The unwieldy Internet addresses called URLs (for “uniform resource locater”) were never meant to appear in print. They are behind-the-scenes directions for a computer mindlessly executing the click of a mouse on a hyperlink. I have excluded them from the notes section of the printed editions of this book. For almost every paper I have cited, the abstract and often the complete text can be found easily with an Internet search, which is much easier than typing, letter by letter, slash by slash, the precise URL. The webpages I refer to can also be readily located. All were accessible as this book was going to press. An online version of the notes, available through my website, talaya.net, will carry links to all of the references, as will the book’s electronic editions.
“We must never feel disarmed”: Primo Levi, The Periodic Table (New York: Schocken Books, 1984), 75.
“I wonder now, though, if the steady presence of music”: Reynolds Price, A Whole New Life (New York: Plume, 1995), 36.
Tuberculosis used to be called ‘consumption’: John Gunther, Death Be Not Proud (Harper Perennial Modern Classics, 1998), 78–79.
CHAPTER 1 Jurassic Cancer
the Dinosaur Diamond Prehistoric Highway: My road trip to Colorado and Utah was in September 2010. For a description of the Morrison Formation and Jurassic Colorado see Ron Blakely and Wayne Ranney, Ancient Landscapes of the Colorado Plateau (Grand Canyon, AZ: Grand Canyon Association, 2008); John Foster, Jurassic West: The Dinosaurs of the Morrison Formation and Their World (Bloomington: Indiana University Press, 2007); “Reconstructing the Ancient Earth,” Colorado Plateau Geosystems website, last modified July 2011 [http://cpgeosystems.com]; and Ron Blakely, e-mail message to author, March 9, 2012.
Giant termite nests: Stephen T. Hasiotis, “Reconnaissance of Upper Jurassic Morrison Formation Ichnofossils, Rocky Mountain Region, USA,” Sedimentary Geology 167, nos. 3–4 (May 15, 2004): 177–268 (reference is on 222–23) [http://www.sciencedirect.com/science/article/pii/S0037073804000090] and Hasiotis, e-mail message to author, March 9, 2012.
Dinosaur Hill: The discovery of the Apatosaurus skeleton is described on two interpretative signs at the site.
it caught the eye of a doctor: The story of Raymond Bunge was told to me by Brian Witzke in an e-mail, August 3, 2010. Some details about Bunge’s life are in “Papers of Raymond Bunge: Biographical Note,” 2011, University of Iowa Libraries Special Collections and University Archives website. [http://www.lib.uiowa.edu/spec-coll/archives/guides/RG99.0002.htm].
an attractive chunk, 5 inches thick: Bruce M. Rothschild, Brian J. Witzke, and Israel Hershkovitz, “Metastatic Cancer in the Jurassic,” Lancet 354 (July 1999): 398. [http://www.ncbi.nlm.nih.gov/pubmed/10437878] More details were provided in e-mails from Rothschild in June 2010, October 2010, November 2010, and July 2011.
layered, onion-skin look: Rothschild, Witzke, and Hershkovitz, “Metastatic Cancer.”
scattered references … to other dinosaur tumors: Rothschild, Witzke, and Hershkovitz, “Metastatic Cancer.”
“This observation extends recognition”: Rothschild, Witzke, and Hershkovitz, “Metastatic Cancer.”
tumors that arise from misguided germ cells: See, for example, Naohiko Kuno et al., “Mature Ovarian Cystic Teratoma with a Highly Differentiated Homunculus: A Case Report,” Birth Defects Research. Part A, Clinical and Molecular Teratology 70, no. 1 (January 2004): 40–46. [http://www.ncbi.nlm.nih.gov/pubmed/14745894]
With a portable fluoroscope: B. M. Rothschild et al., “Epidemiologic Study of Tumors in Dinosaurs,” Die Naturwissenschaften 90, no. 11 (November 2003): 495–500. [http://www.ncbi.nlm.nih.gov/pubmed/14610645]
a picture of him wearing a dinosaur T-shirt: John Whitfield, “Dinosaurs Got Cancer,” Nature News 21 (October 2003), published online October 21, 2003. [http://www.nature.com/news/2003/031021/full/news031020-2.html]
may have been more warm-blooded: Rothschild’s “Epidemiologic Study of Tumors in Dinosaurs” cites the work of Anusuya Chinsamy, including A. Chinsamy and P. Dodson, “Inside a Dinosaur Bone,” American Scientist 83 (1995): 174–80.
Edmontosaurus “mummies”: Phillip L. Manning et al., “Mineralized Soft-Tissue Structure and Chemistry in a Mummified Hadrosaur from the Hell Creek Formation, North Dakota (USA),” Proceedings of the Royal Society B: Biological Sciences 276, no. 1672 (October 7, 2009): 3429–37. [http://rspb.royalsocietypublishing.org/content/276/1672/3429.short]
Rothschild considered the odds: L. C. Natarajan, B. M. Rothschild, et al., “Bone Cancer Rates in Dinosaurs Compared with Modern Vertebrates,” Transactions of the Kansas Academy of Science 110 (2007): 155–58. [http://arxiv.org/abs/0704.1912]
Rothschild and his wife: Bruce M. Rothschild and Christine Rothschild, “Comparison of Radiologic and Gross Examination for Detection of Cancer in Defleshed Skeletons,” American Journal of Physical Anthropology 96, no. 4 (April 1, 1995): 357–63. [http://www.ncbi.nlm.nih.gov/pubmed/7604891]
Autopsies at the San Diego Zoo: M. Effron, L. Griner, and K. Benirschke, “Nature and Rate of Neoplasia Found in Captive Wild Mammals, Birds, and Reptiles at Necropsy,” Journal of the National Cancer Institute 59, no. 1 (July 1977): 185–98. [http://www.ncbi.nlm.nih.gov/pubmed/577508]
paleontologists in South Dakota: They were at the Black Hills Institute of Geological Research.
“a weird mass of black material”: John Pickrell, “First Dinosaur Brain Tumor Found, Experts Suggest,” National Geographic News, November 24, 2003, published online October 28, 2010. [http://news.nationalgeographic.com/news/2003/11/1124_031124_dinocancer.html]
“It certainly would take a bizarre event”: Pickrell, “First Dinosaur Brain Tumor.”
300-million-year pile of geology: That is approximately when the bottommost layers of the plateau, the Morgan Formation and Weber Sandstone, were formed. See Halka Chronic and Lucy M. Chronic, Pages of Stone: Geology of the Grand Canyon and Plateau Country National Parks and Monuments (Seattle: Mountaineers Books, 2004), 90. I also referred to Halka Chronic’s book Roadside Geology of Colorado (Seattle: Mountaineers Books, 2004) and to Annabelle Foos and Joseph Hannibal, “Geology of Dinosaur National Monument,” Cleveland Museum of Natural History (1999), published online by the National Park Service. [http://www.nature.nps.gov/geology/education/foos/dino.pdf.] Two pamphlets written and illustrated by Linda West and published by the Dinosaur Nature Association (Jensen, Utah) were also used as sources: Journey Through Time: A Guide to the Harper’s Corner Scenic Drive (1986) and Harper’s Corner Trail (1977).
jawbone of a primitive armored fish: Luigi L. Capasso, “Antiquity of Cancer,” International Journal of Cancer 113, no. 1 (January 1, 2005): 2–13. [http://www.ncbi.nlm.nih.gov/pubmed/1538951]
Laramide orogeny: For a beautiful account, see John McPhee, Rising from the Plains (New York: Farrar, Straus and Giroux, 1986), 43–55.
ancient elephants, mammoths, and horses: Capasso, “Antiquity of Cancer.”
Hyperostosis, or runaway bone growth: Capasso, “Antiquity of Cancer”; and Raúl A Ruggiero and Oscar D Bustuoabad, “The Biological Sense of Cancer: A Hypothesis,” Theoretical Biology & Medical Modelling 3 (2006): 43. [http://www.ncbi.nlm.nih.gov/pubmed/17173673]
an ancient buffalo and an ancient ibex: Capasso, “Antiquity of Cancer.”
cancer in the mummy of an ancient Egyptian baboon: Alexander Haddow, “Historical Notes on Cancer from the MSS. of Louis Westenra Sambon,” Proceedings of the Royal Society of Medicine 29, no. 9 (July 1936): 1015–28. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2076239]
Even a lone single-celled bacterium: Jules J. Berman, Neoplasms: Principles of Development and Diversity (Sudbury, MA: Jones and Bartlett Publishers, 2009), 67–69.
A bacterium called Agrobacterium tumefaciens: M. D. Chilton et al., “Stable Incorporation of Plasmid DNA into Higher Plant Cells: The Molecular Basis of Crown Gall Tumorigenesis,” Cell 11, no. 2 (June 1977): 263–71. [http://www.ncbi.nlm.nih.gov/pubmed/890735]
A remarkable paper: Philip R. White and Armin C. Braun, “A Cancerous Neoplasm of Plants. Autonomous Bacteria-Free Crown-Gall Tissue,” Cancer Research 2, no. 9 (1942): 597–617. [http://cancerres.aacrjournals.org/content/2/9/597.short]
larval cells can give rise to invasive tumors: Berman, Neoplasms, 69–70.
carp, codfish, skate rays: Capasso, “Antiquity of Cancer.”
Trout, like people, get liver cancer: Berman, Neoplasms, 71.
sharks do get cancer: Gary K. Ostrander et al., “Shark Cartilage, Cancer and the Growing Threat of Pseudoscience,” Cancer Research 64, no. 23 (December 1, 2004): 8485–91. [http://cancerres.aacrjournals.org/content/64/23/8485.abstract]
parathyroid adenoma in turtles: Capasso, “Antiquity of Cancer.”
Amphibians are also susceptible: Berman, Neoplasms, 71.
a strange variation on the theme: Charles Breedis, “Induction of Accessory Limbs and of Sarcoma in the Newt (Triturus viridescens) with Carcinogenic Substances,” Cancer Research 12, no. 12 (December 1, 1952): 861–66. [http://www.ncbi.nlm.nih.gov/pubmed/13009672]
Could this be another clue: Richmond T. Prehn, “Regeneration versus Neoplastic Growth,” Carcinogenesis 18, no. 8 (1997):1439–44. [http://carcin.oxfordjournals.org/content/18/8/1439]
Mammals appear to get more cancer than reptiles or fish: See, for example, Effron, Griner, and Benirschke, “Nature and Rate of Neoplasia.”
Domesticated animals seem to get more cancer: Capasso, “Antiquity of Cancer.”
a close relationship between size and life span: See, for example, John R. Speakman, “Body Size, Energy Metabolism and Lifespan,” Journal of Experimental Biology 208, no. 9 (May 2005): 1717–30. [http://www.ncbi.nlm.nih.gov/pubmed/15855403] For a deeper look at scaling phenomena see James H. Brown and Geoffrey B. West, Scaling in Biology, Santa Fe Institute Studies on the Sciences of Complexity (New York: Oxford University Press, 2000).
Peto’s paradox: R. Peto et al., “Cancer and Aging in Mice and Men,” British Journal of Cancer 32, no. 4 (October 1975): 411–26. [http://www.ncbi.nlm.nih.gov/pubmed/1212409]
The mystery was succinctly posed: John D. Nagy, Erin M. Victor, and Jenese H. Cropper, “Why Don’t All Whales Have Cancer? A Novel Hypothesis Resolving Peto’s Paradox,” Integrative and Comparative Biology 47, no. 2 (2007): 317–28. [http://icb.oxfordjournals.org/content/47/2/317.abstract]
roughly a billion heartbeats: I first wrote about this in “Of Mice and Elephants: A Matter of Scale,” New York Times, January 12, 1999. [http://www.nytimes.com/1999/01/12/science/of-mice-and-elephants-a-matter-of-scale.html] For a detailed analysis see John K.-J. Li, “Scaling and Invariants in Cardiovascular Biology,” in Brown and West, Scaling in Biology, 113–22.
sensible that mice might get more cancer: Naked mole rats, however, appear to never succumb, possibly because of their ability to lower their metabolisms. They also live nine times longer than mice. See Sitai Liang et al., “Resistance to Experimental Tumorigenesis in Cells of a Long-lived Mammal, the Naked Mole-rat,” Aging Cell 9, no. 4 (August 2010): 626–35. For a popular account by two researchers see Thomas J. Park and Rochelle Buffenstein, “Underground Supermodels,” The Scientist, June 1, 2012. [http://the-scientist.com/2012/06/01/underground-supermodels] Daniel Engber wrote about naked mole rats and cancer in “The Anti-Mouse,” Slate, November 18, 2011. [http://www.slate.com/articles/health_and_science/the_mouse_trap/2011/11/naked_mole_rats_can_they_help_us_cure_cancer_.html]
Scientists have proposed several reasons: See, for example, Anders Bredberg, “Cancer Resistance and Peto’s Paradox,” Proceedings of the National Academy of Sciences 106, no. 20 (May 19, 2009): E51; [http://www.pnas.org/content/106/20/E51.short] and George Klein, “Reply to Bredberg: The Voice of the Whale,” on page E52. [http://www.pnas.org/content/106/20/E52.short]
hypertumors: Nagy, Victor, and Cropper, “Why Don’t All Whales Have Cancer?”
thought there must be some kind of connection: F. Galis, “Why Do Almost All Mammals Have Seven Cervical Vertebrae? Developmental Constraints, Hox Genes, and Cancer,” The Journal of Experimental Zoology 285, no. 1 (April 15, 1999): 19–26. [http://www.ncbi.nlm.nih.gov/pubmed/10327647]
“Natural Compounds in Pomegranates”: These titles are from AACR press releases, American Association for Cancer Research website. [http://www.aacr.org/home/public-media.aspx]
CHAPTER 2 Nancy’s Story
two-thirds of cancer cases are preventable: See, for example, 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), xxv. [http://www.dietandcancerreport.org]
the argument is weak at best: Miguel A. Sanjoaquin et al., “Folate Intake and Colorectal Cancer Risk: A Meta-analytical Approach,” International Journal of Cancer 113, no. 5 (February 20, 2005): 825–28 [http://www.ncbi.nlm.nih.gov/pubmed/15499620]; Susanna C. Larsson, Edward Giovannucci, and Alicja Wolk, “Folate and Risk of Breast Cancer: A Meta-analysis,” Journal of the National Cancer Institute 99, no. 1 (January 3, 2007): 64–76 [http://jnci.oxfordjournals.org/content/99/1/64.abstract]; and Jane C. Figueiredo et al., “Folic Acid and Risk of Prostate Cancer: Results from a Randomized Clinical Trial,” Journal of the National Cancer Institute 101, no. 6 (March 18, 2009): 432–35. [http://jnci.oxfordjournals.org/content/101/6/432.short]
folic acid … can increase cancer risk: See, for example, Figueiredo et al., “Folic Acid and Risk of Prostate Cancer”; and Marta Ebbing et al., “Cancer Incidence and Mortality After Treatment with Folic Acid and Vitamin B12,” JAMA: The Journal of the American Medical Association 302, no. 19 (November 18, 2009): 2119–26. [http://www.ncbi.nlm.nih.gov/pubmed/19920236]
administering antifolates: John J. McGuire, “Anticancer Antifolates: Current Status and Future Directions,” Current Pharmaceutical Design 9, no. 31 (2003): 2593–613. [http://www.ncbi.nlm.nih.gov/pubmed/14529544]
among the oldest chemotherapeutic drugs: The pioneer in this research was Sidney Farber. See S. Farber et al., “Temporary Remissions in Acute Leukemia in Children Produced by Folic Acid Antagonist, 4-Aminopteroyl-Glutamic Acid,” New England Journal of Medicine 238, no. 23 (June 3, 1948): 787–93. [http://www.nejm.org/doi/full/10.1056/NEJM194806032382301] The story is told in Siddhartha Mukherjee’s fine book The Emperor of All Maladies: A Biography of Cancer (New York: Scribner, 2010), 27–36.
the mythology surrounding antioxidants: Rudolf I. Salganik, “The Benefits and Hazards of Antioxidants,” Journal of the American College of Nutrition 20 (2001): 464S–72S. [http://www.ncbi.nlm.nih.gov/pubmed/11603657]
a clinical trial in Finland: “The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers,” New England Journal of Medicine 330, no. 15 (April 14, 1994): 1029–35. [http://www.ncbi.nlm.nih.gov/pubmed/8127329]
A similar trial in the United States: Gary E. Goodman et al., “The Beta-Carotene and Retinol Efficacy Trial,” Journal of the National Cancer Institute 96, no. 23 (December 1, 2004): 1743–50. [http://www.ncbi.nlm.nih.gov/pubmed/15572756]
phytochemicals: Lee W. Wattenberg, “Chemoprophylaxis of Carcinogenesis: A Review,” part 1, Cancer Research 26, no. 7 (July 1, 1966): 1520–26. [http://cancerres.aacrjournals.org/content/26/7_Part_1/1520.abstract]
the evidence here is also meager: A randomized controlled study of male doctors recently reported an annual cancer incidence of 1.7 percent among the multivitamin takers compared with 1.8 percent for the placebo group: J. Gaziano et al., “Multivitamins in the Prevention of Cancer in Men,” JAMA: The Journal of the American Medical Association (published online October 17, 2012): 1–10. See the comment section of the paper for references to other studies finding neutral and even negative effects.
5 A Day program: “5 A Day for Better Health Program Evaluation Report: Executive Summary,” National Cancer Institute website, last updated March 1, 2006. [http://dccps.nci.nih.gov/5ad_exec.html]
The evidence, alas: 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]
those most likely to volunteer: Willett, “Fruits, Vegetables, and Cancer Prevention.”
The largest prospective study on diet and health: The European Prospective Investigation into Cancer and Nutrition, or EPIC, is described on the website of the International Agency for Research on Cancer. [http://epic.iarc.fr] For a summary with citations of key EPIC findings, see “Diet and Cancer: the Evidence,” Cancer Research UK website, [http://info.cancerresearchuk.org/healthyliving/dietandhealthyeating/howdoweknow] updated September 25, 2009.
a very weak effect: Willett, “Fruits, Vegetables, and Cancer Prevention”; and Paolo Boffetta et al., “Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation into Cancer and Nutrition,” Journal of the National Cancer Institute 102, no. 8 (April 21, 2010): 529–37. [http://www.ncbi.nlm.nih.gov/pubmed/20371762, http://jnci.oxfordjournals.org/content/early/2010/04/06/jnci.djq072] No evidence was found that fruits and vegetables help ward off cancer of the breast (Carla H. van Gils et al., “Consumption of Vegetables and Fruits and Risk of Breast Cancer,” JAMA: The Journal of the American Medical Association 293, no. 2 [January 12, 2005]: 183–93) [http://jama.ama-assn.org/content/293/2/183.abstract] or cancer of the prostate (Timothy J. Key et al., “Fruits and Vegetables and Prostate Cancer,” International Journal of Cancer 109, no. 1 [March 2004]: 119–24). [http://www.ncbi.nlm.nih.gov/pubmed/14735477]
possible benefits with a few cancers: See, for example, 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]; and 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]
said to nurture a mix of bacteria: Constantine Iosif Fotiadis et al., “Role of Probiotics, Prebiotics and Synbiotics in Chemoprevention for Colorectal Cancer,” World Journal of Gastroenterology 14, no. 42 (November 14, 2008): 6453–57 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773329]; and Janelle C. Arthur and Christian Jobin, “The Struggle Within: Microbial Influences on Colorectal Cancer,” Inflammatory Bowel Diseases 17, no. 1 (January 2011): 396–409. [http://www.ncbi.nlm.nih.gov/pubmed/20848537]
The case for fiber may be a little stronger: See Teresa Norat et al., “The Associations Between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer,” which is available along with other recent EPIC findings on the World Cancer Research Fund’s Diet and Cancer Report website. [http://www.dietandcancerreport.org/cancer_resource_center/continuous_update_project.php] See “Continuous Update Project Report Summary. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer” (2011).
the evidence has been controversial: EPIC’s positive findings were published as 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): 1496–1501. [http://www.ncbi.nlm.nih.gov/pubmed/12737858] For conflicting results from the Nurses’ Health Study, see Scott Gottlieb, “Fibre Does Not Protect Against Colon Cancer,” BMJ: British Medical Journal 318, no. 7179 (January 30, 1999): 281; and C. S. Fuchs, W. C. Willett, et al., “Dietary Fiber and the Risk of Colorectal Cancer and Adenoma in Women,” New England Journal of Medicine 340, no. 3 (January 21, 1999): 169–76. [http://www.ncbi.nlm.nih.gov/pubmed/9895396]
no evidence of a reduction in colorectal polyps: Arthur Schatzkin et al., “Lack of Effect of a Low-Fat, High-Fiber Diet on the Recurrence of Colorectal Adenomas,” New England Journal of Medicine 342, no. 16 (April 20, 2000): 1149–55. [http://www.nejm.org/doi/full/10.1056/nejm200004203421601#t=abstract] Similar controlled studies have also found no relationship. See, for example, D. S. Alberts et al., “Lack of Effect of a High-fiber Cereal Supplement on the Recurrence of Colorectal Adenomas,” New England Journal of Medicine 342, no. 16 (April 20, 2000): 1156–62; and Shirley A. Beresford et al., “Low-fat Dietary Pattern and Risk of Colorectal Cancer,” JAMA: The Journal of the American Medical Association 295, no. 6 (February 8, 2006): 643–54.
no effect on the recurrence of breast cancer: John P. Pierce et al., “Influence of a Diet Very High in Vegetables, Fruit, and Fiber and Low in Fat on Prognosis Following Treatment for Breast Cancer,” JAMA: The Journal of the American Medical Association 298, no. 3 (July 18, 2007): 289–98. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2083253]
brussels sprouts, cabbage: B. N. Ames, M. Profet, and L. S. Gold, “Nature’s Chemicals and Synthetic Chemicals: Comparative Toxicology,” Proceedings of the National Academy of Sciences 87, no. 19 (October 1990): 7782–86 [http://www.pnas.org/content/87/19/7782.abstract] and Bruce N. Ames, “Dietary Carcinogens and Anticarcinogens,” Science 221, no. 4617 (September 23, 1983): 1256–64. [http://www.ncbi.nlm.nih.gov/pubmed/6351251]
eating a lot of red meat: The calculation is for a fifty-year-old. 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] 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]
from 1.28 percent to 1.7 percent: Norat et al., “Meat, Fish, and Colorectal Cancer Risk.”
fish, fish oils, and colon cancer prevention: For evidence that eating fish discourages cancer by encouraging apoptosis and impeding cellular proliferation, see Youngmi Cho et al., “A Chemoprotective Fish Oil- and Pectin-Containing Diet Temporally Alters Gene Expression Profiles in Exfoliated Rat Colonocytes Throughout Oncogenesis,” Journal of Nutrition 141, no. 6 (June 1, 2011): 1029–35. [http://jn.nutrition.org/content/141/6/1029.abstract] For another perspective, see Catherine H. MacLean et al., “Effects of Omega-3 Fatty Acids on Cancer Risk,” JAMA: The Journal of the American Medical Association 295, no. 4 (January 25, 2006): 403–15. [http://www.ncbi.nlm.nih.gov/pubmed/16434631]
mammalian fat … has come under challenge: Ross L. Prentice et al., “Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial,” JAMA: The Journal of the American Medical Association 295, no. 6 (February 8, 2006): 629–42; [http://jama.ama-assn.org/content/295/6/629] and Shirley A. Beresford et al., “Low-Fat Dietary Pattern and Risk of Colorectal Cancer.” For a summary, see “The Nutrition Source: Low-Fat Diet Not a Cure-All,” Harvard School of Public Health website. [http://www.hsph.harvard.edu/nutritionsource/nutrition-news/low-fat]
sugar may pose a greater danger: Gary Taubes, Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health (New York: Vintage, 2008); and Gary Taubes, Why We Get Fat: And What to Do About It (New York: Knopf, 2010).
Obesity … has joined the short list: See, for example, “AACR Cancer Progress Report,” 2012, American Association for Cancer Research website. [http://cancerprogressreport.org]
caloric restriction: The mechanisms are complex, involving insulin regulation and other cellular processes. See Stephen D. Hursting et al., “Calorie Restriction, Aging, and Cancer Prevention,” Annual Review of Medicine 54 (February 2003): 131–52 [http://www.annualreviews.org/doi/abs/10.1146/annurev.med.54.101601.152156]; D. Kritchevsky, “Caloric Restriction and Cancer,” Journal of Nutritional Science and Vitaminology 47, no. 1 (February 2001): 13–19 [http://www.ncbi.nlm.nih.gov/pubmed/11349885]; Sjoerd G. Elias et al., “Transient Caloric Restriction and Cancer Risk (The Netherlands),” Cancer Causes & Control 18, no. 1 (February 2007): 1–5 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1764866]; and David M. Klurfeld et al., “Reduction of Enhanced Mammary Carcinogenesis in LA/N-cp (Corpulent) Rats by Energy Restriction,” Proceedings of the Society for Experimental Biology and Medicine 196, no. 4 (April 1, 1991): 381–84. [http://ebm.rsmjournals.com/content/196/4/381.abstract] In Good Calories, Bad Calories Taubes argues that the anticarcinogenic effects seen in the animal experiments come not from an overall reduction in calories but from limiting sugars and carbohydrates.
a jolt of estrogen: See, for example, Endogenous Hormones and Breast Cancer Collaborative Group, “Circulating Sex Hormones and Breast Cancer Risk Factors in Postmenopausal Women,” British Journal of Cancer 105, no. 5 (2011): 709–22 [http://dx.doi.org/10.1038/bjc.2011.254]; A. Heather Eliassen et al., “Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women,” Journal of the National Cancer Institute 98, no. 19 (October 4, 2006): 1406–15 [http://jnci.oxfordjournals.org/content/98/19/1406.abstract]; and Rudolf Kaaks et al., “Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk,” Journal of the National Cancer Institute 97, no. 10 (May 18, 2005): 755–65. [http://jnci.oxfordjournals.org/content/97/10/755.abstract]
the list of known human carcinogens: National Toxicology Program, Report on Carcinogens, 12th ed. (Research Triangle Park, NC: U.S. Department of Health and Human Services, 2011). Available on the National Toxicology Program website. [http://ntp-server.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15]
possibly increasing the risk of breast cancer: See, for example, F. Clavel-Chapelon, “Differential Effects of Reproductive Factors on the Risk of Pre- and Postmenopausal Breast Cancer,” British Journal of Cancer 86, no. 5 (March 4, 2002): 723–27. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2230628]
A few scientists blame the change on bisphenol A: See, for example, Kembra L. Howdeshell et al., “Environmental Toxins: Exposure to Bisphenol A Advances Puberty,” Nature 401, no. 6755 (October 21, 1999): 763–64 [http://www.nature.com/nature/journal/v401/n6755/full/401763a0.html]; and Laura N. Vandenberg, Ana M. Soto, et al., “Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption,” Endocrine Reviews 30, no. 1 (February 1, 2009): 75–95. [http://edrv.endojournals.org/content/30/1/75.abstract]
a more widely accepted explanation involves nutrition: 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]
the age of menarche … has dropped: Steingraber, “The Falling Age of Puberty,” 20.
Lactation also appears to hold estrogen in check: See World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 239–42.
more menstrual cycles than her great-grandmother: David Plotkin, “Good News and Bad News About Breast Cancer,” The Atlantic, June 1998. [http://www.theatlantic.com/magazine/archive/1998/06/good-news-and-bad-news-about-breast-cancer/5504]
Hormone therapies … associated with some cancers: For an overview see two reports on the National Cancer Institute website “Menopausal Hormone Therapy and Cancer” [http://www.cancer.gov/cancertopics/factsheet/Risk/DES] and “Diethylstilbestrol (DES) and Cancer,” both reviewed December 5, 2011. [http://www.cancer.gov/cancertopics/factsheet/Risk/menopausal-hormones]
obesity, especially in older women: Sabina Rinaldi et al., “Anthropometric Measures, Endogenous Sex Steroids and Breast Cancer Risk in Postmenopausal Women,” International Journal of Cancer 118, no. 11 (June 1, 2006): 2832–39 [http://www.ncbi.nlm.nih.gov/pubmed/16385576]; and Petra H. Lahmann et al., “A Prospective Study of Adiposity and Postmenopausal Breast Cancer Risk,” International Journal of Cancer 103, no. 2 (November 4, 2002): 246–52. [http://onlinelibrary.wiley.com/doi/10.1002/ijc.10799/abstract]
reduce the chances of premenopausal women getting breast cancer: Kaaks et al., “Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk.” Also see Elisabete Weiderpass et al., “A Prospective Study of Body Size in Different Periods of Life and Risk of Premenopausal Breast Cancer,” Cancer Epidemiology, Biomarkers & Prevention 13, no. 7 (July 2004): 1121–27; and L. J. Vatten and S. Kvinnsland, “Prospective Study of Height, Body Mass Index and Risk of Breast Cancer,” Acta Oncologica 31, no. 2 (1992): 195–200. [http://www.ncbi.nlm.nih.gov/pubmed/1622634]
oral contraceptives may slightly raise the odds: “Oral Contraceptives and Cancer Risk,” National Cancer Institute, reviewed March 21, 2012.
Alcohol … with digestive cancers: The evidence for esophageal, liver, and other cancers is examined in Vincenzo Bagnardi et al., “Alcohol Consumption and the Risk of Cancer: A Meta-Analysis,” Alcohol Research and Health: The Journal of the National Institute on Alcohol Abuse and Alcoholism 25, no. 4 (2001): 263–70. [http://pubs.niaaa.nih.gov/publications/arh25-4/263-270.htm]
the risk from hepatitis viruses: Heather M. Colvin and Abigail E. Mitchell, eds., Hepatitis and Liver Cancer (Washington, DC: The National Academies Press, 2010), 29–30. [http://www.nap.edu/catalog.php?record_id=12793]
exposure to aflatoxin: See, for example, P. E. Jackson and J. D. Groopman, “Aflatoxin and Liver Cancer,” Clinical Gastroenterology 13, no. 4 (December 1999): 545–55. [http://www.ncbi.nlm.nih.gov/pubmed/10654919]
Consuming two or three drinks a day: Wendy Y. Chen, Walter C. Willett, et al., “Moderate Alcohol Consumption During Adult Life, Drinking Patterns, and Breast Cancer Risk,” JAMA: The Journal of the American Medical Association 306, no. 17 (November 2, 2011): 1884–90. [http://jama.ama-assn.org/content/306/17/1884]
a woman between the ages of forty and forty-nine: “Risk of Developing Breast Cancer,” Breastcancer.org website, last modified on March 14, 2012. [http://www.breastcancer.org/symptoms/understand_bc/risk/understanding.jsp]
Even tallness is a risk factor: 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]
Ecuadoran villagers with a kind of dwarfism: Jaime Guevara-Aguirre et al., “Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans,” Science Translational Medicine 3, no. 70 (February 16, 2011):70ra13 [http://stm.sciencemag.org/content/3/70/70ra13.abstract] and Mitch Leslie, “Growth Defect Blocks Cancer and Diabetes,” Science 331, no. 6019 (February 18, 2011): 837. [http://www.sciencemag.org/content/331/6019/837.summary]
measured not in small percentages: See, for example, the rankings in the Harvard Cancer Risk Index, described in G. A. Colditz et al., “Harvard Report on Cancer Prevention Volume 4: Harvard Cancer Risk Index,” Cancer Causes & Control 11, no. 6 (July 2000): 477–88. [http://www.ncbi.nlm.nih.gov/pubmed/10880030]
factors of ten to twenty: According to the “Lung Cancer Fact Sheet,” male smokers are twenty-three times more likely to develop lung cancer, and women thirteen times more likely, compared with people who never smoked (American Lung Association website, November 2010). [http://www.lung.org/lung-disease/lung-cancer/resources/facts-figures/lung-cancer-fact- sheet.html]
the figure is more like 1 in 8: Rebecca Goldin, “Lung Cancer Rates: What’s Your Risk?” March 8, 2006, Research at Statistical Assessment Service (STATS) website, George Mason University. [http://stats.org/stories/2006/lung_cancer_rates_mar08_06.htm]
online Memorial Sloan-Kettering cancer prediction tool: See “Cancer Care/Prediction Tools” on the Sloan-Kettering website. [http://www.mskcc.org/cancer-care/adult/lung/prediction-tools]
one-tenth the risk: “Summary Report: Analysis of Exposure and Risks to the Public from Radionuclides and Chemicals Released by the Cerro Grande Fire at Los Alamos June 12, 2002,” New Mexico Environment Department, Risk Assessment Corporation, report no. 5-NMED-2002-FINAL, Risk Assessment Corporation website. [http://www.racteam.com/docs/Cerro_Grande_Fire_Summary_Report.pdf]
some evidence, weak and conflicting: “Vitamin D and Cancer Prevention: Strengths and Limits of the Evidence,” National Cancer Institute website, reviewed June 16, 2010, [http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D] and Cindy D. Davis, “Vitamin D and Cancer: Current Dilemmas and Future Research Needs,” American Journal of Clinical Nutrition 88, no. 2 (August 2008): 565S–69S. [http://www.ncbi.nlm.nih.gov/pubmed/18689403]
among male Finnish smokers: Rachael Z. Stolzenberg-Solomon et al., “A Prospective Nested Case-control Study of Vitamin D Status and Pancreatic Cancer Risk in Male Smokers,” Cancer Research 66, no. 20 (October 15, 2006): 10213–19. [http://www.ncbi.nlm.nih.gov/pubmed/17047087]
a distant second place: Office of Radiation and Indoor Air, EPA Assessment of Risks from Radon in Homes (Washington, DC: United States Environmental Protection Agency, June 2003), EPA website [http://www.epa.gov/radon/risk_assessment.html] , and “WHO Handbook on Indoor Radon: a Public Health Perspective” (Geneva: World Health Organization, September 2009), WHO website. [[http://www.who.int/ionizing_radiation/env/radon/en/index1.html]]
about 7 in 1,000: Office of Radiation and Indoor Air, EPA Assessment of Risks, appendix D, 82. The number they give is, more precisely, 73 out of 10,000.
constant exposure: With some digging one can find that the calculations assume 70 percent of one’s time is spent indoors. Office of Radiation and Indoor Air, EPA Assessment of Risks, 7, 44.
an artist living there had reported: Harry Otway and Jon Johnson, “A History of the Working Group to Address Los Alamos Community Health Concerns,” Los Alamos National Laboratory, January 2000, available on the website of the U.S. Department of Energy, Office of Scientific and Technical Information. [http://www.osti.gov/bridge/purl.cover.jsp?purl=/751963- rNM6nM/webviewable/751963.pdf]
State health officials investigated: William F. Athas and Charles R. Key, “Los Alamos Cancer Rate Study: Phase I,” New Mexico Department of Health and New Mexico Tumor Registry, University of New Mexico Cancer Center, March 1993 (published on the UNM Health Sciences Center website [http://hsc- sandia.health.unm.edu/som/nmtr/LAC%20Cancer%20Rate%20Study–Phase%201.pdf], and William F. Athas, “Investigation of Excess Thyroid Cancer Incidence in Los Alamos County,” Division of Epidemiology, Evaluation, and Planning, New Mexico Department of Health, April 1996. Available on the Department of Energy website. [http://www.doeal.gov/SWEIS/OtherDocuments/312%20athas1996- Investigation%20of%20excess%20thyroid.pdf]
Texas sharpshooter effect: The term was coined in the mid 1970s by the epidemiologist Seymour Grufferman while he was investigating a reported Hodgkin’s lymphoma cluster on Long Island, New York. E-mail to author, June 10, 2012. Also see S. Grufferman, “Clustering and Aggregation of Exposures in Hodgkin’s Disease,” Cancer 39 (1977): 1829–33; K. J. Rothman, “A Sobering Start for the Cluster Busters’ Conference,” American Journal of Epidemiology 132, no. 1 suppl. (July 1990): S6–13 [http://www.ncbi.nlm.nih.gov/pubmed/2356837] and Atul Gawande, “The Cancer-Cluster Myth,” New Yorker, February 8, 1999.
no harmful exposures from chemical or radioactive contamination: Agency for Toxic Substances and Disease Registry, “Public Health Assessment for Los Alamos National Laboratory,” September 8, 2006, available on the website of the U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry. [http://www.atsdr.cdc.gov/hac/pha//LosAlamosNationalLab/LosAlamosNationalLabPHA090806.pdf]
The Long Island cancer cluster: “Report to the U.S. Congress: The Long Island Breast Cancer Study Project” (Washington, DC: Department of Health and Human Services, November 2004). [http://www.cancer.gov/cancertopics/causes/breast/libcsp] The findings are summarized in Deborah M. Winn, “Science and Society: The Long Island Breast Cancer Study Project,” Nature Reviews Cancer 5, no. 12 (December 2005): 986–94 [http://www.ncbi.nlm.nih.gov/pubmed/16341086] and Renee Twombly, “Long Island Study Finds No Link Between Pollutants and Breast Cancer,” Journal of the National Cancer Institute 94, no. 18 (2002): 1348–51. [http://jnci.oxfordjournals.org/content/94/18/1348.short]
“a type of population control”: Patricia Braus, “Why Does Cancer Cluster?” American Demographics, March 1996. [http://connection.ebscohost.com/c/articles/9603061697/why-does-cancer-cluster]
the median age for diagnosis of breast cancer: “SEER Stat Fact Sheets: Breast,” National Cancer Institute, Surveillance, Epidemiology and End Results website. [http://seer.cancer.gov/statfacts/html/breast.html]
“there is an environmental connection”: Braus, “Why Does Cancer Cluster?”
reading about how this might have happened: My first stop was Robert A. Weinberg, “How Cancer Arises,” Scientific American 275, no. 3 (September 1996): 62–70.
CHAPTER 3 The Consolations of Anthropology
When Louis Leakey sat down to recount: He gave at least three versions of the story: L. S. B. Leakey, The Stone Age Races of Kenya (London: Oxford University Press, 1935), 10–11; Leakey, By the Evidence (New York: Harcourt Brace Jovanovich, 1974), 20–22, 35–36; and Leakey, Adam’s Ancestors (London: Methuen & Co., 1934), 202–3. I also referred to Virginia Morell, Ancestral Passions: The Leakey Family and the Quest for Humankind’s Beginnings (New York: Simon & Schuster, 1995), 65–71, 80–93.
deposited … in Early Pleistocene time: Morell, Ancestral Passions, 85.
“not only the oldest known human fragment”: Leakey, Stone Age Races, 9.
Java man and Peking man: Piltdown man had not yet been exposed as a hoax.
One of his detractors thought: P. G. H. Boswell, “Human Remains from Kanam and Kanjera, Kenya Colony,” Nature 135, no. 3410 (March 9, 1935): 371. Morell describes the controversy, including some bungling of the evidence by Leakey, in Ancestral Passions, 69, 80–93. For an excoriating interpretation of the event see Martin Pickford, Louis S. B. Leakey: Beyond the Evidence (London: Janus Publishing Company, 1997). Pickford and the Leakey family have been bitter enemies (Declan Butler, “The Battle of Tugen Hills,” Nature 410, no. 6828 [March 29, 2001]: 508–9), [http://www.nature.com/nature/journal/v410/n6828/full/410508a0.html] and it can be difficult to separate the science from the politics. Pickford is also coauthor (with Eustace Gitonga) of a book about Louis Leakey’s son entitled Richard E. Leakey: Master of Deceit (Nairobi: White Elephant Publishers, 1995).
a more distant relative like Australopithecus: Kenneth P. Oakley, “The Kanam Jaw,” Nature 185, no. 4717 (March 26, 1960): 945–46. [http://www.nature.com/nature/journal/v185/n4717/abs/185945b0.html]
Neanderthal man: Phillip V. Tobias, “The Kanam Jaw,” Nature 185, no. 4717 (March 26, 1960): 946–47. [http://www.nature.com/nature/journal/v185/n4717/abs/185946a0.html]
or Homo habilis: That was the assessment of Harvard anthropologist David Pilbeam, who told Morell that the fossil may be as much as 2 or more million years old (Ancestral Passions, 9, note 11). He reconfirmed that in an e-mail to me, April 30, 2012.
others have come to believe: In “A Reconsideration of the Date of the Kanam Jaw,” Journal of Archaeological Science 2, no. 2 (June 1975): 151–52, Kenneth P. Oakley theorized that the fossil “may have been enclosed in a Middle Pleistocene surface limestone block which was down-faulted in a fissure penetrating the older Kanam Beds.” The Berkeley anthropologist Tim White concluded that the jaw is probably Late Pleistocene. See Eric Delson et al., eds., Encyclopedia of Human Evolution and Prehistory (New York: Garland, 2000), 739.
no more than about 700,000 years old: E-mail to author, May 7, 2012, from Richard Potts, director of the Human Origins Program at the Smithsonian Institution’s National Museum of Natural History in Washington.
carefully cleaning the specimen: Leakey, By the Evidence, 20–22.
diagnosed it as sarcoma of the bone: J. W. P. Lawrence, Esq., “A Note on the Pathology of the Kanam Mandible,” in Leakey, Stone Age Races of Kenya, appendix A, 139.
There was also a thin fracture: For a description of Kanam man’s anatomical details see Leakey, Stone Age Races, 19–23.
impossible to tell what Kanam man’s chin had been like: M. F. Ashley Montagu, “The Chin of the Kanam Mandible,” American Anthropologist 59, no. 2 (April 1, 1957): 335–38. [http://onlinelibrary.wiley.com/doi/10.1525/aa.1957.59.2.02a00140/abstract]
Another anthropologist disagreed: Tobias, “The Kanam Jaw.”
an entirely different cancer: G. Stathopoulos, “Letter: Kanam Mandible’s Tumour,” Lancet 305, no. 7899 (January 18, 1975): 165. [http://www.ncbi.nlm.nih.gov/pubmed/46076]
Others were not so certain: A. T. Sandison, “Kanam Mandible’s Tumour,” Lancet 305, no. 7901 (February 1, 1975): 279. [http://www.ncbi.nlm.nih.gov/pubmed/46423]
Brothwell concluded: Don Brothwell and A. T. Sandison, Diseases in Antiquity: A Survey of the Diseases, Injuries and Surgery of Early Populations (Springfield, IL: Charles C. Thomas, 1967), 330.
scanning the mandible with an electron microscope: J. Phelan, T. G. Bromage, et al., “Diagnosis of the Pathology of the Kanam Mandible,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology 103, no. 4 (April 2007): e20. [http://www.journals.elsevierhealth.com/periodicals/ymoe/article/S1079-2104(07)00036-4]
“bone run amok”: Timothy Bromage, e-mail message to author, July 1, 2010.
“the giant sloth”: Details are from a sign at the museum. My visit there was in May 2011.
Leakey had sliced through the mass: He reported that “a section was cut through the mandible in the region of the first molar” (Stone Age Races, 2). He also mentions x-ray radiographs.
a small group of Greek and Egyptian oncologists: Spiro Retsas, ed., Palaeo-Oncology: The Antiquity of Cancer, 5th ed. (London: Farrand Press, 1986), 7–9.
“As a crab is furnished with claws”: Alexander Haddow, “Historical Notes on Cancer from the MSS. of Louis Westenra Sambon,” Proceedings of the Royal Society of Medicine 29, no. 9 (July 1936): 1015–28. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2076239]
“because it adheres with such obstinacy”: Haddow, “Historical Notes on Cancer,” 24.
“[I]t attaches itself to the body of a young crab”: Haddow, “Historical Notes on Cancer,” 25.
by placing a live crab on top of it: Haddow, “Historical Notes on Can- cer,” 28.
“With treatment they soon die”: Retsas, Palaeo-Oncology, 45.
a category of growth called “praeter naturam”: Erwin H. Ackerknecht, “Historical Notes on Cancer,” Medical History 2, no. 2 (April 1958): 114–19. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1034369]
“a tumor malignant and indurated”: Retsas, Palaeo-Oncology, 46.
“The early cancer we have cured”: Retsas, Palaeo-Oncology, 49.
“When a cancer has lasted long”: L. Weiss, “Metastasis of Cancer: A Conceptual History from Antiquity to the 1990s; Part 2: Early Concepts of Cancer,” Cancer Metastasis Reviews 19, nos. 3–4 (2000): i-xi, 205–17. [http://www.ncbi.nlm.nih.gov/pubmed/11394186]
diagnosed in people fifty-five or older: “Cancer Facts & Figures 2012,” American Cancer Society website. [http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012]
hovering around thirty or forty years: For a discussion of the difficulties of estimating past longevity, see J. R. Wilmoth, “Demography of Longevity: Past, Present, and Future Trends,” Experimental Gerontology 35, nos. 9–10 (December 2000): 1111–29. [http://www.sciencedirect.com/science/article/pii/S0531556500001947]
the Saxon skeleton whose tumorous femur: Brothwell and Sandison, Diseases in Antiquity, 331 and 339, figure 11b.
comb through the bones: One in 100,000 people gets osteosarcoma. See Lisa Mirabello, Rebecca J. Troisi, and Sharon A. Savage, “Osteosarcoma Incidence and Survival Rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program,” Cancer 115, no. 7 (April 1, 2009): 1531–43. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813207]
Iron Age man in Switzerland and a fifth-century Visigoth from Spain: Edward C. Halperin, “Paleo-oncology: The Role of Ancient Remains in the Study of Cancer,” Perspectives in Biology and Medicine 47, no. 1 (2004): 1–14 [http://www.ncbi.nlm.nih.gov/pubmed/15061165];; Brothwell and Sandison, Diseases in Antiquity, 331; and Arthur C. Aufderheide and Conrado Rodriguez-Martin, The Cambridge Encyclopedia of Human Paleopathology (Cambridge: Cambridge University Press, 1998), 379.
a medieval cemetery in the Black Forest Mountains: K. W. Alt et al., “Infant Osteosarcoma,” International Journal of Osteoarchaeology 12, no. 6 (December 24, 2002): 442–48. [http://onlinelibrary.wiley.com/doi/10.1002/oa.647/abstract]
“to die a painful death”: Alt et al., “Infant Osteosarcoma,” 447.
“The large size of the tumor”: Eugen Strouhal, “Ancient Egyptian Case of Carcinoma,” Bulletin of the New York Academy of Medicine 54, no. 3 (March 1978): 290–302. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1807435]
Traces were found in the skull: Kurt W. Alt and Claus-Peter Adler, “Multiple Myeloma in an Early Medieval Skeleton,” International Journal of Osteoarchaeology 2, no. 3 (May 23, 2005): 205–9 [http://onlinelibrary.wiley.com/doi/10.1002/oa.1390020304/abstract]; and C. Cattaneo et al., “Immunological Diagnosis of Multiple Myeloma in a Medieval Bone,” International Journal of Osteoarchaeology 4, no. 1 (May 27, 2005): 1–2. [http://onlinelibrary.wiley.com/doi/10.1002/oa.1390040102/abstract]
Most skeletal cancers by far come from metastases: Tony Waldron, “What Was the Prevalence of Malignant Disease in the Past?” International Journal of Osteoarchaeology 6, no. 5 (December 1, 1996): 463–70. [http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1099-1212(199612)6:5<463::AID-OA304>3.0.CO;2-Y/abstract]
discovered in Egyptian tombs: Eugen Strouhal, “Tumors in the Remains of Ancient Egyptians,” American Journal of Physical Anthropology 45, no. 3 (November 1, 1976): 613–20. [http://www.ncbi.nlm.nih.gov/pubmed/793419]
in a Portuguese necropolis: S. Assis and S. Codinha, “Metastatic Carcinoma in a 14th–19th Century Skeleton from Constância (Portugal),” International Journal of Osteoarchaeology 20, no. 5 (September 1, 2010): 603–20. [http://onlinelibrary.wiley.com/doi/10.1002/oa.1084/abstract]
in the Tennessee River valley: Maria Ostendorf Smith, “A Probable Case of Metastatic Carcinoma from the Late Prehistoric Eastern Tennessee River Valley,” International Journal of Osteoarchaeology 12, no. 4 (July 1, 2002): 235–47. [http://onlinelibrary.wiley.com/doi/10.1002/oa.618/abstract]
in a leper skeleton from a medieval cemetery: Donald J. Ortner, Keith Manchester, and Frances Lee, “Metastatic Carcinoma in a Leper Skeleton from a Medieval Cemetery in Chichester, England,” International Journal of Osteoarchaeology 1, no. 2 (June 1, 1991): 91–98. [http://onlinelibrary.wiley.com/doi/10.1002/oa.1390010204/abstract]
near the Tower of London: M. Melikian, “A Case of Metastatic Carcinoma from 18th Century London,” International Journal of Osteoarchaeology 16, no. 2 (March 1, 2006): 138–44. [http://onlinelibrary.wiley.com/doi/10.1002/oa.1390010204/abstract]
excavated a 2,700-year-old burial mound: Details of the discovery are described on the website of the German Archaeological Institute: “Complete Excavation of the Kurgan Arzhan 2 including an Undisturbed Royal Grave (late 7th century B.C.).” [http://www.dainst.org/en/project/russian-federation-tuva-arzhan] More information is on the website of the State Hermitage Museum in St. Petersburg: “Restoration and Reconstruction of the Arzhan-2 Complex of Artifacts.” [http://www.hermitagemuseum.org/html_En/13/hm13_3_020.html] I described this and some other cases more briefly in “Trying to Estimate Cancer Rates in Ancient Times,” New York Times, December 27, 2010. [http://www.nytimes.com/2010/12/28/health/28cancer.html]
his skeleton was infested with tumors: Michael Schultz et al., “Oldest Known Case of Metastasizing Prostate Carcinoma Diagnosed in the Skeleton of a 2,700-year-old Scythian King from Arzhan (Siberia, Russia),” International Journal of Cancer 121, no. 12 (December 15, 2007): 2591–95. [http://www.ncbi.nlm.nih.gov/pubmed/17918181]
the partially cremated pelvis of a first-century Roman: G. Grévin, R. Lagier, and C. A. Baud, “Metastatic Carcinoma of Presumed Prostatic Origin in Cremated Bones from the First Century A.D.,” Virchows Archiv: An International Journal of Pathology 431, no. 3 (September 1997): 211–14. [http://www.ncbi.nlm.nih.gov/pubmed/9334843]
a skeleton from a fourteenth-century graveyard: T. Anderson, J. Wakely, and A. Carter, “Medieval Example of Metastatic Carcinoma: A Dry Bone, Radiological, and SEM Study,” American Journal of Physical Anthropology 89, no. 3 (November 1992): 309–23. [http://onlinelibrary.wiley.com/doi/10.1002/ajpa.1330890305/abstract]
osteoblastic … osteolytic: Waldron, “What Was the Prevalence?”
show the strongest appetite: Tony Waldron, Palaeopathology (Cambridge: Cambridge University Press, 2009), 185.
A middle-aged woman with osteolytic lesions: M. J. Allison et al., “Metastatic Tumor of Bone in a Tiahuanaco Female,” Bulletin of the New York Academy of Medicine 56, no. 6 (1980): 581–87. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1808324]
a Late Holocene hunter-gather: L. H. Luna et al., “A Case of Multiple Metastasis in Late Holocene Hunter-gatherers from the Argentine Pampean Region,” International Journal of Osteoarchaeology 18, no. 5 (November 14, 2007): 492–506. [http://onlinelibrary.wiley.com/doi/10.1002/oa.950/abstract]
Like 90 percent of human cancers: “Cancer Overview,” Stanford School of Medicine Cancer Institute website. [http://cancer.stanford.edu/information/cancerOverview.html]
For children … only a fraction of cancers are carcinomas: “Disease Information,” St. Jude Children’s Research Hospital website. [http://www.stjude.org/stjude/v/index.jsp?vgnextoid=393d061585f70110VgnVCM1000001e0215acRCRD]
often spread first to the lung or liver: “Metastatic Cancer,” National Cancer Institute website, reviewed May 23, 2011. [http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic] Prostate cancer is drawn to bone, but it would probably have been less frequent when life spans were shorter.
“swellings” and “eatings”: See, for example, Margaret M. Olszewski, “Concepts of Cancer from Antiquity to the Nineteenth Century,” University of Toronto Medical Journal 87, no. 3 (May 2010) [http://utmj.org/ojs/index.php/UTMJ/article/view/1252]; and Retsas, Palaeo-Oncology, 36.
A rectal carcinoma in a 1,600-year-old mummy: A. Rosalie David and Michael R. Zimmerman, “Cancer: An Old Disease, a New Disease or Something in Between?” Nature Reviews Cancer 10, no. 10 (October 2010): 728–33. [http://www.nature.com/nrc/journal/v10/n10/full/nrc2914.html]
on the face of a Chilean child: David and Zimmerman, “Cancer: An Old Disease, a New Disease?”
nine pre-Columbian Incan mummies: Oscar B. Urteaga and George T. Pack, “On the Antiquity of Melanoma,” Cancer 19, no. 5 (May 1, 1966): 607–10. [http://www.ncbi.nlm.nih.gov/pubmed/5326247]
To prepare a pharaoh: Leonard Weiss, “Observations on the Antiquity of Cancer and Metastasis,” Cancer and Metastasis Reviews 19, nos. 3–4 (December 2000): 193–204. [http://www.springerlink.com/content/h2205q07rm735720/abstract]
embalmed tumors can survive: M. R. Zimmerman, “An Experimental Study of Mummification Pertinent to the Antiquity of Cancer,” Cancer 40 (1977): 1358–62. [http://www.ncbi.nlm.nih.gov/pubmed/902245] In an experiment, a liver taken from a patient with metastatic carcinoma was dried in an oven and then rehydrated. Zimmerman observed that “the features of cancer (large, dark staining and highly variable nuclei and invasion of surrounding tissue) are well preserved by mummification and that mummified tumors are actually better preserved than normal tissue.” E-mail to author, November 11, 2010.
Ferrante I of Aragon: The king was also obese and his bones were infused with lead and zinc. See Gino Fornaciari et al., “K-ras Mutation in the Tumour of King Ferrante I of Aragon (1431–94) and Environmental Mutagens at the Aragonese Court of Naples,” International Journal of Osteoarchaeology 9, no. 5 (October 6, 1999): 302–6; [http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1099-1212(199909/10)9:5<302::AID-OA487>3.0.CO;2-V/abstract]; Antonio Marchetti, Gino Fornaciari, et al., “K-RAS Mutation in the Tumour of Ferrante I of Aragon, King of Naples,” Lancet 347, no. 9010 (May 1996): 1272 [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)90798-9/fulltext]; and Laura Ottini, Gino Fornaciari, et al., “Gene-Environment Interactions in the Pre-Industrial Era: The Cancer of King Ferrante I of Aragon (1431–1494),” Human Pathology 42, no. 3 (March 2011): 332–39. [http://www.ncbi.nlm.nih.gov/pubmed/21111451]
counted about two hundred suspected cancer sightings: I started with 176 examples Strouhal had tabulated in what he called the Old World (reference in A. Sefcáková, E. Strouhal, et al., “Case of Metastatic Carcinoma from End of the 8th–early 9th Century Slovakia,” American Journal of Physical Anthropology 116, no. 3 [November 2001]: 216–29) [http://www.ncbi.nlm.nih.gov/pubmed/11596001] and then added in New World cases and cases found since the paper was published.
stumbled on by chance: Strouhal comments on this in “Tumors in the Remains of Ancient Egyptians.”
taphonomic changes: Waldron, Palaeopathology, 21–23; Weiss, “Observations on the Antiquity of Cancer and Metastasis”; and E. Strouhal, “Malignant Tumors in the Old World,” Paleopathology Newsletter no. 85, suppl. (1994): 1–6.
significantly underreported: In Diseases in Antiquity, Brothwell speculates that “the scarcity of tumours has been overemphasized in the past—a fact which in itself may have depressed some detailed searching.” See his chapter “The Evidence for Neoplasms,” 320–45. Also see Waldron, “What Was the Prevalence?”
more likely to appear in certain bones: Waldron, Palaeopathology, 185.
Hoping to cut through the uncertainty: Waldron, “What Was the Prevalence?”
between 0 and 2 percent for males and 4 and 7 percent for females: See figure 1 of Waldron, “What Was the Prevalence?” The numbers were higher for women because of uterine and breast cancer. In the next century cancer in men would come to dominate because of cigarettes and lung cancer.
The next step: Andreas G. Nerlich et al., “Malignant Tumors in Two Ancient Populations: An Approach to Historical Tumor Epidemiology,” Oncology Reports 16, no. 1 (July 2006): 197–202. [http://www.ncbi.nlm.nih.gov/pubmed/16786146]
an article that had just appeared: David and Zimmerman, “Cancer: An Old Disease, a New Disease?”
In a news release from her university: “Scientists Suggest that Cancer Is Man-made,” University of Manchester website, October 14, 2010. [http://www.manchester.ac.uk/aboutus/news/display/?id=6243]
some take the number at face value: See, for example, Luigi L. Capasso, “Antiquity of Cancer,” International Journal of Cancer 113, no. 1 (January 1, 2005): 2–13 [http://www.ncbi.nlm.nih.gov/pubmed/1538951]; and M. S. Micozzi, “Diseases in Antiquity: The Case of Cancer,” Archives of Pathology and Laboratory Medicine 115 (1991): 838–44. [http://www.ncbi.nlm.nih.gov/pubmed/1863198]
the total number of ancient and prehistoric skeletons: The anthropologists I asked were Anne L. Grauer, president of the Paleopathology Association and an anthropologist at Loyola University in Chicago, Heather J. H. Edgar, curator of human osteology at the Maxwell Museum of Anthropology at the University of New Mexico, and Tim D. White, Professor of Integrative Biology at the University of California, Berkeley.
A demographer … made a rough calculation: Carl Haub, “How Many People Have Ever Lived on Earth?” October 2011, Population Reference Bureau website. [http://www.prb.org/Articles/2002/HowManyPeopleHaveEverLivedonEarth.aspx]
CHAPTER 4 Invasion of the Body Snatchers
“rheumatism and debility”: T. R. Ashworth, “A Case of Cancer in Which Cells Similar to Those in the Tumours Were Seen in the Blood After Death,” Australian Medical Journal 14 (1869): 146–47.
secreting “morbid juices”: L. Weiss, “Concepts of Metastasis,” Cancer and Metastasis Reviews 19 (2000): 219–34, which is part 3 of a longer piece, “Metastasis of Cancer: A Conceptual History from Antiquity to the 1990s,” 193–400. [http://www.ncbi.nlm.nih.gov/pubmed/11394186] I also relied on two other articles by Weiss in the same issue: “Observations on the Antiquity of Cancer and Metastasis” (193–204) and “Early Concepts of Cancer” (205–17). Other sources on the history of the cellular idea of cancer include James Stuart Olson, The History of Cancer: An Annotated Bibliography (New York: Greenwood Press, 1989); Erwin H. Ackerknecht, “Historical Notes on Cancer,” Medical History 2, no. 2 (April 1958): 114–19 [http://www.ncbi.nlm.nih.gov/pubmed/11394186]; Margaret M. Olszewski, “Concepts of Cancer from Antiquity to the Nineteenth Century,” University of Toronto Medical Journal 87, no. 3 (May 2010); and W. I. B. Onuigbo, “The Paradox of Virchow’s Views on Cancer Metastasis,” Bulletin of the History of Medicine 34 (1962): 444–49. [http://www.ncbi.nlm.nih.gov/pubmed/13940181] Another valuable resource was Jacob Wolff, The Science of Cancerous Disease from Earliest Times to the Present, first published in 1907. It was translated from German by Barbara Ayoub and reissued in 1989 by Science History Publications and the National Library of Medicine.
“metastatic affections”: Weiss, “Early Concepts of Cancer.”
an idea that was carried by Galen: Ackerknecht, “Historical Notes.”
Descartes saw a connection: Ackerknecht, “Historical Notes.”
A Parisian surgeon: Weiss, “Concepts of Metastasis.”
traveling along the lymph vessel walls: Weiss, “Concepts of Metastasis.”
Even the nervous system: Weiss, “Concepts of Metastasis.”
leprosy and elephantiasis: Ackerknecht, “Historical Notes.”
“cancer juice”: Ackerknecht, “Historical Notes.”
not sharp enough to show: Wolff, Science of Cancerous Disease, 101–3.
a book published in 1838: There is an English version translated by Charles West as On the Nature and Structural Characteristics of Cancer, and Those Morbid Growths Which May Be Confounded with It (London: Sherwood, Gilbert, and Piper, 1840). For an excerpt see Johannes Müller, “On the Nature and Structural Characteristics of Cancer: General Observations on the Minute Structure of Morbid Growths,” CA: A Cancer Journal for Clinicians 23, no. 5 (December 30, 2008): 307–12. [http://onlinelibrary.wiley.com/doi/10.3322/canjclin.23.5.307/abstract]
from a primitive fluid called blastema: Müller’s ideas are summarized in Wolff, Science of Cancerous Disease, 108; and Olszewski, “Concepts of Cancer.”
Virchow, took the next step: Ackerknecht, “Historical Notes.”
“a dissemination of cells”: Onuigbo, “The Paradox of Virchow’s Views.”
all cancer arose from connective tissue: Ackerknecht, “Historical Notes.”
Thiersch helped discredit that idea: Ackerknecht, “Historical Notes.”
“Cancer is incurable”: Quoted in Weiss, “Early Concepts of Cancer.”
encompass 3,914 pages: Wolff, Science of Cancerous Disease, ix.
“may or may not wish to compare”: The introduction is by the medical historian Saul Jarcho, MD.
“When a plant goes to seed”: S. Paget, “The Distribution of Secondary Growths in Cancer of the Breast,” Lancet 133, no. 3421 (1889): 571–73. It was republished as “Stephen Paget’s Paper Reproduced from The Lancet, 1889,” Cancer and Metastasis Reviews 8, no. 2 (1989): 98–101. [http://www.springerlink.com/content/xmm1773487341l71]
it would soon be swamped: Weinberg, Biology of Cancer, 636.
head straight for the brain: “Metastatic Brain Tumor,” published online by the National Library of Medicine, Medline Plus website. [http://www.nlm.nih.gov/medlineplus/ency/article/000769.htm]
Ian Hart and Isaiah Fidler: Their paper is “Role of Organ Selectivity in the Determination of Metastatic Patterns of the B16 Melanoma,” Cancer Research 40 (1980): 2281–87. [http://cancerres.aacrjournals.org/content/40/7/228] Also see Isaiah J. Fidler, “The Pathogenesis of Cancer Metastasis: The ‘Seed and Soil’ Hypothesis Revisited,” Nature Reviews Cancer 3, no. 6 (June 2003): 453–58. [http://www.nature.com/nrc/journal/v3/n6/abs/nrc1098.html]
A video I came across: “Overview of Metastasis,” published online by CancerQuest, Winship Cancer Institute website, Emory University. [http://www.cancerquest.org/metastasis-overview.html]
The process is called anoikis: Lance A. Liotta and Elise Kohn. “Anoikis: Cancer and the Homeless Cell,” Nature 430, no. 7003 (August 26, 2004): 973–74. [http://www.nature.com/nature/journal/v430/n7003/full/430973a.html]
most will perish immediately: For a fascinating account of the intricacies of metastasis, see Weinberg, Biology of Cancer, chapter 14. I also referred to Ann F. Chambers, Alan C. Groom, and Ian C. MacDonald, “Metastasis: Dissemination and Growth of Cancer Cells in Metastatic Sites,” Nature Reviews Cancer 2, no. 8 (August 1, 2002): 563–72 [http://www.nature.com/nrc/journal/v2/n8/abs/nrc865.html]; and Christine L. Chaffer and Robert A. Weinberg, “A Perspective on Cancer Cell Metastasis,” Science 331, no. 6024 (March 25, 2011): 1559–64. [http://www.sciencemag.org/content/331/6024/1559]
jettison enough of their cytoplasm: Weinberg, Biology of Cancer, 593–94. He suggests a more likely explanation is that cancer cells can avoid the capillary trap by passing instead through arterial-venous shunts.
researchers found that after twenty-four hours: For a review see Fidler, “Pathogenesis of Cancer Metastasis.”
cancer in one breast: Weinberg, Biology of Cancer, 636, sidebar 14.8.
a molecular “zip code” identifying the organ: Weinberg, Biology of Can- cer, 637.
priming them for survival: Andy J. Minn, Joan Massagué, et al., “Genes That Mediate Breast Cancer Metastasis to Lung,” Nature 436, no. 7050 (July 28, 2005): 518–24 [http://www.ncbi.nlm.nih.gov/pubmed/16049480]; and Paula D. Bos, J. Massagué, et al., “Genes That Mediate Breast Cancer Metastasis to the Brain,” Nature 459, no. 7249 (June 18, 2009): 1005–9. [http://www.ncbi.nlm.nih.gov/pubmed/19421193]
a premetastatic niche: Rosandra N. Kaplan, Shahin Rafii, and David Lyden, “Preparing the ‘Soil’: The Premetastatic Niche,” Cancer Research 66, no. 23 (December 1, 2006): 11089–93. [http://cancerres.aacrjournals.org/content/66/23/11089]
the travelers can bring their own soil: Dan G. Duda et al., “Malignant Cells Facilitate Lung Metastasis by Bringing Their Own Soil,” Proceedings of the National Academy of Sciences 107, no. 50 (December 14, 2010): 21677–82. [http://www.pnas.org/content/107/50/21677.abstract]
exchange signals with the natives: The process is described in the general references on metastasis listed above.
rejoin the battle at home: Larry Norton and Joan Massagué, “Is Cancer a Disease of Self-seeding?” Nature Medicine 12, no. 8 (August 2006): 875–78 [http://www.ncbi.nlm.nih.gov/pubmed/16892025]; Mi-Young Kim, Joan Massagué, et al., “Tumor Self-seeding by Circulating Cancer Cells,” Cell 139, no. 7 (December 24, 2009): 1315–26 [http://www.ncbi.nlm.nih.gov/pubmed/20064377]; and Elizabeth Comen, Larry Norton, and Joan Massagué, “Clinical Implications of Cancer Self-seeding,” Nature Reviews Clinical Oncology 8, no. 6 (June 2011): 369–77. [http://www.ncbi.nlm.nih.gov/pubmed/21522121]
the ability to initiate angiogenesis: J. Folkman et al., “Isolation of a Tumor Factor Responsible for Angiogenesis,” The Journal of Experimental Medicine 133, no. 2 (February 1, 1971): 275–88. [http://www.ncbi.nlm.nih.gov/pubmed/4332371]
creating connections to the lymphatic system: Viviane Mumprecht and Michael Detmar, “Lymphangiogenesis and Cancer Metastasis,” Journal of Cellular and Molecular Medicine 13, no. 8A (August 2009): 1405–16. [http://www.ncbi.nlm.nih.gov/pubmed/19583813]
signals to a nearby lymph node: Satoshi Hirakawa et al., “VEGF-C-induced Lymphangiogenesis in Sentinel Lymph Nodes Promotes Tumor Metastasis to Distant Sites,” Blood 109, no. 3 (February 1, 2007): 1010–17. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785149]
survival rate can be as high as 90 percent: “Endometrial (Uterine) Cancer: Survival by Stage” [http://www.cancer.org/Cancer/EndometrialCancer/DetailedGuide/endometrial-uterine-cancer-survival-rates] and “How Is Endometrial Cancer Staged?” [http://www.cancer.org/Cancer/EndometrialCancer/DetailedGuide/endometrial-uterine-cancer-staging] Both are on the American Cancer Society website, last revised July 25, 2012.
Beauty Beyond Belief: Packaged and sold by BBB Seed, Boulder, Colorado. [http://www.bbbseed.com]
CHAPTER 5 Information Sickness
experimenting with fruit flies: H. J. Muller, “Artificial Transmutation of the Gene,” Science 66, no. 1699 (July 22, 1927): 84–87. [http://www.sciencemag.org/content/66/1699/84.short]
discovered in his monastery garden: An English translation of Gregor Mendel’s landmark paper, “Experiments in Plant Hybridization” (1865), can be found online at MendelWeb. [http://www.mendelweb.org/Mendel.html]
x-rays were first produced: For a translation of the original paper see W. C. Röntgen, “On a New Kind of Rays” (1895), republished in Wilhelm Conrad Röntgen, Sir George Gabriel Stokes, and Sir Joseph John Thomson, Röntgen Rays: Memoirs by Röntgen, Stokes, and J. J. Thomson (New York: Harper & Brothers, 1899), 3–13. The collection also includes Röntgen’s second and third communications. Like the Curies, he had no reason yet to be fearful of ionizing radiation. He matter-of-factly describes what happens when he shines x-rays into his eyes (pp. 7 and 39–40). [http://books.google.com/books?id=m0hWAAAAMAAJ]
strange-looking chromosomes: For Boveri’s speculations about cancer cells, see “Concerning the Origin of Malignant Tumours,” a translation by Henry Harris of Boveri’s Zur Frage der Entstehung maligner Tumoren (1914), Journal of Cell Science 121 (January 1, 2008): 1–84. [http://jcs.biologists.org/content/121/Supplement_1/1.full] It has also been published as a book: Theodor Boveri, Concerning the Origin of Malignant Tumours, 1st ed. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2007).
to “multiply without restraint”: Boveri, “Concerning the Origin.”
“conceivable at least that mammalian cancer”: Volker Wunderlich, “Early References to the Mutational Origin of Cancer,” International Journal of Epidemiology 36, no. 1 (February 1, 2007): 246–47. [http://ije.oxfordjournals.org/content/36/1/246.short]
“a new kind of cell”: Wunderlich, “Early References.”
Becquerel accidentally discovered: “On Radioactivity, a New Property of Matter,” Nobel Lectures, Physics 1901–1921 (Amsterdam: Elsevier Publishing Company, 1967), 52–70. This lecture, delivered on December 11, 1903, is available on the Nobel Prize website. [http://www.nobelprize.org/nobel_prizes/physics/laureates/1903/becquerel-lecture.html]
Marie Curie noticed: The Curies’ experiments are described in Pierre Curie’s June 6, 1905 Nobel lecture, “Radioactive Substances, Especially Radium,” in Nobel Lectures, Physics 1901–1921 (Amsterdam: Elsevier Publishing Company, 1967). Available at the Nobel Prize website. [http://www.nobelprize.org/nobel_prizes/physics/laureates/1903/pierre-curie-lecture.html] Also see Eve Curie, Madame Curie: A Biography, trans. Vincent Sheean (Garden City, NY: Doubleday, Doran & Co., 1937); and Barbara Goldsmith, Obsessive Genius: The Inner World of Marie Curie (New York: W. W. Norton, 2005).
“a kind of matter in the world”: The film with Greer Garson and Walter Pidgeon was nominated for the 1944 Academy Award for Outstanding Motion Picture. (The winner was Casablanca.)
“One of our joys”: Marie Curie, Pierre Curie (With the Autobiographical Notes of Marie Curie), trans. Charlotte Kellogg (New York: Macmillan Co., 1923), 187.
an optical analog of a sonic boom: More specifically the Curies were seeing Cherenkov radiation.
decorate their teeth, fingernails, and eyebrows: For reports on the Radium Girls, see Frederick L. Hoffman, “Radium (Mesothorium) Necrosis,” Journal of the American Medical Association 85, no. 13 (1925): 961–65 [http://jama.ama-assn.org/content/85/13/961]; R. E. Rowland, Radium in Humans: A Review of U.S. Studies, Argonne National Laboratory, Environmental Research Division, 1994; [http://www.ustur.wsu.edu/Radium/files/RaInHumans.pdf] and Ross Mullner, Deadly Glow: The Radium Dial Worker Tragedy (Washington, DC: American Public Health Association, 1999).
“soot warts”: “Cancer Scroti,” in The Chirurgical Works of Percival Pott, vol. 3 (London: Johnson, 1808), 177–80. [http://books.google.com/books/about/The_chirurgical_works_of_Percival_Pott.html?id=cvS_o4-jIzwC]
The same cancer was later found: 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]
applying coal tar to rabbits’ ears: K. Yamagiwa and K. Ichikawa, “Experimental Study of the Pathogenesis of Carcinoma,” Journal of Cancer Research 3 (1918): 1–29. Republished in CA: A Cancer Journal for Clinicians 27, no. 3 (December 31, 2008): 174–81. [http://onlinelibrary.wiley.com/doi/10.3322/canjclin.27.3.174/abstract]
produced tumors in laboratory animals: See, for example, J. W. Cook, C. L. Hewett, and I. Hieger, “The Isolation of a Cancer-producing Hydrocarbon from Coal Tar,” Journal of the Chemical Society (January 1, 1933): 395–405. [http://pubs.rsc.org/en/content/articlelanding/1933/jr/jr9330000395]
the Ames test: Bruce N. Ames et al., “Carcinogens Are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection,” Proceedings of the National Academy of Sciences 70, no. 8 (August 1973): 2281–85. [http://www.pnas.org/content/70/8/2281.abstract]
studying chicken tumors: Peyton Rous’s papers are “A Transmissible Avian Neoplasm,” Journal of Experimental Medicine 12, no. 5 (September 1, 1910): 696–705 [http://www.ncbi.nlm.nih.gov/pubmed/19867354] and “A Sarcoma of the Fowl Transmissible by an Agent Separable from the Tumor Cells,” Journal of Experimental Medicine 13, no. 4 (April 1, 1911): 397–411. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2124874]
src, ras, fes, myb, myc: The string of revelations, which has been described as the Revolution of 1976, was set off by Harold Varmus and J. Michael Bishop (D. Stehelin, H. E. Varmus, J. M. Bishop, and P. K. Vogt, “DNA Related to the Transforming Gene(s) of Avian Sarcoma Viruses Is Present in Normal Avian DNA,” Nature 260, no. 5547 [March 11, 1976]: 170–73) [http://dx.doi.org/10.1038/260170a0] and is described in Robert Weinberg’s One Renegade Cell: The Quest for the Origin of Cancer (New York: Basic Books, 1999). I also referred to Weinberg’s “How Cancer Arises,” Scientific American 275, no. 3 (September 1996): 62–70; Douglas Hanahan and R. A. Weinberg, “The Hallmarks of Cancer,” Cell 100, no. 1 (January 7, 2000): 57–70; and D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (March 4, 2011): 646–74. Natalie Angier told Weinberg’s story in Natural Obsessions: Striving to Unlock the Deepest Secrets of the Cancer Cell (New York: Warner Books, 1989), and Weinberg gave his own account in Racing to the Beginning of the Road: The Search for the Origin of Cancer (New York: Harmony, 1996).
they were named proto-oncogenes: C. Shih, R. A. Weinberg, et al., “Passage of Phenotypes of Chemically Transformed Cells via Transfection of DNA and Chromatin,” Proceedings of the National Academy of Sciences 76, no. 11 (November 1979): 5714–18 [http://www.ncbi.nlm.nih.gov/pubmed/230490]; and C. J. Tabin, R. A. Weinberg, et al., “Mechanism of Activation of a Human Oncogene,” Nature 300, no. 5888 (November 11, 1982): 143–49. [http://www.ncbi.nlm.nih.gov/pubmed/6290897]
Some mutations are even more wrenching: The best known example is the Philadelphia chromosome, which is involved in chronic myeloid leukemia. For the original report, see Peter Nowell and David Hungerford, “A Minute Chromosome in Chronic Granulocytic Leukemia,” Science 132, no. 3438 (November 1960): 1497.
when a gene called Rb: S. H. Friend, R. A. Weinberg, et al., “A Human DNA Segment with Properties of the Gene That Predisposes to Retinoblastoma and Osteosarcoma,” Nature 323, no. 6089 (October 16, 1986): 643–46 [http://www.ncbi.nlm.nih.gov/pubmed/2877398]; and J. A. DeCaprio et al., “The Product of the Retinoblastoma Susceptibility Gene Has Properties of a Cell Cycle Regulatory Element,” Cell 58, no. 6 (September 22, 1989): 1085–95. [http://www.ncbi.nlm.nih.gov/pubmed/2673542]
both copies must be knocked out: This is known as the two-hit hypothesis. See Alfred G. Knudson, “Mutation and Cancer: Statistical Study of Retinoblastoma,” Proceedings of the National Academy of Sciences 68, no. 4 (April 1971): 820–23. [http://www.ncbi.nlm.nih.gov/pubmed/5279523]
involved in the timekeeping: See, for example, DeCaprio et al., “The Product of the Retinoblastoma Susceptibility Gene.” [http://www.ncbi.nlm.nih.gov/pubmed/2673542]
sits at the center of a web: C. A. Finlay, P. W. Hinds, and A. J. Levine, “The P53 Proto-oncogene Can Act as a Suppressor of Transformation,” Cell 57, no. 7 (June 30, 1989): 1083–93 [http://www.ncbi.nlm.nih.gov/pubmed/2525423]; and M. B. Kastan, B. Vogelstein, et al., “Participation of P53 Protein in the Cellular Response to DNA Damage,” part 1, Cancer Research 51, no. 23 (December 1, 1991): 6304–11. [http://www.ncbi.nlm.nih.gov/pubmed/1933891]
programmed cell death, or apoptosis: J. F. Kerr, A. H. Wyllie, and A. R. Currie, “Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics,” British Journal of Cancer 26, no. 4 (August 1972): 239–57. [http://www.ncbi.nlm.nih.gov/pubmed/4561027]
a principle called the Hayflick limit: L. Hayflick and P. S. Moorhead, “The Serial Cultivation of Human Diploid Cell Strains,” Experimental Cell Research 25, no. 3 (December 1961): 585–621. [http://www.sciencedirect.com/science/article/pii/0014482761901926]
The count is kept by telomeres: The story of the discovery is told in Elizabeth H. Blackburn, Carol W. Greider, and Jack W. Szostak, “Telomeres and Telomerase: The Path from Maize, Tetrahymena and Yeast to Human Cancer and Aging,” Nature Medicine 12, no. 10 (October 2006): 1133–38. [http://www.ncbi.nlm.nih.gov/pubmed/17024208] The key papers are J. W. Szostak and E. H. Blackburn, “Cloning Yeast Telomeres on Linear Plasmid Vectors,” Cell 29, no. 1 (May 1982): 245–55 [http://www.ncbi.nlm.nih.gov/pubmed/6286143]; C. W. Greider and E. H. Blackburn, “Identification of a Specific Telomere Terminal Transferase Activity in Tetrahymena Extracts, Cell 43(1985): 405–13 [http://www.ncbi.nlm.nih.gov/pubmed/3907856]; and C. W. Greider and E. H. Blackburn, “A Telomeric Sequence in the RNA of Tetrahymena Telomerase Required for Telomere Repeat Synthesis,” Nature 337 (1989): 331–37. [http://www.nature.com/nature/journal/v337/n6205/abs/337331a0.html]
accumulating mutations: Accelerating the process may be a phenomenon called genomic instability. See Simona Negrini, Vassilis G. Gorgoulis, and Thanos D. Halazonetis, “Genomic Instability—An Evolving Hallmark of Cancer,” Nature Reviews Molecular Cell Biology 11, no. 3 (March 1, 2010): 220–28. [http://www.nature.com/nrm/journal/v11/n3/abs/nrm2858.html]
As this evolution unfolds: For an overview of the phenomenon, see Hanahan and Weinberg’s “The Hallmarks of Cancer” and “Hallmarks of Cancer: The Next Generation.”
signals are sent to healthy cells: These discoveries grew from early research on the role of the tumor microenvironment. See, for example, D. S. Dolberg and M. J. Bissell, “Inability of Rous Sarcoma Virus to Cause Sarcomas in the Avian Embryo,” Nature 309, no. 5968 (June 7, 1984): 552–56 [http://www.ncbi.nlm.nih.gov/pubmed/6203040]; and D. S. Dolberg, M. J. Bissell, et al., “Wounding and Its Role in RSV-mediated Tumor Formation,” Science 230, no. 4726 (November 8, 1985): 676–78. [http://www.ncbi.nlm.nih.gov/pubmed/2996144]
Macrophages and other inflammatory cells: 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]
compared to bodily organs: Mina J. Bissell and Derek Radisky, “Putting Tumours in Context,” Nature Reviews Cancer 1, no. 1 (October 2001): 46–54. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975572]
CHAPTER 6 “How Heart Cells Embrace Their Fate”
an embryo is so much like a tumor: The complex process of implantation is described in Haibin Wang and Sudhansu K. Dey, “Roadmap to Embryo Implantation: Clues from Mouse Models,” Nature Reviews Genetics 7, no. 3 (March 1, 2006): 185–99. [http://www.nature.com/nrg/journal/v7/n3/abs/nrg1808.html] For some of the parallels with tumorigenesis see Michael J. Murray and Bruce A. Lessey, “Embryo Implantation and Tumor Metastasis: Common Pathways of Invasion and Angiogenesis,” Seminars in Reproductive Medicine 17, no. 3 (March 15, 2008): 275–90. [http://www.ncbi.nlm.nih.gov/pubmed/10797946]
enzymes erode the surface: L. A. Salamonsen, “Role of Proteases in Implantation,” Reviews of Reproduction 4, no. 1 (January 1999): 11–22. [http://www.ncbi.nlm.nih.gov/pubmed/10051098]
molecules help ensure a tight grip: Maaike S. M. van Mourik et al., “Embryonic Implantation: Cytokines, Adhesion Molecules, and Immune Cells in Establishing an Implantation Environment,” Journal of Leukocyte Biology 85, no. 1 (January 2009): 4–19.[http://www.ncbi.nlm.nih.gov/pubmed/18784344]
messages are sent to the immune system: Van Mourik et al., “Embryonic Implantation.”
begins stimulating angiogenesis: D. M. Sherer and O. Abulafia, “Angiogenesis During Implantation, and Placental and Early Embryonic Development,” Placenta 22, no. 1 (January 2001): 1–13. [http://www.ncbi.nlm.nih.gov/pubmed/11162347]
the more parallels they find: Melissa Marino, “In the Beginning: What Developmental Biology Can Teach About Cancer,” Lens online magazine, Vanderbilt Medical Center website, February 2007. [http://www.mc.vanderbilt.edu/lens/article/?id=170]
epithelial-mesenchymal transition: The seminal article is Jean Paul Thiery, “Epithelial-Mesenchymal Transitions in Tumour Progression,” Nature Reviews Cancer 2, no. 6 (June 2002): 442–54. [http://dx.doi.org/10.1038/nrc822] Good reviews include Yibin Kang and Joan Massagué, “Epithelial-Mesenchymal Transitions: Twist in Development and Metastasis,” Cell 118, no. 3 (August 6, 2004): 277–79; [http://www.ncbi.nlm.nih.gov/pubmed/15294153] Jonathan M. Lee et al., “The Epithelial-Mesenchymal Transition: New Insights in Signaling, Development, and Disease,” Journal of Cell Biology 172, no. 7 (March 27, 2006): 973–81; [http://www.ncbi.nlm.nih.gov/pubmed/16567498] Jing Yang and Robert A. Weinberg, “Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis,” Developmental Cell 14, no. 6 (June 2008): 818–29; [http://www.ncbi.nlm.nih.gov/pubmed/18539112] and Raghu Kalluri and Robert A. Weinberg, “The Basics of Epithelial-Mesenchymal Transition,” Journal of Clinical Investigation 119, no. 6 (June 1, 2009): 1420–28. [http://www.jci.org/articles/view/39104] For an account by some naysayers see David Tarin, Erik W. Thompson, and Donald F. Newgreen, “The Fallacy of Epithelial Mesenchymal Transition in Neoplasia,” Cancer Research 65, no. 14 (July 15, 2005): 5996–6001. [http://www.ncbi.nlm.nih.gov/pubmed/16024596] Both sides of the controversy are described in Heidi Ledford, “Cancer Theory Faces Doubts,” Nature 472, no. 7343 (April 21, 2011): 273. [http://www.ncbi.nlm.nih.gov/pubmed/21512545]
holding its annual meeting: Society for Developmental Biology Sixty-Ninth Annual Meeting, August 5–9, 2010, Albuquerque, NM. I also attended the Seventieth Annual Meeting, July 21–22, 2011, in Chicago. For a nice overview of developmental biology, see Sean B. Carroll, Endless Forms Most Beautiful: The New Science of Evo Devo (New York: Norton, 2006). The website of the Society for Developmental Biology [http://www.sdbonline.org] provides a portal to numerous resources like WormAtlas, with detailed and annotated maps of C. elegans, and FlyBrain, which covers the Drosophila nervous system.
“Organogenesis”: The proceedings of the Albuquerque conference are in Developmental Biology 344, no. 1 (2010): 391–542. [http://www.sciencedirect.com/science/journal/00121606/344/1]
wingless, frizzled, smoothened, patched, and disheveled: Though I have tried to be consistent in my own usage, I have not religiously followed the rules for when to render the names and symbols of genes in upper case or lower case or italics or roman. Apologies to the specialists who may find that distracting.
possible treatments for baldness: Andrzej Dlugosz, “The Hedgehog and the Hair Follicle: A Growing Relationship,” Journal of Clinical Investigation 104, no. 7 (October 1, 1999): 851–53. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC408568]
“The quirky sense of humour”: Ken Maclean, “Humour of Gene Names Lost in Translation to Patients,” Nature 439, no. 7074 (January 19, 2006): 266. [http://dx.doi.org/10.1038/439266d]
It now goes by the less evocative name Zbtb7: Tom Simonite, “Pokemon Blocks Gene Name,” Nature 438, no. 7070 (December 14, 2005): 897. [http://www.nature.com/nature/journal/v438/n7070/full/438897a.html]
Since it was discovered in 1993: R. D. Riddle, C. Tabin, et al., “Sonic Hedgehog Mediates the Polarizing Activity of the ZPA,” Cell 75, no. 7 (December 31, 1993): 1401–16. [http://www.ncbi.nlm.nih.gov/pubmed/8269518]
sheep grazing in the mountains: The story of cyclopamine is told in Philipp Heretsch, Lito Tzagkaroulaki, and Athanassios Giannis, “Cyclopamine and Hedgehog Signaling: Chemistry, Biology, Medical Perspectives,” Angewandte Chemie (international ed. in English) 49, no. 20 (May 3, 2010): 3418–27. [http://www.ncbi.nlm.nih.gov/pubmed/20429080]
holoprosencephaly: Max Muenk, “Translational Concepts to Disease: Holoprosencephaly as an Example,” lecture presented July 22, 2011 at the Society for Developmental Biology Seventieth Annual Meeting, Chicago, IL.
one of every 250 early embryos: Erich Roessler, Maximilian Muenke, et al., “Mutations in the Human Sonic Hedgehog Gene Cause Holoprosencephaly,” Nature Genetics 14, no. 3 (November 1996): 357–60. [http://dx.doi.org/10.1038/ng1196-357]
can drive the formation of malignancies: For an overview of sonic hedgehog and cancer see Lee L. Rubin and Frederic J. de Sauvage, “Targeting the Hedgehog Pathway in Cancer,” Nature Reviews Drug Discovery 5, no. 12 (December 2006): 1026–33 [http://dx.doi.org/10.1038/nrd2086]; and Jennifer M. Bailey, Pankaj K. Singh, and Michael A. Hollingsworth, “Cancer Metastasis Facilitated by Developmental Pathways: Sonic Hedgehog, Notch, and Bone Morphogenic Proteins,” Journal of Cellular Biochemistry 102, no. 4 (November 1, 2007): 829–39. [http://onlinelibrary.wiley.com/doi/10.1002/jcb.21509/abstract]
Gorlin syndrome: Ervin H. Epstein, “Basal Cell Carcinomas: Attack of the Hedgehog,” Nature Reviews Cancer 8, no. 10 (October 2008): 743–54. [http://dx.doi.org/10.1038/nrc2503]
a cream containing cyclopamine: Sinan Tabs and Oktay Avci, “Induction of the Differentiation and Apoptosis of Tumor Cells in Vivo with Efficiency and Selectivity,” European Journal of Dermatology 14, no. 2 (April 2004): 96–102. [http://www.ncbi.nlm.nih.gov/pubmed/15196999]
another hedgehog inhibitor: “FDA Approval for Vismodegib,” National Cancer Institute. [http://www.cancer.gov/cancertopics/druginfo/fda-vismodegib]
might help control the genetic switches: More specifically, Dmrt5 is a transcription factor, a molecule that binds to the genome and regulates the output of a gene.
“zinc fingers,” “Dmrt5,” and “Emma Farley”: Emma K. Farley et al., “Novel Transcription Factor Involved in Neurogenesis,” Developmental Biology 344, no. 1 (2010): 493. [http://www.researchgate.net/publication/47383131_Novel_transcription_factor_involved_in_neurogenesis]
so many new scraps of information: Venugopala Reddy Bommireddy Venkata, Cordelia Rauskolb, and Kenneth D. Irvine, “Fat-Hippo Signaling Regulates the Proliferation and Differentiation of Drosophila Optic Neuroepithelia,” Developmental Biology 344, no. 1 (2010): 506 [http://www.researchgate.net/publication/47383178_Fat-Hippo_signaling_regulates_the_proliferation_and_differentiation_of_Drosophila_optic_neuroepithelia]; and Thomas L. Gallagher and Joshua Arribere, “Fox1 and Fox4 Regulate Muscle-specific Splicing in Zebrafish and Are Required for Cardiac and Skeletal Muscle Functions,” Developmental Biology 344, no. 1 (2010): 491–92. [http://www.researchgate.net/publication/47383123_Fox1_and_Fox4_regulate_muscle-specific_splicing_in_zebrafish_and_are_required_for_cardiac_and_skeletal_muscle_functions]
a whimsical turn: Cristina L. Walcher and Jennifer L. Nemhauser, “1 + 1 = 3: When Two Hormones Are Better Than One,” Developmental Biology 344, no. 1 (2010): 487; [http://www.researchgate.net/publication/47383110_113_When_two_hormones_are_better_than_one] and Nowlan Freese and Susan C. Chapman, “Where’d My Tail Go?” Developmental Biology 344, no. 1 (2010): 441. [http://www.researchgate.net/publication/47382941_Where’d_my_tail_go]
six little words: The full title was “How Heart Cells Embrace Their Fate in the Chordate Ciona Intestinalis” by Stacia Ilchena and James Cooley, Developmental Biology 344, no. 1 (2010): 502–3. [http://www.researchgate.net/publication/47383162_How_heart_cells_embrace_their_fate_in_the_chordate_Ciona_intestinalis]
CHAPTER 7 Where Cancer Really Comes From
excavating a canal: Love Canal’s history is described in Allan Mazur, A Hazardous Inquiry: The Rashomon Effect at Love Canal (Cambridge, MA: Harvard University Press, 1998), 8–15.
some 22,000 tons of toxic waste: “Love Canal: A Special Report to the Governor & Legislature,” April 1981, New York Department of Health website. [http://www.health.state.ny.us/environmental/investigations/love_canal/lcreport.htm]
“The odors penetrate your clothing”: “Chemical Waste at Love Canal, October 18, 1977,” Ecumenical Task Force of the Niagara Frontier Records, 1946–1995 (MS 65), University at Buffalo Libraries, Love Canal Collections website. [http://library.buffalo.edu/specialcollections/lovecanal/collections/etf.php]
incorporated the saga into a novel: Joyce Carol Oates, The Falls: A Novel (New York: Ecco, 2004).
the EPA estimated: “U.S. Finds Risk of Cancer High for Residents Near Love Canal; Three Families Inside Fence,” New York Times, November 11, 1979.
admitted to a mathematical error: Irvin Molotsky, “Rep. LaFalce Says Draft Report Inflated Love Canal Cancer Risk; Mathematical Errors Conceded,” New York Times, November 20, 1979.
Another EPA report found: Irvin Molotsky, “Damage to Chromosomes Found in Love Canal Tests,” New York Times, May 17, 1980. The findings were in D. Picciano, “Pilot Cytogenetic Study of the Residents Living Near Love Canal, a Hazardous Waste Site, Mammalian Chromosome Newsletter 21 (1980): 86–93.
dismissed by a panel: Richard J. Meislin, “Carey Panel Discounts 2 Studies on Love Canal Health Problems,” New York Times, October 11, 1980.
A later study for the Centers for Disease Control: Clark W. Heath Jr. et al., “Cytogenetic Findings in Persons Living Near the Love Canal,” JAMA: The Journal of the American Medical Association 251, no. 11 (March 16, 1984): 1437–40. [http://jama.ama-assn.org/content/251/11/1437]
a thirty-year retrospective: “Love Canal Follow-up Health Study,” New York Department of Health website, October 2008. [http://www.health.ny.gov/environmental/investigations/love_canal/docs/report_public_comment_final.pdf] For a critique of the report see appendix T, “Public Comments and Responses, Love Canal Follow-up Health Study,” especially the comments by epidemiologist Richard Clapp, 145–47.
Almost half of the 6,026 residents: Demographic details are described in table 20, page 97 of the “Love Canal Follow-up.”
the birth defect rate: “Love Canal Follow-up,” 42–43. Altogether there were thirty-seven congenital malformations reported among 1,767 singleton births (those not including twins and triplets) between 1960 and 1996. For comparing incidence rates, the study counted only “consistently and reliably reported” cases as defined by the New York State Congenital Malformation Registry, which had complete records only beginning in 1983. Earlier information came from local hospitals and was not considered solid enough to use in the comparisons. (See pages 29–30 of the report for details. Also see table 19, page 96, and appendix A on page 103.)
higher than for the rest of the state: That excluded New York City.
slightly more girls had been born: “Love Canal Follow-up,” 41–43.
no convincing evidence: “Love Canal Follow-up,” 2.
Rachel Carson’s elegant warning: Silent Spring (Boston: Houghton Mifflin Company, 1962).
scathing polemics: Samuel S. Epstein, The Politics of Cancer (San Francisco: Sierra Club Books, 1978) and The Politics of Cancer Revisited (Fremont Center, NY: East Ridge Press, 1998).
a modern epidemic of cancer: The historian Robert N. Proctor captures the zeitgeist in Cancer Wars: How Politics Shapes What We Know and Don’t Know About Cancer (New York: Basic Books, 1995). See particularly 54–74.
“the plague of the twentieth century”: Epstein, Politics of Cancer Revisited, 14.
“a grim game of chemical roulette”: Russell Train in a speech to the National Press Club, February 26, 1976. The story was picked up by the Associated Press and appeared the next day in newspapers, including The Morning Record (Meriden, CT) and the Sarasota Herald-Tribune. [http://news.google.com/newspapers?nid=2512&dat=19760227&id=_KNHAAAAIBAJ&sjid=d_8MAAAAIBAJ&pg=1388,3515703]
“the Great Cancer Wars”: Proctor, Cancer Wars, 74.
Ninety percent of cancer is environmental: For an account of the origin of the misconception, see Proctor, Cancer Wars, 55–57; and (keeping in mind its libertarian bias) Edith Efron, Apocalyptics: Cancer and the Big Lie: How Environmental Politics Controls What We Know About Cancer (New York: Simon & Schuster, 1984), 429–32.
known and suspected agents: See National Toxicology Program, Report on Carcinogens, 12th ed. (Research Triangle Park, NC: U.S. Department of Health and Human Services, 2011). [http://ntp-server.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15]
To get a sense of how strongly cancer was influenced: The migrant studies are summarized in R. Doll and R. Peto, “The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today,” Journal of the National Cancer Institute 66, no. 6 (June 1981): 1191–1308, reference on 1200–01; Proctor, Cancer Wars, 24–26; and Efron, Apocalyptics, 430–32.
seemed to be escalating abruptly: The numbers were published in Earl S. Pollack and John W. Horm, “Trends in Cancer Incidence and Mortality in the United States, 1969–76,” Journal of the National Cancer Institute 64, no. 5 (May 1, 1980): 1091–103 [http://jnci.oxfordjournals.org/content/64/5/1091]; and in Toxic Chemicals and Public Protection: A Report to the President by the Toxic Substances Strategy Committee (Washington, DC: Council on Environmental Quality, May 1980), which is available online through the Hathi Trust Digital Library. [http://catalog.hathitrust.org/Record/007413257]
appeared to be the vindication: For a description of the controversy see Doll and Peto, “Causes of Cancer,” 1279–81; and Efron, Apocalyptics, 434–36.
warned that the comparisons were invalid: Doll and Peto, “Causes of Cancer,” 1280–81; and Efron, Apocalyptics, 435.
accomplished scientists in their field: Doll’s later work was called into question when it was revealed after his death that he had accepted consulting fees from chemical companies. In defending his colleague, Peto said that Doll was open about the connections and gave the money to Green College, Oxford, which he helped found. See Sarah Boseley, “Renowned Cancer Scientist Was Paid by Chemical Firm for 20 Years,” The Guardian, December 7, 2006. [http://www.guardian.co.uk/science/2006/dec/08/smoking.frontpagenews] In the letters section of the next day’s edition other prominent scientists defended Doll’s impartiality (see “Richard Doll Still Deserves Our Respect”). [http://www.guardian.co.uk/science/2006/dec/09/guardianletters?intcmp=239] They included the chief executive of the Medical Research Council, the director of Wellcome Trust, and Martin Rees, the president of the Royal Society.
which numbers to trust: Doll and Peto, “Causes of Cancer,” appendix C, 1270–81.
The situation improved: Doll and Peto, “Causes of Cancer,” 1281.
In 30 percent of cancer deaths, tobacco was a cause: Doll and Peto, “Causes of Cancer,” table 20, 1256.
“most of the types of cancer that are common today”: Doll and Peto, “Causes of Cancer,” 1212.
Any specific case of cancer will have multiple causes: For the dilemmas involved in sorting out the environmental and genetic factors of a disease, see Kenneth J. Rothman and Sander Greenland, “Causation and Causal Inference in Epidemiology,” American Journal of Public Health 95 suppl. 1 (2005): S144–50. [http://www.ncbi.nlm.nih.gov/pubmed/16030331]
They were a component: For a recent assessment see Paolo Boffetta and Fredrik Nyberg, “Contribution of Environmental Factors to Cancer Risk,” BMJ: British Medical Journal 68, no. 1 (December 1, 2003): 71–94 [http://bmb.oxfordjournals.org/content/68/1/71.abstract]; and Richard W. Clapp and Molly M. Jacobs, “Environmental and Occupational Causes of Cancer: New Evidence, 2005–2007,” October 2007, Lowell Center for Sustainable Production website. [http://www.sustainableproduction.org/downloads/EnvandOccCausesofCancer-2007Update-DownloadVersion.pdf]
“there is too much ignorance”: Doll and Peto, “Causes of Cancer,” 1251.
cancer mortality among people under sixty-five: Doll and Peto, “Causes of Cancer,” 1256. For details see 1281–85 and tables D1 and D3.
largely true for older Americans: Doll and Peto, “Causes of Cancer,” 1256. See table D2 for the overall rate and D4 for specific cancers. There appeared to be an increase in brain cancer deaths and smaller increases in other nonrespiratory cancers, but the authors attributed these mostly to better record keeping.
not because we were getting much better: Doll and Peto, “Causes of Cancer,” 1256.
Two smaller studies: J. Higginson and C. S. Muir, “Environmental Carcinogenesis: Misconceptions and Limitations to Cancer Control,” Journal of the National Cancer Institute 63, no. 6 (December 1979): 1291–98; [http://www.ncbi.nlm.nih.gov/pubmed/390201] and E. L. Wynder and G. B. Gori, “Contribution of the Environment to Cancer Incidence: An Epidemiologic Exercise,” Journal of the National Cancer Institute 58, no. 4 (April 1977): 825–32. [http://www.ncbi.nlm.nih.gov/pubmed/321795]
began challenging the report: Samuel S. Epstein and Joel B. Swartz, “Fallacies of Lifestyle Cancer Theories,” Nature 289, no. 5794 (January 15, 1981): 127–30. [http://www.nature.com/nature/journal/v289/n5794/abs/289127a0.html]
When lung cancer rates began rising: David G. Hoel, Devra L. Davis, et al., “Trends in Cancer Mortality in 15 Industrialized Countries, 1969–1986,” Journal of the National Cancer Institute 84, no. 5 (March 4, 1992): 313–20. [http://jnci.oxfordjournals.org/content/84/5/313.abstract]
While epidemiologists kept watch: Bruce Ames’s story is told in Proctor, Cancer Wars, 136–52.
the Ames test: Bruce N. Ames et al., “Carcinogens Are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection,” Proceedings of the National Academy of Sciences 70, no. 8 (August 1973): 2281–85. [http://www.pnas.org/content/70/8/2281.abstract]
By killing esophagus cells: Alcohol may also increase cancer risk by breaking down into carcinogenic acetaldehyde and through other mechanisms. For a summary see “Alcohol Use and Cancer,” American Cancer Society website, last revised January 27, 2012. [http://www.cancer.org/Cancer/CancerCauses/DietandPhysicalActivity/alcohol-use-and-cancer]
a paper in Science: B. N. Ames, “Dietary Carcinogens and Anticarcinogens,” Science 221, no. 4617 (September 23, 1983): 1256–64. [http://www.ncbi.nlm.nih.gov/pubmed/6351251]
In 1997, he reported: B. N. Ames and L. S. Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer: Misconceptions,” FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 11, no. 13 (November 1997): 1041–52. [http://www.ncbi.nlm.nih.gov/pubmed/9367339]
In fact he doubted: Ames and Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer.”
Half of everything tested: B. N. Ames and L. S. Gold, “Chemical Carcinogenesis: Too Many Rodent Carcinogens,” Proceedings of the National Academy of Sciences 87, no. 19 (October 1990): 7772–76. [http://www.pnas.org/content/87/19/7772.abstract]
an experiment costing tens of millions of dollars: Cancer and the Environment (Washington, DC: U.S. Department of Health and Human Services, March 2003), 25.
mitogenesis increases mutagenesis: Ames and Gold, “Chemical Carcinogenesis.”
Toxicologists defended the tests: P. J. Infante, “Prevention Versus Chemophobia: A Defence of Rodent Carcinogenicity Tests,” Lancet 337, no. 8740 (March 1991): 538–40; [http://www.lancet.com/journals/lancet/article/PII0140-6736(91)91310-Q/fulltext] P. F. Infante, “Use of Rodent Carcinogenicity Test Results for Determining Potential Cancer Risk to Humans,” Environmental Health Perspectives 101, suppl. 5 (December 1993): 143–48 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519448]; and I. Bernard Weinstein, “Cell Proliferation: Concluding Remarks,” Environmental Health Perspectives 101, suppl. 5 (December 1993): 159–61. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1519446]
diverting attention from a genuine problem: See, for example, Clapp and Jacobs, “Environmental and Occupational Causes of Cancer”; Devra Lee Davis and Joel Schwartz, “Trends in Cancer Mortality: U.S. White Males and Females, 1968–83,” Lancet 331 (March 1988): 633–36 [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(88)91426-2/abstract]; and Devra Davis, The Secret History of the War on Cancer (New York: Basic Books, 2007).
recent report by a White House advisory group: Reducing Environmental Cancer Risk: What We Can Do Now, 2008–2009 Annual Report (Washington, DC: National Cancer Institute, April 2010). [http://deainfo.nci.nih.gov/advisory/pcp/annualreports/pcp08-09rpt/PCP_Report_08-09_508.pdf]
The alternative would be to administer: Reducing Environmental Cancer Risk, 11.
“has been grossly underestimated”: Reducing Environmental Cancer Risk, introductory letter, unpaginated.
many scientists criticized the report: David C. Holzman, “President’s Cancer Panel Stirs Up Environmental Health Community,” Journal of the National Cancer Institute 102, no. 15 (August 4, 2010): 1106–13. [http://jnci.oxfordjournals.org/content/early/2010/07/28/jnci.djq297.extract]
The National Academy of Sciences has described: “Toxicity Testing in the 21st Century: A Vision and a Strategy (Washington, DC: National Academies Press, 2007). These ideas are beginning to be embodied in the Environmental Protection Agency’s Computational Toxicology Research program. [http://epa.gov/ncct]
death rates from cancer did rise gradually: Ahmedin Jemal et al., “Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels,” Journal of the National Cancer Institute (January 7, 2013). See table 2. A summary with a link to the full report is available on the National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results) website. [http://seer.cancer.gov/report_to_nation]
began decreasing modestly: Adjusted for age, overall cancer mortality was about 199 people per 100,000 in 1975. Ten years later it was 211. By 2009, the latest year for which statistics have been tabulated, it had dropped to 173. See N. Howlader et al., eds., “SEER Cancer Statistics Review,” 1975–2009 (Vintage 2009 Populations), National Cancer Institute, Bethesda, MD, based on November 2011 SEER data submission, posted to the SEER website, 2012. [http://seer.cancer.gov/csr/1975_2009_pops09] The mortality details are in table 2.6 and incidence details in table 2.5. [http://seer.cancer.gov/csr/1975_2009_pops09/browse_csr.php]
Incidence rates tell a similar story: The 2012 report, cited earlier, doesn’t break down the rates so finely. I used table 1 of an earlier annual report: Brenda K. Edwards et al., “Annual Report to the Nation on the Status of Cancer, 1975–2006, Featuring Colorectal Cancer Trends and Impact of Interventions,” Cancer 116, no. 3 (2010): 544–73. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.24760/full]
lack of exercise and excess weight are far more to blame: The American Association for Cancer Research progress report for 2012 attributes 33 percent of cancer to tobacco, 20 percent to excess weight and obesity, 5 percent to lack of exercise, and just 5 percent to diet (figure 9, page 9). The report is on the AACR’s Cancer Progress website. [http://cancerprogressreport.org] The source of the AACR’s numbers is 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]
A twenty-five-year retrospective: Graham A. Colditz, Thomas A. Sellers, and Edward Trapido, “Epidemiology—Identifying the Causes and Preventability of Cancer?” Nature Reviews Cancer 6, no. 1 (January 2006): 75–83. [http://www.ncbi.nlm.nih.gov/pubmed/16372016]
found comparable numbers: “Attributable Causes of Cancer in France in the year 2000,” International Agency for Research on Cancer website. [http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk3/index.php]
neighborhood cancer clusters: K. J. Rothman, “A Sobering Start for the Cluster Busters’ Conference,” American Journal of Epidemiology 132, no. 1 suppl. (July 1990): S6–13 [http://aje.oxfordjournals.org/content/132/supp1/6.full.pdf+html]; and Raymond Richard Neutra, “Counterpoint from a Cluster Buster,” American Journal of Epidemiology 132, no. 1 (July 1, 1990): 1–8. [http://aje.oxfordjournals.org/content/132/1/1.full.pdf] Also see Atul Gawande, “The Cancer Cluster Myth,” New Yorker, February 8, 1999. For an evocative account of a cancer cluster investigation and the lessons learned, see Dan Fagin, Toms River: A Story of Science, Folly and Redemption (New York: Random House, 2013).
even occupational clusters are uncommon: For an assessment see P. A. Schulte et al., “Investigation of Occupational Cancer Clusters: Theory and Practice,” American Journal of Public Health 77, no. 1 (January 1987): 52–56. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1646814]
the same patterns are appearing: Ahmedin Jemal et al., “Global Cancer Statistics,” CA: A Cancer Journal for Clinicians 61, no. 2 (2011): 69–90; [http://onlinelibrary.wiley.com/doi/10.3322/caac.20107/abstract] P. Boyle and B. Levin, eds., World Cancer Report 2008 (Lyon: International Agency for Research on Cancer, 2008); [http://www.iarc.fr/en/publications/pdfs-online/wcr/2008] and 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). Also see D. Max Parkin et al., “Global Cancer Statistics, 2002,” CA: A Cancer Journal for Clinicians 55, no. 2 (February 24, 2009): 74–108. [http://onlinelibrary.wiley.com/doi/10.3322/canjclin.55.2.74/abstract]
reverse smoking: J. J. Pindborg et al., “Reverse Smoking in Andhra Pradesh, India: A Study of Palatal Lesions Among 10,169 Villagers,” British Journal of Cancer 25, no. 1 (March 1971): 10–20. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2008558]
unpacking the most recent SEER statistics: Howlader et al., eds., “SEER Cancer Statistics Review.” For the highlights see Jemal et al., “Annual Report to the Nation.” I also referred to an earlier report, Betsy A. Kohler et al., “Annual Report to the Nation on the Status of Cancer, 1975–2007, Featuring Tumors of the Brain and Other Nervous System,” Journal of the National Cancer Institute 103, no. 9 (May 4, 2011), 1–23. [http://www.ncbi.nlm.nih.gov/pubmed/21454908]
a decline or leveling off: Jemal et al., “Annual Report to the Nation.”
12.1 cases per 100,000, compared with 62.6: Howlader et al., eds., “SEER Cancer Statistics Review,” table 1.4.
Childhood cancers are among the very rarest: Howlader et al., eds., “SEER Cancer Statistics Review,” table 28.1.
Death rates … have fallen to about half: Howlader et al., eds., “SEER Cancer Statistics Review,” table 1.2.
the numbers jump all over the place: Howlader et al., eds., “SEER Cancer Statistics Review,” table 28.2. The figures are for children age fourteen and under. Also see Trevor Butterworth, “Is Childhood Cancer Becoming More Common?” May 28, 2010, Research at Statistical Assessment Service (STATS) website, George Mason University. [http://stats.org/stories/2010/childhood_cancer_may28_10.html]
Every cancer tells a different story: For summaries, see Jemal et al. and the American Cancer Society’s annual reports, “Cancer Facts & Figures,” on the group’s website.
What may appear to be a climb: Martha S. Linet et al., “Cancer Surveillance Series: Recent Trends in Childhood Cancer Incidence and Mortality in the United States,” Journal of the National Cancer Institute 91, no. 12 (June 16, 1999): 1051–58. [http://jnci.oxfordjournals.org/content/91/12/1051.abstract] Also see “Childhood Cancers,” National Cancer Institute website, reviewed January 10, 2008 [http://www.cancer.gov/cancertopics/factsheet/Sites-Types/childhood]; and Butterworth, “Is Childhood Cancer Becoming More Common?”
prostate, lung, colorectal … are all higher: Howlader et al., eds., “SEER Cancer Statistics Review,” tables 1.5 and 1.6.
less cancer than blacks or whites: Howlader et al., eds., “SEER Cancer Statistics Review,” table 2.5.
the incidence of brain cancer: Howlader et al., eds., “SEER Cancer Statistics Review,” table 3.16.
For liver cancer Hawaii tops out: Howlader et al., eds., “SEER Cancer Statistics Review,” table 14.16.
“Nature and nurture affect the probability”: Doll and Peto, “Causes of Cancer,” 1204.
CHAPTER 8 “Adriamycin and Posole for Christmas Eve”
Among the chemicals: National Toxicology Program, Report on Carcinogens, 12th ed. (Research Triangle Park, NC: U.S. Department of Health and Human Services, 2011). [http://ntp-server.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15]
First synthesized in 1844: Michele Peyrone, “Ueber Die Einwirkung Des Ammoniaks Auf Platinchlorür,” Justus Liebigs Annalen Der Chemie 51, no. 1 (January 27, 2006): 1–29. [http://onlinelibrary.wiley.com/doi/10.1002/jlac.18440510102/abstract] For a short biography of the discoverer, see George B. Kauffman et al., “Michele Peyrone (1813–1883), Discoverer of Cisplatin,” Platinum Metals Review 54, no. 4 (Oct 2010): 250–56. [http://www.platinummetalsreview.com/article/54/4/250-256]
how cells behaved in the presence of electricity: Barnett Rosenberg, Loretta Van Camp, and Thomas Krigas, “Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode,” Nature 205, no. 4972 (February 13, 1965): 698–99. [http://www.nature.com/nature/journal/v205/n4972/abs/205698a0.html] Also see Gregory A. Petsko, “A Christmas Carol,” Genome Biology 3, no. 1 (2002) [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC150444]; and Rebecca A. Alderden, Matthew D. Hall, and Trevor W. Hambley, “The Discovery and Development of Cisplatin,” Journal of Chemical Education 83 (2006): 728. [http://pubs.acs.org/doi/abs/10.1021/ed083p728]
“God, you don’t often find things like that”: “Interview with Barnett Rosenberg,” Sesquicentennial Oral History Project contributor, available online at Michigan State University Archives and Historical Collections, February 2, 2001. [http://onthebanks.msu.edu/sohp/Object/2-D-E9/barnett-rosenberg]
Rosenberg went on to test the molecule’s effects: Barnett Rosenberg, Loretta Vancamp, et al., “Platinum Compounds: A New Class of Potent Antitumour Agents,” Nature 222, no. 5191 (April 26, 1969): 385–86. [http://www.nature.com/nature/journal/v222/n5191/abs/222385a0.html]
scientists discovered how that works: See, for example, Huifang Huang et al., “Solution Structure of a Cisplatin-Induced DNA Interstrand Cross-Link,” Science 270, no. 5243 (December 15, 1995): 1842–45. [http://www.sciencemag.org/content/270/5243/1842.abstract] For a review of chemotherapy drugs and crosslinking, see Andrew J. Deans and Stephen C. West, “DNA Interstrand Crosslink Repair and Cancer,” Nature Reviews Cancer 11, no. 7 (July 2011): 467–80 [http://www.nature.com/nrc/journal/v11/n7/abs/nrc3088.html]; and Laurence H. Hurley, “DNA and Its Associated Processes as Targets for Cancer Therapy,” Nature Reviews Cancer 2, no. 3 (March 2002): 188–200. [http://www.nature.com/nrc/journal/v2/n3/full/nrc749.html]
the penicillin of cancer: Stephen Trzaska, “Cisplatin,” Chemical and Engineering News 83, no. 25 (2005): 3. [http://pubs.acs.org/cen/coverstory/83/8325/8325cisplatin.html]
sickening side effects: “Cisplatin,” American Cancer Society website, last revised January 14, 2010. [http://www.cancer.org/Treatment/TreatmentsandSideEffects/GuidetoCancerDrugs/CISPLATIN]
Doxorubicin has its own curious tale: Klaus Mross, Ulrich Massing, and Felix Kratz, “DNA-Intercalators—The Anthracyclines,” in H. M. Pinedo and Carolien Smorenburg, eds., Drugs Affecting Growth of Tumours (Basel, Boston: Birkhäuser Verlag, 2006), 19. [http://books.google.com/books?id=iM6t34xl7wQC]
push down your white blood cell count: “Doxorubicin,” American Cancer Society website, last revised November 7, 2011. [http://www.cancer.org/Treatment/TreatmentsandSideEffects/GuidetoCancerDrugs/doxorubicin]
reports that the risk increases: Giorgio Minotti et al., “Paclitaxel and Docetaxel Enhance the Metabolism of Doxorubicin to Toxic Species in Human Myocardium,” Clinical Cancer Research 7, no. 6 (June 1, 2001): 1511–15. [http://clincancerres.aacrjournals.org/content/7/6/1511.abstract]
Paclitaxel (or Taxol) was originally isolated: Frank Stephenson, “A Tale of Taxol,” Research in Review, Fall 2002, available online at the Florida State University Office of Research website. [http://www.rinr.fsu.edu/fall2002/taxol.html]
The first chemo agents: Alfred Gilman and Frederick S. Philips, “The Biological Actions and Therapeutic Applications of the B-Chloroethyl Amines and Sulfides,” Science 103, no. 2675 (April 5, 1946): 409–36. [http://www.sciencemag.org/content/103/2675/409.extract] For more about the story, see Vincent T. DeVita and Edward Chu, “A History of Cancer Chemotherapy,” Cancer Research 68, no. 21 (November 1, 2008): 8643–53 [http://cancerres.aacrjournals.org/content/68/21/8643.abstract]; and Bruce A. Chabner and Thomas G. Roberts. “Chemotherapy and the War on Cancer,” Nature Reviews Cancer 5, no. 1 (January 1, 2005): 65–72. [http://www.nature.com/nrc/journal/v5/n1/abs/nrc1529.html]
covered under the 1993 Chemical Weapons Convention: Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction (New York: Organisation for the Prohibition of Chemical Weapons, 2005). Available on the OPCW website. [http://www.opcw.org/chemical-weapons-convention]
“UPSC has a propensity”: Alessandro D. Santin et al., “Trastuzumab Treatment in Patients with Advanced or Recurrent Endometrial Carcinoma Overexpressing HER2/neu,” International Journal of Gynecology & Obstetrics 102 (August 2008): 128–31. [http://www.ncbi.nlm.nih.gov/pubmed/18555254]
a cancer of older, thinner women: David M. Boruta II et al., “Management of Women with Uterine Papillary Serous Cancer,” Gynecologic Oncology 115 (2009): 142–53 [http://www.ncbi.nlm.nih.gov/pubmed/19592079]; Amanda Nickles Fader et al., “An Updated Clinicopathologic Study of Early-stage Uterine Papillary Serous Carcinoma (UPSC),” Gynecologic Oncology 115, no. 2 (November 2009): 244–48 [http://www.medscape.org/viewarticle/711270]; C. A. Hamilton et al., “Uterine Papillary Serous and Clear Cell Carcinomas Predict for Poorer Survival Compared to Grade 3 Endometrioid Corpus Cancers,” British Journal of Cancer 94, no. 5 (March 13, 2006): 642–46; [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361201] Sunni Hosemann, “Early Uterine Papillary Serous Carcinoma: Treatment Options Tailored to Patient and Disease Characteristics,” OncoLog 50, nos. 4–5 (April–May 2010): 4-6; [http://www2.mdanderson.org/depts/oncolog/articles/10/4-5-aprmay/4-5-10-compass.html] and Carsten Gründker, Andreas R. Günthert, and Günter Emons, “Hormonal Heterogeneity of Endometrial Cancer,” in Lev M. Berstein and Richard J. Santen, eds., Innovative Endocrinology of Cancer, vol. 630 of Advances in Experimental Medicine and Biology (New York, NY: Springer, 2008), 166–88. [http://www.springerlink.com/content/r086275l87307hj4]
“There are no risk factors”: Felice Lackman and Peter Craighead, “Therapeutic Dilemmas in the Management of Uterine Papillary Serous Carcinoma,” Current Treatment Options in Oncology 4, no. 2 (2003): 99–104.
as few as 5 to 10 percent: Boruta et al., “Management of Women with Uterine Papillary Serous Cancer.” Also see Brij M. Sood et al., “Patterns of Failure After the Multimodality Treatment of Uterine Papillary Serous Carcinoma,” International Journal of Radiation Oncology, Biology, Physics 57, no. 1 (September 1, 2003): 208–16 [http://www.ncbi.nlm.nih.gov/pubmed/12909235]; and Hadassah Goldberg et al., “Outcome After Combined Modality Treatment for Uterine Papillary Serous Carcinoma: A Study by the Rare Cancer Network,” Gynecologic Oncology 108, no. 2 (February 2008): 298–305. [https://www.ncbi.nlm.nih.gov/pubmed/18096209] firstname.lastname@example.org
I found an essay: S. J. Gould, “The Median Isn’t the Message,” Discover 6 (June 1985): 40–42. [http://cancerguide.org/median_not_msg.html]
“All evolutionary biologists know”: Gould, “The Median Isn’t the Message.”
Should she be getting topotecan?: Robert W. Holloway, “Treatment Options for Endometrial Cancer: Experience with Topotecan,” part 2, Gynecologic Oncology 90, no. 3 (September 2003): S28–33. [http://www.ncbi.nlm.nih.gov/pubmed/13129493]
He attached abstracts from three papers: Holly H. Gallion et al., “Randomized Phase III Trial of Standard Timed Doxorubicin Plus Cisplatin Versus Circadian Timed Doxorubicin Plus Cisplatin in Stage III and IV or Recurrent Endometrial Carcinoma,” Journal of Clinical Oncology 21, no. 20 (October 15, 2003): 3808–13; [http://www.ncbi.nlm.nih.gov/pubmed/14551299] David Scott Miller et al., “A Phase II Trial of Topotecan in Patients with Advanced, Persistent, or Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study,” Gynecologic Oncology 87, no. 3 (December 2002): 247–51; [http://www.ncbi.nlm.nih.gov/pubmed/12468321] and Scott Wadler et al., “Topotecan Is an Active Agent in the First-line Treatment of Metastatic or Recurrent Endometrial Carcinoma,” Journal of Clinical Oncology 21, no. 11 (June 1, 2003): 2110–14. [http://www.ncbi.nlm.nih.gov/pubmed/12775736]
Nancy’s oncologist gave us a paper: Alessandro D. Santin, “HER2/neu Overexpression: Has the Achilles’ Heel of Uterine Serous Papillary Carcinoma Been Exposed?” Gynecologic Oncology 88, no. 3 (March 2003): 263–65. [http://www.ncbi.nlm.nih.gov/pubmed/12648572]
receptors that respond to human epidermal growth factors: The mechanism is a little more convoluted than is often described. See “Targeted Therapies for Breast Cancer Tutorial: Inhibition of HER2,” National Cancer Institute website. [http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/breastcancer_htmlcourse/page3]
It is usually just called HER2: The awkward name came about after two laboratories discovered the gene independently (in humans and in rats): Alan L. Schechter, Robert A. Weinberg, et al., “The Neu Oncogene: An erb-B-related Gene Encoding a 185,000-Mr Tumour Antigen,” Nature 312, no. 5994 (December 6, 1984): 513–16 [http://www.nature.com/nature/journal/v312/n5994/abs/312513a0.html]; and A. Ullrich et al., “Human Epidermal Growth Factor Receptor cDNA Sequence and Aberrant Expression of the Amplified Gene in A431 Epidermoid Carcinoma Cells,” Nature 309, no. 5967 (June 31, 1984): 418–25. [http://www.nature.com/nature/journal/v309/n5967/abs/309418a0.html]
A drug called Herceptin: The story of its development is told in Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998).
His name had been mentioned in an episode of The West Wing: Lawrence K. Altman, MD, “Very Real Questions for Fictional President,” Doctor’s World, New York Times, October 9, 2001. [http://www.nytimes.com/2001/10/09/health/the-doctor-s-world-very-real-questions-for-fictional-president.html]
CHAPTER 9 Deeper into the Cancer Cell
neatly described by two scientists: D. Hanahan and R. A. Weinberg, “The Hallmarks of Cancer,” Cell 100, no. 1 (January 7, 2000): 57–70. [http://www.ncbi.nlm.nih.gov/pubmed/10647931]
The idea … goes back decades: C. O. Nordling, “A New Theory on the Cancer-inducing Mechanism,” British Journal of Cancer 7, no. 1 (March 1953): 68–72. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007872] Nordling argued that the need for multiple mutations explains why cancer becomes increasingly frequent with age: “If two mutations were required, the frequency of cancer should increase in direct proportion to age.…If three mutations were required, a cancer frequency proportional to the second power of age might be expected, with four mutations to the third power of age, and so on.” Peter Nowell is often given credit for the first clear description of the idea of cancer as a Darwinian process in “The Clonal Evolution of Tumor Cell Populations,” Science 194, no. 4260 (October 1, 1976): 23–28. [http://www.sciencemag.org/content/194/4260/23.abstract] The theory was put on solid footing with landmark experiments on colorectal cancer. See Bert Vogelstein et al., “Genetic Alterations During Colorectal-tumor Development,” New England Journal of Medicine 319, no. 9 (September 1, 1988): 525–32. [http://www.ncbi.nlm.nih.gov/pubmed/2841597]
“For decades now”: Hanahan and Weinberg, “The Hallmarks of Cancer” (italics added).
don’t necessarily have to occur through mutations: The seminal paper on epigenetics is Andrew P. Feinberg and Bert Vogelstein, “Hypomethylation Distinguishes Genes of Some Human Cancers from Their Normal Counterparts,” Nature 301, no. 5895 (January 6, 1983): 89–92. [http://www.nature.com/nature/journal/v301/n5895/abs/301089a0.html] For a historical overview see Andrew P. Feinberg and Benjamin Tycko, “The History of Cancer Epigenetics,” Nature Reviews Cancer 4, no. 2 (February 2004): 143–53. [http://www.ncbi.nlm.nih.gov/pubmed/14732866] Epigenetic changes in germ cells—sperm or eggs—might even be passed from parent to child, though the significance of that is uncertain.
found to be mutated in different cancers: Päivi Peltomäki, “Mutations and Epimutations in the Origin of Cancer,” Experimental Cell Research 318, no. 4 (February 15, 2012): 299–310. [http://www.ncbi.nlm.nih.gov/pubmed/22182599]
proposed that cancer actually begins with epigenetic disruptions: Andrew P. Feinberg, Rolf Ohlsson, and Steven Henikoff, “The Epigenetic Progenitor Origin of Human Cancer,” Nature Reviews Genetics 7, no. 1 (January 2006): 21–33. [http://www.ncbi.nlm.nih.gov/pubmed/14732866]
a contentious idea called the cancer stem cell theory: Piyush B. Gupta, Christine L. Chaffer, and Robert A. Weinberg, “Cancer Stem Cells: Mirage or Reality?” Nature Medicine 15, no. 9 (2009): 1010–12; [http://www.nature.com/nm/journal/v15/n9/full/nm0909-1010.html] Jerry M. Adams and Andreas Strasser, “Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones?” Cancer Research 68, no. 11 (June 1, 2008): 4018–21; [http://cancerres.aacrjournals.org/content/68/11/4018.abstract] and Peter Dirks, “Cancer Stem Cells: Invitation to a Second Round,” Nature 466, no. 7302 (July 1, 2010): 40–41. [http://www.nature.com/nature/journal/v466/n7302/full/466040a.html] The basic idea was suggested as early as 1937 (J. Furth and M. C. Kahn, “The Transmission of Leukaemia of Mice with a Single Cell,” American Journal of Cancer 31 : 276–82), and cancer stem cells were identified in a blood cancer by Dominique Bonnet and John E. Dick: “Human Acute Myeloid Leukemia Is Organized as a Hierarchy That Originates from a Primitive Hematopoietic Cell,” Nature Medicine 3, no. 7 (July 1, 1997): 730–37. [http://www.nature.com/nm/journal/v3/n7/abs/nm0797-730.html]
the more confusing it seemed: For a taste of the controversy see John E. Dick, “Looking Ahead in Cancer Stem Cell Research,” Nature Biotechnology 27, no. 1 (January 2009): 44–46; [http://www.nature.com/nbt/journal/v27/n1/full/nbt0109-44.html] Elsa Quintana et al., “Efficient Tumour Formation by Single Human Melanoma Cells,” Nature 456, no. 7222 (December 4, 2008): 593–98 [http://www.nature.com/nature/journal/v456/n7222/abs/nature07567.html]; Priscilla N. Kelly et al., “Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells,” Science 317, no. 5836 (July 20, 2007): 337 [http://www.sciencemag.org/content/317/5836/337.abstract]; Richard P. Hill, “Identifying Cancer Stem Cells in Solid Tumors: Case Not Proven,” Cancer Research 66, no. 4 (February 15, 2006): 1891–96 [http://cancerres.aacrjournals.org/content/66/4/1891.abstract]; and Scott E. Kern and Darryl Shibata, “The Fuzzy Math of Solid Tumor Stem Cells: A Perspective,” Cancer Research 67, no. 19 (October 1, 2007): 8985–88. [http://www.ncbi.nlm.nih.gov/pubmed/17908998]
shed their identity and reverted: One hypothesis is that they would make the transformation through the epithelial-mensenchymal transformation, which is discussed in chapter 6 of this book.
the wave of the future: Three papers published in August 2012 set off a surge of publicity in favor of the theory along with a skeptical backlash. For a summary, including citations, see Monya Baker, “Cancer Stem Cells Tracked,” Nature 488, no. 7409 (August 2, 2012): 13–14.
the annual meeting: American Association for Cancer Research, 102nd Annual Meeting, “Innovation and Collaboration: The Path to Progress,” April 2–6, 2011, Orange County Convention Center, Orlando, Florida.
more than 16,000 scientists: “AACR Hosts Successful 102nd Annual Meeting in Orlando,” Previous Annual Meetings, AACR website. [http://www.aacr.org/home/scientists/meetings-workshops/aacr-annual-meeting-2013/previous-annual-meetings/annual-meeting-2011.aspx]
an amazing video flythrough: High-definition stills and videos in two and three dimensions are available on the Amgen website.[http://angiogenesis.amgen.com]
Amgen had been working on an angiogenesis inhibitor: Beth Y. Karlan et al., “Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined with Weekly Paclitaxel in Patients with Recurrent Ovarian Cancer,” Journal of Clinical Oncology 30, no. 4 (February 1, 2012): 362–71. [http://jco.ascopubs.org/content/30/4/362]
extended the lives: The technical term used in the study was “overall survival.”
“Judah is going to cure cancer”: Gina Kolata, “A Cautious Awe Greets Drugs That Eradicate Tumors in Mice, New York Times, May 3, 1998.
“remarkable and wonderful”: Kolata, “A Cautious Awe Greets Drugs.”
metastasizing more vigorously: Erika Check Hayden, “Cutting Off Cancer’s Supply Lines,” Nature News 458, no. 7239 (April 8, 2009): 686–87. [http://www.nature.com/news/2009/090408/full/458686b.html]
add a few months to a patient’s life: Avastin product page, Genentech website. [http://www.gene.com/gene/products/information/oncology/avastin]
the Food and Drug Administration … revoked approval: Andrew Pollack, “F.D.A. Revokes Approval of Avastin for Use as Breast Cancer Drug,” New York Times, November 18, 2011. [http://www.nytimes.com/2011/11/19/business/fda-revokes-approval-of-avastin-as-breast-cancer-drug.html]
standard chemotherapy was accompanied by Herceptin: Edward H. Romond et al., “Trastuzumab Plus Adjuvant Chemotherapy for Operable HER2-positive Breast Cancer,” New England Journal of Medicine 353, no. 16 (October 20, 2005): 1673–84. [http://www.ncbi.nlm.nih.gov/pubmed/16236738] Also see Luca Gianni et al., “Treatment with Trastuzumab for 1 Year After Adjuvant Chemotherapy in Patients with HER2-positive Early Breast Cancer: A 4-year Follow-up of a Randomised Controlled Trial,” Lancet Oncology 12, no. 3 (March 2011): 236–244. [http://www.lancet.com/journals/lanonc/article/PIIS1470-2045(11)70033-X/abstract]
Genentech could reduce the time to market: An early end to a clinical trial is not necessarily considered a good thing. See F. Trotta et al., “Stopping a Trial Early in Oncology: For Patients or for Industry?” Annals of Oncology 19, no. 7 (July 1, 2008): 1347–53 [http://annonc.oxfordjournals.org/content/19/7/1347.abstract]; Margaret McCartney, “Leaping to Conclusions,” BMJ: British Medical Journal 336, no. 7655 (May 31, 2008): 1213–14 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405859]; and Victor M. Montori et al., “Randomized Trials Stopped Early for Benefit: A Systematic Review,” JAMA: The Journal of the American Medical Association 294, no. 17 (November 2, 2005): 2203–9. [http://www.ncbi.nlm.nih.gov/pubmed/16264162]
a serious risk of congestive heart failure: A study of twelve thousand women who took Herceptin found that mortality from breast cancer was reduced by one-third but that there was a fivefold increase in the risk of cardiac toxicity. See Lorenzo Moja et al., “Trastuzumab Containing Regimens for Early Breast Cancer,” Cochrane Database of Systematic Reviews 2012, issue 4, article no. CD006243, published online April 18, 2012. [http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006243.pub2/abstract]
the “crowning achievement”: Scott A. Stuart, Yosuke Minami, and Jean Y. J. Wang, “The CML Stem Cell: Evolution of the Progenitor,” Cell Cycle 8, no. 9 (May 1, 2009): 1338–43. [http://www.ncbi.nlm.nih.gov/pubmed/19342894] For the story of Gleevec, see Terence Monmaney, “A Triumph in the War Against Cancer,” Smithsonian, May 2011. [http://www.smithsonianmag.com/science-nature/A-Victory-in-the-War-Against-Cancer.html]
by strengthening the body’s immunological defenses: For an overview see Ira Mellman, George Coukos, and Glenn Dranoff, “Cancer Immunotherapy Comes of Age,” Nature 480, no. 7378 (December 21, 2011): 480–89; [http://www.nature.com/nature/journal/v480/n7378/abs/nature10673.html] Drew M. Pardoll, “The Blockade of Immune Checkpoints in Cancer Immunotherapy,” Nature Reviews Cancer 12, no. 4 (April 2012): 252–64; [http://www.ncbi.nlm.nih.gov/pubmed/22437870] and David L. Porter et al., “Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia,” New England Journal of Medicine 365, no. 8 (August 10, 2011): 725–33.
the patient’s own immune cells are removed: In another approach, killed cancer cells are used to vaccinate patients against their own tumors in much the way that inactivated viruses are used to make influenza vaccines.
as precipitously as they have for heart disease?: Arialdi M. Miniño et al., “Deaths: Final Data for 2008,” National Vital Statistics Reports 59, no. 10 (December 7, 2011). See figure 6, page 9. [http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf]
losing the War on Cancer?: For a measured argument see Sharon Begley, “We Fought Cancer … And Cancer Won,” Newsweek, September 5, 2008. [http://www.thedailybeast.com/newsweek/2008/09/05/we-fought-cancer-and-cancer-won.html]
founder and chairman of the advisory board: Telome Health Inc. website. [http://www.telomehealth.com]
said that she had lost her slide: The speaker was Lynda Chin and the company is Aveo Oncology. Her husband is Ronald DePinho, who went on to become president of MD Anderson Cancer Center. In 2012 the couple was involved in a dispute over an $18 million grant. The details are reported in Meredith Wadman, “Texas Cancer Institute to Re-review Controversial Grant,” Nature News, May 31, 2012. [http://blogs.nature.com/news/2012/05/texas-cancer-institute-to-re-review-controversial-grant.html] Also see Meredith Wadman, “Texas Cancer-centre Head Apologizes for Promoting Stock on Television,” Nature News, June 1, 2012. [http://blogs.nature.com/news/2012/06/texas-cancer-centre-head-apologizes-for-promoting-stock-on-television.html]
“I really want this stuff to work”: Ervin J. Epstein, plenary talk, American Association for Cancer Research 102nd Annual Meeting, April 3, 2011. He also noted he had been a consultant for Genentech and Novartis and owned some stock in a company called Curis.
pioneering work on viruses and oncogenes: D. Stehelin, H. E. Varmus, J. M. Bishop, and P. K. Vogt, “DNA Related to the Transforming Gene(s) of Avian Sarcoma Viruses Is Present in Normal Avian DNA,” Nature 260, no. 5547 (March 11, 1976): 170–73. [http://dx.doi.org/10.1038/260170a0]
some of the most perplexing questions: Varmus was talking about the Provocative Questions project, which is described on the National Cancer Institute website. [http://provocativequestions.nci.nih.gov] Also see Harold Varmus and Ed Harlow, “Science Funding: Provocative Questions in Cancer Research,” Nature 481, no. 7382 (January 25, 2012): 436–37. [http://www.nature.com/nature/journal/v481/n7382/full/481436a.html]
cancer of the heart: Timothy J. Moynihan, “Heart Cancer: Is There Such a Thing?” Disease and Conditions, Mayo Clinic Health Information website, April 12, 2012. [http://www.mayoclinic.com/health/heart-cancer/AN01288]
the results have been surprising: Michael R. Stratton, Peter J. Campbell, and P. Andrew Futreal, “The Cancer Genome,” Nature 458, no. 7239 (April 9, 2009): 719–24; [http://dx.doi.org/10.1038/nature07943] and P. Andrew Futreal, Michael R. Stratton, et al., “A Census of Human Cancer Genes,” Nature Reviews Cancer 4, no. 3 (March 2004): 177–83. [http://dx.doi.org/10.1038/nrc1299]
hundreds of mutations may potentially be involved: For a particularly striking example, see H. Nikki March et al., “Insertional Mutagenesis Identifies Multiple Networks of Cooperating Genes Driving Intestinal Tumorigenesis,” Nature Genetics 43, no. 12 (2011): 1202–9. [http://www.ncbi.nlm.nih.gov/pubmed/22057237] Part of the challenge is distinguishing between “driver” and “passenger” mutations. See chapter 12 of this book for details.
the phenomenon of polarization: For the relationship to cancer see, for example, Minhui Lee and Valeri Vasioukhin, “Cell Polarity and Cancer—Cell and Tissue Polarity as a Non-canonical Tumor Suppressor,” Journal of Cell Science 121, no. 8 (April 15, 2008): 1141–50. [http://www.abstractsonline.com/Plan/ViewSession.aspx?sKey=8ca64139-76aa-4f7d-8389-af2402ba7613&mKey=%7b507D311A-B6EC-436A-BD67-6D14ED39622C%7d]
the many different kinds of cell death: Melanie M. Hippert, Patrick S. O’Toole, and Andrew Thorburn, “Autophagy in Cancer: Good, Bad, or Both?” Cancer Research 66, no. 19 (October 1, 2006): 9349–51; [http://cancerres.aacrjournals.org/content/66/19/9349.abs] Michael Overholtzer, Joan S. Brugge, et al., “A Nonapoptotic Cell Death Process, Entosis, That Occurs by Cell-in-Cell Invasion,” Cell 131, no. 5 (November 30, 2007): 966–79; [http://www.cell.com/abstract/S0092-8674(07)01394-3] and Peter Vandenabeele et al., “Molecular Mechanisms of Necroptosis: An Ordered Cellular Explosion,” Nature Reviews Molecular Cell Biology 11, no. 10 (October 1, 2010): 700–14. [http://www.nature.com/nrm/journal/v11/n10/abs/nrm2970.html]
the Warburg effect: The metabolic change, involving glycolysis, was described by Otto Warburg in “On the Origin of Cancer Cells,” Science 123, no. 3191 (February 24, 1956): 309–14. [http://www.sciencemag.org/content/123/3191/309] When carried out in the presence of oxygen, the process is called aerobic glycolysis. The result is increased consumption of glucose, which is why cancer cells light up in PET scans.
take in more of the raw material: Matthew G. Vander Heiden, Lewis C. Cantley, and Craig B. Thompson, “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation,” Science 324, no. 5930 (May 22, 2009): 1029–33. [http://www.sciencemag.org/content/324/5930/1029]
The slow burn of chronic inflammation: For a good overview see 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] More references are in my notes for chapter 10.
molecules called sirtuins: For a review see Finkel Toren, Chu-Xia Deng, and Raul Mostoslavsky, “Recent Progress in the Biology and Physiology of Sirtuins,” Nature 460, no. 7255 (July 30, 2009): 587–91. [http://www.ncbi.nlm.nih.gov/pubmed/19641587]
the genes residing in the microbes: Steven R. Gill et al., “Metagenomic Analysis of the Human Distal Gut Microbiome,” Science 312, no. 5778 (June 2, 2006): 1355–59. [http://www.sciencemag.org/content/312/5778/1355.short]
a Human Microbiome Project: Peter J. Turnbaugh et al., “The Human Microbiome Project,” Nature 449, no. 7164 (October 18, 2007): 804–10. [http://www.nature.com/nature/journal/v449/n7164/abs/nature06244.html]
“ ’omics”: Joshua Lederberg christened the microbiome, and in a short essay, “Ome Sweet ’Omics,” he commented on the naming phenomenon: The Scientist 15, no. 7 (April 2, 2001): 8. [http://lhncbc.nlm.nih.gov/lhc/docs/published/2001/pub2001047.pdf]
separate the ridiculome from the relevantome: I thought I had invented these words, but an Internet search turns them up in a PowerPoint presentation: Andrea Califano, Brian Athey, and Russ Altman, “Creating a DBP Community to Enhance the NCBC Biomedical Impact, A National Center for Biomedical Computing Work Group Report,” July 18, 2006, National Alliance for Medical Image Computing website. [http://www.na-mic.org/Wiki/images/5/52/Systems_WG7.ppt]
Horace Freeland Judson’s magnificent book: The Eighth Day of Creation: Makers of the Revolution in Biology, expanded ed. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1996).
microRNAs: Rosalind C. Lee, Rhonda L. Feinbaum, and Victor Ambros, “The C. elegans Heterochronic Gene lin-4 Encodes Small RNAs with Antisense Complementarity to lin-14,” Cell 75 (December 1993): 843–54. [http://www.ncbi.nlm.nih.gov/pubmed/8252621]
the importance … has been overblown: Harm van Bakel et al., “Most ‘Dark Matter’ Transcripts Are Associated with Known Genes,” PLOS Biology 8, no. 5 (May 18, 2010): e1000371; [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000371] and Richard Robinson, “Dark Matter Transcripts: Sound and Fury, Signifying Nothing?” PLOS Biology 8 (May 18, 2010): e1000370. [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000370]
a sweeping new theory: Leonardo Salmena, Pier Paolo Pandolfi, et al., “A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?” Cell 146, no. 3 (August 5, 2011): 353–58. The speaker was the lead author, Pier Paolo Pandolfi. [http://www.cell.com/abstract/S0092-8674(11)00812-9]
Junk that is not junk: Even more of the noncoding DNA appears to have found a purpose with the ENCODE project, whose results were announced with an extravagant multimedia website by the journal Nature. For an old-fashioned overview of the results see Consortium, The ENCODE Project, “An Integrated Encyclopedia of DNA Elements in the Human Genome,” Nature 489, no. 7414 (September 6, 2012): 57–74. Upon publication, a backlash ensued from scientists who thought the results, though important, were hyped. See John Timmer, “Most of What You Read Was Wrong: How Press Releases Rewrote Scientific History,” in the online publication Ars Technica, September 10, 2012.
had published a follow-up: Douglas Hanahan and Robert A Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (March 4, 2011): 646–74. [http://www.ncbi.nlm.nih.gov/pubmed/21376230] The ten-year anniversary of the original “Hallmarks” paper was taken as occasion for a critique: Yuri Lazebnik, “What Are the Hallmarks of Cancer?” Nature Reviews Cancer 10, no. 4 (April 1, 2010): 232–33. [http://www.nature.com/nrc/journal/v10/n4/full/nrc2827.html]
CHAPTER 10 The Metabolic Mess
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]
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]
“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]
“I have many times made the experiment”: Potts, The Chirurgical Works, 179.
Chimney sweeps on the European continent: Waldron, “A Brief History.”
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]
“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]
“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]
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]
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]
“The dogma was that cancer”: All quotations from Riboli are from an interview with the author in London, May 12, 2011.
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]
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]
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/]
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]
“Diets containing substantial amounts”: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 538.
“predominantly plant-based diets”: World Cancer Research Fund/American Institute for Cancer Research, Food, Nutrition, Physical Activity, and the Prevention of Cancer, 522.
“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]
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]
“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.
the European Prospective Investigation into Cancer and Nutrition: Details can be found on the EPIC website. [http://epic.iarc.fr]
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.]
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 (December 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]
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]
too early to make more than tentative conjectures: Key, “Fruit and Vegetables and Cancer Risk.”
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]
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]
that too remains in dispute: Key, “Fruit and Vegetables and Cancer Risk.”
“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.”
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]
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]
older women who had gained 15 to 20 kilograms: Lahmann et al., “Long-term Weight Change and Breast Cancer.”
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]
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]
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]
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]
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]
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]
Rudolf Virchow suggested: Coussens and Werb, “Inflammation and Cancer.”
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.
“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.
“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.abstract]
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]
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]
“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.
“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]
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).
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]
people are able to lead more sedentary lives: Even that, however, is controversial. See Herman Pontzer et al., “Hunter-Gatherer Energetics and Human Obesity,” PLOS ONE 7, no. 7 (July 25, 2012): e40503. [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040503#abstract0]
An official statement from EPIC: “Key Findings,” EPIC Project website. [http://epic.iarc.fr/keyfindings.php]
CHAPTER 11 Gambling with Radiation
a wake of corrosive free radicals: Hongning Zhou et al., “Consequences of Cytoplasmic Irradiation: Studies from Microbeam,” Journal of Radiation Research 50, suppl. A (2009): A59–A65. [http://www.ncbi.nlm.nih.gov/pubmed/19346686]
send signals to neighboring cells: Hongning Zhou et al., “Induction of a Bystander Mutagenic Effect of Alpha Particles in Mammalian Cells,” Proceedings of the National Academy of Sciences 97, no. 5 (February 29, 2000): 2099–104. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC15760]
13.4 percent, may be radon related: Office of Radiation and Indoor Air, EPA Assessment of Risks from Radon in Homes (Washington, DC: United States Environmental Protection Agency, June 2003), iv, available on the EPA website. [http://www.epa.gov/radon/risk_assessment.html]
smoking is also a factor: “Radon and Cancer,” National Cancer Institute website. [http://www.cancer.gov/cancertopics/factsheet/Risk/radon]
The EPA’s scale: “Health Risks,” EPA website, last updated June 26, 2012. [http://www.epa.gov/radon/healthrisks.html]
clusters of two neutrons and two protons: These are, in fact, helium nuclei. Early on it was noticed that radium emits helium as it decays. See William Ramsay and Frederick Soddy, “Experiments in Radioactivity, and the Production of Helium from Radium,” Proceedings of the Royal Society 72 (1903): 204–7. [http://rspl.royalsocietypublishing.org/content/72/477-486/204.full.pdf]
70 percent of their time at home: EPA Assessment of Risks, 7, 44.
The chance of a nonsmoker getting lung cancer: Rebecca Goldin, “Lung Cancer Rates: What’s Your Risk?” March 08, 2006, Research at Statistical Assessment Service (STATS) website, George Mason University. [http://stats.org/stories/2006/lung_cancer_rates_mar08_06.htm]
a laboratory analysis of my eyeglasses: R. L. Fleischer et al., “Personal Radon Dosimetry from Eyeglass Lenses,” Radiation Protection Dosimetry 97, no. 3 (November 1, 2001): 251–58. [http://rpd.oxfordjournals.org/content/97/3/251.abstract]
a method using ordinary household glass: R. W. Field et al., “Intercomparison of Retrospective Radon Detectors,” Environmental Health Perspectives 107, no. 11 (November 1999): 905–10 [http://www.ncbi.nlm.nih.gov/pubmed/10545336]; D. J. Steck, R. W. Field, et al., “210Po Implanted in Glass Surfaces by Long Term Exposure to Indoor Radon,” Health Physics 83, no. 2 (August 2002): 261–71 [http://www.ncbi.nlm.nih.gov/pubmed/12132714]; and Kainan Sun, Daniel J. Steck, and R. William Field, “Field Investigation of the Surface-deposited Radon Progeny as a Possible Predictor of the Airborne Radon Progeny Dose Rate,” Health Physics 97, no. 2 (August 2009): 132–44. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836385]
as long as they have owned the objects: For a few decades, anyway. The half-life of 210Po, one of the radon products that is measured, is twenty-two years.
houses in Grand Junction: Leonard A. Cole, Element of Risk: The Politics of Radon (New York: Oxford University Press, 1994), 10–12.
a construction engineer named Stanley Watras: Cole, Element of Risk, 12.
A study in Winnipeg: E. G. Létourneau et al., “Case-Control Study of Residential Radon and Lung Cancer,” American Journal of Epidemiology 140, no. 4 (1994): 310–22. [http://aje.oxfordjournals.org/content/140/4/310.abstract]
compared the average radon levels: These and other studies are summarized in the Winnipeg paper.
a negative correlation: B. L. Cohen, “Test of the Linear-No Threshold Theory of Radiation Carcinogenesis for Inhaled Radon Decay Products,” Health Physics 68, no. 2 (February 1995): 157–74. [http://www.ncbi.nlm.nih.gov/pubmed/7814250]
the study was flawed: J. H. Lubin, “On the Discrepancy Between Epidemiologic Studies in Individuals of Lung Cancer and Residential Radon and Cohen’s Ecologic Regression,” Health Physics 75, no. 1 (July 1998): 4–10. [http://www.ncbi.nlm.nih.gov/pubmed/9645660]
skewed by an inverse connection: J. S. Puskin, “Smoking as a Confounder in Ecologic Correlations of Cancer Mortality Rates with Average County Radon Levels,” Health Physics 84, no. 4 (April 2003): 526–32. [http://www.ncbi.nlm.nih.gov/pubmed/12705451] For a sampling of the debate that erupted see B. J. Smith, R. W. Field, and C. F. Lynch, “Residential 222Rn Exposure and Lung Cancer: Testing the Linear No-threshold Theory with Ecologic Data,” Health Physics 75, no. 1 (July 1998): 11–17; [http://www.ncbi.nlm.nih.gov/pubmed/9645661] and B. J. Cohen, “Response to Criticisms of Smith et al.,” Health Physics 75, no. 1 (July 1998): 23–28, 31–33. [http://www.ncbi.nlm.nih.gov/pubmed/9645663] Rejoinders and rejoinders to the rejoinders followed.
Perhaps cigarette smoke interfered with the radon monitors: R. W. Field, e-mail to author, June 7, 2012.
hundreds to thousands of picocuries per liter: Cole, Element of Risk, 28.
lung cancer rates among uranium miners: The studies are summarized in “EPA’s Assessment of Risks from Radon,” 8, 11, and in Committee on Health Risks of Exposure to Radon (BEIR VI), National Research Council, Health Effects of Exposure to Radon: BEIR VI (Washington, DC: The National Academies Press, 1999), 76–78. [http://www.nap.edu/catalog.php?record_id=5499]
how long or how often they had smoked: BEIR VI, 77, table 3-2.
a committee of the National Research Council: BEIR VI, 18.
The most ambitious study: R. W. Field et al., “Residential Radon Gas Exposure and Lung Cancer: The Iowa Radon Lung Cancer Study,” American Journal of Epidemiology 151, no. 11 (June 1, 2000): 1091–102. [http://www.cheec.uiowa.edu/misc/radon.html]
about 62 cases per 100,000 men and women: “SEER Stat Fact Sheets: Lung and Bronchus,” Surveillance, Epidemiology, and End Results (SEER) Program website. [http://seer.cancer.gov/statfacts/html/lungb.html]
Three of the analyses: S. Darby et al., “Radon in Homes and Risk of Lung Cancer: Collaborative Analysis of Individual Data from 13 European Case-control Studies,” BMJ: British Medical Journal 330, no. 7485 (January 29, 2005): 223. [http://www.bmj.com/content/330/7485/223] The results are described in Hajo Zeeb and Ferid Shannoun, eds., WHO Handbook on Indoor Radon: A Public Health Perspective (Geneva: World Health Organization, 2009), 12. [http://www.who.int/ionizing_radiation/env/radon/en/index1.html]
consider the matter clinched: For an overview, see Jonathan M. Samet, “Radiation and Cancer Risk: A Continuing Challenge for Epidemiologists,” Environmental Health 10, suppl. 1 (April 5, 2011): S4. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073196]
small doses of radiation are … beneficial: Alexander M. Vaiserman, “Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment,” Dose-Response 8, no. 2 (January 18, 2010): 172–91. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889502] Also see Edward J. Calabrese and Linda A. Baldwin, “Toxicology Rethinks Its Central Belief,” Nature 421, no. 6924 (February 13, 2003): 691–92 [http://www.ncbi.nlm.nih.gov/pubmed/12610596]; L. E. Feinendegen, “Evidence for Beneficial Low Level Radiation Effects and Radiation Hormesis,” British Journal of Radiology 78, no. 925 (January 1, 2005): 3–7 [http://bjr.birjournals.org/content/78/925/3.abstract]; and Jocelyn Kaiser, “Sipping from a Poisoned Chalice,” Science 302, no. 5644 (October 17, 2003): 376–79. [http://www.sciencemag.org/content/302/5644/376.short]
A Johns Hopkins researcher recently concluded: Richard E. Thompson, “Epidemiological Evidence for Possible Radiation Hormesis from Radon Exposure,” Dose-Response 9, no. 1 (December 14, 2010): 59–75. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057636]
low-level x-ray, gamma, and beta radiation: Bobby R. Scott et al., “Radiation-stimulated Epigenetic Reprogramming of Adaptive-response Genes in the Lung: An Evolutionary Gift for Mounting Adaptive Protection Against Lung Cancer,” Dose-Response 7, no. 2 (2009): 104–31. [http://www.ncbi.nlm.nih.gov/pubmed/19543479]
the Chernobyl nuclear power plant: “Chernobyl’s Legacy: Health, Environmental and Socio-economic Impacts,” The Chernobyl Forum: 2003–2005, 2nd revised version, 2012. Available on the International Atomic Energy Agency website. [http://www.iaea.org/Publications/Booklets/Chernobyl/chernobyl.pdf]
an increase in thyroid cancer: For a recent follow-up see Alina V. Brenner et al., “I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chernobyl Accident,” Environmental Health Perspectives 119, no. 7 (July 2011): 933–39. [http://www.ncbi.nlm.nih.gov/pubmed/21406336]
the biggest public health problem … has been psychological: “Chernobyl’s Legacy,” 36.
“a paralyzing fatalism”: Elisabeth Rosenthal, “Experts Find Reduced Effects of Chernobyl,” New York Times, September 6, 2005. [http://www.nytimes.com/2005/09/06/international/europe/06chernobyl.html]
recently opened the Chernobyl site to tourism: Peter Walker, “Chernobyl: Now Open to Tourists,” The Guardian, December 13, 2010. [http://www.guardian.co.uk/world/2010/dec/13/chernobyl-now-open-to-tourists]
a mecca for wildlife: Robert J. Baker and Ronald K. Chesser, “The Chernobyl Nuclear Disaster and Subsequent Creation of a Wildlife Preserve,” Environmental Toxicology and Chemistry 19, no. 5 (May 1, 2000): 1231–32. [http://www.nsrl.ttu.edu/chornobyl/wildlifepreserve.htm]
killed at least 150,000 people: “How Many People Died as a Result of the Atomic Bombings?” Radiation Effects Research Foundation website. [http://www.rerf.or.jp/general/qa_e/qa1.html]
527 excess deaths from solid cancers: Kotaro Ozasa et al., “Studies of the Mortality of Atomic Bomb Survivors, Report 14, 1950–2003: An Overview of Cancer and Noncancer Diseases,” Radiation Research 177, no. 3 (March 2012): 229–43. [http://www.ncbi.nlm.nih.gov/pubmed/22171960]
and 103 from leukemias: David Richardson et al., “Ionizing Radiation and Leukemia Mortality Among Japanese Atomic Bomb Survivors, 1950–2000,” Radiation Research 172, no. 3 (September 2009): 368–82. [http://www.ncbi.nlm.nih.gov/pubmed/19708786] Using incidence instead of mortality figures, the Radiation Effects Research Foundation attributed 1,900 cases of cancer to the bombs. See “How Many Cancers in Atomic-bomb Survivors are Attributable to Radiation?” on the foundation’s website. [http://www.rerf.or.jp/general/qa_e/qa2.html]
Tsutomu Yamaguchi survived both blasts: Mark McDonald, “Tsutomu Yamaguchi, Survivor of 2 Atomic Blasts, Dies at 93,” New York Times, January 7, 2010. [http://www.nytimes.com/2010/01/07/world/asia/07yamaguchi.html]
“cancer in a molten, liquid form”: Siddhartha Mukherjee, The Emperor of All Maladies: A Biography of Cancer (New York: Scribner, 2010), 16.
reburied with Pierre in the Panthéon: Nanny Fröman, “Marie and Pierre Curie and the Discovery of Polonium and Radium,” December 1, 1996, Nobel Prize website. [http://www.nobelprize.org/nobel_prizes/physics/articles/curie]
worried that her body would be dangerously radioactive: D. Butler, “X-rays, Not Radium, May Have Killed Curie,” Nature 377, no. 6545 (September 14, 1995): 96. [http://www.ncbi.nlm.nih.gov/pubmed/7675094]
kept in a lead box at the Bibliothèque Nationale: Fröman, “Marie and Pierre Curie.”
too ill to travel to Stockholm: Marie Curie, Pierre Curie (With the Autobiographical Notes of Marie Curie), trans. Charlotte Kellogg (New York: Macmillan Co., 1923), 125. [http://etext.virginia.edu/toc/modeng/public/CurPier.html]
Pierre described an experiment: “Radioactive Substances, Especially Radium,” June 6, 1905, in Nobel Lectures, Physics 1901–1921 (Amsterdam: Elsevier Publishing Company, 1967). Available on the Nobel Prize website. [http://www.nobelprize.org/nobel_prizes/physics/laureates/1903/pierre-curie-lecture.html]
A targeted drug called Alpharadin: Christopher Parker et al., “Overall Survival Benefit of Radium-223 Chloride (Alpharadin) in the Treatment of Patients with Symptomatic Bone Metastases in Castration-Resistant Prostate Cancer,” 7th NCRI Cancer Conference, November 2011, Liverpool. [http://www.ncri.org.uk/ncriconference/2011abstracts/abstracts/ClinicalShowcase1.html] Also see Deborah A. Mulford, David A. Scheinberg, and Joseph G. Jurcic, “The Promise of Targeted Alpha-particle Therapy,” Journal of Nuclear Medicine 46 suppl. 1 (January 2005): 199S–204S. [http://www.ncbi.nlm.nih.gov/pubmed/15653670]
CHAPTER 12 The Immortal Demon
“Kisses for the Cure”: Anne Landman, “How Breast Cancer Became Big Business,” PR Watch website, June 14, 2008. [http://www.prwatch.org/node/7436]
Stand Up to Cancer telethon: “The Show,” Stand Up to Cancer website. [http://standup2cancer.org/theshow] (There has since been a 2012 broadcast.)
told the story of two cousins: Amy Harmon, “New Drugs Stir Debate on Rules of Clinical Trials,” New York Times, September 18, 2010. [http://www.nytimes.com/2010/09/19/health/research/19trial.html] For more about the trial see Amy Harmon, “Target Cancer,” a series of six articles, New York Times, February 22, 2010, to January 20, 2011. [http://topics.nytimes.com/top/news/health/series/target_cancer/index.html]
a mutation in a gene called BRAF: As a result, the gene produces a distorted version of a protein that is part of a cellular growth pathway. Normally the BRAF protein is actuated only when it interacts with another protein called RAS, but the mutation frees it of this constraint. See “Vemurafenib,” New Treatments, Melanoma Foundation website. [http://www.melanoma.org.nz/About-Melanoma/Diagnosis-and-Treatment/New-Treatments/Vemurafenib] For a description of the cancer and the vemurafenib trials see Paul B. Chapman et al., “Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation,” New England Journal of Medicine 364, no. 26 (June 30, 2011): 2507–16. [http://www.nejm.org/doi/full/10.1056/NEJMoa1103782] For a later study see Jeffrey A. Sosman et al., “Survival in BRAF V600-Mutant Advanced Melanoma Treated with Vemurafenib,” New England Journal of Medicine 366, no. 8 (2012): 707–14. [http://www.nejm.org/doi/full/10.1056/NEJMoa1112302]
Phase III proved so definitive: Andrew Pollack, “Two New Drugs Show Promise in Slowing Advanced Melanoma,” New York Times, June 6, 2011. [http://www.nytimes.com/2011/06/06/health/research/06melanoma.html]
typically living four months longer: The median overall survival was 13.2 vs. 9.6 months for dacarbazine. See Paul B. Chapman et al., “Updated Overall Survival (OS) Results for BRIM-3,” 2012 ASCO Annual Meeting, Journal of Clinical Oncology 30 no. 18, suppl. (June 20, 2012): abstract 8502. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=97795]
sixty-six in the dacarbazine group: “Clinical Trial Result Information,” protocol number NO25026, January 4, 2011, Roche trials database website. [http://www.roche-trials.com/studyResultGet.action?studyResultNumber=NO25026]
half of the people … were dead: Chapman, “Updated Overall Survival (OS) Results.”
“he was running a race”: Alexander Solzhenitsyn, Cancer Ward, trans. Nicholas Bethell and David Burg (New York: Farrar, Straus and Giroux, 1969), 250.
through a fortuitous mutation: Ramin Nazarian et al., “Melanomas Acquire Resistance to B-RAF(V600E) Inhibition by RTK or N-RAS Upregulation,” Nature 468, no. 7326 (November 24, 2010): 973–77. [http://www.nature.com/nature/journal/v468/n7326/abs/nature09626.html]
a paradoxical side effect: Fei Su et al., “RAS Mutations in Cutaneous Squamous-cell Carcinomas in Patients Treated with BRAF Inhibitors,” New England Journal of Medicine 366, no. 3 (January 19, 2012): 207–15. [http://www.nejm.org/doi/full/10.1056/NEJMoa1105358]
experimenting with combinations: In 2012, The New England Journal of Medicine reported encouraging results from a trial involving dabrafenib, a different BRAF inhibitor. It was combined with trametinib, which inhibits MEK, another enzyme in the same cellular pathway. See Keith T. Flaherty et al., “Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations,” New England Journal of Medicine (published online September 29, 2012). [http://www.nature.com/nature/journal/v468/n7326/abs/nature09626.html]
described the jarring effect: Tom Curran, “Oncology as a Team Sport,” Translational Cancer Research Workshop, October 17, 2010.
discovered a gene called reelin: G. D’Arcangelo, T. Curran, et al., “A Protein Related to Extracellular Matrix Proteins Deleted in the Mouse Mutant Reeler,” Nature 374, no. 6524 (April 20, 1995): 719–23; [http://www.ncbi.nlm.nih.gov/pubmed/7715726] and G. G. Miao, T. Curran, et al., “Isolation of an Allele of Reeler by Insertional Mutagenesis,” Proceedings of the National Academy of Sciences 91, no. 23 (November 8, 1994): 11050–54. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC45164]
8 cases in 10 million: Betsy A. Kohler et al., “Annual Report to the Nation on the Status of Cancer, 1975–2007, Featuring Tumors of the Brain and Other Nervous System,” Journal of the National Cancer Institute 103, no. 9 (May 4, 2011), 1–23, table 5.
5 cases per 100,000 among children: Kohler et al., “Annual Report,” 12, table 6.
the most common pediatric brain tumor: Charles M. Rudin et al., “Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449,” New England Journal of Medicine 361, no. 12 (September 17, 2009): 1173–78. [http://www.nejm.org/doi/full/10.1056/NEJMoa0902903#t=abstract]
median age of diagnosis is five: Rudin, “Treatment of Medulloblastoma.”
“a clumsy, staggered walking pattern”: “Medulloblastoma,” American Brain Tumor Association website (2006), 6. [http://www.abta.org/understanding-brain-tumors/types-of-tumors/medulloblastoma.html]
the five-year survival rate was as high as 80 percent: “Medulloblastoma,” 17.
“I met one kid, a teenager”: Curran, “Oncology as a Team Sport.”
research from other labs: For an overview see Ken Garber, “Hedgehog Drugs Begin to Show Results,” Journal of the National Cancer Institute 100, no. 10 (May 21, 2008): 692–97. [http://jnci.oxfordjournals.org/content/100/10/692.extract]
the story of the cyclopean lambs: This is told in chapter 6 of this book.
a meeting on brain genetics and development: Genetic Basis of Brain Development and Dysfunction, March 18–23, 2000, Sagebrush Inn and Conference Center, Taos, New Mexico. [http://www.keystonesymposia.org/index.cfm?e=Web.Meeting.Program&MeetingID=514] The authority on hedgehog signaling was Andrew McMahon at Harvard University.
Curran went on to show: Justyna T. Romer, T. Curran, et al., “Suppression of the Shh Pathway Using a Small Molecule Inhibitor,” Cancer Cell 6, no. 3 (September 2004): 229–40. [http://www.sciencedirect.com/science/article/pii/S1535610804002417]
inhibited bone development: Garber, “Hedgehog Drugs Begin to Show Results.”
there were signs that the drug … was safe: “Experimental Targeted Therapy Shows Early Promise Against Medulloblastomas,” St. Jude Children’s Research Hospital website, June 5, 2010. [http://multivu.prnewswire.com/mnr/stjude/44444]
approved for basal cell carcinoma: “FDA Approval for Vismodegib,” National Cancer Institute website. [http://www.cancer.gov/cancertopics/druginfo/fda-vismodegib]
“forward looking”: Emmy Wang, senior manager, corporate relations, Genentech, e-mail to author on behalf of Fred de Sauvage, March 2, 2012.
a body called the United States Adopted Names Council: For a deciphering of generic drug names see “USAN Stem List,” American Medical Association website. [http://www.ama-assn.org/resources/doc/usan/stem-list-cumulative.pdf]
described the latest findings: José Baselga, keynote (untitled), Translational Cancer Research Workshop, Boston, October 17, 2010.
“super Herceptin” or trastuzumab emtansine: Ion Niculescu-Duvaz, “Trastuzumab Emtansine, an Antibody-drug Conjugate for the Treatment of HER2+ Metastatic Breast Cancer,” Current Opinion in Molecular Therapeutics 12, no. 3 (June 2010): 350–60. [http://www.ncbi.nlm.nih.gov/pubmed/20521224]
drug called pertuzumab: Cormac Sheridan, “Pertuzumab to Bolster Roche/Genentech’s Breast Cancer Franchise?” Nature Biotechnology 29, no. 10 (October 13, 2011): 856–58. [http://www.nature.com/nbt/journal/v29/n10/full/nbt1011-856b.html]
pertuzumab became Perjeta: “FDA Approval for Pertuzumab,” National Cancer Institute website, June 11, 2012. [http://www.cancer.gov/cancertopics/druginfo/fda-pertuzumab]
patients were outraged: Robert Weisman, “Limits on Test Drugs Add to Patients’ Ordeals,” Boston Globe, January 5, 2011. [http://www.boston.com/business/healthcare/articles/2011/01/05/testing_rules_force_patients_to_wait_for_new_drugs]
the agency insisted on waiting: Martin de Sa’Pinto and Katie Reid, “FDA Puts Brakes on Roche, ImmunoGen Cancer Drug,” Reuters, August 27, 2010. [http://www.reuters.com/article/2010/08/27/roche-idUSLDE67Q03620100827]
a rally outside Boston City Hall: The date was December 6, 2011.
“reduced the risk of cancer worsening”: Media release, June 3, 2012, Roche website. [http://www.roche.com/media/media_releases/med-cor-2012-06-03b.htm] Also see Lisa Hutchinson, “From ASCO—Breast Cancer: EMILIA Trial Offers Hope,” Nature Reviews Clinical Oncology 9, no. 8 (August 1, 2012): 430. It was approved February 22, 2013, by the FDA and is sold as Kadcyla.
“smoothes and tightens the skin”: Barbara Ehrenreich, “Welcome to Cancerland,” Harper’s Magazine, November 2001. [http://www.barbaraehrenreich.com/cancerland.htm] Also see Gayle A. Sulik, Pink Ribbon Blues: How Breast Cancer Culture Undermines Women’s Health, (New York: Oxford University Press, 2011).
how many lives that saves: For more on the controversy over breast cancer treatment see Robert A. Aronowitz, Unnatural History: Breast Cancer and American Society (Cambridge: Cambridge University Press, 2007); and David Plotkin, “Good News and Bad News About Breast Cancer,” The Atlantic, June 1998. [http://www.theatlantic.com/magazine/archive/1998/06/good-news-and-bad-news-about-breast-cancer/5504]
A recent epidemiological study of 600,000 women: P. C. Gøtzsche and M. Nielsen, “Screening for Breast Cancer with Mammography,” The Cochrane Library 4 (2009). A summary was published on the Cochrane website April 13, 2011. [http://summaries.cochrane.org/CD001877/screening-for-breast-cancer-with-mammography]
a disturbing number: Timothy J. Wilt et al., “Radical Prostatectomy Versus Observation for Localized Prostate Cancer,” New England Journal of Medicine 367, no. 3 (2012): 203–13. [http://www.nejm.org/action/showCitFormats?doi=10.1056%2FNEJMoa1113162] Also see G. Sandblom et al., “Randomised Prostate Cancer Screening Trial: 20 Year Follow-up,” BMJ: British Medical Journal 342 (March 31, 2011): d1539. [http://www.bmj.com/content/342/bmj.d1539]
About 70 percent of men in their seventies: For a review of the autopsy studies see Richard M. Martin, “Commentary: Prostate Cancer Is Omnipresent, but Should We Screen for It?” International Journal of Epidemiology 36, no. 2 (April 1, 2007): 278–81. [http://ije.oxfordjournals.org/content/36/2/278.extract]
Urologists offer free tickets: The examples are from Gary Schwitzer, “Cheerleading, Shibboleths and Uncertainty,” a presentation on April 23, 2012, Science Writing in the Age of Denial, University of Wisconsin, Madison, WI. The urinal example was provided to Schwitzer by Ivan Oransky, the executive editor of Reuters Health.
one of “the best and brightest”: Tom Junod, “Franziska Michor Is the Isaac Newton of Biology,” Esquire, November 20, 2007. [http://www.esquire.com/features/michor1207]
uncovered some of the early clues: See, for example, J. C. Fisher, “Multiple-Mutation Theory of Carcinogenesis,” Nature 181 (March 1, 1958): 651–52 [http://www.nature.com/nature/journal/v181/n4609/abs/181651b0.html]; P. Armitage and R. Doll, “The Age Distribution of Cancer and a Multi-stage Theory of Carcinogenesis,” British Journal of Cancer 8 (1954): 1–12 [http://www.nature.com/bjc/journal/v91/n12/full/6602297a.html]; and C. O. Nordling, “A New Theory on the Cancer-inducing Mechanism,” British Journal of Cancer 7, no. 1 (March 1953): 68–72. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2007872]
“hitchhiker” or “passenger” mutations: Ondrej Podlaha, Franziska Michor, et al., “Evolution of the Cancer Genome,” Trends in Genetics 28, no. 4 (April 1, 2012): 155–63. [http://www.cell.com/trends/genetics/abstract/S0168-9525(12)00012-1]
the order in which the mutations occur: Camille Stephan-Otto Attolini, Franziska Michor, et al., “A Mathematical Framework to Determine the Temporal Sequence of Somatic Genetic Events in Cancer,” Proceedings of the National Academy of Sciences 107, no. 41 (October 12, 2010): 17604–9. [http://www.ncbi.nlm.nih.gov/pubmed/20864632] [full text: http://www.pnas.org/content/107/41/17604.full.pdf]
so quickly overcome the obstacles: Podlaha, Michor, et al., “Evolution of the Cancer Genome.”
it sometimes pays for adversaries to cooperate: The classic paper is R. Axelrod and W. D. Hamilton, “The Evolution of Cooperation,” Science 211, no. 4489 (March 27, 1981): 1390–96. [http://www.ncbi.nlm.nih.gov/pubmed/7466396]
has suggested how that might apply: Robert Axelrod, David E. Axelrod, and Kenneth J Pienta, “Evolution of Cooperation Among Tumor Cells,” Proceedings of the National Academy of Sciences 103, no. 36 (September 5, 2006): 13474–79. [http://www.pnas.org/content/103/36/13474]
“Cancer isn’t getting smarter”: The Stand Up to Cancer presentation was at the 2011 Annual Meeting of the American Association for Cancer Research, Orlando, FL, April 2–6. The scientist quoted is Angelique Whitehurst.
“an ugly mass, rounded and bulging”: David Quammen, “Contagious Cancer: The Evolution of a Killer,” Harper’s Magazine, April 2008. [http://harpers.org/archive/2008/04/0081988]
scientists have since traced the origin: Elizabeth P. Murchison et al., “Genome Sequencing and Analysis of the Tasmanian Devil and Its Transmissible Cancer,” Cell 148, no. 4 (February 17, 2012): 780–91. [http://www.cell.com/retrieve/pii/S0092867412000815]
“the immortal devil”: Ewen Callaway, “Field Narrows in Hunt for Devil Tumour Genes,” Nature, News and Comment, published online February 16, 2012. [http://www.nature.com/doifinder/10.1038/nature.2012.10046]
spread between hamsters by mosquitoes: W. G. Banfield et al., “Mosquito Transmission of a Reticulum Cell Sarcoma of Hamsters,” Science 148, no. 3674 (May 28, 1965): 1239–40. [http://www.sciencemag.org/content/148/3674/1239.abstract?sid=16f27225-5ed2-4221-a2cc-fe070ff430c0]
CHAPTER 13 Beware the Echthroi
“See if aspirin cures the headache”: My trip to Sandia Crest and the situation in Santa Fe are described in “On Top of Microwave Mountain,” Slate, April 21, 2010. [http://www.slate.com/articles/health_and_science/science/2010/04/on_top_of_microwave_mountain.html]
a book about mass hysteria: Elaine Showalter, Hystories: Hysterical Epidemics and Modern Media (New York: Columbia University Press, 1997).
the threshold set by the Federal Communications Commission: Federal Communications Commission, “Evaluating Compliance with FCC Guidelines for Human Exposure to Radiofrequency Electromagnetic Fields,” OET Bulletin 65 (August 1997): 67. [http://transition.fcc.gov/Bureaus/Engineering_Technology/Documents/bulletins/oet65/oet65.pdf] See part B of table 1, “Limits for Maximum Permissible Exposure (MPE),” for 1,500–100,000 Mhz. (The occupational limit is 5mW/cm2 for six minutes.) For more information see the FCC’s “Questions and Answers About Biological Effects and Potential Hazards of Radiofrequency Electromagnetic Fields,” OET Bulletin 56, 4th ed. (August 1999). [http://transition.fcc.gov/Bureaus/Engineering_Technology/Documents/bulletins/oet56/oet56e4.pdf] Cell phone exposure is also measured in watts per kilogram—the rate of radio frequency energy absorption by the body.
about 100 milliwatts per square centimeter: “Calculating the Energy from Sunlight over a 12–Hour Period,” Math & Science Resources, National Aeronautics and Space Administration website. [http://www.grc.nasa.gov/WWW/k-12/Numbers/Math/Mathematical_Thinking/sun12.htm]
contradictory and inconclusive: For a summary and general information about wireless technologies and health, see Rfcom, a website maintained by the McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa. [http://www.rfcom.ca]
A review by the World Health Organization: “Electromagnetic Fields, Summary of Health Effects,” WHO website. [http://www.who.int/peh-emf/about/WhatisEMF/en/index1.html] Another good source is “Cell Phones and Cancer Risk” on the National Cancer Institute website. [http://www.cancer.gov/cancertopics/factsheet/Risk/cellphones]
has remained extremely low: See table 1.4 of the SEER statistics, N. Howlader et al., eds., “SEER Cancer Statistics Review,” 1975–2009 (Vintage 2009 Populations), National Cancer Institute, Bethesda, MD, based on November 2011 SEER data submission, posted to the SEER website, 2012. [http://seer.cancer.gov/csr/1975_2009_pops09]
slightly but steadily decreasing: N. Howlader et al., eds., “SEER Cancer Statistics Review,” table 1.7.
The most ambitious of these efforts: “The Interphone Study,” International Agency for Research on Cancer, World Health Organization, IARC website. [http://interphone.iarc.fr]
No relationship was found: “IARC Report to the Union for International Cancer Control (UICC) on the Interphone Study,” October 3, 2011, IARC website. [http://interphone.iarc.fr/UICC_Report_Final_03102011.pdf]
odds of being diagnosed with the cancer: This was a hard number to come up with. The statistics available online from SEER don’t break down brain tumors by type, but the agency made the calculation at my request. (E-mail to author from Rick Borchelt, NCI Media Relations, July 12, 2012.) For a somewhat lower estimate, see table 1 of Judith A. Schwartzbaum et al., “Epidemiology and Molecular Pathology of Glioma,” Nature Clinical Practice Neurology 2, no. 9 (2006): 494–503. [http://www.nature.com/nrneurol/journal/v2/n9/full/ncpneuro0289.html] Adding the incidence rates of the different kinds of glioma comes to 0.0049. The article also estimates that 77 percent of primary malignant brain tumors are gliomas. Multiplying SEER’s incidence rate for all gliomas, 0.0061, by 0.77 yields a slightly different value, 0.0047.
a later study by the National Cancer Institute: M. P. Little et al., “Mobile Phone Use and Glioma Risk: Comparison of Epidemiological Study Results with Incidence Trends in the United States,” BMJ: British Medical Journal 344 (March 8, 2012): e1147. [http://www.bmj.com/content/344/bmj.e1147]
to add microwaves: “IARC Classifies Radiofrequency Electromagnetic Fields as Possibly Carcinogenic to Humans,” May 31, 2011, IARC website. [http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf] The IARC classifications are described on the agency’s website, last updated March 27, 2012. [http://monographs.iarc.fr/ENG/Classification/index.php
COSMOS: Joachim Schüz et al., “An International Prospective Cohort Study of Mobile Phone Users and Health (Cosmos): Design Considerations and Enrollment,” Cancer Epidemiology 35, no. 1 (February 2011): 37–43. [http://www.ncbi.nlm.nih.gov/pubmed/20810339]
suggested to widespread disbelief: The original study on power lines and cancer is Nancy Wertheimer and Ed Leeper, “Electrical Wiring Configurations and Childhood Cancer,” American Journal of Epidemiology 109, no. 3 (March 1, 1979): 273–84. [http://aje.oxfordjournals.org/content/109/3/273.abstract]
Robert Weinberg once estimated: Over a lifetime a human body makes on the order of 1016 cells. Divide that by the number of seconds in an 80-year life span, or 2.5 × 109, to get 4 × 106. Robert Weinberg, e-mail to author, November 8, 2010. In Biology of Cancer, page 43, he gives an order of magnitude estimate of 10 million.
we all would eventually get cancer: Interview with Robert Weinberg, August 18, 2010, Whitehead Institute, Boston, MA.
cancer is here “on purpose”: Interview with Robert Austin, October 21, 2010, Princeton University. He expanded on this idea at the first workshop organized by the National Cancer Institute’s Physical Sciences in Oncology program, “Integrating and Leveraging the Physical Sciences to Open a New Frontier in Oncology,” February 26–28, 2008, Arlington, VA. [http://physics.cancer.gov/ps1/pdf/Physical_Oncology_Meeting_Report_PS1_508.pdf]
Maybe … the cells in an organism do the same thing: Guillaume Lambert, Robert H. Austin, et al., “An Analogy Between the Evolution of Drug Resistance in Bacterial Communities and Malignant Tissues,” Nature Reviews Cancer 11, no. 5 (April 21, 2011): 375–82. [http://www.nature.com/nrc/journal/v11/n5/full/nrc3039.html]
an attempt to break the stalemate: The program is called Physical Sciences in Oncology. See Franziska Michor et al., “What Does Physics Have to Do with Cancer?” Nature Reviews Cancer 11, no. 9 (August 18, 2011): 657–70; [http://www.nature.com/nrc/journal/v11/n9/abs/nrc3092.html] and Paul Davies, “Rethinking Cancer,” Physics World (June 2010): 28–33. [http://cancer-insights.asu.edu/wp-content/uploads/2010/01/Physics-World-June-20101.pdf]
studying the mechanical forces: Denis Wirtz, Konstantinos Konstantopoulos, and Peter C. Searson, “The Physics of Cancer: The Role of Physical Interactions and Mechanical Forces in Metastasis,” Nature Reviews Cancer 11, no. 7 (June 24, 2011): 512–22. [http://www.nature.com/nrc/journal/v11/n7/abs/nrc3080.html]
a different level of abstraction: This was the subject of the Third Physical Sciences in Oncology Workshop, “The Coding, Decoding, Transfer, and Translation of Information in Cancer,” October 29–31, 2008, Arlington, VA.
cells can be thought of as oscillators: Donald Coffey, First Physical Sciences in Oncology Workshop, “Integrating and Leveraging the Physical Sciences.”
radio frequency waves to kill cancer cells: Mustafa Raoof and Steven A. Curley, “Non-Invasive Radiofrequency-Induced Targeted Hyperthermia for the Treatment of Hepatocellular Carcinoma,” International Journal of Hepatology 2011 (2011): 1–6. [http://www.hindawi.com/journals/ijhep/2011/676957]
an “ancient genetic toolkit”: Paul Davies, “Cancer: The Beat of an Ancient Drum?” The Guardian, April 25, 2011. [http://www.guardian.co.uk/commentisfree/2011/apr/25/cancer-evolution-ancient-toolkit-genes] For a fuller description of the hypothesis, see P. C. W. Davies and C. H. Lineweaver, “Cancer Tumors as Metazoa 1.0: Tapping Genes of Ancient Ancestors,” Physical Biology 8, no. 1 (February 1, 2011): 015001.
detailed computer simulations: The USC program, like the others, is described on the National Cancer Institute’s Physical Sciences in Oncology website. [http://physics.cancer.gov/centers/adv_usc.asp]
a giant clock: Described on the Long Now Foundation website. [http://longnow.org]
told an audience of oncologists: Coffey, “Integrating and Leveraging the Physical Sciences.”
another of his ambitious machines: Described on the Applied Proteomics website. [http://www.appliedproteomics.com]
concentrating on the proteome: Interviews with Daniel Hillis, November 26, 2010, and David Agus, November 29, 2010, Los Angeles.
working for years on mapping the proteome: See, for example, Bonnie S. Watson et al., “Mapping the Proteome of Barrel Medic (Medicago Truncatula),” Plant Physiology 131, no. 3 (March 2003): 1104–23. [http://www.ncbi.nlm.nih.gov/pubmed/12644662]
continually announcing new discoveries: See, for example, “Comprehensive Molecular Portraits of Human Breast Tumours,” published online in Nature (September 23, 2012). [http://dx.doi.org/10.1038/nature11412]
“Ten Crazy Ideas About Cancer”: Seminar at Arizona State University, September 8, 2011. A summary and video are on ASU’s Center for the Convergence of Physical Science and Cancer Biology website. [http://cancer-insights.asu.edu/2011/08/1458]
mitochondria … might once have been bacteria: L. Margulis, “Archaeal-eubacterial Mergers in the Origin of Eukarya: Phylogenetic Classification of Life,” Proceedings of the National Academy of Sciences 93, no. 3 (February 6, 1996): 1071–76. [http://www.pnas.org/content/93/3/1071]
suspected of playing a part in cancer: Jennifer S. Carew and Peng Huang, “Mitochondrial Defects in Cancer,” Molecular Cancer 1, no. 1 (December 9, 2002): 9; [http://www.molecular-cancer.com/content/1/1/9] and G. Kroemer, “Mitochondria in Cancer,” Oncogene 25, no. 34 (August 7, 2006): 4630–32. [http://www.nature.com/onc/journal/v25/n34/full/1209589a.html]
initiate apoptosis, the cellular suicide routine: Douglas R. Reed and John C. Green, “Mitochondria and Apoptosis,” Science 281, no. 5381 (August 28, 1998): 1309–12. [http://www.sciencemag.org/content/281/5381/1309]
Madeleine L’Engle: A Wrinkle in Time (New York: Farrar, Straus and Giroux, 1962) and A Wind in the Door (New York: Farrar, Straus and Giroux, 1973).
a protein that is used as a biomarker: R. C. Bast Jr. et al., “Reactivity of a Monoclonal Antibody with Human Ovarian Carcinoma,” Journal of Clinical Investigation 68, no. 5 (November 1981): 1331–37. [http://www.ncbi.nlm.nih.gov/pubmed/7028788]
a blunt-edged tool: Charlie Schmidt, “CA-125: A Biomarker Put to the Test,” Journal of the National Cancer Institute 103, no. 17 (September 7, 2011): 1290–91. [http://jnci.oxfordjournals.org/content/103/17/1290]
another invader from the Russian steppes: James A. Young, “Tumbleweed,” Scientific American 264, no. 3 (March 1991): 82–86.
triclopyr: “Dow AgroSciences Garlon Family of Herbicides,” Dow AgroSciences website. [http://msdssearch.dow.com/PublishedLiteratureDAS/dh_0130/0901b80380130084.pdf]
Maxwell’s demon: I have given only a very general description of the thought experiment devised in the nineteenth century by James Clerk Maxwell, which involved sorting hot and cold gas molecules in a closed chamber. For a collection of essays about the demon and the debate it inspired, see Harvey S. Leff and Andrew F. Rex, Maxwell’s Demon: Entropy, Information, Computing (Princeton, NJ: Princeton University Press, 1990).
EPILOGUE Joe’s Cancer
said that about 52,000 people: “Head and Neck Cancers,” National Cancer Institute website. [http://www.cancer.gov/cancertopics/factsheet/Sites-Types/head-and-neck]
“A melanoblastoma is such a swine”: Alexander Solzhenitsyn, Cancer Ward, trans. Nicholas Bethell and David Burg (New York: Farrar, Straus and Giroux, 1969), 202.
a concept called field cancerization: D. P. Slaughter, H. W. Southwick, and W. Smejkal, “Field Cancerization in Oral Stratified Squamous Epithelium: Clinical Implications of Multicentric Origin,” Cancer 6, no. 5 (September 1953): 963–68. [http://www.ncbi.nlm.nih.gov/pubmed/13094644]
“a ticking time bomb”: Boudewijn J. M. Braakhuis et al., “A Genetic Explanation of Slaughter’s Concept of Field Cancerization Evidence and Clinical Implications,” Cancer Research 63, no. 8 (April 15, 2003): 1727–30. [http://cancerres.aacrjournals.org/content/63/8/1727] For other references on field cancerization see Gabriel D. Dakubo et al., “Clinical Implications and Utility of Field Cancerization,” Cancer Cell International 7 (2007): 2; [http://www.ncbi.nlm.nih.gov/pubmed/17362521] and M. G. van Oijen and P. J. Slootweg, “Oral Field Cancerization: Carcinogen-induced Independent Events or Micrometastatic Deposits?” Cancer Epidemiology, Biomarkers & Prevention 9, no. 3 (March 2000): 249–56. [http://www.ncbi.nlm.nih.gov/pubmed/10750662]
William Crookes, the inventor: W. Crookes, “The Emanations of Radium,” Proceedings of the Royal Society of London 71 (January 1, 1902): 405–8. [http://archive.org/details/philtrans03789193]
unveiled it at a gala: Paul W. Frame, “William Crookes and the Turbulent Luminous Sea,” Oak Ridge Associated Universities website. [http://www.orau.org/ptp/articlesstories/spinstory.htm] The piece originally appeared in the Health Physics Society Newsletter.
spinthariscopes with the same engraving: In Robert Bud and Deborah Jean Warner, eds., Instruments of Science: An Historical Encyclopedia (New York: Garland, 1998), 572–73, Helge Kragh writes that the Crookes spinthariscope was produced in the summer of 1903 by several different instrument makers.
“a turbulent, luminous sea”: W. Crookes, “Certain Properties of the Emanations of Radium,” Chemical News 87, no. 241 (1903).