CHAPTER 10 The Metabolic Mess
1. Alexander Fleming discovered penicillin: A. Fleming, “On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. Influenzae,” British Journal of Experimental Pathology 10 (1929): 226–35. The article was republished in Bulletin of the World Health Organization 79, no. 8 (2001): 780–90. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566493] He described the discovery in his Nobel Prize lecture, December 11, 1945: Alexander Fleming, “Penicillin,” in Nobel Lectures, Physiology or Medicine 1942–1962 (Amsterdam: Elsevier Publishing Company, 1964), which is available on the Nobel Prize website. [http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.html] Unknown to Fleming, scientists before him had also noticed penicillin’s effects (see Horace Freeland Judson, The Search for Solutions [London: Hutchinson, 1980], 73–75), and historians have cast doubt on the details of the canonical account: Douglas Allchin, “Penicillin and Chance,” Sociology, History and Philosophy in Science Teaching Resource Center website, University of Minnesota. [http://www1.umn.edu/ships/updates/fleming.htm]
2. Boys thin from malnutrition: H. A. Waldron, “A Brief History of Scrotal Cancer,” British Journal of Industrial Medicine 40, no. 4 (November 1983): 390–401. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1009212]
3. “The fate of these people”: Percivall Pott, The Chirurgical Works of Percival Pott, F.R.S. and Surgeon to St. Bartholomew’s Hospital (London: Printed for T. Lowndes, J. Johnson, G. Robinson, T. Cadell, T. Evans, W. Fox, J. Bew, and S. Hayes, 1783). The book was originally published in 1775, and the quote is from page 178 of a later, expanded edition (London: J. Johnson, 1808). [http://books.google.com/ebooks?id=cvS_o4-jIzwC]
4. “I have many times made the experiment”: Potts, The Chirurgical Works, 179.
5. Chimney sweeps on the European continent: Waldron, “A Brief History.”
6. unknown in Edinburgh: Robert M. Green, MD, “Cancer of the Scrotum,” Boston Medical and Surgical Journal 163, no. 2 (November 17, 1910): 755–59. [http://books.google.com/books?id=Q9YEAAAAYAAJ]
7. “from that of a grain of rice”: K. Yamagiwa and K. Ichikawa, “Experimental Study of the Pathogenesis of Carcinoma,” Journal of Cancer Research 3 (1918): 1–29. Republished along with a short biography of Katsusaburo Yamagiwa in CA: A Cancer Journal for Clinicians 27, no. 3 (May/June 1977): 172–81. [http://onlinelibrary.wiley.com/doi/10.3322/canjclin.27.3.174/abstract]
8. “Every city in Italy”: Bernardino Ramazzini, Diseases of Workers, translated from the Latin text De morbis artificum of 1713 by Wilmer Cave Wright, with an introduction by George Rosen (Chicago: University of Chicago Press, 1940), 191. This edition includes the Latin text on facing pages. Ramazzini wrote about the nuns in a section called “Wet-Nurses,” 189–93. Also see J. S. Felton, “The Heritage of Bernardino Ramazzini,” Occupational Medicine 47, no. 3 (April 1, 1997): 167–79. [http://occmed.oxfordjournals.org/content/47/3/167.abstract]
9. nursing of children: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective (Washington, DC: AICR, 2007), 239–42. [http://www.dietandcancerreport.org/expert_report/index.php]
10. Domenico Rigoni-Stern, observed: I. D. Rotkin, “A Comparison Review of Key Epidemiological Studies in Cervical Cancer Related to Current Searches for Transmissible Agents,” Cancer Research 33, no. 6 (June 1, 1973): 1353–67; [http://cancerres.aacrjournals.org/content/33/6/1353] and Joseph Scotto and John C. Bailar, “Rigoni-Stern and Medical Statistics: A Nineteenth-Century Approach to Cancer Research,” Journal of the History of Medicine and Allied Sciences 24, no. 1 (1969): 65–75. [http://jhmas.oxfordjournals.org/content/XXIV/1/65.extract]
11. “The dogma was that cancer”: All quotations from Riboli are from an interview with the author in London, May 12, 2011.
12. came from laboratory experiments: Some pioneering research was done in the 1940s by Albert Tannenbaum. See “The Initiation and Growth of Tumors. Introduction. I. Effects of Underfeeding,” American Journal of Cancer 38 (1940): 335–50. [http://cancerres.aacrjournals.org/content/amjcancer/38/3/335.short] For some later work see D. Kritchevsky et al., “Calories, Fat and Cancer,” Lipids 21, no. 4 (April 1986): 272–74 [http://www.ncbi.nlm.nih.gov/pubmed/3086652]; D. Kritchevsky, M. M. Weber, and D. M. Klurfeld, “Dietary Fat Versus Caloric Content in Initiation and Promotion of Mammary Tumorigenesis in Rats,” Cancer Research 44, no. 8 (August 1984): 3174–77 [http://www.ncbi.nlm.nih.gov/pubmed/6430545]; G. A. Boissonneault, C. E. Elson, and M. W. Pariza, “Net Energy Effects of Dietary Fat on Chemically Induced Mammary Carcinogenesis in F344 Rats,” Journal of the National Cancer Institute 76, no. 2 (February 1986): 335–38 [http://www.ncbi.nlm.nih.gov/pubmed/3080637]; and M. W. Pariza, “Fat, Calories, and Mammary Carcinogenesis: Net Energy Effects,” American Journal of Clinical Nutrition 45, no. 1 (January 1, 1987): 261–63. [http://www.ajcn.org/content/45/1/261.short]
13. feeding them different amounts and varieties: G. J. Hopkins and K. K. Carroll, “Relationship Between Amount and Type of Dietary Fat in Promotion of Mammary Carcinogenesis,” Journal of the National Cancer Institute 62, no. 4 (April 1979): 1009–12. [http://www.ncbi.nlm.nih.gov/pubmed/107358]
14. Diets too rich in salt: For an overview see Xiao-Qin Wang, Paul D. Terry, and Hong Yan, “Review of Salt Consumption and Stomach Cancer Risk: Epidemiological and Biological Evidence,” World Journal of Gastroenterology 15, no. 18 (May 14, 2009): 2204–13. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682234/]
15. nitrosamines, N-nitroso compounds, and other substances: See, for example, P. Issenberg, “Nitrite, Nitrosamines, and Cancer,” Federation Proceedings 35, no. 6 (May 1, 1976): 1322–26; [http://www.ncbi.nlm.nih.gov/pubmed/4342] and William Lijinsky, “N-Nitroso Compounds in the Diet,” Mutation Research/Genetic Toxicology and Environmental Mutagenesis 443, nos. 1–2 (July 15, 1999): 129–38. [http://www.sciencedirect.com/science/article/pii/S1383574299000150]
16. review some four thousand studies: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 585.
17. “Diets containing substantial amounts”: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 538.
18. “predominantly plant-based diets”: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 522.
19. “especially rich in cancer-protective chemicals”: Jane Brody, “Eat Your Vegetables! But Choose Wisely,” Personal Health, New York Times, January 2, 2001. [http://www.nytimes.com/2001/01/02/health/personal-health-eat-your-vegetables-but-choose-wisely.html]
20. the disappointing follow-up: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer. Updates are posted on the organization’s Diet and Cancer Report website. [http://www.dietandcancerreport.org/cup/current_progress]
21. “in no case now is the evidence … judged to be convincing”: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity and the Prevention of Cancer, 75, 114.
22. the European Prospective Investigation into Cancer and Nutrition: Details can be found on the EPIC website. [http://epic.iarc.fr]
23. only the slightest evidence: Paolo Boffetta et al., “Fruit and Vegetable Intake and Overall Cancer Risk,” Journal of the National Cancer Institute 102, no. 8 (April 21, 2010): 529–37. [http://jnci.oxfordjournals.org/content/early/2010/04/06/jnci.djq072.abstract.]
24. or even of specific cancers: For citations see the response to the Boffetta paper by Christine Bouchardy, Simone Benhamou, and Elisabetta Rapiti, “Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation into Cancer and Nutrition,” Journal of the National Cancer Institute (Decem
ber 16, 2010); [http://jnci.oxfordjournals.org/content/early/2010/12/15/jnci.djq501.short] and T. J. Key, “Fruit and Vegetables and Cancer Risk,” British Journal of Cancer 104, no. 1 (January 4, 2011): 6–11. [http://dx.doi.org/10.1038/sj.bjc.6606032]
25. a small protective effect: Anthony B. Miller et al., “Fruits and Vegetables and Lung Cancer,” International Journal of Cancer 108, no. 2 (January 10, 2004): 269–76 [http://www.ncbi.nlm.nih.gov/pubmed/14639614]; Heiner Boeing et al., “Intake of Fruits and Vegetables and Risk of Cancer of the Upper Aero-digestive Tract,” Cancer Causes & Control 17, no. 7 (September 2006): 957–69 [http://www.ncbi.nlm.nih.gov/pubmed/16841263]; and F. L. Büchner et al., “Fruits and Vegetables Consumption and the Risk of Histological Subtypes of Lung Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC),” Cancer Causes & Control 21, no. 3 (March 2010): 357–71. [http://www.ncbi.nlm.nih.gov/pubmed/19924549]
26. too early to make more than tentative conjectures: Key, “Fruit and Vegetables and Cancer Risk.”
27. people who smoke and drink excessively: M. K. Serdula et al., “The Association Between Fruit and Vegetable Intake and Chronic Disease Risk Factors,” Epidemiology 7, no. 2 (March 1996): 161–65. [http://www.ncbi.nlm.nih.gov/pubmed/8834556]
28. possibly played a small part: F. J. van Duijnhoven et al., “Fruit, Vegetables, and Colorectal Cancer Risk,” American Journal of Clinical Nutrition 89, no. 5 (May 2009): 1441–52. [http://www.ncbi.nlm.nih.gov/pubmed/19339391]
29. that too remains in dispute: Key, “Fruit and Vegetables and Cancer Risk.”
30. “overly optimistic”: Walter C. Willett, “Fruits, Vegetables, and Cancer Prevention: Turmoil in the Produce Section,” Journal of the National Cancer Institute 102, no. 8 (April 21, 2010): 510–11. [http://jnci.oxfordjournals.org/content/102/8/510.short] He is commenting on Boffetta et al., “Fruit and Vegetable Intake.”
31. the ten-year risk of getting colorectal cancer: See Teresa Norat et al., “Meat, Fish, and Colorectal Cancer Risk,” Journal of the National Cancer Institute 97, no. 12 (June 15, 2005): 906–16. [http://www.ncbi.nlm.nih.gov/pubmed/15956652] The study found protective effects of roughly the same magnitude for eating fish. Similar evidence for fiber was reported in Sheila A. Bingham et al., “Dietary Fibre in Food and Protection Against Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition,” Lancet 361, no. 9368 (May 3, 2003): 1496–501. [http://www.ncbi.nlm.nih.gov/pubmed/12737858]
32. have come to conflicting conclusions: See, for example, D. D. Alexander and C. A. Cushing, “Red Meat and Colorectal Cancer: A Critical Summary of Prospective Epidemiologic Studies,” Obesity Reviews 12, no. 5 (May 2011): e472–493; [http://www.ncbi.nlm.nih.gov/pubmed/20663065] and Doris S. M. Chan et al., “Red and Processed Meat and Colorectal Cancer Incidence: Meta-Analysis of Prospective Studies,” PLOS ONE 6, no. 6 (June 6, 2011). [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108955] For earlier work see Scott Gottlieb, “Fibre Does Not Protect Against Colon Cancer,” BMJ: British Medical Journal 318, no. 7179 (January 30, 1999): 281; [http://www.bmj.com//content/318/7179/281.1] and C. S. Fuchs, W. C. Willett, et al., “Dietary Fiber and the Risk of Colorectal Cancer and Adenoma in Women,” New En- gland Journal of Medicine 340, no. 3 (January 21, 1999): 169–76. [http://www.ncbi.nlm.nih.gov/pubmed/9895396] The World Cancer Research Fund concludes on its Diet and Cancer Report website that the case for fiber is getting stronger. [http://www.dietandcancerreport.org/cup/current_progress]
33. older women who had gained 15 to 20 kilograms: Lahmann et al., “Long-term Weight Change and Breast Cancer.”
34. fatness itself … appeared to be the driving force: See, for example, P. H. Lahmann et al., “Long-term Weight Change and Breast Cancer Risk,” British Journal of Cancer 93, no. 5 (September 5, 2005): 582–89; [http://www.ncbi.nlm.nih.gov/pubmed/16136032] and Tobias Pischon et al., “Body Size and Risk of Renal Cell Carcinoma in the European Prospective Investigation into Cancer and Nutrition,” International Journal of Cancer 118, no. 3 (February 1, 2006): 728–38. [http://www.ncbi.nlm.nih.gov/pubmed/16094628]
35. as much of 25 percent of cancer: Graham A. Colditz, Kathleen Y. Wolin, and Sarah Gehlert, “Applying What We Know to Accelerate Cancer Prevention,” Science Translational Medicine 4, no. 127 (March 28, 2012): 127rv4. [http://stm.sciencemag.org/content/4/127/127rv4.abstract?sid=55e7c705-12c3-4aa9-bffb-c7fa7756a739]
36. The reasons are complex: Other important components include the hormone leptin, which is involved in regulating appetite, sex hormone–binding globulins, aromatase (also known as estrogen synthase), and PI3 kinase. See Sandra Braun, Keren Bitton-Worms, and Derek LeRoith, “The Link Between the Metabolic Syndrome and Cancer,” International Journal of Biological Sciences (2011): 1003–15; [http://www.biolsci.org/v07p1003.htm] and Stephanie Cowey and Robert W. Hardy, “The Metabolic Syndrome,” American Journal of Pathology 169, no. 5 (November 2006): 1505–22. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1780220] Also involved is the Warburg effect, in which cancer cells shift to an essentially anaerobic metabolism. For an overview see Gary Taubes, “Unraveling the Obesity-Cancer Connection,” Science 335, no. 6064 (January 6, 2012): 28–32. [http://www.sciencemag.org/content/335/6064/28]
37. age of menarche decreases: See Sandra Steingraber, “The Falling Age of Puberty in U.S. Girls,” August 2007, Breast Cancer Fund website [http://www.breastcancerfund.org/media/publications/falling-age-of-puberty], which includes citations to the research, and Sarah E. Anderson, Gerard E. Dallal, and Aviva Must, “Relative Weight and Race Influence Average Age at Menarche,” part 1, Pediatrics 111, no. 4 (April 2003): 844–50. [http://www.ncbi.nlm.nih.gov/pubmed/12671122]
38. greater body height: See, for example, Jane Green et al., “Height and Cancer Incidence in the Million Women Study,” Lancet Oncology 12, no. 8 (August 2011): 785–94. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70154-1/abstract]
39. also affects the immune system: For a review, see Lisa M. Coussens and Zena Werb, “Inflammation and Cancer,” Nature 420, no. 6917 (December 19, 2002): 860–67; [http://dx.doi.org/10.1038/nature01322] and Gary Stix, “Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?” Scientific American, July 2007, updated online November 9, 2008. [http://www.scientificamerican.com/article.cfm?id=chronic-inflammation-cancer]
40. Rudolf Virchow suggested: Coussens and Werb, “Inflammation and Cancer.”
41. aspirin and other anti-inflammatory drugs: See, for example, Peter M. Rothwell et al., “Effect of Daily Aspirin on Risk of Cancer Metastasis: A Study of Incident Cancers During Randomised Controlled Trials,” The Lancet 379, no. 9826 (April 2012): 1591–1601; and Peter M. Rothwell et al., “Short-term Effects of Daily Aspirin on Cancer Incidence, Mortality, and Non-vascular Death: Analysis of the Time Course of Risks and Benefits in 51 Randomised Controlled Trials,” The Lancet 379, no. 9826 (April 2012): 1602–12.
42. “low grade chronic inflammatory state”: See, for example, World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, 39, box 2.4.
43. “wounds that do not heal”: H. F. Dvorak, “Tumors: Wounds That Do Not Heal; Similarities Between Tumor Stroma Generation and Wound Healing,” New England Journal of Medicine 315, no. 26 (December 25, 1986): 1650–59. [http://www.ncbi.nlm.nih.gov/pubmed/3537791] A few researchers have been exploring the possibility that red meat might encourage colon cancer because it contains, among other carcinogens, a molecule that elicits an inflammatory immune response. See Maria Hedlund et al., “Evidence for a Human-specific Mechanism for Diet and Antibody-mediated Inflammation in Carcinoma Progression,” Proceedings of the National Academy of Sciences 105, no. 48 (December 2, 2008): 18936–41; [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596253] and Pam Tangvoranuntakul et al., “Human Uptake and Incorporation of an Immunogenic Nonhuman Dietary Sialic Acid,” Proceedings of the National Academy of Sciences 100, no. 21 (October 14, 2003): 12045–50. [http://www.pnas.org/content/100/21/12045.abst
ract]
44. also been tied to metabolic syndrome and diabetes: Kathryn E. Wellen and Gökhan S. Hotamisligil, “Inflammation, Stress, and Diabetes,” Journal of Clinical Investigation 115, no. 5 (May 2, 2005): 1111–19. [http://www.ncbi.nlm.nih.gov/pubmed/15864338]
45. diabetes recedes: See, for example, Hutan Ashrafian et al., “Metabolic Surgery and Cancer: Protective Effects of Bariatric Procedures,” Cancer 117, no. 9 (May 1, 2011): 1788–99. [http://www.ncbi.nlm.nih.gov/pubmed/21509756]
46. “shiftwork that involves circadian disruption”: Kurt Straif et al., “Carcinogenicity of Shift-work, Painting, and Fire-fighting,” Lancet Oncology 8, no. 12 (December 2007): 1065–66. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(07)70373-X/fulltext] The article provides pointers to the epidemiological and laboratory studies considered by WHO’s International Agency for Research on Cancer.
47. “Now it is between fifty and sixty kilograms”: The United States Department of Agriculture has estimated that Americans consume 150 pounds a year of various sugars, including high fructose corn syrup. See Agriculture Factbook 2001–2002 (Washington, DC: U.S. Department of Agriculture, March 2003), 20. [http://www.usda.gov/factbook]
48. who argues that carbs and sugar: See Taubes’s books Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health (New York: Vintage, 2008) and Why We Get Fat: And What to Do About It (New York: Knopf, 2010).
49. reducing your energy intake and therefore your insulin load: For the effect of fiber on insulin secretion see, for example, J. G. Potter et al., “Effect of Test Meals of Varying Dietary Fiber Content on Plasma Insulin and Glucose Response,” American Journal of Clinical Nutrition 34, no. 3 (March 1, 1981): 328–34. [http://www.ajcn.org/content/34/3/328.short]
The Cancer Chronicles Page 30