Hidden Valley Road - Inside the Mind of an American Family - Robert Kolker Page 0,123

off—a mechanism that wasn’t working properly in the brothers who got sick. A section of Freedman’s lab began testing the brain cells of rats and learned that the on-off circuit for the inhibitory neuron was controlled by a crucial element of a cell in the hippocampus called the α7 (or alpha-7) nicotinic receptor. The name is complicated, but its reason for being is more or less straightforward. The α7 receptor is a master communicator, sending messages from neuron to neuron so that the circuit can work properly. But in order to do its job, this receptor needs a compound called acetylcholine, which behaves as a neurotransmitter. Freedman wondered if people with schizophrenia had faulty α7 receptors, or simply lacked enough acetylcholine to get those receptors to work the way they should. If Freedman was right, this meant that for some of the Galvin brothers, the machine that was supposed to keep them from losing their minds might, essentially, be out of gas.

To prove this, Freedman needed to move from rats to humans. And so in the late 1990s, he embarked on one of the first genetic studies of his career. He collected data on nine families including the Galvins—104 people in total, including 36 schizophrenia patients. Among those family members who responded badly to the double-click test, Freedman searched for a common genetic pattern. From analyzing those tissue samples, Freedman was able to track down the precise location where the receptor problem took place—a chromosome that was home to a gene called CHRNA7, which the body uses to make the α7 receptor.

In 1997, Freedman identified CHRNA7 as the first gene ever to be definitively associated with schizophrenia. He and his colleagues had made history, and more importantly, he was one crucial step closer to learning how schizophrenia functioned. Now he had to find out what was going wrong with that gene. He already had an important clue: The brains of the families he was studying, including the Galvins, had about half of the number of α7 receptors that typical brains had. The receptors they did have were working just fine. The problem was they lacked enough acetylcholine to get the switch turned on to make more receptors just like them.

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MARGARET REMEMBERED CHAMPAGNE being popped as she walked into Freedman’s lab. She and Wylie were there to get advice about whether Margaret should have children. Freedman and his team had just made their CHRNA7 discovery, and the doctor was happy to take a break from the celebration to explain what this new information might mean to the Galvins.

The last thing Freedman wanted was to discourage Margaret and Wylie from having children. While the brothers and sisters of people with schizophrenia do have a much higher than normal likelihood of having schizophrenia themselves—ten times the chance, actually—the same, he noted, is not true of parents and their children, or uncles and their nieces and nephews. The genetic explosion in Margaret’s family, he maintained, was not necessarily an indicator of some super-gene that would affect successive generations. Schizophrenia has a way of disappearing in families and then reappearing, and there was no reason to believe Margaret’s children were fated to become mentally ill.

It seemed hard to imagine that their risk was as low as anyone else’s, but that was exactly what Freedman was saying. But what about everything his lab had just uncovered about the gene related to schizophrenia? Freedman filled a big whiteboard with information about the place on the chromosome where Margaret’s family’s data had helped point to a trouble spot. Nothing about that genetic irregularity could be used to predict schizophrenia, he said. All it could do was offer a road map to what needed to be treated once it appeared. And he had a pretty good idea of how to do it.

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FREEDMAN’S DISCOVERY WAS not happening in a vacuum. Dozens of other researchers were conducting other studies of mutations of other genes in other chromosomes. By the year 2000, at least five more trouble areas would be isolated, with many more still to come.

The α7 receptor, however, stood out from the crowd because of its special relationship with nicotine. No one experiences this more vividly than habitual smokers: Nicotine has a way of turbocharging the effects of the acetylcholine that