Runs in the family: new findings about schizophrenia rekindle old questions about genes
The New Yorker. 92.7 (Mar. 28, 2016): p26.
Copyright: COPYRIGHT 2016 Conde Nast Publications, Inc.. All rights reserved. Reproduced by
permission of The Conde Nast Publications, Inc.
Byline: BY SIDDHARTHA MUKHERJEE
RUNS IN THE FAMILY
New findings about schizophrenia rekindle old questions about genes and identity.
In the winter of 2012, I travelled from New Delhi, where I grew up, to Calcutta to visit my cousin
Moni. My father accompanied me as a guide and companion, but he was a sullen and brooding
presence, lost in a private anguish. He is the youngest of five brothers, and Moni is his firstborn
nephew-the eldest brother's son. Since 2004, Moni, now fifty-two, has been confined to an
institution for the mentally ill (a "lunatic home," as my father calls it), with a diagnosis of
schizophrenia. He is kept awash in antipsychotics and sedatives, and an attendant watches,
bathes, and feeds him through the day.
My father has never accepted Moni's diagnosis. Over the years, he has waged a lonely campaign
against the psychiatrists charged with his nephew's care, hoping to convince them that their
diagnosis was a colossal error, or that Moni's broken psyche would somehow mend itself. He has
visited the institution in Calcutta twice-once without warning, hoping to see a transformed Moni,
living a secretly normal life behind the barred gates. But there was more than just avuncular love at
stake for him in these visits. Moni is not the only member of the family with mental illness. Two of
my father's four brothers suffered from various unravellings of the mind. Madness has been among
the Mukherjees for generations, and at least part of my father's reluctance to accept Moni's
diagnosis lies in a grim suspicion that something of the illness may be buried, like toxic waste, in
Rajesh, my father's third-born brother, had once been the most promising of the Mukherjee boysthe nimblest, the most charismatic, the most admired. But in the summer of 1946, at the age of
twenty-two, he began to behave oddly, as if a wire had been tripped in his brain. The most obvious
change in his personality was a volatility: good news triggered uncontained outbursts of joy; bad
news plunged him into inconsolable desolation. By that winter, the sine curve of Rajesh's psyche
had tightened in its frequency and gained in its amplitude. My father recalls an altered brother:
fearful at times, reckless at others, descending and ascending steep slopes of mood, irritable one
morning and overjoyed the next. When Rajesh received news of a successful performance on his
college exams, he vanished, elated, on a two-night excursion, supposedly "exercising" at a
wrestling camp. He was feverish and hallucinating when he returned, and died of pneumonia soon
afterward. Only years later, in medical school, did I realize that Rajesh was likely in the throes of an
acute manic phase. His mental breakdown was the result of a near-textbook case of bipolar
Jagu, the fourth-born of my father's siblings, came to live with us in Delhi in 1975, when I was five
years old and he was forty-five. His mind, too, was failing. Tall and rail thin, with a slightly feral look
in his eyes and a shock of matted, overgrown hair, he resembled a Bengali Jim Morrison. Unlike
Rajesh, whose illness had surfaced in his twenties, Jagu had been troubled from his adolescence.
Socially awkward, withdrawn from everyone except my grandmother, he was unable to hold a job
or live by himself. By 1975, he had visions, phantasms, and voices in his head that told him what to
do. He was still capable of extraordinary bursts of tenderness-when I accidentally smashed a
beloved Venetian vase at home, he hid me in his bedclothes and informed my mother that he had
"mounds of cash" stashed away, enough to buy "a thousand" replacement vases. But this episode
was symptomatic: even his love for me extended the fabric of his psychosis and confabulation.
Unlike Rajesh, Jagu was formally diagnosed. In the late nineteen-seventies, a physician in Delhi
examined him and determined that he had schizophrenia. But no medicines were prescribed.
Instead, Jagu continued to live at home, half hidden away in my grandmother's room. (As in many
families in India, my grandmother lived with us.) For nearly a decade, she and my father maintained
a fragile truce, with Jagu living under her care, eating meals in her room and wearing clothes that
she stitched for him. At night, when Jagu was consumed by his fears and fantasies, she put him to
bed like a child, with her hand on his forehead. She was his nurse, his housekeeper, his only friend,
and, more important, his public defender. When my grandmother died, in 1985, Jagu joined a
religious sect in Delhi and disappeared, until his death, a dozen years later.
We lost contact with Moni, too. He shuttled between schools and dropped out of college. The
commanders in his head became stronger and more insistent. In 2004, he was beaten up by a
group of goons, ostensibly for urinating in a public garden. (An internal voice had instructed him,
"Piss here; piss here.") In the winter of that year, after yet another breakdown with hallucinations
and hissing internal voices, he was institutionalized in Calcutta.
When my father and I visited Moni in 2012, I had not seen him for nearly two decades. Even so, I
expected to recognize him. But the person I met in the visiting room bore such little resemblance to
my memory of my cousin that-had his attendant not confirmed the name-I could easily have been
meeting a stranger. He had aged beyond his years. His speech, once effusive and rapid, was
hesitant and fitful; the words emerged with a sudden, surprising force, as if he were spitting out pips
of food that had been put into his mouth.
The most memorable feature of his illness, though, was not the storm within his mind but the lull in
his eyes. The word moni means "gem" in Bengali, but in common usage it also refers to something
ineffably beautiful: the shining pinpricks of light in each eye. But this was precisely what was
missing in Moni. The twin points of light in his eyes had dulled and nearly vanished, as if someone
with a minute brush had painted them gray.
That schizophrenia runs in families was evident even to the person who first defined the illness. In
1911, Eugen Bleuler, a Swiss-German psychiatrist, published a book describing a series of cases
of men and women, typically in their teens and early twenties, whose thoughts had begun to tangle
and degenerate. "In this malady, the associations lose their continuity," Bleuler wrote. "The threads
between thoughts are torn." Psychotic visions and paranoid thoughts flashed out of nowhere. Some
patients "feel themselves weak, their spirit escapes, they will never survive the day. There is a
growth in their heads. Their bones have turned liquid; their hearts have turned into stone. . . . The
patient's wife must not use eggs in cooking, otherwise he will grow feathers." His patients were
often trapped between flickering emotional states, unable to choose between two radically opposed
visions, Bleuler noted. "You devil, you angel, you devil, you angel," one woman said to her lover.
Bleuler tried to find an explanation for the mysterious symptoms, but there was only one seemingly
common element: schizophrenic patients tended to have first-degree relatives who were also
schizophrenic. He had no tools to understand the mechanism behind the heredity. The word "gene"
had been coined just two years before Bleuler published his book. The notion that a mental illness
could be carried across generations by unitary, indivisible factors-corpuscles of information
threading through families-would have struck most of Bleuler's contemporaries as mad in its own
right. Still, Bleuler was astonishingly prescient about the complex nature of inheritance. "If one is
looking for ' the heredity,' one can nearly always find it," he wrote. "We will not be able to do
anything about it even later on, unless the single factor of heredity can be broken down into many
hereditary factors along specific lines."
In the nineteen-sixties, Bleuler's hunch was confirmed by twin studies. Psychiatrists determined
that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of
developing the disease-fiftyfold higher than the risk in the general population. By the early twothousands, large population studies had revealed a strong genetic link between schizophrenia and
bipolar disorder. Some of the families described in these studies had a crisscrossing history that
was achingly similar to my own: one sibling affected with schizophrenia, another with bipolar
disorder, and a nephew or niece also schizophrenic.
"The twin studies clarified two important features of schizophrenia and bipolar disorder," Jeffrey
Lieberman, a Columbia University psychiatrist who has studied schizophrenia for thirty years, told
me. "First, it was clear that there wasn't a single gene, but dozens of genes involved in causing
schizophrenia-each perhaps exerting a small effect. And, second, even if you inherited the entire
set of risk genes, as identical twins do, you still might not develop the disease. Obviously, there
were other triggers or instigators involved in releasing the illness." But while these studies
established that schizophrenia had a genetic basis, they revealed nothing about the nature of the
genes involved. "For doctors, patients, and families in the schizophrenia community, genetics
became the ultimate mystery," Lieberman said. "If we knew the identity of the genes, we would find
the causes, and if we found the causes we could find medicines."
In 2006, an international consortium of psychiatric geneticists launched a genomic survey of
schizophrenia, hoping to advance the search for the implicated genes. With 3,322 patients and
3,587 controls, this was one of the largest and most rigorous such studies in the history of the
disease. Researchers scanned through the nearly seven thousand genomes to find variations in
gene segments that were correlated with schizophrenia. This strategy, termed an "association
study," does not pinpoint a gene, but it provides a general location where a disease-linked gene
may be found, like a treasure map with a large "X" scratched in a corner of the genome.
The results, reported in 2009 (and updated in 2014) in the journal Nature , were a dispiriting
validation of Bleu-ler's hunch about multiple hereditary factors: more than a hundred independent
segments of the genome were associated with schizophrenia. "There are lots of small, common
genetic effects, scattered across the genome," one researcher said. "There are many different
biological processes involved." Some of the putative culprits made biological sense-if dimly. There
were genes linked to transmitters that relay messages between neurons, and genes for molecular
channels that move electrical signals up and down nerve cells. But by far the most surprising
association involved a gene segment on chromosome 6. This region of the genome-termed the
MHC region-carries hundreds of genes typically associated with the immune system.
"The MHC-segment finding was so strange and striking that you had to sit up and take notice,"
Lieberman told me. "Here was the most definitive evidence that something in the immune system
might have something to do with schizophrenia. There had been hints about an immunological
association before, but this was impossible to argue with. It raised an endlessly fascinating
question: what was the link between immune-response genes and schizophrenia?"
Lieberman pulled out a figure from the paper to illustrate the strength of the association. One
method of plotting the results of a gene-association study is called a Manhattan plot, in which the
height of a bar corresponds to the strength of the risk for the disease. In the schizophrenia plot, the
segment on chromosome 6 loomed over all other contenders-about twice the height of most of the
other risk-conferring gene segments. The MHC region, the central repository of most of our
immune-system genes, was like a lone skyscraper towering over the skyline of a newly built
The Delhi of my childhood was a low-rise city. In the nineteen-sixties, my father, having clambered
through the ranks of a Japanese multinational company (it was a folie e deux; he spoke
incomprehensible English, and his managers didn't understand any), had built himself a sizable
two-story house, a far step from the two-room flat in Calcutta that he had shared with his four
brothers and his mother after Partition. The house, he believed, would be his ticket to firm middleclass respectability, but a dyslexic neighborhood sign painter, hired on the cheap to paint
"MUKHERJEE" by the front door, had, to my father's endless chagrin, reversed the letter "J," so
that its tail curled to the right, like the Greek . The incongruous letter remained there throughout
much of my childhood-a discomfiting advertisement to the world that not everything inside the
house was quite normally aligned.
A memory: It is 1981 or 1982, and I am eleven or twelve. My father has returned from a business
trip. It is one of those blistering afternoons when the ceiling fans seem merely to slosh heat around
the room. Two of our neighbors are waiting for him. The air seems tense with anxiety.
My father enters the living room, and the men talk to him for a few minutes. Their voices rise, and
their words sharpen. I can make out the jagged contours of most of the sentences, even through
the walls of the adjacent room, where I am supposed to be doing homework. Jagu has borrowed
money from both of these men-not large sums, but enough to bring them to our house, demanding
repayment. He told one of the men that he needed the cash for medicine (he has never been
prescribed any), and the other that he needed it to buy a train ticket to Calcutta to visit his other
brothers (no such trip had been planned; it would be impossible for Jagu to travel alone). "You
should learn to control him," one of the men says.
My father listens silently, but I can feel a meniscus of rage rising in him, coating his throat with bile.
He walks to the steel closet, where we keep the household cash, and brings it to the men, making a
point of not bothering to count the notes. They should keep the change.
By the time the men leave, I know that there will be a bruising altercation. With the instinctual
certainty of animals that run uphill before a tsunami, our cook has left the kitchen to summon my
grandmother. The tension between my father and Jagu has been building for a while: Jagu's
behavior at home has been particularly disruptive in recent weeks-and this episode seems to have
pushed my father over some edge. A fragile varnish of class and normalcy has cracked.
He walks into Jagu's room and yanks him off the bed. Jagu wails desolately, like a child who is
being punished for a transgression that he does not understand. My father is livid, glowing with
anger, dangerous. He shoves Jagu across the room. It is an inconceivable act of violence for him;
he has never raised a hand. My mother is in the kitchen, crying. I watch the scene rise to an ugly
crescendo from behind the living-room curtains, as if watching a film in slow motion.
And then my grandmother emerges from her room, glowering like a she-wolf. She is screaming at
my father, doubling down on his violence. Her eyes are alight like coals. Don't you dare touch him .
"Get out," she hisses to Jagu, who retreats quickly behind her.
I have never seen her more formidable. Her Bengali furls backward toward its village origins. I can
make out some words, thick with accent and idiom: womb, wash, taint . When I piece the sentence
together, its poison is remarkable: If you hit him, I will wash my womb with water to clean your taint,
she says . I will wash my womb .
My father is frothing with tears now. His head hangs heavily. Wash it, he says under his breath,
pleadingly. Wash it, clean it, wash it.
When Beth Stevens began work as a postdoctoral fellow at Stanford University, in 2004, she was
not interested in studying schizophrenia or bipolar disorder. She was fascinated by the pinpricks of
light in eyes.
The human eye is born restless. Neural connections between the eyes and the brain are formed
long before a child is born, establishing the wiring and the circuitry that allow her to begin
visualizing the world the minute she emerges from the womb. Long before the eyelids open, during
the early development of the visual system, waves of spontaneous activity ripple from the retina to
the brain, like dancers running through their motions before a performance. These waves
reconfigure the wiring of the brain-rehearsing its future circuits, strengthening and loosening the
connections between neurons. (The neurobiologist Carla Shatz, who discovered these waves of
spontaneous activity, wrote, "Cells that fire together, wire together.") This fetal warmup act is crucial
to the performance of the visual system: the world has to be dreamed before it is seen.
During this rehearsal period, synapses between nerve cells are generated in great excess, to be
pruned back during later development. The elimination of synaptic connections, which results in the
constant refinement of neural circuits, like the soldering and resoldering of wires on a circuit board,
is not a feature unique to the visual system. Throughout the brain-particularly in the parts involved
in cognition, memory, and learning-synapse pruning continues into our first three decades, which
suggests that it may be responsible, in part, for the starburst of adaptive learning that characterizes
the first decades of human life. We are hardwired not to be hardwired, and this anatomical plasticity
may be the key to the plasticity of our minds.
In the winter of 2004, having joined the laboratory of Ben Barres, a neuroscientist at Stanford,
Stevens began to study the pruning of synapses in the visual system. "When I began my work in
Ben's lab, little was known about how specific synapses are eliminated," she told me. "The pruning
phenomenon was thought to be quite general." There was evidence of synapse pruning in the
cortex of the brain during learning, cognition, and the formation of memories. But Stevens and
Barres focussed their attention on visual neurons, because they were the easiest to study: the eye
would be the eye to the brain.
In 2007, they announced a startling discovery. Stevens was trying to identify the proteins that
recognized and eliminated neuronal synapses during visual development. "The strangest finding
was that a protein that usually tags and removes pieces of dead cells, bacterial remnants, or
cellular debris was also being reworked to tag and remove the synapses," she said. Mice designed
to lack tagging proteins-called complement proteins-had problems both in clearing cellular debris
and in tagging and pruning their synapses.
The Stevens and Barres study, published in the journal Cell in 2007, documented one of the most
arresting instances of repurposing in biology: a protein designed to ticket germs and junk for
destruction had been co-opted by the nervous system to ticket synapses for destruction. "It
reinforces an old intuition," my psychiatrist friend Hans, in Boston, told me. "The secret of learning
is the systematic elimination of excess. We grow, mostly, by dying."
The following year, Stevens moved to Boston Children's Hospital, to set up her own lab. When I
visited her on a recent icy March morning, the lab was thrumming. Graduate students were folded
over microscopes, like half-open books. One woman sat on her bench determinedly mashing a
freshly biopsied fragment of a human brain into individual cells so th ...
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