The Emperor of All Maladies: A Biography of Cancer (65 page)

Mendel could only visualize these traits or properties in a descriptive sense—as colors, texture, or height moving from generation to generation; he could not see or fathom what conveyed this information from one plant to its progeny. His primitive lamplit microscope, with which he could barely peer into the interior of cells, had no power to reveal the mechanism of inheritance. Mendel did not even have the name for this unit of inheritance;
decades later, in 1909, botanists
would christen it a gene. But the name was still just a name; it offered no further explanation
about a gene’s structure or function. Mendel’s studies left a provocative question hanging over biology for half a century: in what corporal, physical form was a “gene”—the particle of inheritance—carried inside the cell?

In 1910, Thomas Hunt Morgan
, an embryologist at Columbia University in New York, discovered the answer. Like Mendel, Morgan was a compulsive breeder, but of fruit flies, which he raised by the thousands on rotting bananas in the Fly Room on the far edge of the Columbia campus. Again, like Mendel, Morgan discovered heritable traits moving indivisibly through his fruit flies generation upon generation—eye colors and wing patterns that were conveyed from parents to offspring without blending.

Morgan made another observation. He noted that an occasional rare trait, such as white eye color, was intrinsically linked to the gender of the fly: white eyes were found only in male flies. But “maleness”—the inheritance of sex—Morgan knew, was linked to chromosomes. So genes had to be carried on chromosomes—the threadlike structures identified by Flemming three decades earlier. Indeed, a number of Flemming’s initial observations on the properties of chromosomes began to make sense to Morgan. Chromosomes were duplicated during cell division, and genes were duplicated as well and thus transmitted from one cell to the next, and from one organism to the next. Chromosomal abnormalities precipitated abnormalities in the growth and development of sea urchins, and so abnormal genes must have been responsible for this dysfunction. In 1915, Morgan proposed a crucial advance to Mendel’s theory of inheritance: genes were borne on chromosomes. It was the transmission of chromosomes during cell division that allowed genes to move from a cell to its progeny.

The third vision of the “gene
” emerged from the work of Oswald Avery, a bacteriologist at the Rockefeller University in New York. Mendel had found that genes could move from one generation to the next; Morgan had proved that they did so by being carried on chromosomes. In 1926, Avery found that in certain species of bacteria, genes could also be transmitted
laterally
between two organisms—from one bacterium to its neighbor. Even dead, inert bacteria—no more than a conglomeration of chemicals—could transmit genetic information to live bacteria. This implied that an inert chemical was responsible for carrying genes. Avery separated
heat-killed bacteria into their chemical components. And by testing each chemical component for its capacity to transmit genes, Avery and his colleagues reported in 1944 that genes were carried by one chemical, deoxyribonucleic acid, or DNA. What scientists had formerly disregarded as a form of cellular stuffing with no real function—a “stupid molecule,” as the biologist Max Delbruck once called it dismissively—turned out to be the central conveyor of genetic information between cells, the least stupid of all molecules in the chemical world.

By the mid-1940s, three decades after biologists had coined the word, the molecular nature of the gene had come into focus. Functionally, a gene was a unit of inheritance that carried a biological trait from one cell to another or from one generation to the next. Physically, genes were carried within the cell in the form of chromosomes. Chemically, genes were composed of DNA, deoxyribonucleic acid.

But a gene only carries information. The functional, physical, and chemical understanding of the gene begged a mechanistic understanding: How did genetic information become manifest inside the cell? What did a gene “do”—and how?

George Beadle, Thomas Morgan’s student
, switched from Morgan’s fruit flies to an even more primitive organism, the slime mold, to answer these questions. Collaborating with the biochemist Edward Tatum at Stanford University in California, Beadle discovered that genes carried instructions to build proteins—complex, multidimensional macromolecules that were the workhorses of the cell.

Proteins, researchers found in the 1940s, carry out the bulk of cellular functions. They form enzymes, catalysts that speed up biochemical reactions vital to the life of the cell. Proteins are receptors for other proteins or molecules, responsible for transmitting signals from one cell to the next. They can create structural components of the cell, such as the molecular scaffolding that allows a cell to exist in a particular configuration in space. They can regulate other proteins, thus creating minuscule circuits inside the cell responsible for coordinating the life cycle of the cell.

Beadle and Tatum found that a gene “works” by providing the blueprint to build a protein. A protein is a gene realized—the machine built from a gene’s instructions. But proteins are not created directly out of genes. In the late 1950s, Jacques Monod and François Jacob, working in Paris, Sydney Brenner and Matthew Meselson at Caltech, and Francis Crick in Cambridge, discovered that the genesis of proteins from genes requires an intermediary step—a molecule called ribonucleic acid, or RNA.

RNA is the working copy of the genetic blueprint. It is through RNA that a gene is translated into a protein. This intermediary RNA copy of a gene is called a gene’s “message.” Genetic information is transmitted from a cell to its progeny through a series of discrete and coordinated steps. First, genes, located in chromosomes, are duplicated when a cell divides and are transmitted into progeny cells. Next, a gene, in the form of DNA, is converted into its RNA copy. Finally, this RNA message is translated into a protein. The protein, the ultimate product of genetic information, carries out the function encoded by the gene.

An example, borrowed from Mendel and Morgan, helps illustrate the process of cellular information transfer. Red-eyed flies have glowering, ruby-colored eyes because they possess a gene that bears the information to build a red pigment protein. A copy of this gene is created every time a cell divides and it thus moves from a fly to its egg cells, and then into the cells of the offspring fly. In the eye cells of the progeny fly, this gene is “deciphered”—i.e., converted into an intermediate RNA message. The RNA message, in turn, instructs the eye cells to build the red pigment protein, thus giving rise to red-eyed flies of the next generation. Any interruption in this information flow might disrupt the transmission of the red eye trait—producing flies with colorless eyes.

This unidirectional flow of genetic information—DNA
→
RNA
→
protein—was found to be universal in living organisms, from bacteria to slime molds to fruit flies to humans.
In the mid-1950s, biologists termed
this the “central dogma” of molecular biology.

An incandescent century of biological discovery—spanning from Mendel’s discovery of genes in 1860 to Monod’s identification of the RNA copy of genes in the late 1950s—illuminated the inner workings of a normal cell. But it did little to illuminate the workings of a cancer cell or the cause of cancer—except in two tantalizing instances.

The first came from human studies. Nineteenth-century physicians had noted that some forms of cancer, such as breast and ovarian cancer, tended to run in families. This in itself could not prove a hereditary cause: families share not just genes, but also habits, viruses, foods, exposures to chemicals, and neurotic behaviors—all factors, at some time or another, implicated as causes of cancer. But occasionally, a family history was so striking that a hereditary cause (and, by extension, a
genetic
cause) could not be ignored.
In 1872, Hilário de Gouvêa
, a Brazilian ophthalmologist practicing in Rio, treated a young boy with a rare cancer of the eye called a retinoblastoma by removing the eye surgically. The boy had survived, grown up, and married a woman with no family history of cancer. The couple had several children, and two of the daughters developed their father’s retinoblastoma in both eyes—and died. De Gouvêa reported this case as a puzzling enigma. He did not possess the language of genetics, but to later observers, the case suggested an inherited factor that “lived” in genes and caused cancer. But such cases were so rare that it was hard to test this hypothesis experimentally, and de Gouvêa’s report was largely ignored.

The second time scientists circled around the cause of cancer—almost hitting the nerve spot of carcinogenesis—came several decades after the strange Brazilian case. In the 1910s, Thomas Hunt Morgan, the fruit fly geneticist at Columbia, noticed that mutant flies occasionally appeared within his flock of flies. In biology, mutants are defined as organisms that differ from the normal. Morgan noticed that an enormous flock of flies with normal wings might occasionally give birth to a “monster” with rough or scalloped wings. These mutations, Morgan discovered, were the results of alterations in genes and the mutations could be carried from one generation to the next.

But what caused mutations?
In 1928, Hermann Joseph Muller
, one of Morgan’s students, discovered that X-rays could vastly increase the rate of mutation in fruit flies. At Columbia, Morgan had produced mutant flies spontaneously. (When DNA is copied during cell division, a copying error occasionally generates an accidental change in genes, thus causing mutations.) Muller found that he could accelerate the incidence of these accidents. Using X-rays to bombard flies, he found that he could produce hundreds of mutant flies over a few months—more than Morgan and his colleagues had produced using their vast breeding program over nearly two decades.

The link between X-rays and mutations nearly led Morgan and Muller to the brink of a crucial realization about cancer. Radiation was known to cause cancer. (Recall Marie Curie’s leukemia, and the tongue cancers of the radium-watch makers.) Since X-rays also caused mutations in fruit fly genes, could cancer be a disease of
mutations
? And since mutations were changes in genes, could genetic alterations be the “unitary cause” of cancer?