Weinberger: ‘Nature vs. nurture’ a red herring in mental illness

Kreable Young | Staff Photographer
Daniel R. Weinberger, CEO of the Lieber Institute for Brain Development, speaks about mental illness about during his morning lecture Tuesday in the Amphitheater.

Mental illness has always plagued human beings, said Daniel R. Weinberger, yet only in the last 10 years have scientists really begun to understand its genetic causes.

Weinberger, director and CEO of the Lieber Institute for Brain Development, addressed the Amphitheater audience at 10:45 a.m. Tuesday. His presentation was the second of Week Nine’s lecture theme, “Health Care: From Bench to Bedside.

The U.S. BRAIN Initiative and the European Human Brain Project demonstrate the growing interest in mapping the human brain and a broader push for mental health research, Weinberger said.

“This is very much an effort to build computer models of how information is handled in the brain,” he said.

The federal government initially invested $100 million in the BRAIN Initiative, and the European Commission allocated 1 billion euros to the Human Brain Project.

“Clearly, there’s now real money being invested in this, and it puts brain research on the front page of The New York Times,” Weinberger said.

More attention has been paid to the brain disorders afflicting young people, he continued. A third of children in the United States are on brain treatment drugs, and autism is diagnosed two to three times more frequently than it was 10 years ago. Between 1 in 50 and 1 in 100 are on the autism spectrum, Weinberger said, calling it the “most disabling” childhood mental condition.

ADHD, the most common mental disorder in children, is the second most common diagnosis of any kind in children in the U.S., after asthma.

The World Health Organization has stated that four of the most disabling disorders are mental disorders. One in 4 adults suffers from a psychiatric or mental disorder, and 6 percent of those have a serious, lifelong condition, Weinberger said. One in 3 people in the U.S. experiences a significant period of depression at some point in their life, and half of those will experience a recurrence of it.

But the mental illness that takes the biggest toll, “the cancer of mental illness,” Weinberger said, is schizophrenia, which affects 1 percent of the world population. Nature called it “arguably the worst disease affecting mankind.” WHO considers schizophrenia the fourth most costly disease in world societies.

These represent an economic cost of $100 billion a year in terms of care and loss of productivity in the U.S. alone. The personal, emotional cost for families is “inestimable.”

For all of this impact, Weinberger said, “until very recently, we actually knew very little about what mental illness actually is.”

Everything from twin studies to MRI scans have aided in understanding the causes of mental illness, he said.

“The big struggle has been to determine whether it runs in families for the reason that language or religion runs in families, or does it run in families because of something people inherit,” Weinberger said. “That is, is it about the culture of family, or is it about the nature, not the nurture, in that family?”

But since genes have been identified as underlying risk factors for mental illness, the “nature vs. nurture” struggle has been thrown out the window, Weinberger said.

“Genes and environment are critical factors. There is no one critical factor. The argument ‘is it nature vs. nurture’ is really a red herring, because there is no ‘nature vs. nurture,’ ” he said. “All common medical disorders — all of them — heart disease, high blood pressure, stroke, diabetes, cancer, mental illness —  they’re all genetic factors that make your risk greater, that affect your liability or susceptibility, and environmental factors that exaggerate those risk factors.”

Q&A

Q: A year-and-a-half ago — when Milton Tamar introduced us to your remarkable lab — I think there was maybe half the number of fellows there doing research. You had probably 30 of them around a table when we met, and I remember you were talking about this young man, a psychiatrist, a Chinese-American, who was talking about the collaboration in Beijing. And he was saying that they were pulling in enormous data on twins. Can you tell us something about that collaboration, and then how that data comes in and is integrated across these disciplines in your research.

Daniel Weinberger: So, one of the things we’ve tried to do is take these opportunities, because the Lieber Institute for Brain Development [LIBD] is not constrained by the requirements of fitting into a grant or pleasing some government agency, we can say, “Where are the real opportunities to make progress, and let’s commit our personal and material resources to that.” The Holy Grail as I mentioned a little bit, is understanding how genes and environment really matter to an individual human being. I mean, we can use these words and we can build models, but we want to understand what does it really mean? So one of the unusual opportunities in a country like China, is that there has been the wonderful historical experiment, where people have gone from incredibly impoverished rural environments to these hyper-industrialised, ultra-urbanized centers at various stages of their life. Thus creates an enormous environmental change. And one of the things about China is that everything involves huge populations. It’s also much cheaper to do this work in China. And the other thing that happened in China which was kind of interesting is that there was a government program that forbade anyone from having more than one child. But it turns out many people had twins, and twins was the way you defeated the government. If you had twins, you had more than one child. They couldn’t do anything about twins. So we initiated a study with colleagues at Peking University to look at normal brain development comparing identical to fraternal twins, and any comparison of identical to fraternal twins controls for genetics. And then we said we can come by, we’ll take all normal twins living in Beijing, every year by the way in Beijing they have this twin society festival, it’s really an amazing thing. And there’ll be ten thousand twin pairs sitting in the audience. And you look out at this and you can’t believe what you see. You don’t just feel like you have double vision, you feel like you’re a fruit fly with double vision out of ten thousand little facets of your eyes. So we’ have designed a study, which is ongoing and collecting data, where we’ve identified normal twins and the question is … these are normal people, identical/fraternal, always compared to each other, and we have groups of twins that spent the first five years of their life that they spent in abject, terrible poverty. These are poverty situation where people literally don’t have clothing in parts of China, and they’ve moved to the city at different times of life. So we can now try to make sense, by doing brain imaging work, and genetics and other analyses, of what is actually happening to a brain based on this changing environmental experience, which are profound environmental changes, in the context of a controlled genetic analysis. This can’t be done any place else in the world. And the irony of this is, we think this will be a profound understanding of how genes and environments actually interact. It would be very hard to get the public funding to support this because it involves too many instruments working together which is not easy for public funding to support.

Q: We know that genes set the stage for diagnoses. What are your thoughts regarding the effects of chemicals, excess sugar, toxins and hormones in our food and environment affecting the development of our brain and susceptibility to brain disease.

A: Very important question, and I think you heard it in yesterday’s lecture. Everybody’s now thinking that one of the way genes change change the landscape of medicine, is that they make it much more individualized. So there’s all this literature about things like toxins in food, toxins in the environment, the problem with all of this is we haven’t had an way to really do scientific studies based on those observations. Because it’s very clear that there are some societies, where there are tremendous amounts of toxic exposures, and they don’t necessarily have a greater frequency of these problems than in other societies where there’s less of it. But the fact is, for certain individuals environmental exposures can be very critical whereas in other individuals they can be incidental. So the only way we can begin to tease out those questions is we have to be able to have identity defined, not at a purely phenomenological level (like who are your grandparents) but at a much more concrete biological level, what does your genome look like? People have said that the 21st century will be the century of genomic medicine because 20 or 30 years from now, this is already happening in cancer, it’s all over the news, we’re going to increasingly making medical decisions about individuals that are different than the medical decisions we’ll make about another individual who might have the same environmental exposure, because their genome makes that environmental exposure have a different impact than somebody else’s. But we’re not there yet, we don’t have that information now, but we’re moving in that direction.

Q: Can you comment on the connection between drug abuse and schizophrenia?

A: So there’s been a lot of studies published in the last 15 years suggesting that marijuana use — particularly in early adolescence — is associated with the increased frequency of the diagnosis of schizophrenia later in life. And there have been a number of studies like this, and it’s not a perfect literature. And unfortunately in science, for something to be conclusive, there really has to be very good data to justify a conclusive result. So the data here are not conclusive, but they’re very suggestive, and so we’re operating on the assumption that today’s marijuana apparently, is really very different than the 1960s marijuana, it’s much more potent, it has ingredients in it that may be much more psychotogenic, causing psychosis, the only problem with these studies is that we don’t really know if the association is cause or effect. The association is that people who are heavy marijuana smokers when they’re young adolescents have a slight increase in the probability that they’ll manifest schizophrenia later on in life. What we don’t know is, is it possible that they may have been having trouble then already, and then were smoking marijuana to somehow treat themselves or to relax themselves? We can’t disambiguate what is cause and what is effect here, but there’s clearly an association.

Q: Practically speaking, how does your statement earlier that the behavior of a mother in a child’s early life affect the activation or manifestation of traits like fearfulness differ from the earlier thoughts that the mother was the cause of schizophrenia and other diseases?

A: Well, again, this was not about an illness. This was about a characteristic of human temperament, and I think the point I was trying to make was we know that significant childhood stress — we’ve known this for a very long time by the way, but there’s now very good data on this — childhood trauma, abuse, physical abuse, sexual abuse of children, toxic stress, children in horrible toxic environments, wars, famine, etc. this does not lead to good adult adaptation, there’s no question about this. It’s actually very clear now that major childhood abuse is a risk factor not only for the development of psychiatric disorders, but all common medical disorders. Obesity, heart disease, lung disease, a variety of brain diseases, are all associated … risk is increased by severe childhood stress. This is probably because severe childhood stress leads to maladaptive behavior patterns which become risk factors for these medical disorders. So there’s no question about this, but these are extreme states. The other thing we know is, some people are very resilient to these things. The reason the environment is hard to study is because there’s really no environmental factor that human beings experience that is guaranteed to have the same effect on everybody. Some people are very resilient; some people are made stronger by childhood adversity. So we have to begin to look at this in the context of individual biology. What is it about some people that makes them especially sensitive to environmental stress or adversity, and other people that make them much more resilient? So, to put that in the context of psychiatric illness, we know that severe childhood adversity is a risk factor for psychiatric illness, it doesn’t cause it. And many people have had those experiences that haven’t had it, but it’s a risk factor.

Q: Is the high incidence of ADHD seen globally, or just in the U.S.? And if higher in the U.S., why?

A: Again, when you get into this business of the apparent increased frequency of disorders like ADHD, this is not seen in most other Western countries. It’s not seen in the UK. It’s not seen in Denmark, or France, and so what we think is happening here is that there’s increased awareness of this condition. We may have broadened the boundaries of how we diagnose people. My guess is that’s very likely to be the case. There’s a lot of debate among child psychiatrists of what accounts for the both the increase of the diagnostic frequency of autism and ADHD. I think that most people believe that we have become less rigorous in where we draw these boundaries. I think the fact that a third of children have been on a round of what we call psychotropic drugs, probably most of whom are not benefitted from these drugs, is an illustration of the fact that we have broadened these boundaries. Which is not to say, by the way, that ADHD — ADHD exists, and in children who have it that are benefitted by medicines are dramatically improved — but it also probably bleeds into normal expression of problems that could have to with family, or friends, or school or other things. That is not helped by medication. Maybe hurt by medication.

Q: So these questions really aren’t the same, but I’m going to try to put them together. One is: Is it worth doing genetic testing for autism? And the other is, why aren’t we including mental health checkups for our children as they grow? Shouldn’t it be part of the wellness checkups for growth and development?

A: I like the second question, in particular, because it’s a really interesting question. My sense is that we do need to do this. We need to, unfortunately, develop much more objective tools that we don’t have right now, about how we assess this question of normal psychological health and development. We don’t really have the right tools to do that yet. But I think, as the science has become so much more sophisticated, we can ask much more objective questions about how individuals will vary and how they go through life experiences and develop, we will have a better way to do this. My guess is we will be doing this another generation from now. So there’s a lot of debate in the literature about genetic testing for autism, and I think the field is going in the direction of advocating for this. The reason is that most people with autism, most children with autism, have, just like cancer and heart disease, have many different genes that combine like elements in an orchestra to form this kind of music. But there are about five to ten percent of children with the diagnosis of autism, and these are usually people with severe forms of autism where they’re not just very socially disabled and don’t interact with other human beings, but they’re also intellectually disabled, many of these children may have epilepsy, but they’re much more profoundly developmentally disabled. About 10 percent of these children have a diagnosable change in their genome which can be diagnosed with genetic testing. These are called chromosomal abnormalities. And even though they’re not completely diagnostic, and there’s a little gray area here, if you find them in a child with fairly significantly disabling autism, then it’s probably a factor in their developing autism. That doesn’t mean you can use it any differently than you would treat this person if you didn’t have this information. But since much of medical treatment and practice is about understanding causes, this is probably going to be something that’s going to be done routinely in the next five years.

Q: Often observed in the context of bipolar for example, could you talk about the extraordinary intellectual and creative gifts in the presence of bipolar disorder?

A: Again this is a fascinating issue. And we know that bipolar disorder, the reason it’s called “bipolar” is because one pole is this depression, which can be very disabling, and very few people function well when they’re very depressed in any realm, but the other pole is their hypo-manic or slightly manic. This means they don’t need to sleep as much. They have abundance of energy. They feel they can tackle the world. They can write a book in a week. So there’s a history for a number of very talented artists, writers, musicians having taints of bipolar disorder. There probably is some connection. We look at Robin Williams, we look at Philip Seymour Hoffman, and it’s obvious that these people were able to maybe take advantage of some of their mood-related characteristics to be very thoughtful, effective, sympathetic characters on screen. But there, probably, is some link to creativity. The interesting thing about mental illnesses is that the genes for these conditions are the genes for the flavors of human beings. That’s what they are. They’re the flavors that people come in. And they become disabling and illnesses, where you accumulate too many of one type that tip you over the balance. But the reason that these genes, and the form that cause mental illness are so called, “common,” is that, for example, genes that cause schizophrenia. Most of the people here will have a few of them. You have to accumulate enough and have some environmental factors which tip you over the edge. Most of us have not experienced those kinds of combinations of factors, but the variations of genomes are there. And they’re there so that human beings can make it this far through all these millennia of evolution and adversity, because if you think about it human beings aren’t particularly fast runners, they don’t have great eyesight, they can’t smell a forest fire from half-a-mile away or two miles away. They’re not very powerful. How have we survived all these climatic disasters, infections, all these predators that found us to be easy prey? How as a species have we survived this? We have survived because of the diversity in our genomes. There is always somebody that will make it through anything in human history. There are people who are immune to AIDS. There are people who are immune to ebola. There are people who eat the most toxic substances and it doesn’t touch them, they won’t even get indigestion. This is the nature of human evolution and why we have made it so far. So all these variations and the flavors of people can be an asset in certain situations. And some of the genes in bipolar disorder, probably in certain situations, probably make somebody a better artist, maybe a more creative thinker, but in other situations they’re very detrimental. And this is why mental illness is so common and so difficult to approach, because pieces of it are in all of us. But these illnesses are profound disabilities.

—Transcribed by Zachary Lloyd

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