Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (50 page)

9. Author interview with Ernest McCulloch, January 25, 2006.

C
HAPTER
20: The Industrialization of Research and the War on Cancer

1. James T. Patterson,
The Dread Disease: Cancer and Modern American Culture
(Cambridge, Mass.: Harvard University Press, 1987).

2. George G. Crile Jr.,
Cancer and Common Sense
(New York: Viking, 1955), 15–16.

3. Patterson,
The Dread Disease,
182.

4. Vannevar Bush,
Science, the Endless Frontier: A Report to the President
(1945; reprinted Washington, D.C.: National Science Foundation, 1960).

5. C. G. Zubrod, S. Schepartz, J. Leiter, et al., “The chemotherapy program of the National Cancer Institute: history, analysis and plans,”
Cancer Chemotherapy Reports
50 (1966): 349–540.

6. Quoted in
Time,
June 25, 1949, 66–73.

7. Recent disclosures of events dating back to the early 1930s cast a dark shadow upon Rhoads's character. While conducting research in Puerto Rico funded by the Rockefeller Institute, he allegedly injected cancer cells into dozens of individuals without their knowledge or consent as part of an experiment designed to see how humans develop cancer. At least thirteen of his subjects eventually died of the cancer. G. Goliszek,
In the Name of Science: A History of Secret Programs, Medical Research, and Human Experimentation
(New York: St. Martin's Press, 2003), 221–22. In a letter to a friend in 1931, he explained why he chose Puerto Ricans for his research: “The Puerto Ricans are the dirtiest, laziest, most degenerate and thievish race of men ever to inhabit this sphere…. What the island needs is not public health work, but a tidal wave or something to totally exterminate the population.” Carmelo Ruiz-Marrero, “Puerto Ricans Outraged Over Secret Medical Experiments,”
Puerto Rican Herald,
October 21, 2002. These recent allegations regarding Rhoads's human experimentation became a matter of enough concern to the American Association for Cancer Research (AACR) that they changed the name of their Cornelius P. Rhoads Scientific Achievement Award, which they had been presenting annually to outstanding young cancer researchers from 1980 to 2002, to the AACR Award for Outstanding Achievement in Cancer Research.

8. R. and E. Brecher, “They Volunteered for Cancer: Inmates of Ohio State Penitentiary,”
Reader's Digest,
April 1958, 62–66.

9. C. G. Zubrod, S. A. Schepartz, and S. K. Carter, “Historical Background of the National Cancer Institute's Drug Development Thrust,” in
Methods of Development of New Anticancer Drugs: USA-USSR Monograph
(Washington, D.C.: NCI, 1977), 7–11.

10. Quoted in Patterson,
The Dread Disease,
196.

11. Cited in Barbara J. Culliton, “National Cancer Plan: The Wheel and the Issues Go Round,”
Science,
March 30, 1973, 1305–309.

12. Richard A. Rettig,
Cancer Crusade: The Story of the National Cancer Act of 1971
(Princeton, N.J.: Princeton University Press, 1977).

13. Farber's advocacy was perhaps further impelled by his own personal experience. He had had colorectal cancer and would have to use a colostomy bag for the rest of his life.

14. In 1869 Paul Langerhans first described scattered clusters of cells in the pancreas, subsequently identified as the source of insulin and classically known as the islets of Langerhans. See Paul Langerhans,
Beiträge zur mikroskopischen Anatomie der Bauchspeicheldrüse
(Berlin: Gustave Lange, 1869), translated by H. Morrison as
Contributions to the Microscopic Anatomy of the Pancreas
(Baltimore, Md.: Johns Hopkins Press, 1937).

15. Rettig,
Cancer Crusade,
255–56.

16. Ted Kennedy was chairman of the Senate Health Subcommittee. One powerful motive on Nixon's part was to seize the health issue and impair Kennedy's potential candidacy as the Democratic presidential nominee in 1972.

17. D. S. Greenberg and J. E. Randall, “Waging the Wrong War on Cancer,”
Washington Post,
May 1, 1977.

18. The current screening system uses human cell lines grown in culture, allowing automation of the testing of candidate drugs for high-volume screening.

19. Public acceptance of the concept of clinical trials had been galvanized by the voluntary participation of millions of American families in the 1954 double-blind trials of the Salk polio vaccine.

20. C. G. Zubrod, “The cure of cancer by chemotherapy—reflections on how it happened,”
Med Pediatr Oncol
8 (1980): 107–14.

21. Michael B. Shimkin,
As Memory Serves: Six Essays on a Personal Involvement with the National Cancer Institute, 1938 to 1978
(Washington, D.C.: NIH, 1983).

22. J. C. Bailar III and E. Smith, “Progress against cancer,”
N Engl J Med
314 (1986): 1226–32.

23. P. B. Chowka, “Cancer,”
East West,
December 1987.

24. J. C. Bailar III and H. L. Gornik, “Cancer undefeated,”
N Engl J Med
336 (1997): 1569–74.

25. Jordan Goodman and Vivien Walsh,
The Story of Taxol: Nature and Politics in the Pursuit of an Anti-Cancer Drug
(Cambridge: Cambridge University Press, 2001).

26. Jerome Groopman, “The Thirty Years’ War: Have We Been Fighting Cancer the Wrong Way?”
New Yorker,
June 4, 2001, 52–63.

27. Clifton Leaf, “Why We're Losing the War on Cancer (And How to Win It),”
Fortune,
March 22, 2004.

Part III:
A Quivering Quartz String Penetrates
the Mystery of the Heart

The part epigraph is from
Introduction à l’étude de la médecine expérimentale
(Paris: Baillière, 1865). Bernard is known as the founder of experimental medicine.

C
HAPTER
22: An Unexpected Phenomenon: It's Electric!

1. A. Kölliker and H. Müller, “Nachweis der negativen Schwankung des Muskelstromes am naturlich sich contrahierenden Muskel,”
Verhandl Phys Med Gesellsch
6 (1856): 528–33.

2. This episode is reminiscent of an accidental observation made at the end of the eighteenth century by Luigi Galvani, professor of anatomy at the University of Bologna: “When one of my assistants by chance lightly applied the point of a scalpel to the inner crural nerves [main nerves of the legs of a dissected frog] suddenly all the muscles of the limbs were seen so to contract…. Another assistant… observed that this phenomenon occurred when a spark was discharged from the conductor of the [nearby] electrical machine.” L. Galvani, “De viribus electricitatis in motu musculari commentarius,”
De Bononiensi Scientarium et Artium Instituto atque Academia Commentarii
7 (1791): 363–418. Galvani was placed on the right path by this chance finding and went on to confirm that electrical stimulation can induce muscle contraction.

3. E. Besterman and R. Creese, “Waller—pioneer of electrocardiography,”
British Heart Journal
42 (1979): 61–64.

4. A. D. Waller, “The electrocardiogram of man and of the dog as shown by Einthoven's string galvanometer,”
Lancet
1 (1909): 1448–50.

5. W. Einthoven, “Enregistreur galvanométrique de l’électrocardiogramme humain et controle des résultats obtenus par l'emploi de l’électromètre capillaire en physiologie,”
Arch Néerland Sci Exactes Naturelles
9 (1904): 202–209.

6. I. Erschler, “Willem Einthoven—the man. The string galvanometer electrocardiograph,”
Arch Intern Med
148 (1988): 453–55.

7. Einthoven's instrument could not have been designed without recent technological advances. The critical ultrathin quartz filament was first made by another investigator less than twenty years earlier, and Einthoven cleverly adopted it for his use. Its tiny movements were made visible with a projecting microscope lens requiring modern kinds of glass. The brightest available point source of light, the carbon arc, had been developed as a reliable device only in the previous two decades. And the movements of the filament were recorded on a photographic plate that was coated with a recently developed sensitive emulsion. J. Burnett, “The origins of the electrocardiograph as a clinical instrument,”
Med Hist Suppl
5 (1985): 53–76.

8. Einthoven successfully recorded ventricular extra systoles (contractions), heart block (defects in the conduction system between the atria and the ventricles), atrial flutter and fibrillation, and ventricular muscle hypertrophy. His classic article in 1908 illustrating electrocardiograms from a wide variety of cardiac diseases documented the string galvanometer's great practical as well as theoretical importance. Willem Einthoven, “Weiteres über das Elektrokardiogramm,”
Pflügers Arch ges Physiol
122 (1908): 517–84. His three lead combinations for ECG recordings remain standard today.

9. In May 1908, Thomas Lewis, a London physician, had written to Einthoven to ask for a reprint of his landmark 1906 paper “Le télécardiogramme.” This was the beginning of a nearly twenty-year correspondence that resulted in major contributions to the development of clinical echocardiography. Lewis and Einthoven were ideal complements. Despite his medical training, Einthoven was essentially a physicist employing his talents in physiology. Lewis displayed great ingenuity in devising and carrying out experiments to clarify fundamental clinical problems.

10. W. Murrell, “Nitro-glycerine as a remedy for angina pectoris,”
Lancet
1 (1879): 80–81, 113–15, 151–52, 225–27.

11. James B. Herrick, “Historical Note,” in
Diseases of the Coronary Arteries and Cardiac Pain,
ed. Robert L. Levy (New York: Macmillan, 1936), 17.

12. S. A. Levine, “Willem Einthoven: Some historical notes on the occasion of the centenary celebration of his birth,”
Am Heart J
61 (1961): 422–23.

C
HAPTER
23: What a Catheter Can Do

1. Werner Forssmann,
Experiments on Myself: Memoirs of a Surgeon in Germany
(New York: St. Martin's Press, 1974), 85.

2. F. Splittgerber and D. E. Harken, “Catheterization of the right heart, by Werner Forssmann,”
Cardiac Chronicle
4 (1991): 13–15.

3. W. Forssmann, “Über Kontrastdarstellung der Höhlen des lebenden rechten Herzens und der Lungenschlagader,”
Münch Med Wochenschr
1 (1931): 489–92.

4. For studying the metabolism of the heart muscle itself, “the key in the lock” came about through a catheter tip misplaced during cardiac catheterization by Richard Bing at Johns Hopkins.

The heart muscle itself receives nourishing oxygen-rich blood through the coronary arteries and, like any other organ, drains the oxygen-depleted darker blood through a venous outlet. In this case, the outlet is termed the coronary sinus and it drains into the right side of the heart so that the blood can recirculate through the lungs. Bing's account thirty-five years after the chance occurrence is straightforward: “I pushed the catheter into what I thought was the right ventricle but when I drew the blood from the catheter it was black. This was a surprise because when we pulled the catheter back a bit, it was of the color which one expects to find in the right ventricle. We soon realized, working on cadavers, that we had entered the coronary sinus. This opened up a whole new field for me—that of cardiac metabolism.” Richard J. Bing, “Personal Memories of Cardiac Catheterization and Metabolism of the Heart,” in
History and Perspectives of Cardiology: Catheterization, Angiography, Surgery, and Concepts of Circular Control,
ed. H. A. Snellen, A. J. Dunning, and A. C. Arntzenius (The Hague: Leiden University Press, 1981), 43–45. The unintentional catheter probing of the coronary sinus enabled Bing to conduct new studies on the functional needs of the heart itself. Of all the muscles in the body, the heart has unique properties. It generally contracts sixty to one hundred times per minute, twenty-four hours a
day, with only a brief rest between each cardiac cycle. Its nutritional demands are great. It extracts the most oxygen from the blood flowing through it.

5. G. Liljestrand, “1956 Nobel Prize Presentation Speech,” in
Nobel Lectures, Physiology or Medicine,
vol. 3 (Amsterdam: Elsevier, 1964), 502.

6. S. I. Seldinger, “Catheter replacement of the needle in percutaneous arteriography,”
Acta Radiol
39 (1953): 368–76.