Hidden Valley Road: Inside the Mind of an American Family (31 page)

THE SECOND SURPRISE
was about Mimi. For decades, Mimi had insisted that the family illness came from Don’s side. As far as she was concerned, his history of depression proved it, and no one who researched the family ever had reason to disagree with her. “We were looking for something transmitted from the father,” McDonough said.

The SHANK2 mutation, however, came from the mother’s side of the family—suggesting that it could have been Mimi all along who was the carrier of the mutation responsible for the family illness.
Another study of SHANK2 and schizophrenia, published at about the same time as McDonough and DeLisi’s study, noted several more instances of an unaffected mother passing along a mutation to a son who developed the disease. It should also be possible for a father to be an unaffected carrier—SHANK2 is not a sex-specific gene; it is not located on the X or Y chromosome, which determine sex, but on chromosome 11.

Why did six out of ten boys develop serious mental illness, but neither of the two girls? It might simply be chance—a roll of the dice working out for both sisters and four of the ten brothers. It could be that the Galvins’ SHANK2 issue points to, as DeLisi and her coauthors suggested in their study, an “as yet uncharacterized sex-dependent influence” on how the illness develops—though that would not account for the Galvin sons who
didn’t
get the disease.

Or it could be that the mutation on the mother’s side is mingling with something else on the father’s side—that the SHANK2 mutation does nothing by itself, but needs another mutation elsewhere to completely set the table for the disease. Such is the way, sometimes, with genetic mutations.
The geneticist Kevin Mitchell has noted how specific mutations can manifest differently in different people: The same mutation can trigger epilepsy in some people while in others it triggers autism, schizophrenia, or nothing at all. And sometimes, a second rare mutation elsewhere in their genome suggests a combined effect.

It is possible, maybe even likely, that the genetic flaw that caused schizophrenia in the Galvin boys might not be Mimi’s fault or Don’s fault, but both of their faults together—an entirely original cocktail, powerful enough to change all of their lives.

2016

University of Colorado Medical Center, Denver, Colorado

While DeLisi and her new partners at Amgen followed the trail of the SHANK2 gene in Cambridge, Robert Freedman was continuing his work in Denver. Like DeLisi, Freedman had experienced a long period of early promise, followed by a painful reversal of fortune—the excitement of isolating the first gene to play a confirmed role in schizophrenia, and the anguish of watching the drug trials to activate the brain receptor for that gene go nowhere. Freedman had hit a wall, and now he was searching for another way in—a new strategy to help repair or strengthen the one gene he knew made a difference.

One thought he kept coming back to was that when it came to his prized gene, CHRNA7, researchers might have arrived too late to help adult patients like the Galvin brothers. Like many genes, this one is fully developed in the womb, before birth. Freedman tended to think of the development of a baby’s brain as a series of computer upgrades: A fetus starts with a very simple operating system, and as it grows, that operating system installs the next, more sophisticated system. The CHRNA7 gene appears early in utero; its purpose, as far as Freedman could tell, is to help install the final OS, the one that we use as adults. This would mean that by the time a baby is born, the die is cast. If he was right that schizophrenia hinges on the condition of CHRNA7, the only option might be to try to fix it before birth.

Freedman’s task seemed clear: If he could repair flaws in CHRNA7 in the womb, he would have a chance at nipping schizophrenia in the bud, before the disorder ever materialized. If he could manage that, then Freedman might be able to successfully keep an entire generation of people genetically predisposed to getting schizophrenia—and all the generations after that—from ever becoming symptomatic. He could hardly imagine a less realistic goal. The Food and Drug Administration would have to agree to an experimental drug for women who were pregnant, and that seemed, to say the least, unlikely. Medicating fetuses—drugging unborn babies—just wasn’t going to happen.

What Freedman needed was a method that would not involve surgery or synthetic drugs. What he found, somewhat miraculously, was that acetylcholine—the substance that runs the particular information-processing operation of the brain he wanted to target—is not what CHRNA7 needed the most when it was first getting started. What this gene really needed during the fetal stage was a nontoxic, utterly benign nutrient available at every GNC and Vitamin Shoppe in America.

Choline is in a lot of foods people eat every day, including vegetables, meat, eggs, and poultry. Pregnant women dispense choline to their unborn children as part of their daily diet, through their amniotic fluid. Freedman’s idea was simple: What if a mother-to-be of a child who is predisposed to developing schizophrenia took mega-doses of choline, while her child was still in the womb? This could be a nutritional supplement, like the folic acid in the prenatal vitamins that pregnant women are encouraged to take to prevent spina bifida and cleft palate. Maybe then, an at-risk child’s brain would develop healthily, in a way that it otherwise wouldn’t.

The FDA agreed to an experiment. Freedman’s team in Denver conducted a double-blind study in which some expectant mothers received high doses of choline. The women in the control group were observed to ensure that they ate enough meat and eggs, to make sure no one in the study went without at least an adequate amount of choline. When the babies were born, those who got the choline supplements in utero passed Freedman’s double-click test measuring auditory gating: 76 percent of them had normal gating, compared to 43 percent in the control group.
^*
Even babies with the CHRNA7 irregularity had, in more instances, normal auditory gating. The good news continued as the babies got older. At forty months, Freedman’s team observed that the choline group had fewer attention problems and less social withdrawal compared with the control group. Choline seemed to work well on virtually everyone.

Freedman’s study about choline was published in 2016, the same year as the Broad Institute’s C4A study and DeLisi’s SHANK2 study.
In 2017, the American Medical Association approved a resolution that prenatal vitamins should include higher levels of choline to help prevent the onset of schizophrenia and other brain developmental disorders. It had taken thirty years, and he’d hit at least one dead end along the way. Only time can say for sure what difference choline might make over a matter of decades. But thanks in part to his work with the Galvins, Freedman had arrived at a game-changing strategy for the prevention of schizophrenia.

IN THE FALL
of 2015, Freedman traveled to New York for an annual symposium sponsored by the Brain and Behavior Research Foundation, the group once known as NARSAD, which raised millions of dollars for research into new mental illness treatments. The results of Freedman’s choline work had already made the rounds, and Freedman was there to receive one of the highest honors in his field: the Lieber Prize for Outstanding Achievement in Schizophrenia Research.

In New York to celebrate with him was Nancy Gary, who, along with her husband, Sam, had funded a chair in Freedman’s psychiatry department at the University of Colorado. The choline study had captured Nancy’s imagination. Years earlier, she and Sam had funded the construction of a pavilion at the university’s hospital for children with psychiatric disorders. Now, with Nancy in her eighties and Sam in his nineties, they had pledged to support Freedman’s next project, to trace children who’d received choline supplements in utero over several decades of their lives. They understood what might happen if choline really made that much of a difference: Some varieties of schizophrenia could go the way of the cleft palate. “The man is brilliant,” Nancy said. “I would support him in whatever he does, because he’s that good.”

Nancy brought a guest with her on her plane to New York—someone Freedman hadn’t seen in several years, not since she’d been living with her brother Peter in Boulder. Until Nancy reintroduced Lindsay to Freedman, the doctor had no idea of their connection. This felt like a
This Is Your Life
moment for him: One of his most generous benefactors had also been helping the largest family ever to have contributed to his research.

After many years in Boulder, Lindsay and Rick had moved to Vail, where Lindsay still ran her corporate event business and Rick worked as a ski instructor. Together they were raising their children—a girl, Kate, and a boy, Jack, both now teenagers. Lindsay and Nancy had fallen out of touch for several years, until one day they ran into each other on the slopes of Vail, where Jack was in the same ski group as one of Nancy’s grandsons. Nancy was thrilled to reconnect with both Lindsay and Margaret, inviting the sisters to family gatherings in Denver. Mimi did not take part in the reunion—her days of socializing with Nancy Gary were long behind her—but both sisters were excited to be back in regular touch with the family that had made such a difference in their lives.

Lindsay brought her daughter with her to the symposium in New York. Nancy put them up at the Pierre Hotel, and they all sat together to watch Freedman deliver his acceptance speech. “Now, one of the unfortunate things about doing human research on the life cycle is it’s the same as your life cycle,” Freedman said, getting a chuckle out of the audience. “I’ll be one hundred and thirty-five years old by the time we finish this study. A young investigator will have to call me in the nursing home and let me know if this works out just the way I planned.”

Afterward, when the doctor had more time to talk, Nancy beamed as she told Freedman that she’d been the one to send Lindsay to Hotchkiss—air-lifting both her and her sister out of the Galvin family home when things were at their worst.

Lindsay smiled silently, opting not to get into how technically it wasn’t Nancy who paid her Hotchkiss tuition, and that there had been three years when her sister had been pulled out of that house by the Garys and she had not. And she smiled some more as Nancy began praising Lindsay and all she’d done. Here was the one she rescued, Nancy said, the one who survived—the Girl Who Lived.

*
The double-click test, remember, is not a foolproof test for schizophrenia, but a measurement of sensory gating, which is just one of an unknown number of aspects of schizophrenia. Which is why 57 percent of a control group can fail the test, but still not have schizophrenia.

Hi Galvin Gang,

New news on the research front! Harvard study would like to take blood samples of Mimi and Papa’s grand kids that are currently over 18 years of age. This is continued effort in research on schizophrenia.

Mimi and Papa have been active in research since the late 70’s. Dr DeLisi will be sending a phlebotomist this fall. Thought we could make a celebration of it.

I know we all would like to find the cure for this tragic disease. Stand by for when and where to gather.

Love to All!

Mary

Email from Lindsay to family members, September 9, 2016

On a Sunday in November, more than a dozen members of the Galvin family were invited to Margaret’s house in Boulder. The purpose of the gathering was to collect as many DNA samples as possible from Galvin family members who might not be mentally ill, to use as controls against the samples the researchers already had. An assistant of DeLisi’s had flown in for the occasion, along with a phlebotomist who would bring the family’s samples back to Boston.

“It’s like a blood-drawing party,” Margaret said. “It should’ve been on Halloween.”

DeLisi had contacted the Galvins that summer, in advance of the publication of the SHANK2 results. Until then, no one in the family had the slightest idea that their blood samples formed the cornerstone of NIMH’s research into the genetics of schizophrenia—a data set that has played a part in nearly every genetic study of the disease ever since. DeLisi had not been in touch with the family for decades—perhaps not since the late 1980s when a colleague of hers contacted them to follow up on DeLisi’s first visit. Whichever family member took the call refused to set up an appointment and asked them not to call again. It happens sometimes: Families change their minds, or the researcher calls at an inopportune moment.

The family was not named in the study itself, of course. But DeLisi eagerly shared the news of the mutation with Lindsay, who spread the word to her sister and mother. Mimi, who had just turned ninety, was humbled a little by the news. She had spent so many years blaming the illness on Don’s side of the family that there was little for her to say now, except to laugh shyly. But for both Lindsay and Margaret, there was no small amount of schadenfreude, seeing their mother so definitively disproven. And it was exciting for them, too, to see the research that had begun so long ago continuing now with the possibility of something to show for it. For the first time in years, they felt something like hope.

No one at the blood drawing would be told if they carried the SHANK2 mutation or not; the results of the DNA tests would be used anonymously, for research purposes only. “We’re numbers, not names,” Margaret said. Still, she and Lindsay were surprised to see who came and who didn’t—those who wished to acknowledge the genetic issue they might carry, and those who would just as soon behave as if the problem never existed. Their brother Michael came, but he was not pleased; it felt to him like pouring salt on an old wound. Mimi’s sister, Betty, now in her late eighties, had married and had children who seemed free of the mental illness that haunted Mimi’s family. She was still living on the East Coast, too far away to make the trip, and neither did her children or their families. The next generation had especially spotty turnout. Michael’s kids came; Mark’s children did not; and the son that Richard had fathered at the age of seventeen seemed put out even by the suggestion that he should be there.

The medical people told Lindsay that no-shows weren’t so unusual. They’re terrified of the disease, and simply don’t want to think about it.

A WEEK LATER,
Mimi inched from her bedroom, down a short flight of stairs, and over to a seat at her kitchen table on Hidden Valley Road. She moved confidently, but with the help of a walker with a portable oxygen tank hanging over the side.

“I am very arthritic and have replaced joints,” she had said on the phone a few months earlier. “I’m like the Bionic Woman.” She waited for a laugh, then said, “Not funny, dear. Wait till you get there. Two hip surgeries, and I’m ninety, and they’d like to do it again, but I’m too old. I’m simply worn out.”

A clot in her eye made it hard for Mimi to read. “There’s nothing like the feel of a good book in your hand, either,” she said that day in the kitchen, “except that my hands are so bad now I can’t hold a book.” She had hearing aids in both ears that she fiddled with, struggling to understand people in groups. But she could still listen to a Salzburg recording of
Don Giovanni.
“When I’m here alone I can turn up the opera as loud as I want to, or a ballet, or whatever.” Her mind was as sharp as ever; she remained stubbornly herself—intelligent and very well read, strong enough to have endured any number of horrible tragedies, and yet utterly averse to self-reflection.

Both sisters knew all too well how smoothly Mimi could change the subject when she wanted to, redirecting uncomfortable conversations whenever possible to her experiences with the Federation—“I could almost write a book about the people we met through that, the wonderful nights…”—or her teenage years exploring New York, or Don’s military career. She took credit for the idea of making the falcon the Air Force mascot. “A lot of people have claimed they suggested the falcon first,” she said, “but that isn’t true.”

Gently, the sisters tried to move her on to more meaningful material, even if it meant making her uncomfortable. Though she did not raise the subject, she answered a few questions about Nancy Gary, and the years when she and Don and Nancy and Sam had socialized. “We were quite close,” she said. But she never had a one-on-one friendship with Nancy. “Nancy has never been a buddy-buddy person, as far as I can understand,” Mimi said coolly.

“Why would I have gone to live with them, then?” Margaret asked.

Mimi turned to her daughter. “Oh, because we had four kids in the hospital at one—”

“I know—I know that side of the story,” Margaret said. “But why would they have taken me in, had you not been good friends?”

Mimi waved off the question. “I really don’t know. Well, she saw Brian had died, and she called.”

THE MORE ON
the spot Mimi felt, the more she leaned in to her old perfectionism. “I don’t paint anymore,” Mimi said, glancing at Margaret, “mostly because I can’t compete with my daughter.” Margaret had taken up painting, finally, with her own daughters older now, and she was good. She chose natural subjects like her mother’s old paintings, but bolder, more inventive—and was even getting a few sales, right away.

Then Mimi turned and looked at Lindsay. “
She’s
always doing something. She runs
beautiful,
big parties. But she lost that contract!” She chuckled lightly. “She was giving the Anadarko party for a million dollars at a clip.”

Lindsay kept a smile pasted to her face. As casually as possible, she listed a few of her recent events, for an investment company and a health care company.

“In twenty years, she’s built up quite a clientele,” Mimi said. “She said, ‘Mother, I won’t do this very long, it’s not very intellectual.’ But the pay was pretty good. She should have gone on to grad school!”

She turned to Lindsay. “Are you going to retire next year?”

“Hopefully,” Lindsay said.

“Hopefully,” Mimi echoed. “And then she’s going to open a bookstore so she can read!” She gazed at her daughters.

“We both—all three of us—like to read,” she said, beaming with pride. “We’re
all
readers.”

NONE OF THE
boys lived with Mimi anymore. Donald moved to assisted living at Point of the Pines three years earlier, after Mimi, sidelined for several months by a stroke, was too frail to care for him by herself at home. This saddened her. She liked having the company. But Mimi still saw them all, and she continued to snap at the sick boys, particularly Peter and Matt, whose hygiene appalled her.
Zip up your pants! Where’s your belt? Go take a shower.

Margaret and Lindsay understood that, to a point. But would things with the boys be any better if they were wearing ties and sport coats? By now, weren’t digs like this beside the point? “She’s not able to really share how she feels about any particular thing,” Margaret said, out of earshot of her mother. “But she can be really critical about how the rice is being cooked.”

At the kitchen table, the sisters both laughed.

“Mom,” Lindsay teased, “if you had just said ‘Yes’ more often, there would be no schizophrenia.”

Mimi’s reply came quickly. “My problem,” she said, “was I said ‘Yes’ too many times.”

SLOWLY, WITH HER
daughters next to her, Mimi was persuaded to talk about what had really happened—and how she really felt.

She remembered Jim, at the age of sixteen, threatening her with a large pot, and Donald trying to throttle her once when his medicine was misplaced. “It terrified me,” she said. “If it hadn’t been for three or four of the other boys, I think I’d be dead, because he really had me in a stranglehold.”

She had no compunction about saying that Jim and Joe both died of the medicine that was supposed to help them. “Both of those boys would go to the hospital complaining of chest pain and get no attention,” she said, “because they were mentally ill, and they both were dying of heart disease.”

She recalled how shattered she’d been to learn about Father Freudenstein. She and Don suspected nothing, Mimi said, because who would? “Well, we weren’t very savvy parents, not at all. We were as innocent as the day is long, and we let them go.”

She talked about her husband’s fragile mental state, which she felt was connected to his time in the war. “He saw a lot of action. But he never discussed it—I think he just kept it all inside.” His hospitalization during his posting in Canada came ten years after the war. “The Air Force panicked because being an intelligence officer, they wanted him out of there quick. So he was brought to Walter Reed. No disease found. There was no test for PTSD.”

When she talked about being blamed for her sons’ mental illness, she got her back up again. “We were all involved in a discussion with the doctors,” she said, “and they crucified us. We were the worst parents in the world. It made us feel terrible. It traumatized us. Don and I, we were both paralyzed mentally. It just freezes you, because you don’t know what to do. You have nobody to talk to. We were an exemplary family. Everybody used us as a model. And when it first happened we were mortally ashamed.”

She could talk about that shame now, unburdened at last. “Oh, that was the whole thing, it was so embarrassing. The blaming part really traumatized me to the point where I felt I couldn’t tell a friend or anything. It was just all inside, and it was hard, that part. That’s where I think the crutch of the Church kind of helped me. I was accepting it as my lot in life.

“And so I was crushed,” Mimi said. “Because I thought I was such a good mother. I baked a cake and a pie every night. Or at least had Jell-O with whipped cream.”

Between bouts of sympathy for her mother, Margaret remained highly critical of her—how everything in her life was centered around Donald and the other sick boys, to the exclusion of everything else, including the chance to have the relationship she wanted with her. “I never got to have my mom,” Margaret said, “because of Donald.” She viewed her grimly now, as a woman who sowed the wind and reaped the whirlwind. “She got her way,” Margaret said, “and there was a large cost in that in terms of her relationships with her daughters and her other children who were not mentally ill. And so she really lost in the end. She pushed away the people who could have possibly had relationships with her.”

In Margaret’s view, that included her father. “I don’t know, I’m not excusing his affairs, but I don’t think there was a lot of thought going into any of this on either of their parts.”

Margaret could imagine the scenario now in a way she couldn’t when she was younger. Things got out of control because, with such a large family, the miracle would have been that anything ever was under control to begin with.

“I think there was a lack of consciousness in having twelve children in the first place,” Margaret said, “and then thinking that they could raise them to become all-American citizens.”

Margaret and Wylie had their own family now—two teenage daughters, Ellie and Sally—but the frightening aspects of her childhood were still alive inside her. Margaret never forgot how unsafe Donald and her other brothers made her feel as a girl, and so she would not see Donald on her own. She did not want him around her children, either. But now that she was married and well-off with a family, Margaret also felt guilty about having what many of her brothers did not. The act of buying high-priced leggings for her daughters at Lululemon could send her into a tailspin of self-judgment. Her sick brothers never had a chance at this kind of life.