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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.
For medieval Christians, the existence of such a chain of humans provided a most powerful and original understanding of original sin. Since all future humans were encased within all humans, each of us had to have been physically present inside Adam’s body—“floating . . . in our First Parent’s loins,” as one theologian described—during his crucial moment of sin.
By the end of the seventeenth century, preformation was considered the most logical and consistent explanation for human and animal heredity.
“In nature there is no generation,” the Dutch scientist Jan Swammerdam wrote in 1669, “but only propagation.”
Lyell’s work in particular left an impression on him. Lyell had argued (radically, for his time) that complex geological formations, such as boulders and mountains, had been created over vast stretches of time, not by the hand of God but by slow natural processes such as erosion, sedimentation, and deposition.
For Darwin, Lyell’s central idea—of the slow heave of natural forces shaping and reshaping the earth, sculpting nature—would prove to be a potent intellectual spur.
Freaks became norms, and norms became extinct. Monster by monster, evolution advanced.
Mendel himself requested forty reprints, which he mailed, heavily annotated, to many scientists. It is likely that he sent one to Darwin, but there is no record of Darwin’s having actually read
one geneticist wrote, was “one of the strangest silences in the history of biology.” The paper was cited only four times between 1866 and 1900—virtually disappearing from scientific literature.
But his anxieties about class and status were so deep that he could not bear the thought that his own “intelligence” might merely be the by-product of privilege and opportunity.
But in science, a word is a hypothesis. In natural language, a word is used to convey an idea. But in scientific language, a word conveys more than an idea—a mechanism, a consequence, a prediction. A scientific noun can launch a thousand questions—and the idea of the “gene” did exactly that.
The “fittest” babies were then paraded through the fairs. Their pictures were featured prominently on posters, newspapers,
By 1936, less than a decade after Buck v. Bell, a vastly more virulent form of “genetic cleansing” would engulf that continent like a violent contagion, morphing the language of genes and inheritance into its most potent and macabre form.
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.
Unsurprisingly, in both cases, science was deliberately distorted to support state-sponsored mechanisms of “cleansing.” By appropriating the language of genes and inheritance, entire systems of power and statehood were justified and reinforced.
if the protein chain was altered by exactly one amino acid, then its gene had to be different by precisely one triplet (“one triplet encodes one amino acid”). Indeed, as predicted, when the gene encoding the hemoglobin B chain was later identified and sequenced in sickle-cell patients, there was a single change: one triplet in DNA—GAG—had changed to another—GTG. This resulted in the substitution of one amino acid for another: glutamate was switched to valine. That switch altered the folding of the hemoglobin
chain: rather than twisting into its neatly articulated, clasplike structure, the mutant hemoglobin protein accumulated in stringlike clumps within red cells. These clumps grew so large, particularly in the absence of oxygen, that they tugged the membrane of the red cell until the normal disk was warped into a crescent-shaped, dysmorphic “sickle cell.” Unable to glide smoothly through capillaries and veins, sickled red cells jammed into microscopic clots throughout the body, interrupting blood flow and precipitating the excruciating pain of a sickling crisis.
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.
gene, Morgan had noted, was an extraordinary solution to an extraordinary problem. Sexual reproduction demands the collapse of an organism into a single cell, but then requires that single cell to expand back into an organism.
Proteins in the early embryo are deposited preferentially at one end by the mother. They activate and silence genes, thereby defining the embryo’s axis from head to tail. These genes, in turn, activate “mapmaker” genes that make segments and split the body into its broad domains.
A worm was thus constructed from two kinds of inputs—“intrinsic” inputs from genes, and “extrinsic” inputs from cell-cell interactions. Jokingly, Brenner called it the “British model” versus the “American model.” The British way, Brenner wrote, “is for cells to do their own thing and not to talk to their neighbors very much. Ancestry is what counts, and once a cell is born in a certain place it will stay there and develop according to rigid rules.
does not count. . . . What counts is the interactions with its neighbors. It frequently exchanges information with its fellow cells and often has to move to accomplish its goals and find its proper place.”
suppose the activity of the switch depends on the concentration of the protein, and the protein can be layered in a gradient across the body of an organism, with a high concentration at one end and a low concentration at the other. This protein might flick on all twelve of its targets in one part of an organism, eight in another segment, and only three in yet another. Each combination of target genes (twelve, eight, and three) might then intersect with yet other protein gradients, and activate and repress yet other genes.
In a conceptual sense, every virus is a professional gene carrier. 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.
The degradation and identification would be repeated again and again—Arginine . . . snap . . . Lysine . . . snap—until he reached the end of the protein. It was like unstringing a necklace, bead by bead—reversing the cycle used by a cell to build a protein. Piece by piece, the disintegration of insulin would reveal the structure of its chain. In 1958, Sanger won the Nobel Prize for this landmark discovery.
Cut into pieces and dissolved, DNA turned from genetic information to gobbledygook.
Introns are not the exception in human genes; they are the rule. Human introns are often enormous—spanning several hundreds of thousands of bases of DNA.
Every experimental science depends, crucially, on the capacity to perturb a system intentionally, and to measure the effects of that perturbation.
had made the language of genetics recursive. Biologists had spent decades trying to interrogate the nature of the gene—but now it was the gene that could be used to interrogate biology. We had graduated, in short, from thinking about genes, to thinking in genes.
The hormone was called isletin, and then insulin—literally, “island protein.”
Most notably, perhaps, children with Down syndrome have an extraordinary sweetness of temperament, as if in inheriting an extra chromosome they had acquired a concomitant loss of cruelty and malice (if there is any doubt that genotypes can influence temperament
By itself, then, a mutant, or a mutation, can provide no real information about a disease or disorder. The definition of disease rests, rather, on the specific disabilities caused by an incongruity between an individual’s genetic
endowment and his or her current environment—between
Seemingly homogeneous populations were, in fact, strikingly heterogeneous. We had seen the mutants—and they were us.
One commentator noted, “The court asserted that the right of a child to be born free of [genetic] anomalies is a fundamental right.”
After millennia in which most people have produced babies in happy ignorance of the risks they run, we may all have to start acting with the severe responsibility of genetic foresight. . . . We never had to think about medicine like this before.
No newborn should be declared human until it has passed certain tests regarding its genetic endowment.
The Huntingtin protein is found in neurons and in testicular tissue. In mice, it is required for the development of the brain. The mutation that causes the disease is even more mysterious. The normal gene sequence contains a highly repetitive sequence, CAGCAGCAGCAG . . . a molecular singsong that stretches for seventeen such repeats on average (some people have ten, while others may have up to thirty-five).
In Venezuela, even boys and girls as young as twelve years old are now afflicted, some of them carrying strings of seventy or eighty repeats.
Humans with one copy of the mutant CF gene have a slightly diminished capacity to lose salt and water through their membranes and are thus relatively protected from the most devastating complications of cholera (this can be demonstrated using genetically engineered mice). Here too a mutation in a gene can have a dual and circumstantial effect—potentially beneficial in one copy, and lethal in two copies. Humans with one copy of the mutant CF gene may thus have survived cholera epidemics in Europe.
These patterns strongly suggest that schizophrenia is a complex, polygenic illness, involving multiple variants, multiple genes, and potential environmental or chance triggers.
Each cycle of copying amplified the DNA, resulting in an exponential increase in the yield of a gene. The technique was eventually called the polymerase chain reaction, or PCR, and would become crucial for the Human Genome Project.
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 startlingly accurate—had
Within weeks, the genome would be balkanized—carved up into a thousand territorial colonies carrying American, British, and German flags.
“All animals probably have a relatively similar repertoire of proteins that need to be ‘called forth’
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.
At some point in hominid evolution, two medium-size chromosomes in some ancestral ape fused to form one.
We lost a chromosome, but gained a thumb.
