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 viruses, 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