the patents not just filed but issued, we began to publish prolifically. I've had over 200 publications, so I know how much we've published.

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This page last revised on Nov 08, 2007 11:40 EDT