The Gene: An Intimate History

by Siddhartha Mukherjee

chicken, de Vries realized, was merely an egg’s way of making a better egg.

If genes were, indeed, independent particles of information, then it should be possible to select, purify, and manipulate these particles independently from one another. Genes for “desirable” attributes might be selected or augmented, while undesirable genes might be eliminated from the gene pool. In principle, a scientist should be able to change the “composition of individuals,” and of nations, and leave a permanent mark on human identity.

eugenics, the betterment of the human race via artificial selection of genetic traits and directed breeding of human carriers.

(Natures and features last until the grave.)

genotype + environment + triggers + chance = phenotype

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.

a species, after all, is fundamentally defined by its inability to interbreed with another.

Geographic isolation leads to genetic isolation, and to eventual reproductive isolation.

natural variation was a vital reservoir for an organism—an asset that far outweighed its liabilities. Without this variation—without deep genetic diversity—an organism might ultimately lose its capacity to evolve.

Transformation almost never occurs in mammals. But bacteria, which live on the rough edges of the biological world, can exchange genes horizontally

Genes could, in other words, be transmitted between two organisms without any form of reproduction.

Without equality, he argued, eugenics would degenerate into yet another mechanism by which the powerful could control the weak.

There was, perhaps, no more bizarre illustration of the conflation between cleansing and racial cleansing than a law that barred Jews from employing “German maids” in their houses.

The word genocide shares its root with gene—and for good reason: the Nazis used the vocabulary of genes and genetics to launch, justify, and sustain their agenda. The language of genetic discrimination was easily parlayed into the language of racial extermination.

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.

Junk science props up totalitarian regimes.

And totalitarian regimes produce junk science.

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.

How can thousands of cell types arise from an embryo out of the same set of genes? The regulation of genes—the selective turning on and off of certain genes in certain cells, and at certain times—must interpose a crucial layer of complexity on the unblinking nature of biological information.

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.

Mutations occur when DNA is damaged by chemicals or X-rays, or when the DNA replication enzyme makes a spontaneous error in copying genes. But a second mechanism of generating genetic diversity exists: genetic information can be swapped between chromosomes. DNA from the maternal chromosome can exchange positions with DNA from the paternal chromosome—potentially generating a gene hybrid of maternal and paternal genes. Recombination is also a form of “mutation”—except whole chunks of genetic material are swapped between chromosomes.

The development of the human embryo is also likely achieved through three similar levels of organization. As with the fly, “maternal effect” genes organize the early embryo into its main axes—head versus tail, front versus back, and left versus right—using chemical gradients. Next, a series of genes analogous to the segmentation genes in the fly initiates the division of the embryo into its major structural parts—brain, spinal cord, skeleton, skin, guts, and so forth. Finally, organ-building genes authorize the construction of organs, parts, and structures—limbs, fingers, eyes, kidneys, liver, and lungs.

Genes operate in the same manner. Individual genes specify individual functions, but the relationship among genes allows physiology. The genome is inert without these relationships. 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.”

Genetic mutations are selected over millennia, one scientist observed at the meeting, but cultural mutations can be introduced and selected in just a few years.

The biochemist’s approach pivots on concentration: find the protein by looking where it’s most likely to be concentrated, and distill it out of the mix. The geneticist’s approach, in contrast, pivots on information: find the gene by searching for differences in “databases” created by two closely related cells and multiply the gene in bacteria via cloning. The biochemist distills forms; the gene cloner amplifies information.

Most genes in the human genome are, recall, interrupted by stretches of DNA called introns, which are like garbled stuffers placed in between parts of a message. Rather than the word genome, the actual gene reads gen . . . . . . . . . om . . . . . . e. The introns in human genes are often enormous, stretching across vast lengths of DNA, making it virtually impossible to clone a gene directly (the intron-containing gene is too long to fit into a bacterial plasmid).

reverse transcriptase, the enzyme that could build DNA from RNA. The use of reverse transcriptase made gene cloning vastly more efficient. Reverse transcriptase made it possible to clone a gene after the intervening stuffer sequences had been snipped off by the cell’s splicing apparatus.

entity, not a pathological or moral one. A mutation doesn’t imply disease, nor does it specify a gain or loss of function. In a formal sense, a mutation is defined only by its deviation from the norm (the opposite of “mutant” is not “normal” but “wild type”—i.e.,

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.

The structure of the human genome can thus be likened to a sentence that reads— This . . . . . . is the . . . . . . str . . . uc . . . . . . ture . . . , , , . . . of . . . your . . . ( . . . gen . . . ome . . . ) . . . —where the words correspond to the genes, the ellipses correspond to the spacers and stuffers, and the occasional punctuation marks demarcate the regulatory sequences of genes.

Illness is used to define wellness. Abnormalcy marks the boundaries of normalcy. Deviance demarcates the limits of conformity.

(Some scientists propose that mitochondria originated from some ancient bacteria that invaded single-celled organisms. These bacteria formed a symbiotic alliance with the organism; they provided energy, but used the organism’s cellular environment for nutrition, metabolism, and self-defense. The genes lodged within mitochondria are left over from this ancient symbiotic relationship; indeed, human mitochondrial genes resemble bacterial genes more than human ones.)

The exclusively female origin of all the mitochondria in an embryo has an important consequence. All humans—male or female—must have inherited their mitochondria from their mothers, who inherited their mitochondria from their mothers, and so forth, in an unbroken line of female ancestry stretching indefinitely into the past. (A woman also carries the mitochondrial genomes of all her future descendants in her cells; ironically, if there is such a thing as a “homunculus,” then it is exclusively female in origin—technically, a “femunculus”?)

For modern humans, that number has reached one: each of us can trace our mitochondrial lineage to a single human female who existed in Africa about two hundred thousand years ago. She is the common mother of our species. We do not know what she looked like, although her closest modern-day relatives are women of the San tribe from Botswana or Namibia.

Yet, careful students of genetics knew that the Y chromosome was an inhospitable place for genes. Unlike any other chromosome, the Y is “unpaired”—i.e., it has no sister chromosome and no duplicate copy, leaving every gene on the chromosome to fend for itself. A mutation in any other chromosome can be repaired by copying the intact gene from the other chromosome. But a Y chromosome gene cannot be fixed, repaired, or recopied from another chromosome; it has no backup or guide (there is, however, a unique internal system to repair genes in the Y chromosome). When the Y chromosome is assailed by mutations, it lacks a mechanism to recover information. The Y is thus pockmarked with the potshots and scars of history. It is the most vulnerable spot in the human genome.

In 1955, Gerald Swyer, an English endocrinologist investigating female infertility, had discovered a rare syndrome that made humans biologically female but chromosomally male. “Women” born with “Swyer syndrome” were anatomically and physiologically female throughout childhood, but did not achieve female sexual maturity in early adulthood. When their cells were examined, geneticists discovered that these “women” had XY chromosomes in all their cells. Every cell was chromosomally male—yet the person built from these cells was anatomically, physiologically, and psychologically female. A “woman” with Swyer syndrome had been born with the male chromosomal pattern (i.e., XY chromosomes) in all of her cells, but had somehow failed to signal “maleness” to her body.

Women with Swyer syndrome are not “women trapped in men’s bodies.” They are women trapped in women’s bodies that are chromosomally male (except for just one gene). A mutation in that single gene, SRY, creates a (largely) female body—and, more crucially, a wholly female self. It is as artless, as plain, as binary, as leaning over the nightstand and turning a switch on or off.

is now clear that genes are vastly more influential than virtually any other force in shaping sex identity and gender identity—although in limited circumstances a few attributes of gender can be learned through cultural, social, and hormonal reprogramming. Since even hormones are ultimately “genetic”—i.e., the direct or indirect products of genes—then the capacity to reprogram gender using purely behavioral therapy and cultural reinforcement begins to tip into the realm of impossibility. Indeed, the growing consensus in medicine is that, aside from exceedingly rare exceptions, children should be assigned to their chromosomal (i.e., genetic) sex regardless of anatomical variations and differences—with the option of switching, if desired, later in life. As of this writing, none of these children have opted to switch from their gene-assigned sexes.

Those who promise us paradise on earth never produced anything but a hell.

defined by two properties. It can give rise to other functional cell types, such as nerve cells or skin cells, through differentiation. And it can renew itself—i.e., give rise to more stem cells, which can, in turn, differentiate to form the functional cells of an organ.

But embryonic stem cells, or ES cells, which arise from the inner sheath of an animal’s embryo, are vastly more potent; they can give rise to every cell type in the organism—blood, brains, intestines, muscles, bone, skin. Biologists use the word pluripotent to describe this property of ES cells.

most beautiful theory can be slayed by an ugly fact.

The prospect of a genetic diagnosis for schizophrenia and bipolar disorder thus involves confronting fundamental questions about the nature of uncertainty, risk, and choice. We want to eliminate suffering, but we also want to “keep those sufferings.” It is easy to understand Susan Sontag’s formulation of illness as the “night-side of life.” That conception works for many forms of illness—but not all. The difficulty lies in defining where twilight ends or where daybreak begins. It does not help that the very definition of illness in one circumstance becomes the definition of exceptional ability in another. Night on one side of the globe is often day, resplendent and glorious, on a different continent.

you could sequence genomes hoping to find match-made medicines to alleviate specific mutations, but that would be a rare outcome. Prenatal diagnosis and the termination of pregnancies still remained the simplest choice for such rare devastating diseases—but also ethically the most difficult to confront. “The more technology evolves, the more we enter unknown territory. There’s no doubt that we have to face incredibly tough choices,”

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.

But what about that perennial fantasy of human genetics, the alteration of genes in reproductive cells to create permanently amended human genomes—“germ-line gene therapy”? What about the creation of the “post-humans” or “trans-humans”—i.e., human embryos with permanently modified genomes?

We are at a similar moment—a quickening—for human genome engineering. Consider the following steps in sequence: (a) the derivation of a true human embryonic stem cell (capable of forming sperm and eggs); (b) a method to create reliable, intentional genetic modifications in that cell line; (c) the directed conversion of that gene-modified stem cell into human sperm and eggs; (d) the production of human embryos from these modified sperm and eggs by IVF . . . and you arrive, rather effortlessly, at genetically modified humans.

Variations in genes contribute to variations in features, forms, and behaviors. When we use the colloquial terms gene for blue eyes or gene for height, we are really referring to a variation (or allele) that specifies an eye color or height. These variations constitute an extremely minor portion of the genome. They are magnified in our imagination because of cultural, and possibly biological, tendencies that tend to amplify differences. A six-foot