Six hundred African-American families with early-adolescent children were recruited for the study. The families were randomly assigned to two groups. In one group, the children and their parents received seven weeks of intensive education, counseling, emotional support, and structured social interventions focused on preventing alcoholism, binge behaviors, violence, impulsiveness, and drug use. In the control group, the families received minimal interventions. Children in the intervention group and in the control group had the 5HTTLRP gene sequenced.
The first result of this randomized trial was predictable from prior studies: in the control group, children with the short variant—i.e., the “high risk” form of the gene—were twice as likely to veer toward high-risk behaviors, including binge drinking, drug use, and sexual promiscuity as adolescents, confirming earlier studies that had suggested an increased risk within this genetic subgroup. The second result was more provocative: these very children were also the most likely to respond to the social interventions. In the intervention group, children with the high-risk allele were most strongly and rapidly “normalized”—i.e., the most drastically affected subjects were also the best responders. In a parallel study, orphaned infants with the short variant of 5HTTLRP appeared more impulsive and socially disturbed than their long-variant counterparts at baseline—but were also the most likely to benefit from placement in a more nurturing foster-care environment.
In both cases, it seems, the short variant encodes a hyperactive “stress sensor” for psychic susceptibility, but also a sensor most likely to respond to an intervention that targets the susceptibility. The most brittle or fragile forms of psyche are the most likely to be distorted by trauma-inducing environments—but are also the most likely to be restored by targeted interventions. It is as if resilience itself has a genetic core: some humans are born resilient (but are less responsive to interventions), while others are born sensitive (but more likely to respond to changes in their environments).
The idea of a “resilience gene” has entranced social engineers. Writing in the New York Times in 2014, the behavioral psychologist Jay Belsky argued, “Should we seek to identify the most susceptible children and disproportionately target them when it comes to investing scarce intervention and service dollars? I believe the answer is yes.” “Some children are—in one frequently used metaphor—like delicate orchids,” Belsky wrote, “they quickly wither if exposed to stress and deprivation, but blossom if given a lot of care and support. Others are more like dandelions; they prove resilient to the negative effects of adversity, but at the same time do not particularly benefit from positive experiences.” By identifying these “delicate orchid” versus “dandelion” children by gene profiling, Belsky proposes, societies might achieve vastly more efficient targeting with scarce resources. “One might even imagine a day when we could genotype all the children in an elementary school to ensure that those who could most benefit from help got the best teachers.”
Genotyping all children in elementary school? Foster-care choices driven by genetic profiling? Dandelions and orchids? Evidently, the conversation around genes and predilections has already slipped past the original boundaries—from high-penetrance genes, extraordinary suffering, and justifiable interventions—to genotype-driven social engineering. What if genotyping identifies a child with a future risk for unipolar depression or bipolar disease? What about gene profiling for violence, criminality, or impulsivity? What constitutes “extraordinary suffering,” and which interventions are “justifiable”?
And what is normal? Are parents allowed to choose “normalcy” for their children? What if—obeying some sort of Heisenbergian principle of psychology—the very act of intervention reinforces the identity of abnormalcy?
This book began as an intimate history—but it is the intimate future that concerns me. A child born to a parent with schizophrenia, we now know, has between a 13 to 30 percent chance of developing the disease by age sixty. If both parents are affected, the risk climbs to about 50 percent. With one uncle affected, a child runs a risk that is three- to fivefold higher than the general population. With two uncles and a cousin affected—Jagu, Rajesh, Moni—that number jumps to about tenfold the general risk. If my father, my sister, or my paternal cousins were to develop the disease (the symptoms can emerge later in life), the risk would again leap severalfold. It is a matter of waiting and watching, of spinning and respinning the teetotum of fate, of assessing and reassessing my genetic risk.
In the wake of the monumental studies on the genetics of familial schizophrenia, I have often wondered about sequencing my genome, and the genomes of selected members of my family. The technology exists: my own lab, as it turns out, is equipped to extract, sequence, and interpret genomes (I routinely use this technology to sequence the genes of my cancer patients). What is missing, still, is the identity of most of the gene variants, or combinations of variants, that increase the risk. But there is little doubt that many of these variants will be identified, and the nature of risk conferred by them quantified, by the end of the decade. For families such as mine, the prospect of genetic diagnosis will no longer remain an abstraction, but will transform into clinical and personal realities. The triangle of considerations—penetrance, extraordinary suffering, and justifiable choice—will be carved into our individual futures.
If the history of the last century taught us the dangers of empowering governments to determine genetic “fitness” (i.e., which person fits within the triangle, and who lives outside it), then the question that confronts our current era is what happens when this power devolves to the individual. It is a question that requires us to balance the desires of the individual—to carve out a life of happiness and achievement, without undue suffering—with the desires of a society that, in the short term, may be interested only in driving down the burden of disease and the expense of disability. And operating silently in the background is a third set of actors: our genes themselves, which reproduce and create new variants oblivious of our desires and compulsions—but, either directly or indirectly, acutely or obliquely, influence our desires and compulsions. Speaking at the Sorbonne in 1975, the cultural historian Michel Foucault once proposed that “a technology of abnormal individuals appears precisely when a regular network of knowledge and power has been established.” Foucault was thinking about a “regular network” of humans. But it could just as easily be a network of genes.
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I. Implicating a new mutation as the cause of a sporadic disease is not easy: an incidental mutation might be found by pure chance in a child and have nothing to do with the disease. Or specific environmental triggers might be required to release the disease: the so-called sporadic case may actually be a familial case that has been pushed over some tipping point by an environmental or genetic trigger.
II. An important class of mutations linked to schizophrenia is called copy number variation, or CNV—deletions of genes or duplications/triplications of the same gene. CNVs have also been found in cases of sporadic autism and other forms of mental illness.
III. This method—of comparing the genome of a child with the sporadic or de novo variant of a disease versus the genome of his or her parents—was pioneered by autism researchers in the 2000s, and radically advanced the field of psychiatric genetics. The Simons Simplex Collection identified 2,800 families in which parents were not autistic, but only one child was born with an autism spectrum disorder. Comparison of the parental genome to the child’s genome revealed several de novo mutations found in such children. Notably, several genes mutated in autism are also found to be mutated in schizophrenia, raising the possibility of deeper genetic links between the two diseases.
IV. The strongest, and most intriguing, gene linked to schizophrenia is a gene associated with the immune system. The gene, called C4, comes in two closely related forms, called C4A and C4B, which sit, cheek by jowl, next to each other on the genome. Both forms encode proteins that may be used to recognize, eliminate, and destroy viruse
s, bacteria, cell debris, and dead cells—but the striking link between these genes and schizophrenia remained a tantalizing mystery.
In January 2016, a seminal study partly solved the puzzle. In the brain, nerve cells communicate with other nerve cells using specialized junctions or connections called synapses. These synapses are formed during the development of the brain, and their connectivity is the key to normal cognition—just as the connectivity of wires on a circuit-board is key to a computer’s function.
During brain development, these synapses need to be pruned and reshaped, akin to the cutting and soldering of wires during the manufacture of a circuit-board. Astonishingly, the C4 protein, the molecule thought to recognize and eliminate dead cells, debris, and pathogens, is “repurposed” and recruited to eliminate synapses—a process called synaptic pruning. In humans, synaptic pruning continues throughout childhood and into the third decade of adulthood—precisely the period of time that many symptoms of schizophrenia become manifest.
In patients with schizophrenia, variations in the C4 genes increase the amount and activity of the C4A and C4B proteins, resulting in synapses that are “over-pruned” during development. Inhibitors of these molecules might restore the normal number of synapses in a susceptible child’s or adolescent’s brain.
Four decades of science—twin studies in the 1970s, linkage analysis in the 1980s, and neurobiology and cell biology in the 1990s and 2000s—converge on this discovery. For families such as mine, the discovery of C4’s link to schizophrenia opens remarkable prospects for the diagnosis and treatment of this illness—but also raises troubling questions about how and when such diagnostic tests or therapies may be deployed.
V. The distinction between “familial” and “sporadic” begins to tangle and collapse at a genetic level. Some genes mutated in familial diseases also turn out to be mutated in the sporadic disease. These genes are most likely to be powerful causes of the disease.
VI. The mutation or variation linked to the risk for a disease may not lie in the protein-coding region of a gene. The variation may lie in a regulatory region of a gene, or in a gene that does not code for proteins. Indeed, many of the genetic variations currently known to affect the risk for a particular disease or phenotype lie in regulatory, or noncoding regions of the genome.
Genetic Therapies: Post-Human
What do I fear? Myself? There’s none else by.
—William Shakespeare, Richard III, act 5, scene 3
There is in biology at the moment a sense of barely contained expectations reminiscent of the physical sciences at the beginning of the 20th century. It is a feeling of advancing into the unknown and [a recognition] that where this advance will lead is both exciting and mysterious. . . . The analogy between 20th-century physics and 21st-century biology will continue, for both good and ill.
—“Biology’s Big Bang,” 2007
In the summer of 1991, not long after the Human Genome Project had been launched, a journalist visited James Watson at the Cold Spring Harbor lab in New York. It was a sultry afternoon, and Watson was in his office, sitting by a window overlooking the gleaming bay. The interviewer asked Watson about the future of the Genome Project. What would happen once all the genes in our genome had been sequenced and scientists could manipulate human genetic information at will?
Watson chuckled and raised his eyebrows. “He ran a hand down his sparse strands of white hair . . . and a puckish gleam came into his eye. . . . ‘A lot of people say they’re worried about changing our genetic instructions. But those [genetic instructions] are just a product of evolution designed to adapt us for certain conditions that may not exist today. We all know how imperfect we are. Why not make ourselves a little better suited to survival?’ ”
“That’s what we will do,” he said. He looked at his interviewer and laughed suddenly, emitting that distinctive, high-pitched chortle that had become familiar to the scientific world as a prelude to a storm. “That’s what we will do. We’ll make ourselves a little better.”
Watson’s comment returns us to the second concern raised by the students at the Erice meeting: What if we learn to intentionally alter the human genome? Until the late 1980s, the only mechanism to reshape the human genome—to “make ourselves a little better” in a genetic sense—was to identify highly penetrant and seriously deleterious genetic mutations (such as those that cause Tay-Sachs disease or cystic fibrosis) in utero and terminate the pregnancy. In the 1990s, preimplantation genetic diagnosis (PGD) allowed parents to preemptively select and implant embryos without such mutations, substituting the moral dilemma of the termination of a life with the moral dilemma of choice. Still, human geneticists operated within the aforementioned triangle of boundaries: highly penetrant genetic lesions, extraordinary suffering, and justifiable, noncoerced interventions.
The advent of gene therapy in the late 1990s changed the terms of this discussion: genes could now be changed intentionally in human bodies. This was the rebirth of “positive eugenics.” Rather than eliminating humans carrying deleterious genes, scientists could envision correcting defective human genes, thereby making the genome a “bit better.”
Conceptually, gene therapy comes in two distinct flavors. The first involves modifying the genome of a nonreproductive cell—say a blood, brain, or muscle cell. The genetic modification of these cells affects their function, but it does not alter the human genome for more than one generation. If a genetic change is introduced into a muscle or blood cell, the change is not transmitted into a human embryo; the altered gene is lost when the cell dies. Ashi DeSilva, Jesse Gelsinger, and Cynthia Cutshall are all examples of humans treated with non-germ-line gene therapy: in all three cases, blood cells—but not germ-line cells (i.e., sperm and egg)—were altered by the introduction of foreign genes.
The second, more radical, form of gene therapy is to modify a human genome so that the change affects reproductive cells. Once a genomic change has been introduced into a sperm or egg—i.e., into the germ line of a human being—the change becomes self-propagating. The change is incorporated permanently into the human genome and transmitted from one generation to the next. The inserted gene becomes inextricably linked to the human genome.
Germ-line gene therapy in humans was not conceivable in the late 1990s: no reliable technique existed to transmit genetic changes into a human sperm or egg cell. But even non-germ-line therapy trials had been halted. Jesse Gelsinger’s “biotech death,” as the New York Times Magazine described it, had sent such tremors of anguish through the field that virtually all gene-therapy trials in the United States were frozen. Companies went bankrupt. Scientists left the field. The trial scorched the earth of all forms of gene therapies, leaving a permanent scar on the field.
But gene therapy has returned—step by cautious step. The seemingly stagnant decade between 1990 and 2000 was a decade of introspection and reconsideration. First, the litany of errors in the Gelsinger trial had to be meticulously dissected. Why had the introduction of a supposedly harmless virus carrying a gene into the liver caused such a devastating, fatal reaction? As physicians, scientists, and regulators sifted through the trial, the reasons for the failed experiment became evident. The vectors used to infect Gelsinger’s cells had never been properly vetted in humans. But most important, Gelsinger’s immune response to the virus should have been anticipated. Gelsinger had likely been naturally exposed to the strain of adenovirus that had been used in the gene-therapy experiment. His brisk immune response was not an aberration; it was the perfectly habitual response of a body fighting a pathogen that it had previously encountered, possibly during infection by a cold. In choosing a common human virus as their vehicle for gene delivery, gene therapists had made a crucial error of judgment: they had neglected to consider that genes were being delivered into a human body with a history, with scars, memories, and prior exposures. “How could such a beautiful thing go so, so wrong?” Paul Gelsinger had asked. We now know how: because—seeking only beauty—scientists were
unprepared for catastrophe. The doctors pushing the frontiers of human medicine had forgotten to account for the common cold.
In the two decades that followed Gelsinger’s death, the tools used in the original gene-therapy trials have largely been replaced by second- and third-generation technologies. New viruses are now used to deliver genes into human cells, and novel methods to monitor gene delivery have been developed. Many of these viruses have been purposefully selected because they are easy to manipulate in the lab and do not elicit the immune response that spiraled so devastatingly out of control in Gelsinger’s body.
In 2014, a landmark study published in the New England Journal of Medicine announced the successful use of gene therapy to treat hemophilia. Hemophilia, the terrifying bleeding disease caused by a mutation in a blood-clotting factor, threads through the history of the gene in a continuous strand; it is the DNA in the story of DNA. It was the illness that had affected the Czarevitch Alexei from his birth in 1904 and thus inserted itself into the epicenter of political life in Russia in the early twentieth century. It was one of the first X-linked diseases to be identified in humans, thereby pointing to the physical presence of a gene on a chromosome. It was one of the first diseases to be definitively ascribed to a single gene. It was also one of the first genetic diseases for which an artificially engineered protein was created, by Genentech in 1984.
The idea of using gene therapy for hemophilia had first been broached in the mid-1980s. Since hemophilia is caused by the lack of a functional clotting protein, it was conceivable to use a virus to deliver the gene into cells so the body could produce the missing protein and thus restore the clotting of blood. In the early 2000s, after a nearly two-decade delay, gene therapists decided to try gene therapy for hemophilia again. Hemophilia comes in two major variants, classified by the particular clotting factor that is missing in blood. The variant of hemophilia chosen for the gene-therapy test was hemophilia B, in which the gene for clotting factor IX is mutated and fails to produce a normal protein.