The Emperor of All Maladies: A Biography of Cancer (77 page)

Since the early 1970s, this maturation arrest of APL cells had prompted scientists to hunt for a chemical that might force these cells to mature. Scores of drugs had been tested on APL cells in test tubes, and only one had stood out—retinoic acid, an oxidized form of vitamin A. But retinoic acid, researchers had found, was a vexingly unreliable reagent. One batch of the acid might mature APL cells, while another batch of the same chemical might fail. Frustrated by these flickering, unfathomable responses, biologists and chemists had turned away after their initial enthusiasm for the maturation chemical.

In the summer of 1985
, a team of leukemia researchers from China traveled to France to meet Laurent Degos, a hematologist at Saint Louis Hospital in Paris with a long-standing interest in APL. The Chinese team, led by Zhen Yi Wang, was also treating APL patients, at Ruijin Hospital, a busy, urban clinical center in Shanghai, China. Both Degos and Wang had tried standard chemotherapy agents—drugs that target rapidly growing cells—to promote remissions in APL patients, but the results had been dismal. Wang and Degos spoke of the need for a new strategy to attack this whimsical, lethal disease, and they kept circling back to the peculiar immaturity of APL cells and to the lapsed search for a maturation agent for the disease.

Retinoic acid, Wang and Degos knew, comes in two closely related molecular forms, called cis-retinoic acid and trans-retinoic acid. The two forms are compositionally identical, but possess a slight difference in their molecular structure, and they behave very differently in molecular reactions. (Cis-retinoic acid and trans-retinoic acid have the same atoms, but the atoms are arranged differently in the two chemicals.) Of the two forms, cis-retinoic acid had been the most intensively tested, and it had produced the flickering, transient responses. But Wang and Degos wondered if trans-retinoic acid was the true maturation agent. Had the unreliable responses in the old experiments been due to a low and variable amount of the trans-retinoic form present in every batch of retinoic acid?

Wang, who had studied at a French Jesuit school in Shanghai, spoke a lilting, heavily accented French. Linguistic and geographic barriers breached, the two hematologists outlined an international collaboration. Wang knew of a pharmaceutical factory outside Shanghai that could produce pure trans-retinoic acid—without the admixture of cis-retinoic acid.
He would test the drug on APL patients at the Ruijin Hospital. Degos’s team in Paris would follow after the initial round of testing in China and further validate the strategy on French APL patients.

Wang launched his trial in 1986 with twenty-four patients. Twenty-three experienced a dazzling response. Leukemic promyelocytes in the blood underwent a brisk maturation into white blood cells. “
The nucleus became larger
,” Wang wrote, “and fewer primary granules were observed in the cytoplasm. On the fourth day of culture, these cells gave rise to myelocytes containing specific, or secondary, granules . . . [indicating the development of] fully mature granulocytes.”

Then something even more unexpected occurred: having fully matured, the cancer cells began to die out. In some patients, the differentiation and death erupted so volcanically that the bone marrow swelled up with differentiated promyelocytes and then emptied slowly over weeks as the cancer cells matured and underwent an accelerated cycle of death. The sudden maturation of cancer cells produced a short-lived metabolic disarray, which was controlled with medicines, but the only other side effects of trans-retinoic acid were dryness of lips and mouth and an occasional rash. The remissions produced by trans-retinoic acid lasted weeks and often months.

Acute promyelocytic leukemia still relapsed, typically about three to four months after treatment with trans-retinoic acid. The Paris and Shanghai teams next combined standard chemotherapy drugs with trans-retinoic acid—a cocktail of old and new drugs—and remissions were prolonged by several additional months. In about three-fourths of the patients, the leukemia remission began to stretch into a full year, then into five years. By 1993, Wang and Degos concluded that 75 percent of their patients treated with the combination of trans-retinoic acid and standard chemotherapy would never relapse—a percentage unheard of in the history of APL.

Cancer biologists would need another decade to explain the startling Ruijin responses at a molecular level. The key to the explanation lay in the elegant studies performed by Janet Rowley, the Chicago cytologist. In 1984, Rowley had identified a unique translocation in the chromosomes of APL cells—a fragment of a gene from chromosome fifteen fused with a fragment of a gene from chromosome seventeen. This created an activated “chimeric” oncogene that drove the proliferation of promyelocytes and blocked their maturation, thus creating the peculiar syndrome of APL.

In 1990, a full four years after Wang’s clinical trial in Shanghai, this culprit oncogene was isolated by independent teams of scientists from France, Italy, and America. The APL oncogene, scientists found, encodes a protein that is tightly bound by trans-retinoic acid. This binding immediately extinguishes the oncogene’s signal in APL cells, thereby explaining the rapid, powerful remissions observed in Shanghai.

The Ruijin discovery was remarkable: trans-retinoic acid represented the long-sought fantasy of molecular oncology—an oncogene-targeted cancer drug. But the discovery was a fantasy lived backward. Wang and Degos had first stumbled on trans-retinoic acid through inspired guesswork—and only later discovered that the molecule could directly target an oncogene.

But was it possible to make the converse journey—starting
from
oncogene and going
to
drug? Indeed, Robert Weinberg’s lab in Boston had already begun that converse journey, although Weinberg himself was largely oblivious of it.

By the early 1980s, Weinberg’s lab had perfected a technique to isolate cancer-causing genes directly out of cancer cells. Using Weinberg’s technique, researchers had isolated dozens of new oncogenes from cancer cells.
In 1982, a postdoctoral scientist
from Bombay working in Weinberg’s lab, Lakshmi Charon Padhy, reported the isolation of yet another such oncogene from a rat tumor called a neuroblastoma. Weinberg christened the gene
neu
, naming it after the type of cancer that harbored this gene.

Neu
was added to the growing list of oncogenes, but it was an anomaly. Cells are bounded by a thin membrane of lipids and proteins that acts as an oily barrier against the entry of many drugs. Most oncogenes discovered thus far, such as
ras
and
myc
, are sequestered inside the cell (
ras
is bound to the cell membrane but faces into the cell), making them inaccessible to drugs that cannot penetrate the cell membrane. The product of the
neu
gene, in contrast, was a novel protein, not hidden deep inside the cell, but tethered to the cell membrane with a large fragment that hung outside, freely accessible to any drug.

Lakshmi Charon Padhy even had a “drug” to test. In 1981, while isolating his gene, he had created an antibody against the new
neu
protein. Antibodies are molecules designed to bind to other molecules, and the binding can occasionally block and inactivate the bound protein. But anti
bodies are unable to cross the cell membrane and need an exposed protein outside the cell to bind.
Neu
, then, was a perfect target, with a large portion, a long molecular “foot,” projected tantalizingly outside the cell membrane. It would have taken Padhy no more than an afternoon’s experiment to add the
neu
antibody to the neuroblastoma cells to determine the binding’s effect. “
It would have been an overnight test
,” Weinberg would later recall. “I can flagellate myself. If I had been more studious and more focused and not as monomaniacal about the ideas I had at that time, I would have made that connection.”

Despite the trail of seductive leads, Padhy and Weinberg never got around to doing their experiment. Afternoon upon afternoon passed. Introspective and bookish, Padhy shuffled through the lab in a threadbare coat in the winter, running his experiments privately and saying little about them to others. And
although Padhy’s discovery was published
in a high-profile scientific journal, few scientists noticed that he might have stumbled on a potential anticancer drug (the
neu
-binding antibody was buried in an obscure figure in the article). Even Weinberg, caught in the giddy upswirl of new oncogenes and obsessed with the basic biology of the cancer cell, simply forgot about the
neu
experiment.
^*

Weinberg had an oncogene and possibly an oncogene-blocking drug, but the twain had never met (in human cells or bodies). In the neuroblastoma cells dividing in his incubators,
neu
rampaged on monomaniacally, single-mindedly, seemingly invincible. Yet its molecular foot still waved just outside the surface of the plasma membrane, exposed and vulnerable, like Achilles’ famous heel.

*
In 1986, Jeffrey Drebin and Mark Greene showed that treatment with an anti-
neu
antibody arrested the growth of cancer cells. But the prospect of developing this antibody into a human anticancer drug eluded all groups.

In Ersilia, to establish the relationships
that sustain the city’s life, inhabitants stretch strings from the corners of the houses, white or black or gray or black-and-white according to whether they mark a relationship of blood, of trade, authority, agency. When the strings become so numerous that you can no longer pass among them, the inhabitants leave: the houses are dismantled.

—Italo Calvino

Weinberg may briefly have forgotten about the therapeutic implication of
neu
, but oncogenes, by their very nature, could not easily be forgotten.
In his book
Invisible Cities
, Italo Calvino describes a fictional metropolis in which every relationship between one household and the next is denoted by a piece of colored string stretched between the two houses. As the metropolis grows, the mesh of strings thickens and the individual houses blur away. In the end, Calvino’s city becomes no more than an interwoven network of colored strings.

If someone were to draw a similar map of relationships among genes in a normal human cell, then proto-oncogenes and tumor suppressors such as
ras, myc
,
neu
, and
Rb
would sit at the hub of this cellular city, radiating webs of colored strings in every direction. Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division, and the division of cells is so central to our physiology that genes and pathways that coordinate this process intersect with nearly every other aspect of our biology. In the laboratory, we call this the six-degrees-of-separation-from-cancer rule: you can ask any biological question, no matter how seemingly distant—what makes the heart fail, or why worms age, or even how birds learn songs—and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor.

It should hardly come as a surprise, then, that
neu
was barely forgot
ten in Weinberg’s laboratory when it was resurrected in another.
In the summer of 1984
, a team of researchers, collaborating with Weinberg, discovered the human homolog of the
neu
gene. Noting its resemblance to another growth-modulating gene discovered previously—the Human EGF Receptor (HER)—the researchers called the gene
Her-2
.

A gene by any other name may still be the same gene, but something crucial had shifted in the story of
neu
. Weinberg’s gene had been discovered in an academic laboratory. Much of Weinberg’s attention had been focused on dissecting the molecular mechanism of the
neu
oncogene.
Her-2
, in contrast, was discovered on the sprawling campus of the pharmaceutical company Genentech. The difference in venue, and the resulting difference in goals, would radically alter the fate of this gene. For Weinberg,
neu
had represented a route to understanding the fundamental biology of neuroblastoma. For Genentech,
Her-2
represented a route to developing a new drug.