Hidden Valley Road: Inside the Mind of an American Family (28 page)

Neither Lindsay nor Margaret believed her, at least at first. This seemed like another one of Mimi’s deflections, a smoke screen of denial to keep criticism away from her—and perhaps to even backhandedly blame the boys’ mental illness on Don’s genes. But without wanting to, the sisters began to think of their father differently. What if post-traumatic stress disorder from the war had seeped into everything their father did during their childhoods? Did he somehow pass along his own traumas to the boys? And the most troubling question of all: Could Don have been the source of the violent streak in the family that culminated in what Donald did to Jean, and Brian to Noni—and Jim to them? Both Margaret and Lindsay had spent so many years focusing on their mother and all that she did and didn’t do. Here were a new set of questions they had never thought to ask.

The sisters were even less prepared for their mother’s next announcement. Mimi said that in the years before his stroke, there had been many other women in Don’s life—at least six, by her count. The first had been in Norfolk, Virginia, just after the war, when Don was traveling up and down the Atlantic on the USS
Juneau
. Mimi told both Margaret and Lindsay about how she was supposed to have gone on one of those voyages, too, with Donald and Jim, who were still little. This, she said, was the trip where Don met the wife of a senior officer, and started an affair. If Mimi had been able to take that trip, she told Margaret, that affair might never have happened. Mimi found out about it later, she said, and they transferred away from Norfolk. But Don would not be held down forever.

This surprised both sisters. But in some strange way, this new view of their father also filled a gap in their understanding of their parents’ relationship. Lots of what they’d seen at home made more sense to them now. Like how their father, at the height of his powers, always seemed to be somewhere else. And those dinner parties at the Crocketts’, where the neighbors’ wives called their father Romeo. The more they thought about it, the more the affairs explained so much of their childhood—even, perhaps, Mimi’s quest for a perfect household.

Mimi had come forward with all this now to show her daughters that Don was human, not perfect, deserving of the same scrutiny as herself or anyone else. Now it was Mimi they wanted to understand better. Why did she stay with Don all that time? Did she stay because she wanted to—or because, after she’d had the children he’d wanted, she had no choice? Why did she agree to be at her husband’s mercy, while he was at liberty to do as he pleased?

Margaret thought of a painting of her mother’s, now in Lindsay’s possession, of Pinocchio, hanging on a string being held in the hooked beak of a falcon. For Margaret, that painting was a fair metaphor for her mother’s true feelings—made to care for twelve children, while her husband was off somewhere else. She wondered if all of those traits she’d ascribed to her mother—the inability to be truly present or vulnerable—were really more her father’s. Say what you wanted about Mimi, but she never left. She never stopped trying.

1998

University of Colorado Medical Center, Denver, Colorado

Throughout the 1990s, most of the Colorado-based members of the Galvin family—Mimi and Don, Lindsay, Margaret, Richard, Michael, Mark, and the sick brothers Donald, Joe, Matt, and Peter—went to Denver and submitted to long days of testing in Robert Freedman’s lab. Whenever Freedman had the chance to discuss his research, his description of sensory gating and vulnerability, of schizophrenia brains having difficulty pruning information, made sense, at least to Lindsay. She thought of how sometimes one of her brothers would be especially sensitive to something she thought was background noise, like the hum of a fan.

Freedman had never thought of his brain-electrophysiology experiments—the double-click test that measured a patient’s sensory gating abilities—as a foolproof test for schizophrenia. He saw them as one of many potential strategies for having a look inside the brains of his test subjects. With the Galvins, Freedman found that many family members could not inhibit the second click, including some nonmentally ill family members like Lindsay, but some of them could. The next step was to see if the ones who failed shared a certain genetic trait that others did not.

This put Freedman in unfamiliar territory. He was a central nervous system guy, not a geneticist like Lynn DeLisi. “I was late to genetics,” he said. “Lynn was way ahead of me.”

What he did know about was brain function. He understood how the hippocampus—that seahorse-shaped swath of brain matter located in both the left and right lobes of the brain—is the part of the brain that helps with situational awareness, figuring out at any given moment where you are, why you’re there, and how you got there. He’d seen, and his double-click tests had affirmed, how that process requires not just neurons, or brain cells, to bring in sensory information, but the inhibitory interneurons that erase the brain’s whiteboard of situational information instantaneously. Without the inhibitory interneurons, we would end up processing the same information all over again—wasting time and effort, grinding our gears, becoming disoriented and, perhaps, anxious and paranoid and even delusional.

Now, Freedman wondered if there was something at the cellular level that these inhibitory interneurons turned on and 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
α
7 (or alpha-7) nicotinic receptor. The name is complicated, but its reason for being is more or less straightforward. The
α
7 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
α
7 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
α
7 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
α
7 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.

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.

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
α
7 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 this receptor needs in order to function, and smokers—or the
α
7 receptors in their brains—like it when their acetylcholine is turbocharged. This is the feeling cigarettes can give smokers—that way nicotine has of focusing their minds for short periods, or calming them. Could it just be a coincidence, Freedman wondered, that many schizophrenia patients—Peter Galvin among them—can’t get enough cigarettes? For very brief moments, nicotine may offer them at least some relief from their delusions. If Freedman could amplify that effect—mimic it in a lab, bottle it, and send it out to everyone diagnosed with schizophrenia—could it treat the symptoms of the illness more effectively and less harmfully than Thorazine?

First, he needed more proof.
In 1997, Freedman devised an experiment: He gave nicotine to people with schizophrenia, usually many pieces of Nicorette chewing gum, and then measured their brain waves with his double-click test. Sure enough, people with schizophrenia who chewed three pieces of Nicorette passed the test with flying colors. They responded to the first sound and didn’t respond to the second, just like people without schizophrenia. The effects didn’t last after the nicotine wore off, but Freedman still was stunned.

His study won applause from a lot of his colleagues, including Richard Wyatt, Lynn DeLisi’s old boss at NIMH, who called the Nicorette experiment “
important and exciting” and the promise of nicotine “intuitively very strong.” Freedman went all-in on nicotine. He made plans to develop a drug that did what nicotine did to the
α
7 receptor, only better—so well that schizophrenia patients could find relief from their delusions not for minutes but hours, or even days. He secured funding for a drug trial from NARSAD, the National Association for Research on Schizophrenia and Depression (now known as the Brain and Behavior Research Foundation), a donor-supported group that serves as the American Cancer Society for mental illness. “We thought perhaps we could make a better nicotine,” he said.

He found a natural substance called anabaseine that mimicked the function of nicotine. A researcher in Florida had been cultivating a synthetic version with no solid idea of what use the drug might have. He told Freedman he’d been waiting for ten years for someone like him to call. Freedman cultivated the drug, called DMXBA (short for 3-2,4 dimethoxybenzylidene anabaseine), and started testing it. The drug had the same effects as nicotine in the double-click test.
And when, in 2004, he tested the drug on a group of schizophrenia patients in a double-blind controlled study, the results seemed miraculous. One subject who got the real drug, not the placebo, told Freedman that she had been having trouble finishing a short story she’d been writing, but now she was able to concentrate enough to do it. Another said, “I’m not noticing my voices.” The mother of a third told Freedman that for the first time, her son was able to take in the scenery around him—to be amused by watching rabbits in the yard, undistracted by his own hallucinations.

Within a year several different pharmaceutical companies were hard at work creating versions of his drug. They couldn’t just buy his because its patent, owned by the University of Florida, had been in existence too long: No company wanted to buy a patent that was just a few years away from expiring. “There isn’t much financial incentive for using the drug that we’ve gotten to work in clinical trials,” Freedman said, “so they had to go out and make their own.”

As an unpaid advisor, Freedman told each company the properties of the drug, hoping they would design their versions using the principles he suggested. A few companies made it pretty far. One company, Forum Pharmaceuticals, worked on trials that were halted after too many subjects experienced constipation. Another company, AbbVie, the research division of Abbott Laboratories, made it to the third phase of clinical trials with a drug based on DMXBA with mixed results, and then stopped their research. The problem, as Freedman saw it, was that they insisted on a once-a-day dose. Freedman’s team had tried that, but found that his drug only worked when administered in three or four small doses over the course of a day. Abbott thought it would never be able to market a drug that had to be taken that frequently, on such a rigorous schedule. (Think of Peter Galvin, skipping out on his drug regimen constantly, only to have yet another psychotic break.) Their once-a-day dose failed, too. “I think the company’s pharmacologists were smart enough to know all this,” Freedman said, “but their marketing people rule how they make drugs. And so, they sort of were doomed to failure.”

Freedman saw the experience as an object lesson in how pharmaceutical companies work. “It was disappointing, because I think they could have gotten a good drug out of what they were doing.” After all that promise, he was back where he started. To jump-start the
α
7 receptor and strengthen the brain’s ability to process information, Freedman would have to find another way.