Ideas

IDEAS | Jim Kozubek

Fixing genes won’t fix us

João Fazenda for The Boston Globe

Methadone Mile is a stretch of road along Massachusetts Avenue that begins in the South End and stretches north to the Charles River. On the other side of the river is Cambridge. For the past few years, I lived far north on this road in a $600-a-month room in a house with red paint peeling from its front clapboards. I was employed as a data scientist at the Brigham and Women’s Hospital, walking that Avenue each morning and afternoon through people in various stages of despondence, some fallen on the sidewalk, to one of my offices at the Broad Institute of MIT and Harvard.

Cambridge installed a half-million-dollar toilet near Mass. Ave in Harvard Square a year and a half ago, but that was to keep troubled people out of cafes. The big money is going toward a much different approach to longstanding social and public-health problems. Not far away, the really big, beautiful structures keep sprouting out of the ground, including Novartis’ recently completed $600 million campus, and the neighboring $1.4 billion Broad Institute with its 11 floors of steel and glass.

The Broad this winter won a federal court decision which will allow it to keep the rights to a genome editing tool Crispr-Cas9, which enables the precise modification of genes. With that long-running legal question settled, the work of precise gene editing is poised to take off, and the biotechnology revolution that’s already transforming streetscapes in the Boston area will attract ever more public and private investment.

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Remarkable is the existing divide in income inequality in Cambridge; ironic is the perception that we are going to solve social problems with more data and expensive technology which allows us to start hacking into our biology.

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Science is threatening a new era of “market-based eugenics,” whereby gene editing in combination with in vitro fertilization techniques will allow us to engineer our way to a society with fewer instances of diseases like schizophrenia. The implications are enormous and one of the most complex ethical questions is central mission of the science itself. But the movement toward psychiatric genetics is also dangerous in its subtler message: The idea that social problems are biology problems can channel more resources to wealthy scientists while diverting it from social services.

Federal agencies, for instance, have in recent years taken a position to fund psychiatric research that entails a biomarker, or “neuro-signature,” which supports a drug-maker model yet downplays other pressing realities such as underlying socio-economic factors, and indeed, other treatment theories, such as psychotherapy.

In other words, at the expense of social services and broader access to resources, we’re betting the house that we can engineer our way out of problems through biochemical transformations. But what if we can’t?

Genetics and neurobiology captivate our generation, but most of the genetics that contribute to complex disorders are heritable only in the broad sense, meaning no single genetic variant contributes very much to the risk that a patient will develop a given condition. Then comes the longstanding riddle into how scientists could use a biomarker or blueprint of 30,000 genes to predict the status of an individual brain with its 100 trillion synaptic connections. The reality is that brains are idiosyncratic, and no two are exactly alike.

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In the meantime, there are exact links between poverty and consequences to health. One study showed that children who endure stress and abuse acquired an “epigenetic” effect of turning down the expression of a gene which is critical to brain circuitry and long-term memory. A second study reported a similar effect, suggesting an acquired deficiency in how the brain handles stress, and reducing the quantity of a neurotrophin which contributes to helping brain cells grow. What neuroscientists call “plasticity,” the brain’s ability to subtly change its architecture had a downside as well as an upside. But, then there is the revolution in adult neurogenesis the ability to grow new neurons even in adulthood. Nothing in the brain, it seems, is set in stone.

The Broad is funded in part with $650 million from the philanthropist Ted Stanley to investigate psychiatric disorders, and now has a claim to a portfolio of Crispr systems for which it has a strong financial incentive to market and sell. The Broad’s director, Eric Lander, has referred to a coming “revolution” in the treatment of psychiatric disease, as well as conditions such as autism (which is probably an artifact of evolutionary variation, a way of being in the world, rather than a modern “disease”) while strikingly, his institution’s landmark paper published a year ago, which included an enormous data set of more than 64,000 people, found the strongest single genetic variant could increase the risk for schizophrenia by only a quarter of a single percentage point from 1 percent in the general population to 1.25 percent. And, we don’t know which of these variants are pleiotropic, meaning they can enhance or diminish the beneficial or deleterious effects of other variants they are inherited with; the same genetic variant may provide advantages in immune cells and disadvantages in brain cells.

Indeed, there are no superior genes, only locally adapted ones. And many of the genetic variants that carry risk may provide an evolutionary advantage, or alter concentration, creativity, or sensitivity, when inherited along with the right set of other genetic variants. One theory, called the inverted-U even suggests that stress and creative output can be graphed together to a degree; while too much chronic stress eventually leads to exhaustion, whereby performance and creativity plummet. This is one explanation for why people with mental illness may exhibit bouts of creativity early in their development.

That’s true for other genetic trade-offs as well. In 2016, Tobias Lenz, a scientist at the Max-Planck Institute for Evolutionary Biology in Germany, studied 6,500 people and found evidence that those with a more effective immune system, for instance, also had an increased risk of heritable diseases including schizophrenia. Lenz, a Broad collaborator, told a writer at the time, “To some extent it tells us that we will never be able to get rid of deleterious variation because of such complex trade-offs.”

But when Crispr came along, scientists clamored that we would begin hacking into life, as if biology were tantamount to a computer, rather than a fallible, locally adapted organism — in the words of Stephen Jay Gould, “a quirky mass of imperfections, working well enough (often admirably); a jury-rigged set of adaptations built of curious parts made available by past histories.”

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To imagine a future without autism, or psychiatric disorders is contrary to evolution, which churns out organisms with new variation — not an ever more perfect product of engineering feats.. Nevertheless, the analogies of computer circuits to improvised biology remain the most potent tropes of our generation. After its schizophrenia paper was published, the Broad released a video, titled “Opening Schizophrenia’s Black Box,” implying that it may one day be possible to hack into brain circuitry and repair mental disorders with drugs or other therapies.

The theory of evolution is tragic in that it suggests a nature that is radically decentralized, deeply unsettling, and a threat to social order. By comparison, the modern scientist has embodied the social order, seemingly in control of nature through technology, clandestine knowledge, and access to the gene. Francis Bacon’s concept of the “scientific priesthood” suggests scientists will unlock the secrets of nature to the public benefit. Yet Soren Kierkegaard protested against the “objectivity” of science, and thought that it was a means of avoiding the anxiety that is inherent to human existence.

In other words, there’s ample room to question the hype around genetic editing, and our own motives for embracing it. Genetics is not about to lead to a paradigm shift in public health. We know that chronic stress matters to brain function and the changing norms of how brain handles stress and blood pressure has contributed to unexplained poor health and low life expectancy. The costs of our health care system are undergoing a dramatic shift. The domination of high technology comes at the expense of simpler, cheaper, more egalitarian options: fitness, nutrition, and promotion of social and economic mobility. There may be elements of nature that we can never entirely control, even as new technologies add to the illusion that we might — even as that illusion reinforces deep inequalities in how our resources are distributed and spent.

Jim Kozubek is the author of “Modern Prometheus: Editing the Human Genome with Crispr-Cas9.”