Persistence Prevails for John Scott Recipients

PHOTO CREDIT: Lori Desantis, Children's Hospital of Boston ANGIOGENESIS HONORS: Children's Hospital of Boston researcher Judah Folkman (far right) received the 1998 John Scott Award from the Philadelphia Board of Directors of City Trusts for his work in studying angiogenesis and angiogenesis inhibitors. Folkman, who refuses to be photographed alone, is joined by Harvard Medical School colleagues (from right) Donald Ingber, Michael O'Reilly, and Robert D'Amato. After being built up by a New York Times article1 in May and torn down by a Wall Street Journal story2 in November, M. Judah Folkman spoke of the thin line between persistence and obstinance as he accepted on Nov. 20 the 1998 John Scott Award for his work in angiogenesis. Baruch S. Blumberg, who also received the $10,000 award from the Philadelphia Board of Directors of City Trusts, also mentioned persistence, as well as the importance of collaboration, when he was honored for his work in developing a liver cancer-preventing hepatitis B vaccine. Both scientists have spent more than 30 years trying to understand broad basic scientific issues that have enormous clinical implications; both have taken great pains to credit others who have contributed to their work; and both have experienced skeptical reception to their work during its early stages. However, skepticism has subsided for Blumberg, senior adviser to the president of the Fox Chase Cancer Center in Philadelphia. Blumberg received the 1976 Nobel Prize in physiology or medicine for work leading to a hepatitis B vaccine, now widely used around the world. The most controversial aspect of that work may have been Blumberg's early hypothesis that the vaccine also reduces liver cancer,3 a hypothesis that has since been borne out in epidemiological studies. For Folkman, controversy has occasionally flared up. During his acceptance speech, the director of the Surgical Research Laboratories at Children's Hospital in Boston and professor of surgery at Harvard Medical School recounted some of that controversy. Folkman noted that he identified the importance of blood vessels to tumors in the early 1960s, but he couldn't get his hypothesis published until 1971.4 He and colleagues worked for 10 more years establishing indirect proof of principle and an additional five before they identified angiostatin as a molecule that thwarts cancer in mice by stopping the growth of blood vessels in tumors.5 That paper prompted more skepticism when other scientists tried but failed to duplicate the results with angiostatin samples his labs shipped to them. Dry ice, in which the proteins were shipped, killed them, Folkman says. Then in 1996, Folkman and colleagues reported another molecule, endostatin, that had tumor-shrinking abilities similar to angiostatin and could be used in tandem with it for even greater efficacy in mouse models.6 Endostatin--and Folkman--came under criticism in the Nov. 12, 1998, front page Wall Street Journal story, which claimed many groups could not reproduce Folkman's results. "In contrast to recent press reports, these proteins have been reproduced," Folkman said during his speech. He also hinted that proceeding in the face of criticism, has, at times, been difficult: "How does one know when to keep going and when to cut one's losses?" He added that continuing his work has meant a balancing act somewhere between persistence and obstinance. "How do you know when you've crossed the line?" However, the "miserable feeling of not understanding nature's rules" has kept him going, he concluded. In an interview following the award ceremony, Folkman discussed some rules of angiogenesis that have, so far, eluded him and other researchers. One "big mystery," discovered by accident, is the tumor's limited ability to rebound after treatment with angiogenesis inhibitors. "We only wanted to demonstrate whether or not an angiogenesis inhibitor that was very powerful like endostatin could be given for a long time without getting drug resistance. Because if it got drug resistance, then you would have to limit the time you would have to give it," Folkman says. Michael O'Reilly, a postdoc in Folkman's lab, repeatedly administered endostatin to mice with xenograft tumors, then suspended treatment when the tumors shrank to microscopic size. The tumors returned after each of four such cycles. After six, they did not.7 The dormancy of the tumors following the sixth cycle surprised Folkman. "They were there. They weren't cured. They were just tiny, tiny, and they were not angiogenic." The tumors' behavior was akin to HIV still being present in the body after being treated with protease inhibitors, but not proliferating to the point of causing clinical symptoms. However, in mice at least, the tumors did not return after six or more cycles of treatment concluded, unlike HIV, which returns after patients stop taking protease inhibitors. "We waited and waited and thought they'd come back in a few months," Folkman recalls. "But they basically ended up pretty dormant throughout another half-year of the animal's life." The researchers performed similar experiments on other tumor types and found that each tumor type had a different "clock" or timetable of regeneration. The series of experiments told the researchers that cycles of treatment didn't cause an immune response. "Then the question is, 'Where's the clock?'" Folkman ponders. "Is it in the tumor? Or is it in the host?" He acknowledges that the mouse models with xenografted tumors may not behave exactly as tumors in people.8 "You have to accept that the model isn't perfect. But, the model discovered something." Discovering the next step, the switch that triggers the angiogenesis clock to start ticking again, remains an area of focus. "We do know that if you make a wound in the area where the dormant, microscopic tumor is, it will start, or if you move it, it will start." Folkman speculates that the switch could be biochemical or biophysical. Folkman also thinks that finding the receptors that bind angiostatin and endostatin will improve antiangiogenesis techniques. "As soon as they are known, it means that chemists have a chance to try to find a substitute for the protein--a small molecule that could land on the receptor and do what the whole protein does." He also predicts that other groups will find more angiogenesis inhibitors that may be more stable and effective than angiostatin and endostatin: "There are going to be many angiogenesis inhibitors. They just keep coming." Despite the potential clinical applications of angiogenesis inhibitors, Folkman says he remains fascinated by the basic science behind angiogenesis--how the networks of veins, arteries, and capillaries grow, develop, and connect. He suspects that tumors control this process differently than healthy cells. "The endothelial [cells] have the whole program to make the whole blood vascular network--they don't need any help," Folkman says. "The tumor just says 'On or Off.'" Vascular development in embryos is just beginning to get pieced together, he concludes.9 PHOTO CREDIT: Fox Chase Cancer Center Baruch S. Blumberg Blumberg's research started with similar basic science questions. The geneticist studied the variation between proteins occurring in the blood of different individuals. He was more interested in the population genetics of people living in extreme environments--ranging from outback Australia to sub-Saharan Africa. He and colleagues studied polymorphisms in the serum lipid proteins of those populations. "It did not start off as a search for the virus or the vaccine," Blumberg said during his acceptance speech. "We were trying to answer the question of why some became sick when others who are exposed do not." However, his population genetics studies led to the identification of an antigen against hepatitis B, which, in turn, led to an assay to screen for the disease, and, finally, a vaccine against it. "The hepatitis vaccine--I don't know how to put it--just fell out," Blumberg notes in an interview prior to the award ceremony. After vaccine usage became widespread, he and other epidemiologists noted drops in liver cancer. That hypothesis was not initially universally accepted, but as data grew, so did the belief in that correlation. "We had hypothesized, back in the '70s, that this was a (preventive) cancer vaccine." Populations who received the vaccination experienced significantly lower rates of liver cancer.10 "Hepatitis B vaccine is a potent cancer vaccine in that it prevents cancer." Blumberg notes that several other viruses have since been linked to cancer, and suspects that several more will be identified. Those links, if proved, could mean more preventive cancer vaccines. Blumberg, from an intellectual standpoint, favors preventive vaccines over others, now under development, that aim to treat tumors once they form. "It's a hell of a lot better to not get sick," he concludes. G. Kolata, New York Times, May 3, 1998, page 1. R.T. King Jr., Wall Street Journal, Nov. 12, 1998, page 1. M.H. Chang et al., New England Journal of Medicine, 336:1855-9, 1997. J. Folkman, New England Journal of Medicine, 285:1182-6, 1971. M.S. O'Reilly et al., Cell, 71:315-28, 1994. M.S. O'Reilly et al., Cell, 88:277-85, 1997. T. Boehm et al., Nature, 390:404-7, 1997. R. Lewis, The Scientist, 12[21]:10, Oct. 26, 1998. H.U. Wang, et al., Cell, 93: 741-753, May 29, 1998. M.H. Chang et al., New England Journal of Medicine, 336:1855-9, 1997.

Persistence Prevails for John Scott Recipients

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