Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (48 page)

4. W. T. London, A. I. Sutnick, and B. S. Blumberg, “Australia antigen and acute viral hepatitis,”
Ann Intern Med
70 (1969): 55–59.

5. Blumberg,
Hepatitis B,
65.

6. S. Krugman, J. P. Giles, and J. Hammond, “Infectious hepatitis: Evidence for two distinctive clinical, epidemiological, and immunological types of infection,”
Journal of the American Medical Association
200 (1967): 365–73. Reprinted as a landmark article,
JAMA
252 (1984): 393–401.

7. J. P. Giles, R. W. MacCallum, L. W. Berndtson Jr., and S. Krugman, “Viral hepatitis: Relation of Australia/SH antigen to the Willow-brook MS-2 strain,”
N Engl J Med
281 (1969): 119–22.

8. David J. Rothman and Sheila M. Rothman,
The Willowbrook Wars
(New York: Harper and Row, 1984), 260.

9. Two HAV vaccines, HAVRIX and VAQTA, are FDA-approved and commercially available and provide long-term protection. In a period of just over two decades, knowledge of viral hepatitis grew from the belief in the early 1970s that there were only two viruses, hepatitis A and hepatitis B, to the recognition that there are at least five—A through E. The hepatitis C virus was identified in 1989 by investigators at the Chiron Corporation in California working in collaboration with investigators at the Centers for Disease Control (CDC) in Atlanta. It is responsible for most chronic viral hepatitis cases in the United States, with an estimated 170,000 new cases annually. Parenteral transmission of HVC is well established as occurring via needles and through sex between males. CDC investigators estimated that in 1990 there were 3.5 million HCV carriers in the United States. Chronic HBV and HCV infections appear to be the link to the development of primary hepatocellular carcinoma. This is the most common cancer worldwide and accounts for approximately 1 million deaths annually. It is relatively rare in the United States, but many parts of Africa and Asia have an extremely high incidence. The hepatitis D virus (HDV), identified in 1977, can exist only in the presence of hepatitis B infection. It is estimated that there are at least 70,000 HDV carriers in the United States. Hepatitis E, while presumably an old and perhaps even an ancient disease, was first recognized in 1980 through the study of serum and fecal samples from an extensive waterborne hepatitis outbreak in India.

10. E. Norby, “Introduction to Baruch Blumberg,” in
Nobel Lectures, Physiology or Medicine 1971–1980,
ed. J. Lindsten (Singapore: World Scientific, 1992).

11. M. L. M. Luy, “Investigative coup: Discovery of the Australia antigen. An interview with Dr. Baruch S. Blumberg,”
Modern Medicine
42 (1974): 41–44.

12. Author interview with Baruch Blumberg, January 25, 2004.

C
HAPTER
8: “This Ulcer ‘Bugs’ Me!”

1. K. Schwartz, “Über penetrierende Magen—und Jejunalgeschwüre,”
Beitr Klin Chir
67 (1910): 96–128.

2. B. W. Sippy, “Gastric duodenal ulcer: Medical cure by an efficient removal of gastric juice corrosion,”
JAMA
64 (1915): 1625–30.

3. E. Palmer, “Investigation of the gastric
spirochaetes
of the human,”
Gastroenterology
27 (1954): 218–20.

4. Terence Monmaney, “Marshall's Hunch,”
New Yorker,
September 20, 1993, 64–72.

5. W. I. B. Beveridge,
The Art of Scientific Investigation
(New York: Vintage, 1950), 6.

6. B. J. Marshall, “History of the discovery of
C. pylori,
”in
Campylobacter pylori in Gastritis and Peptic Ulcer Disease,
ed. Martin J. Blaser (New York: Igaku-Shoin, 1989), 7–22.

7. Claude Bernard,
An Introduction to the Study of Experimental Medicine,
trans. Henry Copley Greene (New York: Macmillan, 1927).

8. Author interview with Martin Blaser, M.D., professor and chairman of the Department of Medicine, New York University School of Medicine, December 16, 2003.

9. Quoted in Monmaney, “Marshall's Hunch.”

10. J. R. Warren and B. J. Marshall, “Unidentified curved bacilli on gastric epithelium in active chronic gastritis,”
Lancet
1 (1983): 1273–75.

11. B. J. Marshall and J. R. Warren, “Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration,”
Lancet
1 (1984): 1311–15.

12. B. J. Marshall, J. A. Armstrong, D. B. McGechie, and R. J. Clancy, “Attempt to fulfill Koch's postulates for pyloric
Campylobacter,
”
Medical Journal of Australia
142 (1985): 436–39.

13. E. J. S. Boyd and K. G. Worsley, “Etiology and pathogenesis of peptic ulcer,” in
Bockus Gastroenterology,
4th ed., ed. J. Edward Berk (Philadelphia: W. B. Saunders, 1985).

14. Author interview with Barry Marshall, March 14, 2000.

15. B. J. Marshall, C. S. Goodwin, J. R. Warren, et al., “A prospective double-blind trial of duodenal ulcer relapse after eradication of
Campylobacter pylori,
”
Lancet
2 (1988): 1437–41.

16. Quoted in S. Chazan, “The Doctor Who Wouldn't Accept No,”
Reader's Digest,
October 1993, 118–23.

17. D. Y. Graham and M. F. Go, “
Helicobacter pylori:
Current status,”
Gastroenterology
105 (1993): 279–82.

18. Thomas S. Kuhn,
The Structure of Scientific Revolutions,
2nd ed. (Chicago: University of Chicago Press, 1970), 150.

19. Quoted in Monmaney, “Marshall's Hunch.”

Part II:
The Smell of Garlic Launches the War on Cancer

C
HAPTER
9: Tragedy at Bari

1. Quoted in Glenn B. Infield,
Disaster at Bari
(New York: Macmillan, 1971), 121.

2. As in World War I, Germany's mustard gas was manufactured by the IG Farben chemical conglomerate. It was also used by the Spanish army in Morocco and the Italians in Abyssinia, now called Ethiopia.

3. S. L. A. Marshall,
World War I
(Boston: Houghton Mifflin, 1985), 167–69, 322.

4. In World War I as many as fifty different toxic agents were employed on the battlefields by at least one of the combatants, most of them proving relatively ineffective. Mustard, the most effective chemical incapacitator, was delivered in artillery and mortar shells, which on detonation sent out a liquid spray within a twenty-yard radius. Augustin M. Prentiss,
Chemicals in War: A Treatise on Chemical Warfare
(New York: McGraw-Hill, 1937). Large quantities of the agent were delivered on a wide front against enemy forces. In one offensive drive, the Germans used 1,700 batteries firing chemical shells on a seventy-mile front, an average of one battery every seventy-two yards. In a three-day German assault against British lines in early 1918, the Germans fired 120,000 to 150,000 mustard shells. D. K. Clark,
Effectiveness of Chemical Weapons in WWI
(Bethesda, Md.: Johns Hopkins University, 1959). U.S. troops were not involved in gas attacks until February 25, 1918, when they were hit by German shells containing the choking gas, phosgene. A similar agent, di-phosgene (German “green cross”), conveyed a chocolate-like smell across the battlefield. Four months later, the American forces initiated their own offensive use of toxic gas.

5. Evidence of this general nature had been noted as early as 1919 from the effects of chemical warfare in World War I. Autopsies had been conducted by the University of Pennsylvania's department of research medicine on seventy-five soldiers who had been killed in an accident with mustard gas. The examiners were surprised to find extreme reductions in the numbers of white blood cells and noted it to be caused by direct depression of blood cell formation. These observations were obscured by the debilitating and deadly blistering and respiratory consequences, and the potential significance of the blood changes was overlooked. E. B. Krumbhaar and H. D. Krumbhaar, “The blood and bone marrow in yellow cross mustard (mustard gas) poisoning,”
Journal of Medical Research
40 (1919): 497–506.

6. Alfred Gilman and Louis Goodman are known today to every medical student for their classic textbook
The Pharmacologic Basis of Therapeutics.
When it made its first appearance in 1938, not only was no section of the book devoted to cancer, but the word “cancer” did not even appear in the index. They went on to become the first to discover an effective drug against cancer.

7. The bizarre constellation of symptoms in the casualties at Bari is explained by the cascade of poisonous breakdown products. An initial action led to the excessive tearing. This was followed by a paralytic effect, which caused the profound apathy and weakness. A successive blistering action produced the brawny edema of the skin exposed to the dilute solution of mustard in the fuel oil. Several actions led to the virtual disappearance of white blood cells.

8. The capability to transplant cancerous tumors in mice had been known since the work of Carl Jensen, a Danish veterinarian in 1903. This was a significant discovery because it enabled cancer research in the laboratory using animals. Now a researcher could observe not only the growth of cancer but also the effects of agents upon it. In animals such as mice, which have a short life span, tumors grow much more rapidly than in human beings.

9. Alfred Gilman, “The initial clinical trial of nitrogen mustard,”
Am J Surg
105 (1963): 574–78.

10. Ibid.

11. A. Gilman and F. Phillips, “The Biological Actions and Therapeutic Applications of the B-chloranthyamines and Sulfides,”
Science
103 (1946): 409–15.

12. Cornelius P. Rhoads, “Report on a cooperative study of nitrogen mustard (HN2) therapy of neoplastic disease,”
Trans Assoc Am Physicians
60 (1947): 110–17.

13. Similar government suppression was later seen with the consequences of atom bomb testing in the 1950s, Agent Orange in Vietnam in the 1960s, and neurotoxins in the first Gulf War in 1991.

14. Arthur I. Holleb and Michael Braun Randers-Pehrson,
Classics in Oncology
(New York: American Cancer Society, 1987), 383.

C
HAPTER
10: Antagonists to Cancer

1. L. Wills, P. W. Clutterbuck, and P. D. F. Evans, “A new factor in the production and cure of macrocytic anaemias and its relation to other haemopoietic principles curative in pernicious anaemia,”
Biochem J
31 (1937): 2136–47.

2. R. Leuchtenberger, C. Leuchtenberger, D. Laszlo, and R. Lewisohn, “The Influence of ‘Folic Acid’ on Spontaneous Breast Cancers in Mice,”
Science
101 (1945): 46.

3. S. Farber, L. K. Diamond, R. D. Mercer, R. F. Sylvester Jr., and J. A. Wolf, “Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroylglutamic acid (Amino-pterin),”
N Engl J Med
238 (1948): 787–93.

4. M. C. Li, R. Hertz, and D. B. Spencer, “Effect of methotrexate upon choriocarcinoma and chorioadenoma,”
Proc Soc Exp Biol Med
93 (1956): 361–66.

5. In 1952 Gertrude Elion and colleagues introduced 6-mercaptop-urine, a potent antagonist of a factor essential to a cell's nucleus.

6. Other antimetabolites currently in use, in addition to methotrexate and 6-mercaptopurine, include 6-thioguanine, 5-fluorouracil (5-FU), and arabinosyl cytosine. All antimetabolites act primarily during the DNA synthetic phase of the cell cycle.

7. Several of the drugs used for cancer therapy have become important components as well as treatments for other diseases: immunosuppressive regimens for rheumatoid arthritis (methotrexate and cyclophosphamide), multiple sclerosis (Novantrone), organ transplantation (methotrexate and azathioprine), and psoriasis (methotrexate), as well as for sickle cell anemia (hydroxyurea) and the parasitic disease leishmaniasis (miltefosine).

C
HAPTER
11: Veni, Vidi, Vinca: The Healing Power of Periwinkle

1. John Mann,
Murder, Magic, and Medicine
(Oxford: Oxford University Press, 1992), 213.

2. R. L. Noble, C. T. Beer, and J. H. Cutts, “Role of chance observations in chemotherapy:
Vinca rosea,
”
Ann N Y Acad Sci
76 (1958): 882–94.