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.
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