BOSTON -- At a cancer conference hosted by Michael Milken in September, noted researcher Judah Folkman treated scientists to a mesmerizing presentation of his latest work, with vivid lab photos and graphs showing antitumor agents to be unambiguously effective in mice. Crowding around afterward were Mr. Milken, the former junk-bond king, as well as Intel Corp. Chairman Andrew Grove, a CNN cameraman and an attendee who clapped Dr. Folkman on the back and said, "Beautiful talk, Judah."
Dr. Folkman is used to warm receptions. As the father of the concept of attacking tumors by cutting off their blood supply, he has become one of the world's most visible cancer fighters. At Children's Hospital here, people stand aside as he passes in hallways hung with his citations. A 1997 Fortune profile pegged him as a likely Nobel Prize winner. And last May he and his cancer strategy burst into the national consciousness after being prominently featured in a New York Times story. In an instant, hopes of countless cancer patients brightened, and Dr. Folkman was being treated as a medical prophet.
But the public acclaim stands in contrast to doubts and frustration within parts of the research community. A number of experts say they haven't been able to verify Dr. Folkman's findings: that an agent called endostatin can cause large tumors in mice to shrink and lie dormant, and that this plus a second agent called angiostatin can make such tumors vanish. In science, the critical test of experimental data is that they can be reproduced by other scientists working independently.
One collaborator, the National Cancer Institute, is so concerned about its inability to do so that it had begun to form a panel of outside experts to investigate, when Dr. Folkman agreed to give institute scientists a 10-day demonstration in his lab later this month. Dr. Folkman also was queried about the issue by Boston's Dana-Farber Cancer Institute following Internet rumors he would retract his research in the scientific journal Nature -- rumors that Dr. Folkman says have no basis. (Nature declines to comment.) Meanwhile, Genentech Inc. scientists tried to duplicate Dr. Folkman's results for a year, then gave up. Says Genentech Chief Executive Arthur Levinson: "We want to know what's going on."
EntreMed Inc., a tiny biotech company that licensed the two biological agents, hired Harvard cell biologist Bjorn Olsen to look into endostatin. Using endostatin variants he made, he couldn't reproduce Dr. Folkman's results, Dr. Olsen says. Dr. Olsen, who had originally helped the Folkman lab isolate the substance, suggests it would be foolish to test the agent in humans without a better understanding of how it works and possible modification.Human tests don't appear likely soon. The National Cancer Institute has delayed human testing of endostatin for at least a year. As for angiostatin, Bristol-Myers Squibb Co., which licensed it from EntreMed in 1995, has no set timetable for human tests because "it requires a lot more work," says William Koster, senior vice president for drug discovery.
For more than two years, Bristol-Myers couldn't produce consistent angiostatin results, with one batch showing some effect but the next showing little or nothing. Recently, the company did succeed in making small batches that reliably slow tumor growth in mice, Dr. Koster says, but he adds that practical problems in trying the substance on human beings abound. Says the company's senior vice president of pharmaceutical development, Christopher Cimarusti: "There's a difference between a lab curiosity and something you can take forward in man."
The Caveats
That distinction, while eminently clear to scientists such as Dr. Folkman, is often lost in the public's understanding of the immensely complicated quest for a cancer cure. Dr. Folkman didn't seek the publicity he received for his efforts in May, and he declined numerous requests for television interviews afterward. He agonizes over false hopes raised in cancer patients, and he makes a point of stressing that it is a long journey from lab to bedside for any drug candidate, including his own.
Yet some researchers who have worked or competed with Dr. Folkman say he has been so single-minded in promoting his theories that he has promised too much too soon. Dr. Folkman has been publicizing antitumor findings and securing large corporate grants since 1972, but no commercial cancer drugs have resulted.
When one compound hasn't lived up to its hopes, he has proposed a new and better one. His career thus seems to illustrate an inherent tension within modern-day, high-stakes medical science: the conflict between the advisability of great caution in reporting data and the need to sell projects to sponsors so the promising research can continue.
"Judah's really opened up the field, but some scientists think he's the boy who cried wolf," says David Cheresh, a Scripps Research Institute scientist also noted in the cancer field.
Dr. Folkman says his results have been reproduced again and again in his own laboratory. At least three different groups in his lab have done so using scientific protocols he has perfected over 30 years. If others have difficulty reproducing his experiments, he says, this is simply because of the extraordinary skill levels required in producing the complex molecules and working with them. There are many techniques that must be learned over time, he says. Likening such skills to those that produced a Stradivarius violin, he notes, "There's no way you can get that skill in a short time."
As for promising too much, he says, "In the pharmaceutical world, one in 1,000 drugs makes it all the way. Does that mean it's crying wolf? If it fails, it fails for unpredictable reasons, so I don't see what the complaint is."
A Surgeon First
Before turning to cancer research, Dr. Folkman distinguished himself as a wunderkind surgeon, becoming chief of surgery at Children's Hospital at age 34. Seeing hundreds of bloody tumors, he came up with the idea of starving them of blood-blocking "angiogenesis," the process by which new blood vessels spring up to feed a growing tumor. He published dozens of provocative papers, trained many of the field's prominent investigators, and won more than 50 scientific awards. He began to teach at Harvard and built his lab into one of Harvard's biggest, with a budget of $8 million a year and more than 100 scientists.
Now 65, Dr. Folkman still works 75-hour weeks and makes time after hours to return calls from cancer patients. He has never tried to get rich on his research, consigning all rights and license payments to Harvard-affiliated Children's Hospital in accordance with Harvard policy. "Judah, with his vision, has made a tremendous contribution," says Isaiah Fidler, a department chairman at the University of Texas' M.D. Anderson Cancer Center in Houston. "He is one of the most decent, compassionate people I have ever met in my life, and he's a brilliant scientist."
But right from the start, Dr. Folkman had to battle for respect -- and funding. His approach was unconventional, and big government grants weren't forthcoming. In response, he vigorously promoted his findings to drug companies. In 1972, he used a time-lapse film to show medical writers how blocking something called tumor angiogenesis factor stunted a tumor. Monsanto Co. gave Dr. Folkman and a colleague $23 million, a grant so large that Harvard formed a panel to monitor it.
The company today describes the project as one "that taught Monsanto a lot about how it can work with institutions," but not one that led to products. Dr. Folkman says, "They quit too early; they could have had the whole field." The collaboration ended in 1984.
Other Compounds
Dr. Folkman had by then moved on to a new crop of antitumor agents. A Boston-area biotech company, Repligen Corp., financed $40 million of Folkman-led research on one of them, called "platelet factor 4," only to find that it wasn't effective in humans, at least at the doses tested. Dr. Folkman says, "It was a very good drug, but you can't get it potent enough."
Dr. Folkman stirred brief excitement with two well-known substances, cortisone and the blood thinner heparin. His 1983 Science magazine report on the combination told of "complete regression" of tumors in most mice tested. But in 1985, two teams of researchers reported they hadn't been able to reproduce his results.
To Dr. Folkman, this just illustrates his point that it can take time for others to learn how. He says that while the two labs indeed couldn't match his results, numerous other labs from several countries eventually did. But the combination proved too toxic, and went no further.
At any rate, by this time Dr. Folkman had pulled his next experimental compound literally out of thin air. It was an airborne fungus that landed in a petri dish set up for testing in his lab. That serendipity, reminiscent of the discovery of penicillin, launched a $1 million-a-year deal with Takeda Pharmaceuticals of Japan. But human trials of the fungus have continued inconclusively for almost seven years, while the National Cancer Institute gave up testing the fungus in cancer patients after it left some too dizzy to walk, says an investigator. Dr. Folkman believes the fungus may prove useful at lower dosages in conjunction with other therapies.
Looking for Support
Eventually, Dr. Folkman's lack of commercial success in cancer began to catch up to him. At one point in late 1992, he says, he had to temporarily divert certain grant money to pay researchers' salaries.
The quest for funds was a time-consuming burden. Drug-company envoys trooped through the lab and his co-workers were asked to give demonstrations lasting hours, says a former cell biologist in his lab. After striking out with big companies, Dr. Folkman says, he finally mailed out fliers to small companies.
One, EntreMed, of Rockville, Md., got aboard, but it was too small to develop a drug by itself. Then in early 1995, Bristol-Myers Squibb gave Dr. Folkman its annual cancer-research award. At the award dinner, Dr. Folkman pitched his lab's newly discovered angiostatin to the company's research chief. Bristol-Myers licensed the agent but didn't pursue it nearly as aggressively as Dr. Folkman wanted. Last year when the Folkman lab announced a second substance that could cut off tumor's blood supply -- endostatin -- EntreMed began studying it, as did the National Cancer Institute, Genentech and others.
There things stood when Dr. Folkman's efforts received a burst of publicity in May. EntreMed stock briefly soared sevenfold. Top brass at Bristol-Myers, caught by surprise, contacted their own scientists, who called in collaborators from Dr. Folkman's lab, EntreMed and the National Cancer Institute. "We decided to work very hard to bring angiostatin to a successful conclusion, to really understand it and decide what role it had," says Bristol-Myers' Dr. Cimarusti.
Complex Molecules
Just creating the complex substance is a laboratory challenge, he says. "Angiostatin is a very, very large molecule. It's comparable to the hardest we have ever attempted here." Scientists must join a string of protein constituents so they fold into a precise three-dimensional shape.
Endostatin is even trickier to work with. Dr. Folkman says it is so fragile that to get it from his Boston lab to the National Cancer Institute in Bethesda, Md., it must be hand-carried. He speculates that small details of experimental lab conditions may be partly to blame for other labs' trouble in reproducing his data, details such as the way mice are injected or the freeze-thaw cycle involved in shipping endostatin.
Dr. Olsen, the EntreMed consultant, thinks otherwise. He has been able to get dozens of endostatin variants to slow the proliferation of blood-vessel cells, but only slightly. He says one possibility is that some unknown contaminant was the cause of the tumor-shrinking power in mice that Dr. Folkman found -- a notion Dr. Folkman rejects, citing three proofs of purity he performed.
As for EntreMed, its chairman, John Holaday, says, "I'm not going to let delays in mouse studies hinder us in our approach, which is to test human endostatin in people." EntreMed still needs a corporate partner before it can begin such tests.
Leon Rosenberg, Bristol-Myers' former research chief, points to subjective factors that can muddy laboratory results. "You had people who worked in Judah's lab trying to tell the difference between one plus and four plus" in blood-vessel inhibition, which are minute differences, he says. "That was often in the eye of the beholder."
Similar criticism dogged a study Dr. Folkman once co-wrote on treating life-threatening birthmarks. The 1992 New England Journal of Medicine article was corrected not once but twice over the next three years because measurement was more subjective and side effects more substantial than had been stated. Says Dr. Folkman: "It could have been carelessness."
Others' Studies
As to his latest biological agents, however, Dr. Folkman says that several studies by people outside his lab should help dispel doubt about his dramatic data. One, published in Nature last July, said angiostatin enhanced the effects of radiation therapy. It was "a stunning paper," Dr. Folkman says.
But he was one of the three outsiders who "peer-reviewed" it -- and the only reviewer who had no misgivings, according to one of the study's authors. Dr. Folkman says he would never endorse a study that wasn't top notch merely to bolster his own work. His critics are "jealous," Dr. Folkman says, because of the recent publicity he has received, and he finds the doubts about his work "very depressing."
The National Cancer Institute will soon have an opportunity to study Dr. Folkman's methods firsthand, by sending in its own team of scientists to his lab. The institute, says Robert Wittes, its deputy director of extramural science, is "frustrated" that its researchers can't reproduce Dr. Folkman's "striking observations" after almost a year of trying. "We are all puzzled by this and feel we need to get to the bottom of this before we move forward," he says.
Even if Dr. Folkman doesn't find a powerful cancer drug himself, his pioneering work may lead others to effective therapies using his approach of blocking cancer's blood supply. Companies such as Bayer AG, British Biotech PLC and Agouron Pharmaceuticals Inc. are testing their own such agents in final-stage clinical trials.
Dr. Folkman's long struggle for a human-cancer breakthrough just demonstrates that pioneering science is like a "marathon," says longtime associate Jordan Gutterman at the M.D. Anderson Cancer Center. It's a race he thinks Dr. Folkman is destined to win. "His body of work is extraordinary, and my strong opinion is that it will be borne out in time."
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