The Gene: An Intimate History

by Siddhartha Mukherjee

A genotype is an organism’s genetic composition. It can refer to one gene, a configuration of genes, or even an entire genome. A phenotype, in contrast, refers to an organism’s physical or biological attributes and characteristics—the color of an eye, the shape of a wing, or resistance to hot or cold temperatures.

And second, some genes are activated by external triggers or by random chance. In flies, for instance, a gene that determines the size of a vestigial wing depends on temperature: you cannot predict the shape of the wing based on the fly’s genes or on the environment alone; you need to combine the two pieces of information.

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.

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

reproductive incompatibility, ultimately derived from genetic incompatibility, drove the origin of novel species.

Without this variation—without deep genetic diversity—an organism might ultimately lose its capacity to evolve.

To decipher the structure of DNA, Wilkins had decided to corral a set of biophysical techniques invented in nearby Cambridge—crystallography and X-ray diffraction. To understand the basic outline of this technique, imagine trying to deduce the shape of a minute three-dimensional object—a cube, say. You cannot “see” this cube nor feel its edges—but it shares the one property that all physical objects must possess: it generates shadows. Imagine that you can shine light at the cube from various angles and record the shadows that are formed. Placed directly in front of the light, a cube casts a square shadow. Illuminated obliquely, it forms a diamond. Move the light source again, and the shadow is a trapezoid. The process is almost absurdly laborious—like sculpting a face out of a million silhouettes—but it works: piece by piece, a set of two-dimensional images can be transmuted into a three-dimensional form. X-ray diffraction arises out of analogous principles—the “shadows” are actually the scatters of X-rays generated by a crystal—except to illuminate molecules and generate scatters in the molecular world, one needs the most powerful source of light: X-rays. And there’s a subtler problem: molecules generally refuse to sit still for their portraits. In liquid or gas form, molecules whiz dizzily in space, moving randomly, like particles of dust. Shine light on a million moving cubes and you only get a hazy, moving shadow, a molecular version of television static. The only solu...

A unit of heredity must carry the code to build a metabolic or cellular function specified by a protein. “A gene,” Beadle wrote in 1945, “can be visualized as directing the final configuration of a protein molecule.” This was the “action of the gene” that a generation of biologists had been trying to comprehend: a gene “acts” by encoding information to build a protein, and the protein actualizes the form or function of the organism.

A protein is created from twenty simple chemicals named amino acids—Methionine, Glycine, Leucine, and so forth—strung together in a chain. Unlike a chain of DNA, which exists primarily in the form of a double helix, a protein chain can twist and turn in space idiosyncratically, like a wire that has been sculpted into a unique shape. This shape-acquiring ability allows proteins to execute diverse functions in cells. They can exist as long, stretchable fibers in muscle (myosin). They can become globular in shape and enable chemical reactions—i.e., enzymes (DNA polymerase). They can bind colored chemicals and become pigments in the eye, or in a flower. Twisted into saddle clasps, they can act as transporters for other molecules (hemoglobin). They can specify how a nerve cell communicates with another nerve cell and thus become the arbiters of normal cognition and neural development.

The messenger was generated afresh when a gene was translated. Like DNA, these RNA molecules were built by stringing together four bases—A, G, C, and U (in the RNA copy of a gene, remember, the T found in DNA is substituted for U). Notably, Brenner and Jacob later discovered the messenger RNA was a facsimile of the DNA chain—a copy made from the original. The RNA copy of a gene then moved from the nucleus to the cytosol, where its message was decoded to build a protein. The messenger RNA was neither an inhabitant of heaven nor of hell—but a professional go-between. The generation of an RNA copy of a gene was termed transcription—referring to the rewriting of a word or sentence in a language close to the original. A gene’s code (ATGGGCC . . .) was transcribed into an RNA code (AUGGGCC . . .). The process was akin to a library of rare books that is accessed for translation. The master copy of information—i.e., the gene—was stored permanently in a deep repository or vault. When a “translation request” was generated by a cell, a photocopy of the original was summoned from the vault of the nucleus. This facsimile of a gene (i.e., RNA) was used as a working source for translation into a protein. The process allowed multiple copies of a gene to be in circulation at the same time, and for the RNA copies to be increased or decreased on demand—facts that would soon prove to be crucial to the understanding of a gene’s activity and function.

The genome was an active blueprint—capable of deploying selected parts of its code at different times and in different circumstances.

“The genome contains not only a series of blue-prints [i.e., genes], but a co-ordinated program . . . and a means of controlling its execution,”

Genes specified proteins that switched on genes that specified proteins that switched on genes—and so forth, all the way to the very first embryological cell. It was genes, all the way.3

There is a recursion here that is worth noting: like all proteins, DNA polymerase, the enzyme that enables DNA to replicate, is itself the product of a gene.4 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.

1985, the cancer biologist Stanley Korsmeyer discovered that a gene named BCL2 is recurrently mutated in lymphomas.2 BCL2, it turned out, was the human counterpart to one of Horvitz’s death-regulating worm genes, called ced9. In worms, ced9 prevents cell death by sequestering the cell-death-related executioner proteins (hence the “un-dead” cells in the worm mutants). In human cells, the activation of BCL2 results in a cell in which the death cascade is blocked, creating a cell that is pathologically unable to die: cancer.

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.”

The paucity of medicines has one principal reason: specificity. Nearly every drug works by binding to its target and enabling or disabling it—turning molecular switches on or off. To be useful, a drug must bind to its switches—but to only a selected set of switches; an indiscriminate drug is no different from a poison. Most molecules can barely achieve this level of discrimination—but proteins have been designed explicitly for this purpose. Proteins, recall, are the hubs of the biological world. They are the enablers and the disablers, the machinators, the regulators, the gatekeepers, the operators, of cellular reactions. They are the switches that most drugs seek to turn on and off. Proteins are thus poised to be some of the most potent and most discriminating medicines in the pharmacological world. But to make a protein, one needs its gene—and here recombinant DNA technology provided the crucial missing stepping-stone. The cloning of human genes allowed scientists to manufacture proteins—and the synthesis of proteins opened the possibility of targeting the millions of biochemical reactions in the human body. Proteins made it possible for chemists to intervene on previously impenetrable aspects of our physiology. The use of recombinant DNA to produce proteins thus marked a transition not just between one gene and one medicine, but between genes and a novel universe of drugs.

The difference between a more complex organism and a simpler one, “between a human and a nematode worm, is not that humans have more of those fundamental pieces of apparatus, but that they can call them into action in more complicated sequences and in a more complicated range of spaces.” It was not the size of the ship, yet again, but the way the planks were configured. The fly genome was its own Delphic boat.

(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.)

But the cellular material of the embryo comes exclusively from the egg; the sperm is no more than a glorified delivery vehicle for male DNA—a genome equipped with a hyperactive tail. Aside from proteins, ribosomes, nutrients, and membranes, the egg also supplies the embryo with specialized structures called mitochondria

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.

Now imagine an ancient tribe of two hundred women, each of whom bears one child. If the child happens to be a daughter, the woman dutifully passes her mitochondria to the next generation, and, through her daughter’s daughter, to a third generation. But if she has only a son and no daughter, the woman’s mitochondrial lineage wanders into a genetic blind alley and becomes extinct (since sperm do not pass their mitochondria to the embryo, sons cannot pass their mitochondrial genomes to their children). Over the course of the tribe’s evolution, tens of thousands of such mitochondrial lineages will land on lineal dead ends by chance, and be snuffed out. And here is the crux: if the founding population of a species is small enough, and if enough time has passed, the number of surviving maternal lineages will keep shrinking, and shrinking further, until only a few are left. If half of the two hundred women in our tribe have sons, and only sons, then one hundred mitochondrial lineages will dash against the glass pane of male-only heredity and vanish in the next generation. Another half will dead-end into male children in the second generation, and so forth. By the end of several generations, all the descendants of the tribe, male or female, might track their mitochondrial ancestry to just a few women. 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.

“dyslexia wasn’t a problem. When most people had to hunt, a minor genetic variation in your ability to focus attention was hardly a problem, and may even have been an advantage [enabling a hunter to maintain his focus on multiple and simultaneous targets, for instance]. When most people have to make it through high school, the same variation can become a life-altering disease.”

The SRY gene indubitably controls sex determination in an on/off manner. Turn SRY on, and an animal becomes anatomically and physiologically male. Turn it off, and the animal becomes anatomically and physiologically female. But to enable more profound aspects of gender determination and gender identity, SRY must act on dozens of targets—turning them on and off, activating some genes and repressing others, like a relay race that moves a baton from hand to hand. These genes, in turn, integrate inputs from the self and the environment—from hormones, behaviors, exposures, social performance, cultural role-playing, and memory—to engender gender. What we call gender, then, is an elaborate genetic and developmental cascade, with SRY at the tip of the hierarchy, and modifiers, integrators, instigators, and interpreters below. This geno-developmental cascade specifies gender identity.

The circular flow of biological information— —is, perhaps, one of the few organizing rules in biology.

We now know that cells have ancient detectors that recognize viral genes and stamp them with chemical marks, like cancellation signs, to prevent their activation.

Stem cells fulfill this function, especially after catastrophic cell loss. A stem cell is a unique type of cell that is 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. A stem cell is somewhat akin to a grandfather that continues to produce children, grandchildren, and great-grandchildren, generation upon generation, without ever losing his own reproductive fecundity. It is the ultimate reservoir of regeneration for a tissue or an organ.

Most stem cells reside in particular organs and tissues and give rise to a limited repertoire of cells. Stem cells in the bone marrow, for instance, only produce blood cells. There are stem cells in the crypts of the intestine that are dedicated to the production of intestinal cells. 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.

With ES cells, however, scientists learned to make genetic changes not randomly, but in targeted positions in the genome, including within the genes themselves. You could choose to change the insulin gene and—through some rather basic but ingenious experimental manipulations—ensure that only the insulin gene was changed in the cells. And because the gene-modified ES cells could, in principle, generate all the cell types in a full mouse, you could be sure that a mouse with precisely that changed insulin gene would be born. Indeed, if the gene-modified ES cells eventually produced sperm and egg cells in the adult mice, then the gene would be transmitted from mouse to mouse across generations, thus achieving vertical hereditary transmission.

Stem cells are the only cells in the body that can renew themselves and therefore provide a long-term solution to a gene deficiency. Without a source of self-renewing or long-lived cells, you might insert genes into the human body, but the cells carrying the genes would eventually die and vanish. There would be genes, but no therapy.