The Seed of Mental Illness Might Be Planted Before Birth
If you’re feeling nostalgic, it’s easy to smile at the memory of the blinding promise of the Human Genome Project — that highly publicized effort in the 1990s to map out and understand the structure, organization, and function of every single human gene. This was like a moon shot for biology. If the project could successfully figure out the DNA blueprint for building a human, nothing about what we know about virtually any genetic disease would be the same. Soon, all you’d have to do is compare the genomes of a sampling of afflicted people with a control group, and whatever quirk existed in the genome of the sick people would stick out like a sore thumb. Just like that, drug companies would have a gene to target, and we’d have cured a dozen different diseases before lunchtime.
It was a nice dream. But we know better now. A generation has passed since we’ve sequenced the human genome (they got it done in 2003), and instead of finding a smoking-gun mutation responsible for complex conditions like autism or bipolar disorder or schizophrenia, we’ve found hundreds of different mutations (or “variants,” as researchers call them), and none of these variants seem to be quirky enough to cause anything.
I got to know several of the leading researchers into the genetics of mental illness when researching Hidden Valley Road, my account of one extraordinary family’s experience with schizophrenia. Don and Mimi Galvin of Colorado Springs, Colorado, had six sons with schizophrenia, quite the genetic petri dish for researchers to examine. And sure enough, the two separate teams that looked into the Galvins years later found variants that could play a role in the family illness. The catch is, other families with schizophrenia don’t have these same variants. Everybody’s got something, but not everybody’s got the same thing.
So what do we do now?
The answer, we’re learning, might not be found in the brain’s genes, but in how the brain develops. Protecting a genetically vulnerable brain from developing mental illness — making it more resilient before birth, if possible — is the new holy grail for this generation of brain researchers. Thanks to work that began with the Galvin family, the American Medical Association now recommends expectant mothers add choline to their nutritional regimen to strengthen brain health for fetuses during pregnancy. But the organ that might be most responsible for brain development, it turns out, may not be the brain at all.
Last month, researchers from the Lieber Institute for Brain Development at Johns Hopkins and the University of North Carolina School of Medicine published research showing that genes found in the placenta can serve almost as a bellwether for coming issues in the developing brain of a fetus. The big complication these genes relate to is cognitive development — which, researchers know, often translates into a risk factor for schizophrenia.
The placenta? Yes, that’s right. Could it be that after all this time, when it comes to the culprit for mental illness, we’ve been looking in the wrong place?
A few weeks ago, I Zoomed with the Lieber Institute’s co-founder, Daniel Weinberger, a brain researcher who has been at the forefront of practically every new trend in schizophrenia research in our lifetime. It was Weinberger who, back in 1987 at the National Institute for Mental Health, reframed the conception of schizophrenia as a “developmental disorder,” in which abnormalities that patients possessed at birth, or even in utero, set off a chain of events that, in essence, sent their brains off the rails gradually, over time. All genes did, he said, was establish a blueprint for brain development and function. The rest happened later, with the help of the environment.
The problem with the environment is that it’s everywhere and everything. Researchers now argue about what might be playing the part of a trigger — marijuana, bacteria, head injuries, autoimmune diseases, brain-inflammation disorders, parasitic microbes. It’s like picking a horse at the track: It’s impossible to know which one may win, and there might be another horse on some other track that’s even faster. Where, Weinberger often wondered, can you find something that really has an impact on brain development all the time, for everyone? What does everyone have that we can easily target?
Weinberger’s team at Hopkins has published a series of papers in journals, starting in 2015, showing that many of the genes related to schizophrenia were more abundantly expressed during fetal life than in postnatal life. There was more proof, it seemed to him, that the genetic vulnerability to developing schizophrenia happens right away, before you’re even born. That’s when Weinberger thought of something different: studies, back in the 1990s, of identical twins where one had schizophrenia and one didn’t. About 85% of the time, the affected twin was the second-born twin, and weighed less throughout gestation. This caused him to wonder: What if the genetic issue happening in utero is actually an environmental issue, too — a gestational issue, a pregnancy issue?
“That made it impossible,” Weinberger told me, “not to say, ‘What the heck is going on in the placenta?’”
A quick pause here to talk a little bit about the placenta — though to be fair, Weinberger could go on for hours about it. “The placenta is the most neglected organ in the human being,” he told me. “It’s the only organ that’s not routinely sent to the laboratory for examination. It’s most typically thrown out in the delivery room. It’s not explored scientifically.”
Weingerger’s team at Lieber, including researcher Gianluca Ursini, published a paper in Nature Medicine in 2018 which looked at about 3,000 people in populations from Japan, Germany, the U.S. and Italy and found that the risk of developing schizophrenia later in life is five times the normal risk for people who have two separate issues: They’re born after a complicated pregnancy, and they happen to have bunch of the genetic variants that have been associated with schizophrenia. “The two of them interacted multiplicatively,” Weinberger said, “and resulted in a much greater risk than either one by themselves did, or if you just added them up. This was a true gene-by-environment interaction. And then we said, okay, well, how does this happen?”
If this were a murder mystery, the placenta would be the butler — hiding in plain sight, the prime suspect. The placenta has an active role in informing and molding the human brain, during gestation. “So we did want this sequencing of genes expressed in placentas,” Weinberger said, “and we showed that schizophrenia genes are not only abundantly expressed in the placenta, but when there’s a complicated pregnancy they’re turned on — those genes are turned on!”
Now, in case you’re reading this and thinking that this research might make mothers overly worry or even blame themselves, Weinberger and the other researchers aren’t looking at this placenta research as a blind exercise in mother-blaming. The environment acts in other ways, too, of course, after you’re born, both positively and negatively, to strengthen your brain or make it more vulnerable. What’s happening in the placenta may be best seen as a red flag, Weinberger says — one of the first ones ever that might be helpful for people over time. “We showed that our measures of schizophrenia genes in the placenta — and not schizophrenia genes that weren’t about the placenta — predicted the size of the brain at birth of these babies and their cognitive development over the next two years of life.” How can you ignore that?
This placenta research is fascinating if for no other reason than because it brings us back to the nature-nurture argument that’s so completely permeated mental illness research all along. Here are a bunch of geneticists saying they know that it’s a genetic condition, and yet we are still looking for environmental markers — because they know that it’s environmental as well.
“The assumption always was that every one of these risk factors push you a little closer to that edge,” Weinberger said. “And there’s something that ultimately pushes you over the edge. Your genes push you closer. Environmental stressors and marijuana, or maybe placental risk or complicated pregnancy, these things push you closer to the edge. But something pushes you over the edge. And the fact that a first psychotic break generally occurs in early adult life is probably a combination of the critical domains of brain development that are dependent on that time of life in triggering a level of dysfunction. And then the question becomes, were you destined to fall off that edge because of the trajectory reaching this particular moment — or did something have to push you over that edge?”
It’s the placenta’s dual nature that makes this most visible to researchers. The placenta is a fetal organ, just like the fetal heart and the fetal brain, but at the same time, Weinberger said, “what is clear is that the placenta is very sensitive to the molecular experience of the mother’s bloodstream. The stress that the mother’s under. Drugs the mother takes. Whether she’s abused by her husband or her partner.”
The Lieber Institute is going all in on placentas. One team, led by Jennifer Erwin, is building placentas from stem cells that have high genetic risk. “She has little placentas growing in a dish,” Weinberger said. “They’re mindbogglingly cool.” She is stressing them the same way a placenta gets stressed in a mother, “with steroids and immunological inflammatory chemicals. It’s like science fiction.” The idea is to discover a chemical or molecular chain of events that is the true culprit for activating these genes.
For their next trick, Weinberger and his colleagues are working with the University of Colorado’s Robert Freedman, whose work with the Galvin family preceded his epiphany about choline and brain health, on a project to try to predict — using genes turned on and off in the placenta — which children respond best to choline. “Bob Freedman’s choline treatment, this may actually be treating the placenta,” Weinberger said.
“It may be the placenta where it is doing its major therapeutic good. In principle, this is a strategy for prevention.”