Going Against the Grain
Pursuing unconventional approaches yields best results, says renowned biology researcher Judah Folkman

At a conference when Dr. Jeffrey M. Isner, M73, a pioneering gene therapy researcher at Tufts University School of Medicine, presented his ideas about injecting the protein controlling vessel growth directly into ailing heart muscle, Dr. Judah Folkman reported he overheard one researcher comment, “This is what we get for letting M.D.s play in the lab.”

At the annual Isner lecture, Dr. Judah Folkman spoke about his career and his latest research interest: the naturally occurring inhibitor endostatin and its ability to lower blood pressure. PHOTO: JODI HILTON

“I don’t think they believed me,” Isner told Folkman after the session.

“He was a master of understatement,” Folkman said of Isner. “But I told him, ‘They are only experts on the past. There are no experts on the future.’ ”

Folkman was speaking at the second annual endowed memorial lectureship on November 7 in honor of Isner, a Tufts professor of medicine who died in 2001 at age 53. The Andrus Professor of Pediatric Surgery at Harvard Medical School and director of the vascular program at Children’s Hospital in Boston, Folkman founded the field of angiogenesis in 1971 with his then-controversial hypothesis that all tumor growth depends on the growth of new blood vessels. Blocking this vessel growth, he argued, would halt or possibly reverse tumor growth. Thirty-six years later, his idea is the basis of thousands of research papers and was the key to developing a class of cancer-fighting drugs called angiogenesis inhibitors. But when he first presented the notion to his colleagues, Folkman was met with disbelief, even derision.

“No one believed tumors needed vessels, and no one believed vessels around tumors were anything but inflamed with dying cells,” he said of the academic dogma in 1971. The next year, Folkman received his “favorite grant rejection.” It read, “It is well known that endothelial cells cannot be grown outside the body, and even if they could, how would you see them?”

Two years later, Robert Langer, a prominent bioengineer now at MIT, joined Folkman’s lab and taught Folkman about the “obvious quotient.” If a research proposal was not obvious to grant reviewers, Langer would send the idea to the patent office. “He’d include a note that said, ‘Yesterday, 21 government scientists found this idea not obvious.’ He holds more than 600 patents today,” said Folkman.

Despite his colleagues’ dismissal of angiogenesis, Folkman and his team of “very courageous post-docs” were able to isolate angiogenic factors, the proteins and enzymes that stimulate vessel growth in the body. Eventually, Folkman discovered inhibitors, chemicals that would block vessel growth, some of which were naturally occurring.

“That body of work began to catch the attention of the pharmaceutical and biotech companies,” said Folkman, who added he has no connection with any of the companies. By 2003, Velcade became the first angiogenesis inhibitor to be approved by the FDA for treatment of multiple myeloma or mantle cell lymphoma. So impressive were the data for another inhibitor called Avastin in the treatment of colon cancer that the crowd of scientists at a conference where the results were announced burst into applause. Seated in the audience, Folkman overheard one young researcher say, “If only Folkman were alive to see this.”

The approvals keep coming. Last year, an inhibitor called Lucentis received FDA go-ahead to treat macular degeneration, a disease of the retina that can lead to blindness. Forty percent of patients treated with Lucentis regained enough sight to drive a car. Another inhibitor has been approved to treat lung cancer in China. As of 2006, 1.2 million patients worldwide were treated with angiogenesis inhibitors, and 20 more versions of the drugs are currently in phase III trials, with more in the pipeline behind them. “And we are beginning to see how many [inhibitors] target VEGF or its receptors,” said Folkman, referring to the protein controlling vessel growth that Isner was working with.

Today, Folkman is curious about the naturally occurring inhibitor endostatin and its ability to lower blood pressure, and he hopes other researchers will follow his lead. In the meantime, Folkman and his colleagues have been testing the relationship between endostatin and blood pressure in lab mice. In doing so, the team has noticed another hard-to-explain phenomenon.

“Notice that the researchers are all women,” said Folkman. “We have never been able to have a male do this experiment. You cannot get a stable blood pressure when men are in the room. How does a mouse know you’re a male or a female? We have no idea.”

And speaking of gender differences, Folkman concluded his talk with photos of his granddaughter, who, at seven years old, already wants to go into the family business. But when Max, a boy in her second-grade class, told her girls couldn’t be doctors, Folkman advised her to tell him that more than half of the students at Harvard Medical School are “brilliant young women.” When Folkman checked back with his granddaughter, he asked her how Max had responded to that statistic.

“Nothing,” she said. “Max said nothing.”

“Maybe you’ve changed his mind,” Folkman told his granddaughter. “In my experience, critics never apologize.”

The Isner Lectureship was established with the generous support of the Isner family and the Jeffrey M. Isner Foundation for New Directions in Cardiovascular Research. The third annual Isner Lecture will be held at Tufts Medical School on Wednesday, November 5, 2008, and will be presented by Eli Keshet, professor of molecular biology at the Hadassah Hebrew University School of Medicine.

Jacqueline Mitchell is a senior health sciences writer in Tufts’ Office of Publications. She can be reached at jacqueline.mitchell@tufts.edu. This story ran in the December 2007 issue of the Tufts Journal.