TIME (Jim Kozubek) – In the 1960s, Thomas Kuhn suggested that scientific ideas undergo fits of revolution, challenging the foundation of establishment science. But it was Peter Galison who emphasized the impact of a tool or method, and encouraged the notion that technology creates the tangible breach or disruption of a field. Alfred Hersey, in a similar spirit, once told a colleague, “ideas come and go, but a method lasts.”
CRISPR-Cas9, the new gene modification tool, which has been heralded as a means for inserting ourselves into evolution, is itself evolving as a technology, even as you read this. That technology itself can evolve means there is greater urgency for how we think of our biology: either as a machine (which can break down and get new spare parts) or as part of ecology (whereby breakdown is not necessarily bad and can be part of growth, renewal or reorganization). CRISPR may be used to repair a gene that has a deficient product, such as an enzyme or receptor, or alter code that merely suggests of risk. Ideas on how to use it change hourly. The method is here to last. The ethics will only get more fraught. But there is a bigger obstacle to the emergence of “designer babies” and Gattaca-type dystopian futures: the principles of evolution.
Before that, though, some background: CRISPR is a molecule that can be programmed to target a specific sequence in a genome. It guides an enzyme, such as Cas9, to chop the code like tiny molecular scissors. Scientists began using Cas9 to cause “blunt end” breaks in DNA. This tends to initiate a jerry-rigged repair; the break is cobbled back together, incorporating small bits of available DNA or a repair template of other genetic material that scientists might add. A Cas9 repair is not always precise, but as the old saying goes, “a carpenter doesn’t blame his tools.” But researchers have since found Cpf1, another such enzyme, which hacks into double-stranded DNA and leaves a “sticky end” break that leaves one strand dangling off the end. This template allows for more precise gene edits. And in December, U.C. Berkeley scientists reported discovering yet more enzymes—CasX and CasY—which promise to make the technology even more versatile and exacting. In short, technical limitations are evaporating.
On the immediate horizon, we are starting to see the silhouette of what Marcy Darnovsky, director of the Center for Genetics and Society, calls “market-based eugenics.” Peter Marks, deputy director of the Center for Biologics Evaluation and Research and the U.S. Food and Drug Administration, told me in an email that in the United States, the FDA has chosen to regulate CRISPR-Cas9 as a drug, since it results in the chemical modification of a cell (like drugs do). This means that the agency can use normal channels to regulate any specific application in humans. Indeed, lawmakers put a rider into an omnibus spending bill that prevents the agency from reviewing applications that relate to the heritable code of a human embryo. But something is also going on in the background. We know that, for instance, many potential mothers of newborns with Down syndrome choose to abort, and it’s not hard to envision a slippery slope of in vitro techniques, perhaps gene modifications, applied to conditions such as autism or psychiatric risk. The consumer will is there.
The industrial will is there, too. While the EPA and FDA work in the public interest, many NIH-backed scientists have ulterior interests, mainly to use federal (taxpayer) funding as grist to start their own business, to patent techniques, and to engage in lawsuits. Mark Zuckerberg and Priscilla Chan established a new “Biohub” which retains exclusive rights to patents, a similar scenario devised by the Sean Parker Foundation. The Broad Institute is armed with $650 million from the philanthropist Ted Stanley to investigate psychiatric disorders, as well as the claim to a robust patent portfolio of CRISPR systems for which it has a strong financial incentive to market and sell as much as possible. Indeed, the Broad’s director Eric Lander has referred to “a revolution in psychiatric disease” and NIH chief Francis Collins said psychiatric genomics stands “poised for rapid advances.” Whether I agree with them (I don’t) should be separated from the ambition to “industrialize the human genome”—and why the alteration of our biology evokes hubris, and our applications and intents can go wrong.
First, numerous studies of late have demonstrated that thousands of genetic variants straddled over the entire genome contribute to autism and psychiatric risk, as well as personality traits, and even intelligence. SHANK3, DIXDC1, DISC1 and C4, some of our most promising candidate genes for autism or schizophrenia, contain variants which actually only increase risk by a fraction of a percentage point. For another, called GRIN1, childhood stress can lessen its gene expression and impair learning. Though neuropsychiatric conditions are highly heritable, no single genetic variant contributes much to the risk of inheriting them, and so it’s not particularly feasible to correct through gene modification. The journalist David Dobbs has elsewhere referred to these as “Many Assorted Genes of Tiny Significance,” or MAGOTS.
Biology is robust against breakdown. It straddles risk like a money manager, and that straddling of risk over the entire genome is one reason there are so few single “targets” for many of these psychological and cognitive traits. Indeed, many of these genetic variants may be pleiotropic, meaning they have different, often unrelated effects in different cells or tissues. The severity of their enhancing or diminishing effects may also vary, depending on their genetic background, the other genetic variants they’re inherited with.
Second, scientists tend to think of men as machines, genes as their broken parts and variations in life as problems to be solved—aberrations outside the normal curve. This assumes there is a right way for genes to be. In reality, Darwin showed us that evolution does not progress toward an ideal model or a more perfect form, but instead is a work of tinkering toward adaptation in local niches. Nowhere in nature does it say how a gene should function.
Furthermore, genetic variants that predispose us to risk or supposed weaknesses are precisely the same ones that turn out to have small fitness advantages (they make us better at numbers, more sensitive, alter concentration…). This is one reason I am a “neurodiversity advocate.” Evolution works at the margins, and it does so through trade-offs: Often, you don’t get an advantage without risking a disadvantage. This is not trivial.
In 1966, Richard Lewontin and John Hubby proposed the idea of “balancing selection,” which suggests that harmful versions of genes, known as alleles, can remain in the population to contribute to genetic diversity. These versions can be useful in the case when individuals have one copy of the rare version of the gene and a copy of a more common, surefire form (this makes the individual “heterozygous”). The infamous APOE4 variant, the single strongest risk variant for late-onset Alzheimer’s disease, remains at 15% frequency in the population—one reason is that it may also up Vitamin D. A variation in a gene called COMT can increase dopamine levels by four-fold in the frontal cortex, which can increase concentration—perhaps helpful if you have one copy, though it makes you more prone to being jittery if you have two copies (which 5% of us do).
Even some variants that are highly compromising stick around by piggy-backing on other useful genes that are under natural selection. Last year, Tobias Lenz, a scientist at the Max-Planck Institute for Evolutionary Biology in Germany, reported that a region of the genome called the major histocompatibility complex, which creates an immune system component that detects an array of infections, is littered with mutations. Many of these mutations also associate with human diseases, cancer, autoimmune disease and schizophrenia. The advantage of altering immune system genes, then, may come with a tradeoff of removing genes that are “hitchhiking” nearby and dispose an associated risk for cancer or neuropsychiatric disorders. Losing the bad can mean losing the good, too.
There are no superior genes. Genes have a long and layered history, and they often have three or four unrelated functions, which balance against each other under selection. Those risky variants that can, in the right scenario, say, make us better at numbers are actually helpful to remain in the population in low frequencies. Indeed, versions of hundreds of genes that predispose us to psychiatric risks remain in the population at stable rates, while autism spectrum disorder and schizophrenia each occur at about one percent—hinting at a tradeoff of risk for advantage.
In his 2015 book NeuroTribes, Steve Silberman argued against “framing autism as a contemporary aberration,” instead suggesting it had roots in “very old genes that are shared widely in the general population while being concentrated more in certain families than in others. Whatever autism is, it is not a unique product of modern civilization. It is a strange gift from our deep past, passed down through millions of years of evolution.”
In 1995, Arnold Ludwig reported a 77 percent rate of psychiatric disorders in eminent fiction writers. The link between creativity and madness is an old debate—but there are plausible theories for how this works. One in the scientific literature is that subclinical traits—which we often characterize as schizotypal or psychoticism—or even psychological traits like “openness to experience” enable people to perform better on measures of creativity. However, if these tendencies become overly pronounced in the cases of severe mental illness, the aptitude for productivity and creativity plummet—a concept broadly referred to as the “inverted U.” In effect, mild amounts of stress and disorientation can contribute to outside-of-the-box thinking, but a full spiral into a psychotic episode results in a rapid decline in insight.
As Steven Pinker told me, “There are several possible explanations of why the trait of openness to experience could be an individual adaptation. As with any trait that varies among individuals, there is the challenge of explaining why it does not take a single, optimal value in all members of the species. Among the possibilities are that it’s the result of mutations that have not been weeded out yet; that different values are adaptive in different kinds of environments; and that it’s frequency-dependent: it’s only adaptive when it’s not too common.”
But thousands of genetic variants do indeed add up to influence psychiatric risk. That these variants stay in the human population at small frequencies also suggests that they may conceal a fitness benefit in some genetic backgrounds, for some people—one reason we should not be so quick to clip snippets of code out of our genomes. Some of those with psychiatric risk—Carrie Fisher, David Foster Wallace, Kurt Cobain—turn out to illuminate reality in ways those inside the normal curve cannot. They demonstrate the limits of the human condition, mthe ultimate failure to achieve any security and the impossibility of control. That we could do any better than that through biotechnology is unlikely; that we should want to is at best dubious and, at worst, morally questionable. “Blessed be the meek, for they shall inherit the earth.”
We’ve known for a long time the folly of genetic determinism: 30,000 genes cannot model 100,000,000,000,000 (a hundred trillion) synaptic connections in the brain. We also know that chronic stress and limiting social and economic factors are critically important to health, including cancer rates, cardiovascular and mental health, as articulated through well-known phenomena such as the “Glasgow effect.” Yet the NIMH has taken the position to only fund research that entails a “neuro-signature,” which conveniently supports a drugmaker model and ignores the context of conditions. We are investing billions into data, yet every day I walked to work in Cambridge, I walked past “methadone mile,” where there are plenty of homeless people suffering from panic and schizophrenia, without adequate resources—save for a half-million-dollar toilet. The promise that we can use gene modification, or even data, to eliminate psychiatric disorders is a fool’s errand. Chronic stress matters. And genetic risk variants remain in the population because they’re advantageous to certain people, given the right genetic background or conditions. Those risk variants are speculating—evolution, always and forever, takes chances.