Judah Folkman spent his life in dogged pursuit of a cure for cancer. For most of his career he was ridiculed and called a charlatan. But his discoveries were eventually hailed world wide and launched a new field of study: angiogenesis. Over 1000 laboratories are now studying angiogenesis, and more than 1.2m patients are taking antiangiogenic drugs for cancer and other diseases.
The son of a rabbi and a social worker, Folkman’s interest in medicine was sparked as a young boy when his father took him on visits to his congregants who were in hospital. Folkman told his father that he too wanted to help patients but he wanted to do it as a doctor. He entered Harvard Medical School at the age of 19.
Folkman’s first discoveries came early in his career. In 1961 he was drafted into military service aboard a naval vessel. He was given the task of finding out whether blood could be dried and reconstituted. To test the experimental blood, Folkman bathed a cultured rabbit thyroid in the blood. The gland thrived. But Folkman went one step further, he wanted to see if the blood could support new growth, so he injected the thyroid with cancer cells, the fastest growing cells he could think of. What he observed would fascinate and drive him for the rest of his career: the cancer cells grew into tiny tumours, but they all stopped growing at about 1 mm in size, something that doesn’t happen normally in living animals or humans.
Curious about why the cells would stop growing and thinking that they might have died, Folkman injected the arrested cancer cells from the rabbit thyroid into mice. The cancers grew rapidly. He noted that the mouse tumours had abundant blood vessel growth while there was none in the cultured thyroid tumours. He suspected that the cancer cells in live animals were sending out some sort of chemical signal that recruited the cancer’s “own private blood supply”—giving it life and allowing it to grow.
His military service over, Folkman returned to work as a surgeon at Harvard, becoming, at 34, the youngest chief of surgery at the Children’s Hospital in Boston. When operating Folkman noted that the cancers he held in his hands were “hot and red and bloody.” He became more convinced than ever that blood supply was critical to cancers. He began laboratory research at night and weekends to test his theory that cancer cells elaborated a chemical signal that recruited blood vessels. He inserted cancer cells where normally there are no blood vessels—in the corneas of rabbits. What he observed next excited him: blood vessels began to shoot out from the limbus of the cornea in a direct line towards the cancer cells. Once they reached the tiny tumours, the cancers grew explosively.
But Folkman’s colleagues weren’t impressed. One well-known pathologist dismissed his findings as the byproduct of non-specific inflammation. It seemed that Folkman was at a dead end when other researchers reported that uric acid crystals they’d placed in rabbit corneas also triggered blood vessel growth. But Folkman was relentless. According to Robert Cooke, author of Dr Folkman’s War: Angiogenesis and the Struggle to Defeat Cancer, at one point Folkman showed a paper he had written to John Enders and asked if he was “giving too much away” in the paper, allowing someone to steal his ideas. Enders, told Folkman not to worry, that his ideas were “theft-proof” because no one would believe them.
In the 2001 Public Broadcasting System documentary “Cancer Warrior,” Folkman said it is hard to know when one has crossed the “fine line between persistence and obstinacy” or “pig-headedness.”
It took years, but in 1983 Folkman and his colleagues triumphed when they isolated a protein from the urine of cancerous mice that, when placed in a pellet in rabbit cornea, triggered a torrent of blood vessel growth. Folkman immediately began to pursue work to find a substance that could block his newly discovered angiogenic factor, believing that if he could halt blood vessel growth into a cancer, it would be rendered harmless. Eventually he discovered two antiangiogenic molecules that he dubbed angiostatin and endostatin. In one test he injected 20 mice with cancer cells, 10 being treated with angiostatin. The necropsy results were compelling: the 10 untreated mice were riddled with cancer, the 10 treated mice were free of disease.
The pendulum began to swing, and Folkman’s reputation soared. Researchers took up the cause of angiogenesis. Drug companies raced to be first to develop antiangiogenesis agents. The floodgates broke in 1998, when a story in the New York Times quoted Nobel laureate James Watson as saying that Folkman would cure cancer in two years. Although Watson would later say he was misquoted, the damage was done. Thousands of patients descended on oncologists begging for treatment with angiogenesis inhibitors. Folkman reminded everyone that the cure he’d found was for mice.
If Folkman’s reputation as a researcher was undergoing a remarkable transformation, his reputation as a kindly surgeon never changed. He was revered as a rare surgeon who not only excelled in the operating theatre but who made himself available at all hours to patients and their families to give counsel and comfort—even giving them his home phone number. After he stopped working as a surgeon, he would still respond to over 10 phone calls each night, responding to questions from patients around the globe.
As Folkman became a cause célèbre, inflated expectations led to disappointment when clinical trials of antiangiogenic agents in humans proved far less spectacular than they had in mice. To make matters worse, other researchers had trouble replicating Folkman’s findings. Some physicians who had referred patients to him said some of his claims were bloated. In a moment that would prove embarrassing to Folkman and two of his colleagues, Harvard University was forced to issue an apology about a paper they published in the New England Journal of Medicine about the efficacy of angiogenesis inhibition in the treatment of large haemangiomas. The university acknowledged that multiple errors in the paper all “tend to improve the apparent success of the therapy.”
Nor was the first commercial application of antiangiogenesis treatment for cancer without pitfalls. Bevacizumab (Avastin, Genentech), approved to treat colon cancer, extended the lives of patients a modest five months. And the price was high, both in side effects and cost: patients paid upwards of $100 000 a year for the drug in 2006. Folkman was not deterred by early modest successes in cancer treatment, saying that many successful treatments take decades to refine.
Unexpectedly, his quest to cure cancer may contribute more to diseases other than cancer. Antiangiogenic agents are now credited with saving the vision of many patients with macular degeneration, and studies are under way to treat a wide array of diseases.
Author Robert Cooke says Folkman was widely thought to be in line for a Nobel prize. “He had at least four developments, each of which deserved a Nobel. While still a student at Harvard, he developed one of the first implantable pacemakers. He developed the leaky plastics used to make implantable drugs. And he discovered proangiogenic and antiangiogenic agents.” Unfortunately, said Cooke, “They don’t award the Nobel prize posthumously.”
Father of angiogenesis
Moses Judah Folkman, professor of cell biology, Harvard Medical School, and director of the vascular biology department, Children’s Hospital, Boston (b 1933; q Harvard 1957), died from a heart attack on 14 January 2008.