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Compound Interest

chemopreventive point of view. Leaf explained the situation in his 2004 article:

"When you add it all up, Americans have spent, through taxes, donations, and private R&D, close to $200 billion, in inflation-adjusted dollars, since 1971. What has that national investment netted so far? . . . In short, scientists now know (or think they know) nearly all the biochemical steps that a healthy cell uses to multiply, to shut down its growth, and to sense internal damage and die at the right time—as well as many of the genes that encode for these processes. . . .

"Yet somehow, along the way, something important has gotten lost. The search for knowledge has become an end unto itself rather than the means to an end. And the research has become increasingly narrow, so much so that physician-scientists who want to think systemically about cancer or the organism as a whole—or who might have completely new approaches—often can't get funding. . . . The money goes almost entirely to researchers who focus on very specific genetic or molecular mechanisms within the cancer cell or other tissue. The narrower the research niche, it sometimes seems, the greater the rewards the researcher is likely to attain."

Sporn is even harsher in his criticism of research funding decisions. "The NIH study sections look askance at people who want to look at problems in any global way," he says. "They force everybody to fragment their ideas to the point that the data become trivial." He's especially frustrated with what he sees as an overwhelming emphasis on oncogenomics—the study of genes involved in cancer.

He explained his thinking on this point in an article published in the July 2006 issue of Nature Clinical Practice Oncology. "Cancer is genetic," Sporn wrote, but "everything in biology is genetic! If cancer is merely a genetic disease, why is it that there are so many more heavy smokers, most of whom incur DNA damage, than there are cases of lung cancer? . . . [Cancer] is a transactional disease. Cancer does not arise because something is wrong with one specific molecule; the problem is that the functional

Organic chemists Tadashi Honda, left, and Gordon Gribble have worked closely with Sporn for over a decade on chemopreventive compounds. A molecular model of one of their compounds is depicted below (as well as on the cover of this issue), with Honda's lab notebook open to the day in 1998 when they identified CDDO; their first breakthrough compound, it is nearly half a million times more active than the natural triterpenoid that it's derived from.

relationships between a set of critical molecules have been disrupted."

Another problem Sporn sees with focusing too much on genetics is that tumors are genetically unstable. "As carcinomas progress, they become increasingly heterogenous," he wrote in Lancet in 1996. "The cells in advanced metastatic carcinomas may have numerous genetic abnormalities, and these abnormalities may vary from one cell to the next within the carcinoma. . . . Thoughts of gene therapy directed at single oncogenes or tumour suppressor genes in such a context seem hopelessly naive."

Sporn emphasized this point in his recent AACR talk. "We're spending immense amounts of money to detect genetic abnormalities that might predispose [people] to carcinogenesis," he told fellow scientists, "but we're spending peanuts on what to do after we have obtained such data. Something's wrong here. There has to be some better balance."

"Our relationship is similar to a pair of wheels on a bicycle," Honda adds. "Good collaboration between biologists and chemists is definitely necessary for the discovery of drugs."

Major drug companies aren't keen on investing in chemoprevention either. One might assume that a chemopreventive drug would have commercial appeal because it could be marketed to a broad population and would need to be taken for many years. But any drug has side effects, and the risk that apparently healthy people are willing to accept "is very, very, very low," explains Leaf. "You have to be . . . 'safer than thou' with a chemopreventive agent, and that's phenomenally expensive" for a pharmaceutical company to test and develop. The cost of running large, lengthy clinical trials—not to mention the

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