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Cancer Warrior

Dr. Judah Folkman Dr. Judah Folkman
Dr. Folkman Speaks

In 1961, while conducting medical research in a U.S. Navy lab, Dr. Judah Folkman stumbled upon a hidden secret about how cancer grows. Before the decade was out, he was forming the theory that would occupy the rest of his professional life. He called that theory angiogenesis, and in it he postulated that tumors could not grow larger than the head of a pin without a blood supply. He also believed that the tumor secreted some mystery factor that stimulated new blood vessels to form, bringing nutrition to the tumor and allowing it to grow.

But Dr. Folkman went even further: He also proposed that if the new blood-vessel growth to the tumor could be blocked, that might offer an entirely new way to treat cancer. After decades of work, Dr. Folkman and his team are now watching as clinical trials begin with two recently discovered angiogenesis inhibitors, endostatin and angiostatin. In this interview, drawn from those conducted for "Cancer Warrior" by NOVA producer Nancy Linde, hear Dr. Folkman talk about his team's ground-breaking discoveries and his hopes and fears for the new therapy.

NOVA: What was your first "Eureka" moment with angiogenesis?

Dr. Folkman: The first one was in the 1960s when we saw that in the isolated organs growing in the glass chambers in the Navy that the tumors implanted there all stopped at the same size. There should have been a bell-shaped curve like in all biology, but all the same size meant that something was stopping them. It took a few years to figure out it was the absence of blood vessels. I had a feeling this is really something important. I didn't have any idea that it would be some 30 years to try to understand the process by which tumors are able to recruit their own private blood supply and just keep going.

NOVA: Such moments must be worth everything, especially since they're so few and far between.

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Dr. Folkman: Most research is failure. You go years and years and years, and then every once in a while there is a tremendous finding, and you realize for the first time in your life that you know something that hour or that day that nobody else in history has ever known, and you can understand something of how nature works.

NOVA: When did you first lay out your theory?

Dr. Folkman: A 1971 paper in the New England Journal of Medicine presented the idea in a much larger form. One, that the blood vessels in a tumor were new, and the tumor had to recruit them. Two, that it recruited the vessels by sending out some factor, which we called TAF, tumor angiogenesis factor, because we didn't know what it was that was diffusible. (Diffusion means like if you put some ink on a table cloth, it travels, but not a long distance.) Thirdly, we put forward the idea that these diffusible proteins would bring in the vessels. And fourthly, that if you could turn this process off the tumors should stay as small as they had in the thyroid gland and in the lining of the abdomen that I had seen in surgery, where they are all the same size and tiny but without blood vessels.

NOVA: Did you ever fear you were jumping the gun, since much of the verifying research had yet to be done?

Dr. Folkman: I remember in some early grants I wrote that I outlined what I thought would be the whole future—there would be possible inhibitors and stimulators [of angiogenesis], and there would be pure proteins. You never these days lay all that out in a grant; you focus it. Well, I got cold feet and thought, Oh I'm giving away too much.

Dr. Judah Folkman Judah Folkman and his team had to conduct hundreds of experiments before the scientific community began to accept their unconventional ideas.
Now, Dr. John Ender's lab was right next to mine. He had won the Nobel Prize for the polio virus and was a very great scholarly gentleman. I showed him this grant and said I'm worried that I'm giving away too much. He read it right there. I remember him taking out his pipe, and he said "It is theft-proof. You'll be able to work at your own pace I figure for 10 years before anybody is going to believe this." He thought maybe these ideas were right but that I'd never be able to convince anybody without dozens of experiments. It turned out that hundreds of experiments were necessary over many years.

NOVA: Especially because you were a surgeon and not a researcher?

Dr. Folkman: Surgery has the disadvantage that the training takes so long and is so physically demanding. It's like training for the Olympics practically. There's often little time for any kind of research or scholarly work, and surgeons often do not have any ability to have the very long period of scientific training that basic scientists have. And so surgeons often are ridiculed because they are thought not to be able to do research. Yet many great, interesting, and important advances have come from surgeons.

NOVA: Which is harder in your experience, being a doctor or being a researcher?

Dr. Folkman: Clinical medicine has tremendous feedback, so the people who work in it are willing to work night and day. Patients just call you up all the time and say you saved my son's life and all that. Research is the opposite. It's just years of frustration. You have to live with experiments that don't work and grants that don't get funded. You have nothing to show for it. You've got critics all over, and scientists are sometimes mean to each other; they criticize the ideas in the name of scientific skepticism. It's not an easy life. You know that line, "I've been rich, and I've been poor, and rich is better"? Well, it's easier to be a physician than to be a researcher. I've been both, and physician is easier.

Dr. Judah Folkman in lab Judah Folkman: "I kept saying the ideas, I think, are right, and it will just take a long time for people to see them."

NOVA: What gave you the confidence to go on?

Dr. Folkman: Well, I always thought of it in an amused way, because I knew something that no one else knew, and I had been at the operating table. It wasn't the surgeons who were criticizing, it was basic scientists, and I knew that many of them had never seen cancer except in a dish. I knew that they had not experienced what I had experienced. The idea of tumors growing in three dimensions and needing blood vessels in the eye, in the peritoneal cavity, in the thyroid, and many other places, and the whole concept of in situ cancers and tumors waiting dormant—I had seen all that. So I kept saying the ideas, I think, are right, and it will just take a long time for people to see them.

NOVA: So when did perception of your work start to change among researchers?

Dr. Folkman: By about the end of the `70s people began to say, Okay, they are new vessels, we agree. But it's a side effect of dying tumor cells. It's like pus in a wound. When Robert Auerbach came [to our lab] as a sabbatical professor, that was the conventional thinking. But he did the experiment that disproved that as a single, crystal-clear paper. He put live tumor cells in one eye of a rabbit, and he put dying tumor cells in the other, and no blood vessels came to those, only to the live ones. He said they must be live in order to recruit the private blood supply. That single paper changed a lot of people's thinking.

I would say the watershed year for complete change of thinking amongst scientists was about 1989. By then there were such strong experiments coming from our lab, from Genentec's lab, and from Europe that tumors not only induced new vessels but were angiogenesis-dependent, that most scientists began to accept that. But it took a long time.

NOVA: In 1984, your team published a paper in Science about the discovery of the first angiogenic factor the year before. That must have stirred things up.

Folkman Watch clip of Judah Folkman on "persistence and obstinancy."
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Dr. Folkman: That paper had great transforming power. Almost overnight many, many, many critics were transformed into competitors, because people began to see that there was a molecule in this field. That was the first; there are now 17.

I was beginning to wonder whether there would ever been an angiogenic factor. We had spent so many years on it. In general, if you don't find something in four or five years, people say it's not there. In research, there's a very fine line between persistence and obstinacy. You do not know whether if you're persistent a little while longer you'll make it, or whether you're just being obstinate, [and it] doesn't exist. And, of course, you can keep on going, stay with an idea too long—[that's] called pigheadedness. I was beginning to think we had crossed that line and were spending money and had nothing to show for it.

When that came that was a great sense of relief, that it actually did exist. It's like Sputnik. The U.S. had all the information to put up a satellite, but we didn't until Russia did. Then suddenly we said, Oh you can do it. Once people saw that it was possible [to find angiogenic factors], they began to look and found other ones.

Continue: Finding angiogenesis inhibitors

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