The Gene: An Intimate History

by Siddhartha Mukherjee

Films such as Das Erbe (“The Inheritance,” 1935) and Erbkrank (“Hereditary Disease,” 1936), created by the Office of Racial Policy, played to full houses in theaters around the country to showcase the ills of “defectives” and “unfits.”

In October 1935, the Nuremberg Laws for the Protection of the Hereditary Health of the German People sought to contain genetic mixing by barring Jews from marrying people of German blood or having sexual relations with anyone of Aryan descent.

CG and i talked about this

To justify the exterminations, the Nazis had already begun to describe the victims using the euphemism lebensunwertes Leben—lives unworthy of living.

The eerie phrase conveyed an escalation of the logic of eugenics: it was not enough to sterilize genetic defectives to cleanse the future state; it was necessary to exterminate them to cleanse the current state.

In 1936, the University of Munich, an institution richly endowed by Hitler, awarded a PhD to a young medical researcher for his thesis concerning the “racial morphology” of the human jaw—an attempt to prove that the anatomy of the jaw was racially determined and genetically inherited. The newly minted “human geneticist,” Josef Mengele, would soon rise to become the most epically perverse of Nazi researchers, whose experiments on prisoners would earn him the title Angel of Death.

The Nazis had embraced genetics as a tool for racial cleansing. In the Soviet Union in the 1930s, left-wing scientists and intellectuals proposed that nothing about heredity was inherent at all. In nature, everything—everyone—was changeable. Genes were a mirage invented by the bourgeoisie to emphasize the fixity of individual differences, whereas, in fact, nothing about features, identities, choices, or destinies was indelible. If the state needed cleansing, it would not be achieved through genetic selection, but through the reeducation of all individuals and the erasure of former selves. Brains—not genes—had to be washed clean. As with the Nazis, the Soviet doctrine was also bolstered and reinforced by ersatz science. In

Phrasing

Although Nazi doctrine was unsurpassed in its virulence, both Nazism and Lysenkoism shared a common thread: in both cases, a theory of heredity was used to construct a notion of human identity that, in turn, was contorted to serve a political agenda.

Junk science props up totalitarian regimes. And totalitarian regimes produce junk science.

Quote of the book so far

When Hermann Muller arrived in Berlin in 1932, the city was home to the world’s preeminent scientific minds. Einstein was writing equations on the chalkboards of the Kaiser Wilhelm Institute of Physics. Otto Hahn, the chemist, was breaking apart atoms to understand their constituent subatomic particles. Hans Krebs, the biochemist, was breaking open cells to identify their constituent chemical components.

The only way to eradicate transformation was to digest the material with an enzyme that, of all things, degraded DNA. DNA? Was DNA the carrier of genetic information? Could the “stupid molecule” be the carrier of the most complex information in biology?

Science [would be] ruined if—like sports—it were to put competition above everything else. —Benoit Mandelbrot

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.

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.

DNA provided instructions to build RNA. RNA provided instructions to build proteins. Proteins ultimately enabled structure and function—bringing genes to life.

To Monod, diauxie suggested that genes could be regulated by metabolic inputs. If enzymes—i.e., proteins—were being induced to appear and disappear in a cell, then genes must be being turned on and off, like molecular switches (enzymes, after all, are encoded by genes).

First, when a gene was turned on or off, the DNA master copy was always kept intact in a cell. The real action was in RNA: when a gene was turned on, it was induced to make more RNA messages and thereby produce more sugar-digesting enzymes. A cell’s metabolic identity—i.e., whether it was consuming lactose or glucose—could be ascertained not by the sequence of its genes, which was always constant, but by the amount of RNA that a gene was producing.

A functional circuit of genes was switched on and off, as if operated by a common spool or a master switch. Monod called one such gene module an operon.II

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.

In biology, there is an old distinction between two camps of scientists—anatomists, and physiologists. Anatomists describe the nature of materials, structures, and body parts: they describe how things are. Physiologists concentrate, instead, on the mechanisms by which these structures and parts interact to enable the functions of living organisms; they concern themselves with how things work.

In 1985, the cancer biologist Stanley Korsmeyer discovered that a gene named BCL2 is recurrently mutated in lymphomas.II 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 “undead” 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.

A cake is a developmental consequence of sugar, butter, and flour meeting each other in the right proportion, at the right temperature, and the right time. Human physiology, by analogy, is the developmental consequence of certain genes intersecting with other genes in the right sequence, in the right space.

By the early 1970s, as biologists began to decipher the mechanism by which genes were deployed to generate the astounding complexities of organisms, they also confronted the inevitable question of the intentional manipulation of genes in living beings. In April 1971, the US National Institutes of Health organized a conference to determine whether the introduction of deliberate genetic changes in organisms was conceivable in the near future.

Little did they know...

No such method to manipulate genes (even in simple organisms) was available in 1971, the panelists noted—but its development, they felt confident, was only a matter of time. “This is not science fiction,” one geneticist declared. “Science fiction is when you [. . .] can’t do anything experimentally . . . it is now conceivable that not within 100 years, not within 25 years, but perhaps within the next five to ten years, certain inborn errors . . . will be treated or cured by the administration of a certain gene that is lacking—and we have a lot of work to do in order to prepare society for this kind of change.”

a glass of ice water is sweating on a tray on the dining room table.

Phrasing

Viruses have a simple structure: they are often no more than a set of genes wrapped inside a coat—a “piece of bad news wrapped in a protein coat,” as Peter Medawar, the immunologist, had described them.

But what if Cohen cut out an antibiotic-resistance gene from one plasmid and shuttled it to another plasmid? Wouldn’t a bacterium previously killed by the antibiotic now survive, thrive, and grow selectively, while the bacteria carrying the non-hybrid plasmids would die?

Literally every 208 exam question

considerable caution in performing this research.” To mitigate the risks, the document proposed a four-level scheme to rank the biohazard potentials of various genetically altered organisms, with recommended containment facilities for each level (inserting a cancer-causing gene into a human virus, for instance, would merit the highest level of containment, while placing a frog gene into a bacterial cell might merit minimal containment).

In the aftermath of the Asilomar Conference, several historians of science have tried to grasp the scope of the meeting by seeking an analogous moment in scientific history. There is none.

A final feature of Asilomar deserves commentary—notably for its absence. While the biological risks of gene cloning were extensively discussed at the meeting, virtually no mention was made of the ethical and moral dimensions of the problem.

There is an illuminated moment in the development of a child when she grasps the recursiveness of language: just as thoughts can be used to generate words, she realizes, words can be used to generate thoughts. Recombinant DNA had made the language of genetics recursive.

In 1869, a Berlin medical student, Paul Langerhans, had looked through a microscope at the pancreas, a fragile leaf of tissue tucked under the stomach, and discovered minute islands of distinct-looking cells studded across it. These cellular archipelagoes were later named the islets of Langerhans,

the urine and the dog’s blood, both were overflowing with sugar. The dog had become severely diabetic. Some factor synthesized in the pancreas, they realized, must regulate blood sugar, and its dysfunction must cause diabetes. The sugar-regulating factor was later found to be a hormone, a protein secreted into the blood by those “islet cells” that Langerhans had identified. The hormone was called isletin, and then insulin—literally, “island protein.”

The identification of insulin in pancreatic tissue led to a race to purify it—but it took two further decades to isolate the protein from animals. Ultimately, in 1921, Banting and Best extracted a few micrograms of the substance out of dozens of pounds of cow pancreases. Injected into diabetic children, the hormone rapidly restored proper blood sugar levels and stopped their thirst and urination. But the hormone was notoriously difficult to work with: insoluble, heat-labile, temperamental, unstable, mysterious—insular.

no one had ever produced a recombinant human protein in a cell for medicinal use—that the audacity paid off. On October 26, 1982, the US Patent and Trademark Office (USPTO) issued a patent to Genentech to use recombinant DNA to produce a protein such as insulin or somatostatin in a microbial organism. As one observer wrote: “effectively, the patent claimed, as an invention, [all] genetically modified microorganisms.” The Genentech patent would soon become one of the most lucrative, and most hotly disputed, patents in the history of technology.

By the mid-1970s, though, hemophiliacs were being treated with injections of concentrated factor VIII. Distilled out of thousands of liters of human blood, a single dose of the clotting factor was equivalent to a hundred blood transfusions. A typical patient with hemophilia was thus exposed to the condensed essence of blood from thousands of donors. The emergence of the mysterious immunological collapse among patients with multiple blood transfusions pinpointed the cause of the illness to a blood-borne factor that had contaminated the supply of factor VIII—possibly a novel virus. The syndrome was renamed acquired immunodeficiency syndrome—AIDS.

I had no idea

It is tempting to write the history of technology through products: the wheel; the microscope; the airplane; the Internet. But it is more illuminating to write the history of technology through transitions: linear motion to circular motion; visual space to subvisual space; motion on land to motion in air; physical connectivity to virtual connectivity.

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.

The unifying diagnosis came to us in a flash of shame the next week when he had an MRI of his brain. The ventricles of the brain, which bathe the brain in fluid, were swollen and dilated, and the tissue of the brain had been pushed out to the edges. The condition is called normal pressure hydrocephalus (NPH).

“Incomplete penetrance” meant that even if a mutation was present in the genome, its capacity to penetrate into a physical or morphological feature was not always complete.

In contrast to Galton’s and Priddy’s method, the major advance of newgenics, its proponents insisted, was that scientists were no longer selecting phenotypes as surrogates for the underlying genetic determinants. Now, geneticists had the opportunity to select genes directly—by examining the genetic composition of a fetus.

In Huntington’s disease, the mutation is not an alteration of one amino acid or two, but an increase in the number of repeats, from less than thirty-five in the normal gene to more than forty in the mutant.

That one of the most elemental diseases in human history happens to arise from the corruption of the two most elemental processes in biology is not a co-incidence: cancer co-opts the logic of both evolution and heredity; it is a pathological convergence of Mendel and Darwin. Cancer cells arise via mutation, survival, natural selection, and growth. And they transmit the instructions for malignant growth to their daughter cells via their genes. As biologists realized in the early 1980s, cancer, then, was a “new” kind of genetic disease—the result of heredity, evolution, environment, and chance all mixed together.

The most important technical breakthrough, perhaps, came from Kary Mullis, a biochemist studying gene replication.

The technique was eventually called the polymerase chain reaction, or PCR, and would become crucial for the Human Genome Project.

Computational scientists in charge of assembling the genome worked week upon week to put the gene fragments in order, but the complete sequence was still missing.

A pesky, mysterious three-hundred-base-pair sequence called Alu appears and reappears millions of times,

Every cell possesses a subcellular structure called a mitochondrion that is used to generate energy. Mitochondria have their own mini-genome, with only thirty-seven genes, about one six-thousandth the number of genes on human chromosomes.

(Some scientists propose that mitochondria originated from some ancient bacteria that invaded single-celled organisms.

Consider the genesis of a single-celled embryo produced by the fertilization of an egg by a sperm. The genetic material of this embryo comes from two sources: paternal genes (from sperm) and maternal genes (from eggs). 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.

Wheb you're 3 weeks into MD1 and all the embryo lectures thus far make no sense

Eric Turkheimer strongly validated this theory by demonstrating that genes play a rather minor role in determining IQ in severely impoverished circumstances. If you superpose poverty, hunger, and illness on a child, then these variables dominate the influence on IQ. Genes that control IQ only become significant if you remove these limitations.