The Search for Mental Illness and Addiction in the Brain, Part I: The Disappointment of the Human Genome Project

The ideal image many people had of the genome as a straightforward template that stamps out human beings in a predictable way was, and is, a fantasy. And this is nowhere more evident than in the case of human personality traits and mental illness.
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In April, President Obama announced the new BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative, which many hope (expect?) will find the sources of -- and solve -- the mysteries and distress of mental illness and addiction. It will not. It cannot.

Before addressing the BRAIN initiative, let's return to the Human Genome Project -- a similarly massive enterprise whose results are far short of (really, in a totally different universe from) what both laypeople and popular commentators imagined when that project was initiated.

BRAIN was announced just before the 10-year anniversary of the completion of the genome project. On April 14, 2003, scientists announced that they had completed compiling the three billion letters of genetic code that comprise the human genome. As to the function of all this DNA -- not so fast. This long and expensive effort (its initial phase cost perhaps $1 billion, or 10 times the budget for BRAIN) represented only the creation of a framework from which to pursue further research to explore the meaning of the human genome.

Interviewed a decade after the completion of the mapping of the genome, after several more billions had been spent on research, the director of the National Human Genome Research Institute, Eric Greene, summarized what we have learned.

What about the naysayers who asked, "Where are the cures for diseases that we were promised?"

We are understanding cancer and rare genetic diseases. There are incredible stories now where we are able to draw blood from a pregnant woman and analyze the DNA of her unborn child. Increasingly, we have more informed ways of prescribing medicine because we first do a genetic test. We can use microbial DNA to trace disease outbreaks in a matter of hours. These are just game changers. It's a wide field of accomplishment, and there is a logical story to be told.

Note, first, the disappointed expectations conveyed in the New York Times interviewer's question. And notice how measured is Greene's response. Certainly, notice that he makes no claims of uncovering the genetic sources of human personality traits, behavior syndromes, or mental illnesses.

In fact, after a series of disappointments, genetic researchers have abandoned the search for distinct genes that cause schizophrenia, depression, bipolar disorder, alcoholism, drug addiction, etc. No individual genes -- or collections of genes -- have been identified that determine these conditions, or even a large part of any one of them. Instead, geneticists are now looking for common genetic roots for a variety of mental illnesses (including autism, ADHD, depression, schizophrenia, and bipolar disorder) that manifest in different ways due to additional genetic and environmental influences. Nonetheless, according to Jordan Smoller, a coordinator of the research, "these genetic associations individually can account for only a small amount of risk for mental illness, making them insufficient for predictive or diagnostic usefulness by themselves."

Meanwhile, the former editor of The New England Journal of Medicine, Marcia Angell, asks: "The Epidemic of Mental Illness: Why?" One explanation for the epidemic is that we are simply more likely to identify and to label psychiatric conditions. On the other hand, so many more cases of depression and autism are being diagnosed that all of them seem hard to pin on greater awareness and recognition alone. According to the CDC, autism diagnoses are now made in nearly 1 out of 50 boys, whereas in 1980 autism incidence was 1 in 10,000!

Going beyond the possibility of finding genetic sources for particular conditions, the Human Genome Project -- more than anything -- substantially revised our understanding of how our genes operate, but not in the way we imagined it would. To begin with, there was the remarkable discrepancy between the estimates of the number of genes we have and the actual figure. The consensus (there is still some uncertainty) places this number at fewer than 25,000, a figure lower than all expectations, given that estimates reached 70,000 and higher. One reason for the surprise (nay, amazement) over the

It turns out that the overwhelming majority of DNA on our chromosomes is not organized as specific genes. Initially thought to be "junk," much of this DNA (referred to as "switches") is now thought to catalyze processes that then proceed to different genetic outcomes. One expert commented, "The system, though, is stunningly complex, with many redundancies. Just the idea of so many switches was almost incomprehensible." And its implications still are. Not only do such switches impact the course of genetic development (ontology), but the form and expression of genes are influenced by such random events as the mingling of DNA along the chromosomes during gestation. So too do environmental stimuli impact the expression of genes, including such seemingly casual influences as temperature and light. On top of these factors, interactions leading to different genetic outcomes occur between the mother's genes and perinatal genes and the genes within the fetus's genome. Taken together, the picture of the genome that has emerged is one of a seething mass of activity, of change, often unpredictable, and of interactions between different components of the genome and the genome and its environment.

The ideal image many people had of the genome as a straightforward template that stamps out human beings in a predictable way was, and is, a fantasy. And this is nowhere more evident than in the case of human personality traits and mental illness. After all is said and done, there are no bright neon signs in all of that DNA blaring: "introverted/extroverted," let alone "schizophrenic," "autistic," "bipolar," et al. After a half-century of genetic research and investigation of the human genome, the summary of what we know about mental disorders is both vague and vast. According to the CDC: "Scientists believe that many mental disorders result from the complex interplay of multiple genes with diverse environmental factors." Indeed, in many ways, the failure to find straightforward genetic relationships with behavior and mental disorders inspired the clamor for BRAIN.

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