Dollars for Your Thoughts

The story of how the late lawyer and entrepreneur Franklin C. Salisbury joined forces with the late Nobel laureate Albert Szent-Györgyi is legendary within the National Foundation for Cancer Research (NFCR) that they cofounded in 1973. Two years before that, Salisbury read an article about Szent-Györgyi, who had won the 1937 prize in physiology or medicine for the discovery of vitamin C. At the Marine Biological Laboratory in Woods Hole, Mass., the famed Hungarian scientist was working on his "bioelectronic theory" concerning the cause of cancer, but major funding bodies considered it too risky to warrant backing. His theory reasoned that closed-shell molecules need oxygen to accept an electron, thereby creating the electronically desaturated state conducive to most life forms. In other words, oxygen turns proteins into radicals. Parts of Szent-Györgyi's theory have fallen by the wayside over the years, including the specific mechanisms of cancer development, but his thinking nevertheless is seminal to the study of free radicals and antioxidants, a field embracing cancer among many diseases, and occupying thousands of researchers. Salisbury was no stranger to such then-unconventional scientific notions. In 1949, he became a founding director of Atlantic Research Corp., which grew into the world's leading solid rocket fuel manufacturer. He later helped set up Orbit Industries, a pioneer in electronic equipment for telephone systems. After reading about Szent-Györgyi's plight, Salisbury sent a donation. The heartfelt reply he received began, "I am deeply touched by your great generosity and compassion." Although there seems to be uncertainty about the exact sum Salisbury sent, a fair approximation is $25 (US). Courtesy of Ronald PethigRonald Pethig A couple of years later, a British electronics engineer in his early 30s named Ronald Pethig listened closely as Szent-Györgyi described aspects of his bioelectronic theory at a symposium in Boston honoring his 80th birthday. Also in attendance was Hans Krebs, whose 1953 Nobel Prize in physiology or medicine for elucidating the citric acid cycle or Krebs Cycle was enabled by Szent-Györgyi's prior research. Pethig found himself sitting next to a couple of "rich ladies" who listened as Krebs asked Pethig if he believed a word of what Szent-Györgyi had said. The younger scientist stoutly declared that he did think it made sense, although quantification was necessary. Krebs asked who Pethig was, and Pethig explained that he worked in Szent-Györgyi's lab, with one other person. Krebs asked why the team was so small, and Pethig replied that funds were scarce. The next day, the "rich ladies" sent $15,000 to Szent-Györgyi. That next day was also the first time Pethig met Salisbury, who had visited Woods Hole on previous occasions. When Salisbury learned of the $15,000, it and other money went into the first of many direct mail campaigns to raise funds for the foundation, Pethig says. The investment was parlayed into $40,000, and the foundation's concept took flight of a "laboratory without walls" to back promising ideas from good scientists, even without data to support them. High Risk, High Return Courtesy of Franklin C. SalisburyAdventure Funding: Franklin C. Salisbury (right), shown with Donald K. Engelman of Yale University, has expanded NFCR's efforts in cancer research. Salisbury and Szent-Györgyi must have quickly focused on their common qualities—idealism and a willingness to take calculated risks—because, refreshingly, those are still the dominant characteristics of the Bethesda, Md.-based NFCR, which exclusively funds basic research into cancer. Salisbury's son, Franklin C. Salisbury Jr., finished law school and joined the NFCR at his father's behest in 1993, four years before Franklin Sr. died. His son has expanded the foundation's activities from its original emphasis on oxidation and free radicals into many other avenues of cancer research, but has retained the focus on providing what one recipient, Yale University molecular biophysics and biochemistry professor Donald K. Engelman, calls "adventure money." Szent-Györgyi's way of doing science included an acceptance of mistakes as the price of innovation, Pethig recalls. "I think now people are very frightened of making mistakes, depending on the level of their career. They're frightened to make a mistake if it means they may never get a research grant again." For Szent-Györgyi, on the other hand, "if one of his ideas was soundly criticized, then that gave him hope that it was actually a really good idea." Although NFCR support often amounts to a tiny percentage of a given lab's annual budget, it usually comes at a time when no other backing is available. Essentially, NFCR gives money for developing proof of concept, which then can attract more funds from wealthier sources. The foundation is a comparatively small operation, with 18 staff in pleasant but unremarkable offices, and a research funding outlay of $9.94 million last year. Over the years, it has expended roughly $190 million on basic research. A handful of fellows who have long been associated with the foundation receive annual amounts to use for virtually any cancer-related research they choose, but much of the funds are distributed in the form of project contracts with sponsoring universities, which are allotted 15% of the total for overheads. The advantage of contracts over grants, Salisbury points out, is flexibility. The three-year contracts, usually for about $100,000 annually, are peer reviewed periodically, and can be rewritten on request of the principal investigator, to take the research in any new direction indicated by recent findings. This "blue sky" philosophy has generated impressive results. Salisbury gives the example of Yale University chemical engineer Csaba Horvath. "Every drug in the world made today is made through a process he developed with our funding, called HPLC (high performance liquid chromatography). You wouldn't believe the criticism we underwent from the mainstream: 'What are you doing funding a chemical engineer? What does that have to do with cancer?'" Courtesy of Franklin C. Salisbury, Jr.An NFCR Success Story: Harold Dvorak, chief of Beth Israel Deaconess Medical Center and Harvard Medical School, used monies from the foundation to study what became vascular endothelial growth factor (VEGF). Another notable NFCR success story is that of Harold Dvorak at Beth Israel Deaconess Medical Center and Harvard Medical School, who discovered a molecule almost a quarter century ago but could get no funding to study it. In 1980, the elder Salisbury called and offered Dvorak $30,000 annually for the research. In a 2000 letter to Salisbury Jr., Dvorak recalled wondering "if this was manna from heaven or a practical joke." He accepted the money and went on to establish that his molecule,1 now called vascular endothelial growth factor (VEGF), is the protein primarily responsible for blood vessel formation in tumors. Many Success Stories Among the foundation's numerous other triumphs are: the discovery of progesterone receptors in breast cancer by the University of Colorado Health Sciences Center's Kathryn B. Horwitz; leading research by Bert Volgelstein, head of the molecular genetics lab at Johns Hopkins Kimmel Comprehensive Cancer Center, on what has become the most studied gene in medicine, the p53 tumor suppressor; and the discovery by Helmut Sies of Heinrich Heine University that lycopenes in tomatoes prevent oxidation and have significant anticancer effects. Nobel Prize winners funded by the foundation to take their research in new directions have included University of Colorado biochemist Thomas R. Cech, physicist Ivar Giaever of Rensselaer Polytechnic Institute, and Cambridge University biochemist Cesar Milstein. Keith U. Ingold, distinguished research scientist in chemical biology at the National Research Council in Ottawa, Canada, received NFCR funding for two decades. In a 1994 letter to Salisbury Sr., he recalled that, in the late 1970s, he had completed a quarter-century of chemistry lab work involving free radicals and wanted to apply his findings to medical science, but he could get no backing. Then, "the NFCR appeared and, like a fairy godmother, agreed to provide sufficient funds to support one technician." In a very short time, his lab proved that vitamin E scavenges free radicals.2 Toxicology professor Martyn T. Smith, an erstwhile member of the so-called Oxygen Club that was originally funded by NFCR at the University of California, Berkeley, has used NFCR funds to turn toward genetics, discovering a mutation that can protect against some types of acute leukemia by regulating folate processing.3 "Now I can write a paper on folate genes and can get federal money," he remarks, "but if had I tried to three years ago, I couldn't." Smith codirects the NFCR Center for Genomics and Nutrition at UC-Berkeley, one of six research centers the foundation has established over recent years to supplement its project contracts and fellowships. The centers, in such far-flung institutions as Yale University, the Institute of Medicinal Biotechnology in Beijing, Oxford University,4 and Free University in Berlin, focus on different aspects of basic cancer research, among them molecular analysis and imaging, molecular oncology, RNA, protein chemistry, and computational drug discovery. Two more centers are due to open soon, one of them under the directorship of associate pathology professor Danny R. Welch at Pennsylvania State University Hershey Medical Center. It will focus on the mechanisms of metastasis, which has received relatively little funding from federal bodies. "NIH funds science that is likely to succeed, and while this sounded good on a theoretical basis, there really wasn't much precedent for it," Welch explains. With NFCR money, his lab has discovered four metastasis suppressor genes, the first in 1996.5 The field is now growing quickly, with 12 such genes isolated. "I believe our eight centers close the loop of discovery," comments chemist and NFCR science director Sujuan Ba. The centers are a win-win situation, she thinks, because they fund programs rather than projects, allowing scientists even more freedom to explore innovative ideas. In return, the foundation gets higher visibility, the potential for better leveraging of its funds, and the likelihood of synergistic interactions among the centers. Ba's goals include increasing NFCR's funding to $10 million within five to eight years, and bringing discoveries into the clinical arena. "We'd like to play an important role in translational research, because right now, I don't believe the bottleneck in cancer research is in the basic sciences," she declares. "We can generate a lot of hits, but they're all in the Petri dish." Steve Bunk (sbunk@the-scientist.com) is a contributing editor. References 1. D.R. Senger et al., "Tumor cells secrete a vascular-permeability factor that promotes accumulation of ascites-fluid," Science, 219:983-5. 1983. (Cited in 915 papers according to the Web of Science, ISI, Philadelphia.) 2. G.W. Burton et al., "First proof that vitamin E is major lipid-soluble, chain-breaking antioxidant in human blood plasma," Lancet, 2:327, 1982. 3. C.F. Skibola et al., "Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults," Proceedings of the National Academy of Sciences, 96:12810-5, 1999. 4. L. Hand, "Aiming a world of computers at anthrax," The Scientist, 16[3]:17, Feb. 4, 2002, and L. Hand, "Computing for cancer research," The Scientist, 15[10]:1, May 14, 2001. 5. J.H. Lee et al., "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene," Journal of the National Cancer Institute, 88:1700-3, 1996.

Dollars for Your Thoughts

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