The Gene: Part Four

Other families were afflicted by osteogenesis imperfecta, a disease caused by a mutation in a gene for collagen, a protein that forms and strengthens bone.

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 or personality, then a single encounter with a Down child can lay that idea to rest).

These illnesses lay on the opposite end of the One Gene-One Disease paradigm; they were Many Genes-Many Diseases.

Unlike Marfan or Down syndrome, where a single potent mutation or a chromosomal aberration was necessary and sufficient to cause the disease, the effect of any individual gene in polygenic syndromes was dulled.

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 a mutation, the circumstances of a person’s existence, and his or her goals for survival or success. It is not mutation that ultimately causes disease, but mismatch.

If the entry of genetics into the human world carried one immediate lesson, it was this: the imperfect was not just our paradise; it was also, inextricably, our mortal world.

The most remarkable feature of X-Men was not its growing, multifarious menagerie of mutant characters—a wolf man with steel claws or a woman able to summon English weather on command—but the reversed roles of the victim and the victimizer.

As the legal scholar Alexander Bickel described it, “The individual’s [i.e., mother’s] interest, here, overrides society’s interest in the first three months and, subject only to health regulations, also in the second; in the third trimester, society is preeminent.”

Ad hoc judges were not called in to classify men and women as “imbeciles,” “morons,” and “idiots,” nor was chromosome number decided as a matter of personal taste.

But coupled to this was the desire to instigate an equally expansive, laissez-faire form of “positive eugenics”—a means to select for favorable genetic attributes.

Although Graham’s “genius bank” was ridiculed and eventually disbanded, its early advocacy of “germinal choice”—that individuals should be free to pick and choose the genetic determinants of their offspring—was hailed by several scientists.

...but selecting “genius genes”...was considered a perfectly tenable prospect for the future.

Support from scientists, intellectuals, writers, and philosophers poured into the movement. Francis Crick staunchly backed neo-eugenics, as did James Watson.

As McKusick and his colleagues were discovering with increasing lucidity, the interactions between human genes and illnesses were vastly more complicated than newgenics might have anticipated.

For Down syndrome, where the chromosomal abnormality was distinct and easily identifiable, and where the link between the genetic lesion and the medical symptoms was highly predictable, prenatal testing...might seem justifiable.

We suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacing.

In the summer of 1968, when Wexler was twenty-two, her mother, Leonore Wexler, was chastised by a policeman for walking erratically while crossing a street in Los Angeles.

Part of the macabre denouement of Huntington’s is the late onset of the illness.

Nancy and Alice were still asymptomatic, but they each carried a 50 percent chance of being affected, with no genetic test for the disease.

A few years earlier, Milton Wexler had heard from a Venezuelan neurologist of two neighboring villages, Barranquitas and Lagunetas, on the shores of Lake Maracaibo in Venezuela with a striking prevalence of Huntington's disease.

There is something in the man’s walk that seems profoundly unnatural. A few steps, and his body begins to move with jerking, staccato gestures, while his hand traces sinuous arcs in midair.

There is something in the man’s walk that seems profoundly unnatural. A few steps, and his body begins to move with jerking, staccato gestures, while his hand traces sinuous arcs in midair.

They assiduously collected and assembled a family tree of the Venezuelan kindred.

It was a strange region of the genome, largely barren, with a few unknown genes within it. For the team of geneticists, it was like the sudden landing of a boat on a derelict beachhead, with no known landmarks in sight.

IT15 was found to encode an enormous protein—a biochemical behemoth containing 3,144 amino acids, larger than nearly any other protein in the human body (insulin has a mere 51 amino acids).

The longer protein is thought to be aggregated into pieces in neurons, and these pieces accumulate in tangled spools inside cells, possibly leading to their death and dysfunction.

The secretions of the lung were so viscous that they blocked the airways with gobs of mucus.

Other scientists, anticipating this biological revolution, had been less sanguine about it. As the geneticist J. B. S. Haldane had described it in 1923, once the power to control genes had been harnessed, “no beliefs, no values, no institutions are safe.”

Cells and intracellular organelles were revealed, raising questions about the inner anatomy and physiology of a cell, and demanding yet more powerful microscopes to understand the structures and functions of these subcellular compartments.

In principle, the technology to sequence an entire organismal genome had been invented, but the sheer size of the effort had made scientists balk.

That cancer was the result of alterations of such endogenous genetic pathways—a “distorted version of our normal selves,” as Harold Varmus, the cancer biologist, put it—was ferociously disquieting: for decades, scientists had hoped that some pathogen, such as a virus or bacterium, would be implicated as the universal cause of cancer, and might potentially be eliminated via a vaccine or antimicrobial therapy.

Populist anxieties about genes, mental illness, and crime were fanned further with the publication in the summer of 1985 of Crime and Human Nature: The Definitive Study of the Causes of Crime, an incendiary book written by James Q. Wilson, a political scientist, and Richard Herrnstein, a behavioral biologist.

Even die-hard believers of the genetic theory of schizophrenia had to admit that the etiology of the illness was largely unknown, that acquired influences had to play a major triggering role (hence the 50—not 100—percent concordance among identical twins), and that the vast majority of schizophrenics lived in the terrifying shadow of their illness but had no history of criminality whatsoever.

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.

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.

In the hushed, reverential minute that followed the end of the presentations, Venter did not hesitate to drive a switchblade through his competitors’ spines: “Oh, and by the way, we [have] just started sequencing human DNA, and it looks as if [the technical hurdles are] going to be less of a problem than they had been with the fly.”

Clinton had sent his aides a note with a terse, two-word dictum—“Fix this!”—appended to the margin.

Venter mulled over the possibility and acquiesced—but with several caveats.

Venter mulled over the possibility and acquiesced—but with several caveats.

Like so many truces, the fragile armistice between Venter and Collins barely outlived its tortuous birth.

Not every part of the genome was amenable to cloning and sequencing, and assembling nonoverlapping segments was vastly more complicated than had been anticipated, like solving a puzzle containing pieces that had fallen into the cracks of furniture.

On February 15 and 16, 2001, the Human Genome Project consortium and Celera published their papers in Nature and Science, respectively.

On February 15 and 16, 2001, the Human Genome Project consortium and Celera published their papers in Nature and Science, respectively.

An enormous proportion—a bewildering 98 percent—is not dedicated to genes per se, but to enormous stretches of DNA that are interspersed between genes (intergenic DNA) or within genes (introns).

These fragments are vastly more common than genes, resulting in yet another major idiosyncrasy of our genome: much of the human genome is not particularly human.