The Cancer Chronicles (11 page)

The clues had been lingering barely visible since the early 1900s when a German biologist,
Theodor Boveri, wondered why cancer cells had
strange-looking
chromosomes. Maybe, he speculated, they were damaged in a way that knocked out “factors,” whatever they
might be, that would normally rein in growth, allowing the cells
to “multiply without restraint.”

Reverting to a more primitive state, a cancer cell abandoned its communal obligation to replicate only when “the needs of the whole organism require it.” What had been a responsible member of an organization became like a single-minded paramecium whose only aim, Boveri wrote, is to egotistically propagate itself. Half a century before
DNA was decoded, he even ventured that a cancer cell goes native because “chemical and physical interventions” damage some of its internal workings without killing the cell outright. He was writing in 1914. Five years later, inspired by Boveri, the geneticists
Thomas Hunt Morgan and
Calvin B. Bridges found it “
conceivable at least that mammalian cancer may be due to recurrent somatic
mutation of some gene.” Another scientist spoke of cancer as “
a new kind of cell” in which “an ever recurring process of mutation is taking place, with a tendency, however, to deviate more and more from the normal type.” It is as impressive as it is frustrating how close they came to the mark.

Evidence had also been accumulating that radioactivity, like x-rays, was capable of causing mutations. Since
ancient Rome,
uranium had been mined and extracted from a rock called
pitchblende for use as a yellow pigment in making glass and ceramics. No one knew of its more exotic qualities until 1896 when Henri
Becquerel accidentally discovered that uranium salts wrapped in opaque paper or shielded with aluminum would fog photographic plates. He thought at first that the crystals were absorbing sunlight and then reemitting these piercing rays. What a chill he must have felt when he realized that the uranium was not sucking up the energy but producing it—this invisible and piercing light.

The situation only grew stranger when
Marie
Curie noticed that pitchblende retained its power even after the uranium was removed—in fact, the leftover ore was far more radioactive than the purified uranium itself. There must be something else in the rock that was even hotter. She and her husband, Pierre, isolated
and named a new radioactive element,
polonium (after Poland, her native land), only to find that the rock remaining was still extremely radioactive. Something still hidden inside was shooting out these incredible rays.

“Pierre, what if there is
a kind of matter in the world that we’ve never even dreamed of.…What if there exists a matter that is not inert but alive?” That’s Greer Garson, playing Curie in the 1943 movie
Madame Curie,
in a scene as erudite as it is melodramatic. In a drafty shed at the University of Paris she sifts through piles of pitchblende and extracts the tiniest speck of what she names
radium. In the best part of the movie she and Pierre come upon the shed at night and find it shining with an eerie
glow. The real story, uncompressed and undramatized, is just as moving. Here is how Curie described it in her own writings: “
One of our joys was to go into our workroom at night; we then perceived on all sides the feebly luminous silhouettes of the bottles or capsules containing our products. It was really a lovely sight and one always new to us. The glowing tubes looked like faint, fairy lights.” What the Curies were witnessing were contrails of light produced by charged particles shooting through the air,
an optical analog of a sonic boom.

Radium also glows when its rays strike a phosphorescent chemical like
zinc sulfide, and before long the two substances were mixed to produce glow-in-the-dark watch dials. Painting the numbers was a painstaking task—the hook at the top of a 2 thinning just so to produce the narrow downstroke, thickening again to form the base line. The numerals 3, 6, and 8 were equally demanding. To clean the tips of the brushes and keep them pointed, workers were trained to wet and shape them with their lips and tongues. Assuming that the paint was harmless, some of the dial painters—they became known in news reports as the
Radium Girls—used it to
decorate their teeth, fingernails, and eyebrows. It must have been great for Halloween.

Mistaken by the body for calcium, radium became incorporated into their bones, where it sat firing off high-speed electrons, alpha particles, and gamma rays, killing cells or transforming them and
eventually giving some of the women
cancer. Here was the paradox again: Curie herself had been promoting radium, like x-rays, as a therapy for shrinking cancerous tumors. But here it was producing tumors from healthy cells. In 1927 when the Radium Girls were making headlines,
Muller’s paper appeared, speculating that the mutagenic power of x-rays might be responsible for their ability to cause cancer. If so, then the same was probably true for radium’s fairy light.

Long before invisible rays became a suspect, doctors were seeing clues that cancer could also be caused by more tangible stuff. In 1775 a London surgeon realized that “
soot warts,” sores appearing on the
scrotums of
chimney sweeps, were not venereal disease but a malignancy—apparently caused when skin came into contact with the black tars and dust left by burnt coal.
The same cancer was later found in workers who manufactured paraffin and other
coal tar distillates, and by the early twentieth century scientists were producing
carcinomas by repeatedly
applying coal tar to
rabbits’ ears. Coal tar was found to consist of a witch’s brew of
carbon-based compounds—
benzene,
aniline,
naphthalene,
phenols—and during the next few decades scientists discovered that many of them
produced tumors in laboratory animals. It would have been unethical for them to expose human subjects to the carcinogens to see if they caused cancer. They didn’t have to. With the growth of the cigarette industry, people were performing the experiment on themselves.

By the time the century was half through we knew that
radiation caused both mutations and cancer. We knew that a host of different chemicals also caused cancer, and many of these were soon shown to be mutagens. They altered a cell’s genetic software by changing snippets of the DNA code. In the early 1970s
Bruce Ames (the scientist best known for showing that ordinary fruits and vegetables contain carcinogens) came up with a striking demonstration. Instead of fruit flies, he worked with
salmonella bacteria—strains that had lost the recipe for making
histidine, an amino acid they needed in order to reproduce. If placed in a dish of nutrients with a dash of this vital
ingredient, the bacteria would grow, but only until they had depleted the supply. Then the whole colony would die. Ames discovered that if carcinogens were added to the mix, some of the salmonella would keep on living, expanding and overtaking the dish. The chemicals were presumably producing mutations at random. But each bacterium’s genome carried so little information, and there were so many of the microbes—billions of them—that the mutations would include ones that happened to restore the ability to synthesize histidine.

The procedure came to be called
the
Ames test—a fast and dirty way to see if a chemical might be mutagenic. In instance after instance, chemicals that passed the Ames test also produced
tumors in laboratory animals. The case almost seemed clinched. What causes cancer, whether chemical or energetic, does so by altering genetic information. The pieces of a theory were falling into place, except for a stubborn exception—at least some cancers appeared to be caused neither by chemicals nor penetrating rays but by
viruses.

In retrospect that is not so surprising. Existing on the boundary between chemistry and life, viruses are packets of information—streamlined sequences of DNA or RNA wrapped in a protective sheath. They are wandering
genomes so simple that some consist of only three genes. Like the handmade Internet viruses they later inspired, they infiltrate their hosts (the biological computers called cells) and commandeer the internal machinery. There the invader’s genes are dutifully duplicated and repackaged again and again, the viral copies spreading to other cells where they robotically carry out the same routine—life itself stripped of its capacity to do anything except reproduce.

A few viruses operate in an even more convoluted way. They copy and splice their genes directly into a cell’s
chromosomes. This infiltrating algorithm orders the host itself to replicate at an accelerated pace. It becomes a cancer cell. The earliest example was reported in 1910 by
Peyton Rous, a scientist at the
Rockefeller Institute for Medical Research who was
studying chicken tumors. He began by extracting fluid from an irregularly shaped glob growing in the
breast of a Plymouth Rock hen and then injecting it into another bird. Thirty-five days later the first chicken had died from the cancer, a
sarcoma, and the second chicken had developed a tumor of the same kind. Material taken from the tumor could, in turn, be used to spread the cancer to another bird. And so it went from fowl to fowl. The transforming agent turned out to be a
retrovirus—the kind that can smuggle
cancer-causing
genes into otherwise healthy cells.

There was
src,
which was part of the virus that caused sarcoma in chickens. Another gene, called
ras,
induced sarcoma in rats, while
fes
did the same in felines.
Myc
and
myb
induced blood cell cancers,
myelocytomatosis and
myeloblastosis, in poultry. If that is where the research had ended it would have made for a tidy picture. Cancer could be caused when chemicals or radiation mutated preexisting genes, or when viruses surreptitiously inserted entirely new ones—
oncogenes, they were called—already capable of causing cancer. Two fundamental ways of modifying genetic information. But the real story turned out to be far more interesting.

There was a problem reconciling Rous’s discovery with what appeared to be happening in the world. Cancer wasn’t acting like a
contagious disease sweeping through populations like polio. It arose sporadically in various places. Even Rous’s chicken virus spread only when it was injected, and try as he might he couldn’t transfer it to other animals—pigeons, ducks, rats, mice, guinea pigs, rabbits. Only with great difficulty could it be induced in other chickens except closely related Plymouth hens. Even more suggestive, scientists were not finding the retroviruses inside human tumors. What they were discovering instead was that genomes of creatures throughout the animal kingdom contained what appeared to be naturally occurring versions of
src, ras, fes, myb, myc
—not ones that had been smuggled in. These were not broken, mutated genes like their viral counterparts. Their purpose was to govern how healthy cells divide, the process biologists call
mitosis.

This is apparently what was happening: Occasionally a virus going about its rounds would accidentally copy one of these innocent
“host” genes into its own genome. Passed along from virus to virus, the gene mutated into a form that caused
cancer. But all that was a fluke. The virus was an accidental player in the story, the place where the first of these genes happened to have been discovered. Some cancers can be directly caused by a viral invasion—human
papillomavirus and
cervical cancer,
hepatitis viruses and
liver cancer. But these are exceptions. Far more often cancer arose when the original gene, sitting secure in its own cell, underwent a random mutation, one caused externally by a
carcinogen or internally by an unprovoked copying error. One way or another the gene’s normal function became distorted, tipping the cell toward malignancy. Since genes like these were capable of transmogrifying into a cancer gene,
they were named
proto-oncogenes. Had their true function been discovered before their aberrant one, they would be called something else.

Studying the genes more closely, researchers discovered how they regulate the ways in which cells grow and multiply in harmony. Some of the genes controlled the production of receptors that protruded from a cell’s surface—molecules tuned to respond to signals from other cells. When these molecular antennae received a message they would relay the information internally to their own cell’s nucleus—instructions to activate the machinery for dividing into daughter cells. If the gene became mutated the cell might produce too many receptors or overly sensitive ones. Spooked into responding to silence, they would pummel the cell with false alarms. Still other broken genes might unleash messages urging the cell’s neighbors to flood it with more growth-stimulating chemicals. Or, in its hyped-up state, the cancer cell might overreact to its own signals, screaming at itself to grow.

Genes related to
src
are mutated in
colon and many other cancers. Crippled
ras
genes show up in a variety of human malignancies—pancreatic, colorectal,
thyroid,
melanoma,
lung. All that it takes to turn a good
ras
into a bad
ras
is a single point mutation—a G flipped to T, A, or C—a random typo in a message hundreds of letters long.
Other mutations occur during cellular division when a normal
gene is copied too many times. Repeating
ras
genes are found in lung,
ovarian,
bladder, and other
cancers. Stuttering
myc
s help give rise to a childhood brain cancer called
neuroblastoma.
Some mutations are even more wrenching: A
chromosome might break and then join with another, placing two previously distant genes side by side. In
Burkitt’s lymphoma, a mutation like this shoves a
myc
gene next to an overbearing stranger that drives its new partner to overexpress itself, churning out signals that cause the cell to divide and divide and divide.

It was a terrifying possibility—that a single mutation might be enough to shift a gene into overdrive and give rise to a deadly tumor. But not even an oncogene wields so much power. Researchers found that inserting one or even two
oncogenes into a cell was usually not enough to ignite a cancer—unless the cell had already accumulated some earlier defects. Living systems are governed by a gyroscopic balance in which an extreme force from one direction is met with a countervailing shove. While the 1970s was the decade of the oncogene, in the 1980s scientists began discovering
anti-oncogenes—genes whose purpose was to respond to rapid bursts of cellular division by slowing the process down.