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contemporaries and prompted no experiment. So in 1914, Boveri ex-
panded his speculation into one of the most famous books in the his-
tory of biomedical science, entitled The Origin of Malignant Tumors; in
154 Opening the Black Box of Cancer
the canon of cancer research, it is easily equivalent to the Principia of
Newton in classical physics. The central argument was as follows:
The unlimited tendency to rapid proliferation in malignant tumor
cells [could result] from a permanent predominance of the chromo-
somes that promote division. . . Another possibility [to explain can-
cer] is the presence of definite chromosomes which inhibit division
. . . Cells of tumors with unlimited growth would arise if those in-
hibiting chromosomes were eliminated . . . [Since] each kind of
chromosome is represented twice in the normal cell, the depression
of only one of these two might pass unnoticed.18
To modern students of genetics and cancer, these are breathtaking
conclusions: in the assumption that specific chromosomal elements
govern cell division; in the clear description of what we now call ge-
netic dominance and recessiveness, decades before these concepts be-
came clear from experiments in fruit flies; and in the anticipation by
almost a century of the genetic malady in cancer cells.
The prescience of Boveri finally became clear in 1960, when Peter
Nowell and David Hungerford teamed up to identify the Philadel-
phia Chromosome, an abnormality found consistently in cells of
chronic myelogenous leukemia, and the first chromosomal anomaly
specifically associated with any neoplasm, named for the city in which
it was discovered. The optical resolution available to Hungerford and
Nowell failed to reveal the detailed nature of the Philadephia Chromo-
some, so it was 1973 before Janet Rowley showed that the abnormal-
ity arises from a physical mishap known as reciprocal translocation.
Chromosomes 9 and 22 exchange portions of one of their arms, and
one product of this exchange is the Philadelphia Chromosome. Why
and how this happens, we do not yet know.
We do now know, however, of more than two hundred chromo-
somal aberrations that are consistently associated with one or another
type of cancer. Each of these represents an explicit manifestation of
the genetic mayhem in cancer cells. In many instances, the physical
joints formed by the translocations and the genes residing there have
been isolated by using the procedures of recombinant DNA. In mak-
ing these isolations, scientists are drilling to the very core of tumori-
Opening the Black Box of Cancer 155
Chromosomes and
cancer. Title page of the
monograph that gave
Theodor Boveri a last-
ing place in medical
history.
[To view this image, refer to
the print version of this title.]
genesis, spotlighting genes that might be contributing to the malady.
These are extraordinary developments. When I graduated from medi-
cal school in 1962, cytogenetics was not yet even a diagnostic proce-
dure, and the possibility of isolating pieces of DNA from focal points
of a chromosome was beyond even fantasy.
Cytogenetics succeeded in pointing to the genetic apparatus as the
ailing organ of the cancer cell. But the implication that malfunction-
ing genes might propel neoplastic growth could not be tested with
microscopy. Instead, it was the study of viruses that produced the first
explicit example of cancer genes the fourth of our converging
themes.
156 Opening the Black Box of Cancer
Viruses and Cancer
At the turn of this century, the germ theory of disease had gained
great currency, owing mainly to the work of Robert Koch in Germany
and Louis Pasteur in France. It seemed for a while as if all diseases
might have microbial causes. Since no effort to implicate bacteria
in cancer had succeeded, it was only natural that the discovery of
viruses in 1898 1900 would lead immediately to inquiries about
whether these agents might cause cancer. The first step was to ask
whether cancer could be transmitted from one host to another by tu-
mor extracts that had been filtered to remove bacteria and other cells.
The only microbes that were likely to pass through the filters were vi-
ruses.
The first success came in 1908, when the Danish scientists Vilhelm
Ellerman and Oluf Bang reported that they could transmit leukemia
from one chicken to another with an infectious extract of blood cells.
The work was dismissed as unimportant because leukemias were not
in those days considered to be malignancies, and because chickens
were not interesting. Peyton Rous at the Rockefeller Institute in New
York City thought otherwise. In 1909, a farmer from Long Island ap-
peared at the institute with a prize Plymouth Rock hen that had devel-
oped a tumor in the muscle of its right breast. The farmer hoped that
the hen might be cured. He was referred to Peyton Rous, one of the
few scientists at the Institute who had displayed an interest in cancer.
After what must have been some slick talking, Rous killed the chicken
and performed two landmark experiments.
First, he succeeded in transplanting the tumor cells from one
chicken to another. This was a notable achievement, particularly be-
cause Rous had the good sense to perform the transplantations with
chickens from the flock of the same farmer, thus displaying both an
early awareness of transplantation immunity and negotiating skills of
the highest order.
The second experiment took Rous to a new level of immediate con-
troversy and eventual triumph. He prepared an extract of the tumor
cells and passed it through a filter, much as Ellerman and Bang had
Opening the Black Box of Cancer 157
done with the chicken leukemias. Rous then injected the extract into
healthy chickens, which proceeded to develop tumors similar to those
in the original hen. It appeared that the filtered extracts contained an
infectious agent more than likely, a virus that could elicit tumors.
The experiment succeeded only after the tumor cells had been trans-
planted several times from one chicken to another, suggesting that the
infectious agent might have emerged during the transplantations. It
would be three decades before the deep significance of this nuance be-
came apparent from the work that earned the Nobel Prize for Harold
Varmus and myself more of that shortly.
Rous realized that he had discovered a virus that causes cancer.19
Neither Rous nor anyone else of his time really knew what a virus
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