The Emperor of All Maladies: A Biography of Cancer (68 page)

Src
was a prototypical kinase—although a kinase on hyperdrive. The protein made by the viral
src
gene was so potent and hyperactive that it phosphorylated anything and everything around it, including many crucial proteins in the cell.
Src
worked by unleashing an indiscriminate volley of phosphorylation—throwing “on” dozens of molecular switches. In
src
’s case, the activated series of proteins eventually impinged on proteins that controlled cell division.
Src
thus forcibly induced a cell to change its state from nondividing to dividing, ultimately inducing accelerated mitosis, the hallmark of cancer.

By the late 1970s, the combined efforts of biochemists and tumor virologists had produced a relatively simple view of
src
’s ability to transform cells. Rous sarcoma virus caused cancer in chickens by introducing into cells a gene,
src
, that encoded a hyperactive overexuberant kinase. This kinase turned “on” a cascade of cellular signals to divide relentlessly. All of this represented beautiful, careful, meticulously crafted work. But with no human cancer retroviruses in the study, none of this research seemed relevant immediately to human cancers.

Yet the indefatigable Temin still felt that viral
src
would solve the mystery of human cancers. In Temin’s mind, there was one riddle yet to be solved: the evolutionary origin of the
src
gene. How might a virus have “acquired” a gene with such potent, disturbing qualities? Was
src
a viral kinase gone berserk? Or was it a kinase that the virus had constructed out of bits of other genes like a cobbled-together bomb? Evolution, Temin knew, could build new genes out of old genes. But where had Rous sarcoma virus found the necessary components of a gene to make a chicken cell cancerous?

At the University of California in San Francisco (UCSF), in a building perched high on one of the city’s hills, a virologist named J. Michael Bishop became preoccupied with the evolutionary origin of viral
src.
Born in rural Pennsylvania, where his father had been a Lutheran minister, Bishop had studied history at Gettysburg College, then drastically altered his trajectory to attend Harvard Medical School. After a residency
at Massachusetts General Hospital, he had trained as a virologist. In the 1960s, Bishop had moved to UCSF to set up a lab to explore viruses.

UCSF was then a little-known, backwater medical school. Bishop’s shared office occupied a sliver of space at the edge of the building, a room so cramped and narrow that his office-mate had to stand up to let him through to his desk. In the summer of 1969, when a lanky, self-assured researcher from the NIH, Harold Varmus, then on a hiking trip in California, knocked on Bishop’s office door to ask if he might join the lab to study retroviruses, there was hardly any standing room at all.

Varmus had come to California seeking adventure. A former graduate student in literature, he had become enthralled by medicine, obtained his M.D. at Columbia University in New York, then learned virology at the NIH. Like Bishop, he was also an academic itinerant—wandering from medieval literature to medicine to virology. Lewis Carroll’s
Hunting of the Snark
tells the story of a motley crew of hunters that launch an agonizing journey to trap a deranged, invisible creature called the Snark. That hunt goes awfully wrong. Unpromisingly, as Varmus and Bishop set off to understand the origins of the
src
gene in the early 1970s,
other scientists nicknamed the project
“the hunting of the sarc.”

Varmus and Bishop launched their hunt using a simple technique—a method invented, in part, by Sol Spiegelman in the 1960s. Their goal was to find cellular genes that were distantly similar to the viral
src
gene—and thus find
src
’s evolutionary precursors. DNA molecules typically exist as paired, complementary strands, like yin and yang, that are “stuck” together by powerful molecular forces. Each strand, if separated, can thus stick to another strand that is complementary in structure. If one molecule of DNA is tagged with radioactivity, it will seek out its complementary molecule in a mixture and stick to it, thereby imparting radioactivity to the second molecule. The sticking ability can be measured by the amount of radioactivity.

In the mid-1970s, Bishop and Varmus began to use the viral
src
gene to hunt for its homologues, using this “sticking” reaction.
Src
was a viral gene, and they expected to find only fragments or pieces of
src
in normal cells—ancestors and distant relatives of the cancer-causing
src
gene. But the hunt soon took a mystifying turn. When Varmus and Bishop looked in normal cells, they did not find a genetic third or fifth cousin of
src.
They
found a nearly identical version of viral
src
lodged firmly in the normal cell’s genome.

Varmus and Bishop, working with Deborah Spector and Dominique Stehelin, probed more cells, and again the
src
gene appeared in them: in duck cells, quail cells, and geese cells. Closely related homologues of the
src
gene were strewn all over the bird kingdom; each time Varmus’s team looked up or down an evolutionary branch, they found some variant of
src
staring back. Soon, the UCSF group was racing through multiple species to look for homologues of
src
. They found
src
in the cells of pheasants, turkeys, mice, rabbits, and fish. Cells from a newborn emu at the Sacramento zoo had
src.
So did sheep and cows. Most important, so did human cells. “
Src,
”
Varmus wrote in
a letter in 1976, “. . . is everywhere.”

But the
src
gene that existed in normal cells was not identical to the viral
src.
When Hidesaburo Hanafusa, a Japanese virologist at Rockefeller University in New York, compared the viral
src
gene to the normal cellular
src
gene, he found a crucial difference in the genetic code between the two forms of
src
. Viral
src
carried mutations that dramatically affected its function. Viral
src
protein, as Erikson had found in Colorado, was a disturbed, hyperactive kinase that relentlessly tagged proteins with phosphate groups and thus provided a perpetually blaring “on” signal for cell division. Cellular
src
protein possessed the same kinase activity, but it was far less hyperactive; in contrast to viral
src
, it was tightly regulated—turned “on” and turned “off”—during cell division. The viral
src
protein, in contrast, was a permanently activated switch—“an automaton,” as Erikson described it—that had turned the cell into a dividing machine. Viral
src
—the cancer-causing gene—was cellular
src
on overdrive.

A theory began to convulse out of these results, a theory so magnificent and powerful that it would explain decades of disparate observations in a single swoop:
perhaps
src,
the precursor to the cancer-causing gene, was endogenous to the cell.
Perhaps viral
src
had
evolved
out of cellular
src
. Retrovirologists had long believed that the virus had introduced an activated
src
into normal cells to transform them into malignant cells. But the
src
gene had not originated in the virus. It had originated from a precursor gene that existed in a cell—in
all
cells. Cancer biology’s decades-long hunt had started with a chicken and ended, metaphorically, in the egg—in a progenitor gene present in all human cells.

Rous’s sarcoma virus, then, was the product of an incredible evolutionary accident. Retroviruses, Temin had shown, shuttle constantly out of the
cell’s genome: RNA to DNA to RNA. During this cycling, they can pick up pieces of the cell’s genes and carry them, like barnacles, from one cell to another. Rous’s sarcoma virus had likely picked up an activated
src
gene from a cancer cell and carried it in the viral genome, creating more cancer. The virus, in effect, was no more than an accidental courier for a gene that had originated in a cancer cell—a parasite parasitized by cancer. Rous had been wrong—but spectacularly wrong. Viruses did cause cancer, but they did so, typically, by tampering with genes that originate in cells.

Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself.

Varmus and Bishop’s experiments had precisely such a crystallizing, zippering effect on cancer genetics. The crucial implication of the Varmus and Bishop experiment was that a precursor of a cancer-causing gene—the “proto-oncogene,” as Bishop and Varmus called it—was a normal cellular gene. Mutations induced by chemicals or X-rays caused cancer not by “inserting” foreign genes into cells, but by activating such
endogenous
proto-oncogenes.

“
Nature,” Rous wrote in 1966
, “sometimes seems possessed of a sardonic humor.” And the final lesson of Rous sarcoma virus had been its most sardonic by far. For nearly six decades, the Rous virus had seduced biologists—Spiegelman most sadly among them—down a false path. Yet the false path had ultimately circled back to the right destination—from viral
src
toward cellular
src
and to the notion of internal proto-oncogenes sitting omnipresently in the normal cell’s genome.

In Lewis Carroll’s poem, when the hunters finally capture the deceptive Snark, it reveals itself not to be a foreign beast, but one of the human hunters sent to trap it. And so it had turned out with cancer. Cancer genes came from
within
the human genome. Indeed the Greeks had been peculiarly prescient yet again in their use of the term
oncos
. Cancer was intrinsically “loaded” in our genome, awaiting activation. We were destined to carry this fatal burden in our genes—our own genetic “oncos.”

Varmus and Bishop were awarded the Nobel Prize for their discovery of the cellular origin of retroviral oncogenes in 1989. At the banquet in Stockholm, Varmus, recalling his former life as a student of literature, read lines from the epic poem
Beowulf
, recapitulating the slaying of the dragon in that story: “
We have not slain our enemy
, the cancer cell, or figuratively torn the limbs from his body,” Varmus said. “In our adventures, we have only seen our monster more clearly and described his scales and fangs in new ways—ways that reveal a cancer cell to be, like Grendel, a distorted version of our normal selves.”

*
The term
oncogene
had been coined earlier by two NCI scientists, Robert Huebner and George Todaro, in 1969, although on scant evidence.

†
Art Levinson, in Mike Bishop’s lab at UCSF, also discovered this phosphorylating activity; we will return to Levinson’s discovery in later pages.