The Gene: An Intimate History

by Siddhartha Mukherjee

Three profoundly destabilizing scientific ideas ricochet through the twentieth century, trisecting it into three unequal parts: the atom, the byte, the gene.

Genes reside on chromosomes—long, filamentous structures buried within cells that contain tens of thousands of genes linked together in chains.II Humans have forty-six such chromosomes in total—twenty-three from one parent and twenty-three from another. The entire set of genetic instructions carried by an organism is termed a genome (think of the genome as the encyclopedia of all genes, with footnotes, annotations, instructions, and references). The human genome contains about between twenty-one and twenty-three thousand genes that provide the master instructions to build, repair, and maintain humans.

during respiration, for instance, sugar combines chemically with oxygen to make carbon dioxide and energy.

Genes, the Pajama paper argued, were not just passive blueprints. Even though every cell contains the same set of genes—an identical genome—the selective activation or repression of particular subsets of genes allows an individual cell to respond to its environments. The genome was an active blueprint—capable of deploying selected parts of its code at different times and in different circumstances.

Proteins act as regulatory sensors, or master switches, in this process—turning on and turning off genes, or even combinations of genes, in a coordinate manner.

Built into every genome, then, are the codes for proteins that will allow that genome to reproduce. This additional layer of complexity—that DNA encodes a protein that allows DNA to replicate—is important because it provides a critical node for regulation. DNA replication can be turned on and turned off by other signals and regulators, such as the age or the nutritional status of a cell, thus allowing cells to make DNA copies only when they are ready to divide. This scheme has a collateral rub: when the regulators themselves go rogue, nothing can stop a cell from replicating continuously. That, as we will soon learn, is the ultimate disease of malfunctioning genes—cancer.

Genes make proteins that regulate genes. Genes make proteins that replicate genes. The third R of the physiology of genes is a word that lies outside common human vocabulary, but is essential to the survival of our species: recombination—the ability to generate new combinations of genes.

The human genome contains 3,095,677,412 base pairs—representing

Normal cells could acquire these cancer-causing mutations through four mechanisms. The mutations could be caused by environmental insults, such as tobacco smoke, ultraviolet light, or X-rays—agents that attack DNA and change its chemical structure. Mutations could arise from spontaneous errors during cell division (every time DNA is replicated in a cell, there’s a minor chance that the copying process generates an error—an A switched to a T, G, or C, say). Mutant cancer genes could be inherited from parents, thereby causing hereditary cancer syndromes such as retinoblastoma and breast cancer that coursed through families. Or the genes could be carried into the cells via viruses, the professional gene carriers and gene swappers of the microbial world.

In all four cases, the result converged on the same pathological process: the inappropriate activation or inactivation of genetic pathways that controlled growth, causing the malignant, dysregulated cellular division that was characteristic of cancer.

To Stevens, this suggested a simple theory of sex determination. When sperm was created in the male gonad, it was made in two forms—one bearing the nublike male chromosome, and another bearing the normal-size female chromosome—in roughly equal ratios. When sperm bearing the male chromosome—i.e., “male sperm”—fertilized the egg, the embryo was born male. When “female sperm” fertilized an egg, the result was a female embryo. Stevens’s work was corroborated by that of her close collaborator, the cell biologist Edmund Wilson, who simplified Stevens’s terminology, calling the male chromosome Y, and the female X. In chromosomal terms, male cells were XY, and females were XX. The egg contains a single X chromosome, Wilson reasoned. When a sperm carrying a Y chromosome fertilizes an egg, it results in an XY combination, and maleness is determined. When a sperm carrying an X chromosome meets a female egg, the result is XX, which determines femaleness. Sex was not determined by right or left testicles, but by a similarly random process—by the nature of the genetic payload of the first sperm to reach and fertilize an egg.

Comparing identical twins to fraternal twins partially solved the problem, since fraternal twins share the same environment, but share only half the genes, on average.

In India, parts of which are home to some of the most blatantly sexist subcultures in the world, attempts to use PGD to “diagnose” the gender of a child were reported as early as 1995. Any form of sexual selection for male children was, and still is, prohibited by the Indian government, and PGD for gender selection was soon banned. Yet the government ban seems to have hardly staved the problem: readers from India and China might note, with some shame and sobriety, that the largest “negative eugenics” project in human history was not the systemic extermination of Jews in Nazi Germany or Austria in the 1930s. That ghastly distinction falls on India and China, where more than 10 million female children are missing from adulthood because of infanticide, abortion, and neglect of female children. Depraved dictators and predatory states are not an absolute requirement for eugenics. In the case of India, perfectly “free” citizens, left to their own devices, are capable of enacting grotesque eugenic programs—against females, in this case—without any state mandate. Currently,