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December 9, 1997
Science Desk

A Lonely Warrior Against Cancer

THERE are few greater hazards to a scientist's career than perceiving a truth before the means exist to test it. Repeated assertion of one's insight will first invite insistent demands for proof, then skepticism, followed by silence, ridicule and often the loss of research funds.

One who has survived this grave peril, with his sense of humor intact, is Dr. Judah Folkman, director of the surgical research laboratories at Children's Hospital in Boston. Some 35 years ago, from an accidental observation made as a young researcher, he divined that tumors must somehow induce the body to build the blood vessels that feed them.

In pursuit of this insight, more than 100 laboratories and as many as 40 biotechnology companies are now engaged in identifying the chemical signals the body uses to construct and dismantle a temporary new blood supply in events like wound healing and menstruation. Cancer cells use the same system, and indeed cannot form a tumor until they have acquired the ability to switch on the formation of new blood vessels, a process called angiogenesis.

The idea of shutting down angiogenesis, by countermanding these signals, holds high promise as a cancer therapy, and the first generation of such drugs is now undergoing clinical trials. But in 1971, when Dr. Folkman began to promote the concept, the conventional view was that tumors did not need a special blood supply and that any extra vessels were just a response to inflammation.

For most of the time since, he has been a lonely voice, turned down by grant-giving committees, spurned by journal editors, lampooned by medical students. At one moment of need in 1974 he accepted a $23 million grant from the Monsanto Company. Harvard, where he has a joint appointment at the medical school, had never before accepted industry money of this magnitude and his academic colleagues roundly denounced him for selling the university's soul.

Derek Bok, then the president of Harvard, came to his support. Dr. Folkman recalled a colleague observing at the time that the university "was an intellectual wild game preserve, and it was the job of the president to see the larger animals didn't eat the smaller ones."

Escaping the Harvard carnivores, Dr. Folkman was allowed to keep the Monsanto money, which he and Dr. Bert Vallee used to isolate one of the first inducers of angiogenesis. But he continued to pay the penalty for being a surgeon trespassing on biochemists' turf.

"He's very enthusiastic and very creative but because of that he is always out on the periphery," said Douglas Hanahan, a cancer biologist at the University of California, San Francisco, who has collaborated with Dr. Folkman. "He's been very visionary about complex processes so it has been easy for biochemists to be skeptical."

Only in the last five years or so have his ideas become fully accepted and been shown, by his laboratory and others, to have a firm foundation in molecular biology. He is no longer a voice in the wilderness but principal founder of a growing field of research, one perceived in academe and the pharmaceutical industry as holding considerable promise for the treatment of cancer.

Recently Dr. Michael O'Reilly in his laboratory discovered two natural agents, known as angiostatin and endostatin, that are powerful inhibitors of angiogenesis. Many agents can make a tumor slow down for a while, until its cells develop resistance. But endostatin forces large aggressive tumors in experimental mice to shrink back down to a microscopic size at which they have no need for a private blood supply. And as Dr. Folkman and colleagues reported last month, the vessel-making cells on which endostatin acts do not develop resistance.

"He saw things others didn't see," said Robert S. Kerbel, a cancer biologist at the Sunnybrook Health Science Center in Toronto, "but on top of that he had the persistence to stick with it and almost single-handedly has opened up this very substantial field of research."

Judah Folkman took an unusual route into scientific research. His father, a rabbi in Columbus, Ohio, used to visit patients in the local hospital. As a reward for good behavior the previous week he would allow Judah, 7, to accompany him. The excitement of these visits emboldened Judah one day to tell his father he wanted to be a doctor, not a rabbi, when he grew up. "So," said his father, "you can be a rabbi-like doctor."

Trained as a surgeon at the Massachusetts General Hospital, he soon became interested in research. While working for the Navy in 1960 on blood substitutes, he used his apparatus, a tube that held a rabbit's thyroid gland irrigated with an artificial solution instead of blood, to see if the perfused gland could support the growth of tumors. The cancer cells he seeded into the gland formed small tumors but all stayed the same size, as if once reaching a certain point they could grow no further under those conditions.

It was this observation that led him to suppose that growing tumors must induce their own blood supply, probably through secreting some factor into the surrounding tissue. But it was not until 1971 that he was able to complete further experiments and publish his ideas.

Interest was not overwhelming at first. Dr. Philippe Shubik of Green College of Oxford University, who was one of the early pioneers of the field, said, "Our work wasn't ignored but it didn't excite people terribly much because we weren't saying we would cure cancer." Dr. Folkman, however, was saying just that. "What made Folkman stand alone was his saying that the key point is to target the blood vessels to stop cancer," said Dr. Robert Auerbach, an angiogenesis expert at the University of Wisconsin.

The difficulty lay in proving the concept. It took many years to learn how to make laboratory cultures of the cells that form the new hair-thin blood vessels known as capillaries. "The biochemistry that needed to be done to isolate the factors was very complex," Dr. Auerbach said. "Folkman realized he needed outstanding biochemists to do the work and he got them."

Dr. Folkman's grant application was turned down on at least one occasion by a committee of outside scientists who advise the National Cancer Institute. A former member of the institute's board said it narrowly reversed the decision after he distributed a newspaper article about Dr. Folkman's research.

"We had some grants turned down and others accepted," Dr. Folkman said. "It wasn't something I was bitter about." Still, "for 10 years there was almost nothing but criticism every time I gave a paper," he said. In 1973 he showed that tumors inserted in the clear cornea of a rabbit's eye would visibly induce blood vessels to grow toward them. "So then people said, 'O.K., tumors do make new vessels, but it is a side effect,'" Dr. Folkman recalled.

A critic then showed that a crystal of uric acid placed in the cornea would do the same thing, suggesting that any kind of inflammation would induce new blood vessels. "That silenced us for a couple of years," Dr. Folkman said. "By the mid-1970's I thought the critics were right." Only later was it understood that scavenger cells called macrophages move in to mop up the uric acid, and the macrophages secrete chemicals that cause angiogenesis.

Little by little, he and others managed to put together the proofs the theory required. Factors that induce angiogenesis were found and then, even more interestingly, factors that inhibit it. Making new blood vessels, rather like blood clotting, is a high-risk activity for the body and is governed by complex controls.

When new blood vessels are needed, as in menstruation and wound healing, the process is quickly cut off once the task is done. Blood vessels that get out of control invariably cause serious problems, like macular degeneration or hemangioma, a disease of newborns.

The switch that flicks angiogenesis on and off seems to be the local state of balance between inducers and inhibitors of the process. It is curious that many tumors should secrete inhibitors as well as inducers of angiogenesis. But the result, as has been known to surgeons for a century, is that a primary tumor often keeps lesser, metastatic tumors in check. When the primary tumor is removed, the metastatic tumors flourish. Presumably the balance of rival factors favors angiogenesis in the primary tumor and repression of angiogenesis elsewhere.

Though Dr. Folkman began his work by seeking inducers of angiogenesis, it is the inhibitors that are of more immediate interest for cancer therapy. A first generation of angiogenesis inhibitors, including thalidomide and a drug called TNP470, are already in clinical trials and have shown promise, thalidomide in treating brain tumors and TNP470 with hemangioma. The next generation, angiostatin, endostatin and two substances found by other researchers, promise to be much more powerful, Dr. Folkman said.

He is both impatient and fearful of the obstacles that still lie ahead. Sitting at the conference table in his suite of laboratories in a Children's Hospital research building, he talks of the frustrations faced by Howard Florey, developer of penicillin, in getting the drug into production. He has seen these obstacles firsthand in the case of Norplant, an implantable form of contraceptive based in part on a patent he held; kept out of the United States for years, the contraceptive was approved but has failed to win widespread acceptance because of litigation.

He asks a colleague to bring out the apparatus in which he made his original observation of the tumors on the thyroid gland. Then he fetches a Petri dish with a chick embryo a few days old. The heart is beating and a delicate network of blood vessels has started to sprout across the yolk. A single drop of endostatin can reverse the process, forcing the capillaries to fade and the lacy network to clear.

Between the thyroid apparatus and the Petri dish, lying next to each other on the table, stretch 35 years of work. The project is close to fruition but not yet complete. "I am really worried because I have been at this a long time," Dr. Folkman said. "I have watched wonderful things in the laboratory not make it to the clinic."

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