The Gene: An Intimate History

by Siddhartha Mukherjee

Perhaps wisely, he had been deliberately cagey about the implications of his theory for human evolution: the only line in Origin regarding human descent—“light will be thrown on the origin of man and his history”—might well have been the scientific understatement of the century.

It is a testament to Darwin’s scientific audacity that he was not particularly bothered by the prospect of human descent from apelike ancestors. It is also a testament to his scientific integrity that what did bother him, with far fiercer urgency, was the integrity of the internal logic of his own theory. One particularly “wide blank” had to be filled: heredity.

A theory of heredity, Darwin realized, was not peripheral to a theory of evolution; it was of pivotal importance. For a variant of gross-beaked finch to appear on a Galápagos island by natural selection, two seemingly contradictory facts had to be simultaneously true. First, a short-beaked “normal” finch must be able to occasionally produce a gross-beaked variant—a monster or freak (Darwin called these sports—an evocative word, suggesting the infinite caprice of the natural world. The crucial driver of evolution, Darwin understood, was not nature’s sense of purpose, but her sense of humor). And second, once born, that gross-beaked finch must be able to transmit the same trait to its offspring, thereby fixing the variation for generations to come. If either factor failed—if reproduction failed to produce variants or if heredity failed to transmit the variations—then nature would be mired in a ditch, the cogwheels of evolution jammed. For Darwin’s theory to work, heredity had to possess constancy and in-constancy, stability and mutation.

Mendel, as we shall see, was an instinctual gardener—a breeder of plants, a counter of seeds, an isolator of traits; Darwin was a garden digger—a classifier of plants, an organizer of specimens, a taxonomist. Mendel’s gift was experimentation—the manipulation of organisms, cross-fertilization of carefully selected sub-breeds, the testing of hypotheses. Darwin’s gift was natural history—the reconstruction of history by observing nature. Mendel, the monk, was an isolator; Darwin, the parson, a synthesizer.

By the late 1800s, the problem of heredity had acquired a nearmystical aura of glamour, like a Fermat’s Last Theorem for biologists. Like Fermat—the odd French mathematician who had tantalizingly scribbled that he’d found a “remarkable proof” of his theorem, but failed to write it down because the paper’s “margin was too small”—Darwin had desultorily announced that he had found a solution to heredity, but had never published it. “In another work I shall discuss, if time and health permit, the variability of organic beings in a state of nature,” Darwin had written in 1868.

Natural selection was not operating on organisms but on their units of heredity. A chicken, de Vries realized, was merely an egg’s way of making a better egg.

Memories sharpen the past; it is reality that decays.

Phenotype, in short, drags genotypes behind it, like a cart pulling a horse. It is the perennial conundrum of natural selection that it seeks one thing (fitness) and accidentally finds another (genes that produce fitness). Genes that produce fitness become gradually overrepresented in populations through the selection of phenotypes, thereby allowing organisms to become more and more adapted to their environments. There is no such thing as perfection, only the relentless, thirsty matching of an organism to its environment. That is the engine that drives evolution.

First they came for the Socialists, and I did not speak out— Because I was not a Socialist. Then they came for the Trade Unionists, and I did not speak out— Because I was not a Trade Unionist. Then they came for the Jews, and I did not speak out— Because I was not a Jew. Then they came for me—and there was no one left to speak out for me.

The gene, Schrödinger posited, had to be made of a peculiar kind of chemical; it had to be a molecule of contradictions. It had to possess chemical regularity—otherwise, routine processes such a copying and transmission would not work—but it also had to be capable of extraordinary irregularity—or else, the enormous diversity of inheritance could not be explained. The molecule had to be able to carry vast amounts of information, yet be compact enough to be packaged into cells. Schrödinger imagined a chemical with multiple chemical bonds stretching out along the length of the “chromosome fiber.” Perhaps the sequence of bonds encoded the code script—a “variety of contents compressed into [some] miniature code.” Perhaps the order of beads on the string carried the secret code of life. Similarity and difference; order and diversity; message and matter. Schrödinger was trying to conjure up a chemical that would capture the divergent, contradictory qualities of heredity—a molecule to satisfy Aristotle. In his mind’s eye, it was almost as if he had seen DNA.

X-ray pictures would help, of course—but trying to determine structures of biological molecules using experimental methods, Crick argued, was absurdly laborious—“like trying to determine the structure of a piano by listening to the sound it made while being dropped down a flight of stairs.”

That humans and worms have about the same number of genes—around twenty thousand—and yet the fact that only one of these two organisms is capable of painting the ceiling of the Sistine Chapel suggests that the number of genes is largely unimportant to the physiological complexity of the organism. “It is not what you have,” as a certain Brazilian samba instructor once told me, “it is what you do with it.”

Earlier, Walter Gilbert, the DNA-sequencing pioneer, had prepared an edge-of-napkin calculation of the costs and personnel involved. To sequence all 3 billion base pairs of human DNA, Gilbert estimated, would take about fifty thousand person years and cost around $3 billion—one dollar per base. As Gilbert, with characteristic panache, strode across the floor to inscribe the number on a chalkboard, an intense debate broke out in the audience. “Gilbert’s number”—which would turn out to be start lingly accurate—had reduced the genome project to tangible realities. Indeed, put in perspective, the cost was not even particularly large: at its peak, the Apollo program had employed nearly four hundred thousand people, with a total cumulative cost of about $100 billion. If Gilbert was right, the human genome could be had for less than one-thirtieth of the moon landing. Sydney Brenner later joked that the sequencing of the human genome would perhaps ultimately be limited not by cost or technology, but only by the severe monotony of its labor. Perhaps, he speculated, genome sequencing should be doled out as a punishment to criminals and convicts—1 million bases for robbery, 2 million for homicide, 10 million for murder.

It encodes about 20,687 genes in total—only 1,796 more than worms, 12,000 fewer than corn, and 25,000 fewer genes than rice or wheat. The difference between “human” and “breakfast cereal” is not a matter of gene numbers, but of the sophistication of gene networks. It is not what we have; it is how we use it.

As a consequence of this constant genetic bombardment, the human Y chromosome began to jettison information millions of years ago. Genes that were truly valuable for survival were likely shuffled to other parts of the genome where they could be stored securely; genes with limited value were made obsolete, retired, or replaced. As information was lost, the Y chromosome itself shrank—whittled down piece by piece by the mirthless cycle of mutation and gene loss. That the Y chromosome is the smallest of all chromosomes is not a coincidence: it is a victim of planned obsolescence, destined to a male-only convalescence home where it can vanish, puffing its last cigar, into oblivion. In genetic terms, this suggests a peculiar paradox. Sex, one of the most complex of human traits, is unlikely to be encoded by multiple genes. Rather, a single gene, buried rather precariously in the Y chromosome, must be the master regulator of maleness.1 Male readers of that last paragraph should take notice: we barely made it.

Dopamine, a neurotransmitter—a molecule that transmits chemical signals between neurons in the brain—is especially involved in the recognition of “reward” to the brain. It is one of the most potent neurochemical signals that we know: a rat, given a lever to electrically stimulate the dopamine-responsive reward center in the brain, will stimulate itself to death because it neglects to eat and drink.

Technologists seek to liberate us from the constraints of our current realities through those transitions. Science defines those constraints, drawing the outer limits of the boundaries of possibility. Our greatest technological innovations thus carry names that claim our prowess over the world: the engine (from ingenium, or “ingenuity”) or the computer (from computare, or “reckoning together”). Our deepest scientific laws, in contrast, are often named after the limits of human knowledge: uncertainty, relativity, incompleteness, impossibility.

Of all the sciences, biology is the most lawless; there are few rules to begin with, and even fewer rules that are universal. Living beings must, of course, obey the fundamental rules of physics and chemistry, but life often exists on the margins and interstices of these laws, bending them to their near-breaking limit. The universe seeks equilibriums; it prefers to disperse energy, disrupt organization, and maximize chaos. Life is designed to combat these forces. We slow down reactions, concentrate matter, and organize chemicals into compartments; we sort laundry on Wednesdays. “It sometimes seems as if curbing entropy is our quixotic purpose in the universe,” James Gleick wrote. We live in the loopholes of natural laws, seeking extensions, exceptions, and excuses. The laws of nature still mark the outer boundaries of permissibility—but life, in all its idiosyncratic, mad weirdness, flourishes by reading between the lines. Even the elephant cannot violate the law of thermodynamics—although its trunk, surely, must rank as one of the most peculiar means of moving matter using energy.

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.

The desire to homogenize and “normalize” humans must be counter-balanced against biological imperatives to maintain diversity and abnormalcy. Normalcy is the antithesis of evolution.