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tion to Ignaz Semmelweiss in the matter of puerperal fever.8
Out of the germ of truth embedded in Virchow s ideas, there even-
tually emerged an overarching view of how cancer cells arise. The
American pathologist Peter Nowell brought this view to its final form
in the 1970s. The errant cell that initiates the genesis of a cancer is not
in itself malignant. But the progeny of that cell continue to change,
step by step. Each step represents a genetic event that is favored be-
cause it makes the cellular lineage more robust. Over time, the ma-
lignant state is reached: emerging cancer cells acquire the ability to
proliferate indefinitely, to invade adjacent tissue, to disseminate as
metastases, to evoke the provision of a new blood supply, to elude the
defenses that usually eliminate incipient cancer cells. Thus, every tu-
mor represents the outcome of an individual experiment in cellular
evolution, driven by relentless selection for advantage.9 Nothing in
biology makes sense except in the light of evolution, not even an out-
law like cancer.10
The Extrinsic Causes of Cancer
If cancer begins as a single cell that eventually progresses to a full-
blown malignancy, then what drives the deadly sequence of events? At
the outset, there seemed to be two possible answers: cancer might arise
from spontaneous events intrinsic to our bodies our cells might go
astray of their own accord or there might be extrinsic agents that
elicit the mischief. There is no inherent reason that these two possibili-
ties should be mutually exclusive, but for at least two centuries, the fo-
cus has been mainly on extrinsic causes.
In a magisterial summary published in 1981, Richard Doll and
Richard Peto argued that 80 percent or more of cancers in the United
States are in principle preventable because they arise from various ex-
trinsic causes such as diet, lifestyle, personal habits, and environmental
factors.11 That view has gained great credibility in the interim. In addi-
tion, however, we have convinced ourselves that the various extrinsic
146 Opening the Black Box of Cancer
causes of cancer might be united by a common mechanism; and para-
doxically, that such a mechanism can also explain the competing in-
trinsic view of carcinogenesis.12 The unifying mechanism is damage to
DNA, the second of our converging themes.
In 1761, John Hill, a London physician, published the claim that in-
halation of snuff caused nasal cancer. This is reputed to be the first for-
mal report of an external cause of cancer. In our time, the evocative
word snuff has been replaced by the disarming term smokeless to-
bacco. But its consequences for human health remain every bit as om-
inous. Hill was anticipated in spirit by King James I of England, who
in 1604 railed against the evils of smoking in an edict he entitled
Counterblast to Tobacco. The king also encouraged the public exhi-
bition of human lungs blackened by tobacco smoke in an effort to dis-
courage smoking.
Fourteen years after Hill s publication about snuff, Percival Pott
achieved lasting fame when he reported that the chimney sweeps of
Britain were highly prone to cancer of the scrotum, and attributed this
to the soot of incompletely burned coal. French sweeps were said to
be less afflicted, perhaps because they washed more frequently than
the Brits (a national difference some say persists to this day). Danish
chimney sweeps had a similar problem, which was ameliorated by the
use of protective clothing in what is generally viewed as the first suc-
cessful program for cancer prevention. Tobacco provided one addi-
tional hint when, in 1795, Samuel T. von Soemmerring noted that pipe
smokers suffered an unusually high incidence of lip cancer.
These crude efforts at what we now call epidemiology were far
ahead of their time, and recognition of their significance languished
until late in the nineteenth century. Then the industrial revolution ex-
posed humans to large quantities of noxious agents. Within decades,
paraffin oils, mining dust, arsenic, aniline dyes, and asbestos came un-
der suspicion. The importance of physical agents also became appar-
ent, in the form of skin cancers attributed to excessive sunlight, as well
as those affecting experimentalists working with the newly discovered
X-rays. During the twentieth century, numerous physical and chemi-
cal agents were implicated as causes of cancer by observation of large
Opening the Black Box of Cancer 147
populations. Two particular heroes of that story stand out from a mer-
itorious crowd.
The first was Wilhelm C. Hueper, a German physician who immi-
grated to the United States in 1923 with a well-established interest in
occupational disease.13 Heuper was hired by the Du Pont company to
pursue the relationship between exposure to chemicals known as aro-
matic amines and bladder cancer. But when his findings proved em-
barrassing to his corporate employers, he was fired. He used his en-
forced leisure to write a magnum opus entitled Occupational Tumors
and Allied Diseases, the first authoritative treatise on the occupational
causes of cancer.
Hueper spent the remainder of his career at the National Cancer In-
stitute in Bethesda, Maryland, where his efforts to study occupational
hazards were resisted and even censored. By the time he retired, how-
ever, his once heretical message about carcinogens in the workplace
was national dogma, and concern about environmental carcinogens
had become, if anything, overwrought. Hueper s story has a curious
postscript: until virtually the end of his career, he vigorously dis-
counted the mounting evidence that smoking is a major cause of lung
cancer.
Hueper should have listened more carefully to our second hero,
Ernst Wynder. While still a medical student in the 1940s, Wynder en-
countered a hint that there might be a connection between smoking
and lung cancer (not a new idea even then, but one that had been paid
little heed). He initiated his own study of the issue and quickly accu-
mulated provocative data. Wynder solicited the patronage of one of
his faculty Evarts Graham, a distinguished thoracic surgeon and a
heavy smoker. Graham was at first skeptical, but when he saw the final
results from Wynder s study, he bought the argument and stopped
smoking (to no avail Graham died of lung cancer a few years later).
Wynder and Graham published their first set of data in 1950, claim-
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