As if co-discovering the double-helical structure of DNA weren’t enough for one lifetime, the Nobel laureate Jim D. Watson, PhD, has put a forth a novel hypothesis that—if true—would up-end much of the current thinking about cancer. In an article published in the journal Open Biology, Watson takes aim at an essential problem in oncology, writing in his introduction, “Although the mortality from many cancers, particularly those of hematopoietic cells, has been steadily falling, the more important statistic may be that so many epithelial cancers (carcinomas) and effectively all mesenchymal cancers (sarcomas) remain largely incurable.”

In addressing this issue, Watson emphasizes the role of the gene transcription activator Myc, which has been found to be a key driver of cancers of blood-forming lymphocytes, small-cell lung cancer, and possibly other late-stage cancers such as receptor-negative and ductal breast cancers. High levels of Myc, he says, “may turn out to be an essential feature of much of the truly incurable cancer.” Cells with high levels of Myc proceed less efficiently through the mitotic cycle and which may imply that multiple vulnerabilities with increased susceptibility to chemotherapy may exist.

Watson devotes much of the article to a discussion of reactive oxygen species (ROS), which have a double nature with regard to cancer. On one hand, they promote apoptosis, the process by which stressed or damaged cells undergo programmed death, and are thereby “a positive force for life,” Watson says. On the other, ROS have the capacity “to irreversibly damage key proteins and nucleic acid molecules (e.g., DNA and RNA).” Watson suggests that many cancer chemotherapies and ionizing radiation produce apoptosis by accelerating the synthesis of ROS.

Under normal conditions, ROS are continually neutralized by antioxidative proteins including glutathione, superoxide dismutase, catalase, and thioredoxin, the synthesis of which is controlled, in part, by the Nrf2 transcription factor. The synthesis of Nrf2 is in turn promoted by the RAS, RAF, and MYC oncogenes. Thus, Watson controversially states, “The fact that cancer cells largely driven by RAS and Myc are among the most difficult to treat may thus often be due to their high levels of ROS-destroying antioxidants.”

Watson directly challenges the many scientists who have long promoted antioxidants as the first line of defense against cancer, even suggesting that antioxidants in the diet “may have caused more cancers than they have prevented.” In the most quotable sentence in the paper, he writes, “Blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.”

Watson ends his article with a call for a renewed and accelerated effort to develop curative treatments for cancer. He criticizes the “never frantic” pace of work toward this goal and finds it telling that there is no influential general—“an Eisenhower or even better a Patton”—leading the war on cancer. He specifically recommends a shift in emphasis in cancer research away from drugs targeting growth-promoting molecules of signal transduction pathways (such as HER2, RAS, RAF, and others) and toward anti-Myc drugs. According to Watson’s estimates, identifying the remaining major molecular targets for anticancer drugs would cost approximately $500 million to $1 billion.

Naturally, Watson’s hypotheses are being met with caution. Reuters quoted a leading cancer researcher (who asked not to be identified for fear of offending Watson) as saying, “There are a lot of interesting ideas in it, some of them sustainable by existing evidence, others that simply conflict with well-documented findings.”

Watson calls the paper “among my most important work since the double helix.”