From The Quarterly, Fall 2010
Dr. Ming Tsuang is optimistic. When he surveys the current state of knowledge about the causes of schizophrenia and other serious brain and behavioral disorders, he does not hesitate in assuring listeners that the rate of advance in our knowledge is rapid.
It is in the very nature of scientific investigation, he observes: “Progress, thankfully, cannot be stopped.”
Not only does he think we will know much more about disease causation; Dr. Tsuang—a NARSAD Scientific Council Member, Distinguished Investigator and this year’s Lieber Prize winner for outstanding career achievements in schizophrenia research—is also sanguine about new knowledge leading to the first reliable biologically based diagnostic tests for schizophrenia and for conditions that indicate a young person is on the road to developing it or other illness in which psychosis is present, including a type of bipolar depression. Predictive tests, once developed, promise to give substance, at last, to what long have been mere dreams of preventive intervention.
What makes Dr. Tsuang’s optimism about our present course particularly noteworthy is his vast experience in the field of psychiatric epidemiology and genetics, and his remarkable record of achievement. With more than 600 scientific papers and 17 books in his name (as author or co-author), covering a broad swath of subject matter in psychiatry and genetics, he is an undisputed scientific leader whose opinion carries weight. Currently a Distinguished University Professor of the University of California, and chair and director of the department of behavioral genomics at UC San Diego after 20 years at Harvard, Dr. Tsuang has been elected to the Institute of Medicine and the National Academy of Sciences among many other honors.
Dr. Tsuang’s evidence did not support his adviser’s theory
He has been in the thick of the hunt for genetic and environmental linkages in serious mental illness since the mid-1960s, when he performed his Ph.D. in psychiatric genetics at the University of London. By this time he had already earned his M.D. at the College of Medicine at National Taiwan University, Taipei. In 1981, again in London, he would add a doctorate of science to his list of achievements, this time in the area of psychiatric epidemiology and genetics, fields whose future he would help to shape in the coming decades.
Prior to arriving in London to pursue his Ph.D., Dr. Tsuang read an influential paper, “Monogenic Theory of Schizophrenia,” published in a leading British medical journal. The paper was written by one of the pioneers in psychiatric genetics, Dr. Eliot Slater, director of the Medical Research Council, Psychiatric Genetics Unit, Maudsley Hospital at the University of London.
Dr. Slater would become Dr. Tsuang’s mentor during his time in London. Dr. Slater hypothesized that schizophrenia was caused by a single gene. Dr. Tsuang decided to research whether this theory could be substantiated. The result was his evidence did not support the theory. Dr. Tsuang was very impressed by Dr. Slater’s response; he encouraged him to publish his results in the British Journal of Psychiatry. Despite his theory being different from his adviser’s, he received his Ph.D. from the University of London in 1965.
Dr. Tsuang’s thesis presented evidence suggesting that both schizophrenia and affective disorders “were very likely polygenic—caused by multiple genes acting at the same time—and that many of these multiple contributing genes probably overlapped.” This is now common knowledge. But it is important to understand that he arrived at his conclusion 30 years before the advent of molecular genetics and the revolutionary wave of new technologies that made it possible. “I took an evidence-based approach in this and subsequent research, and it has always guided me,” he says today. “It is something I always encourage in my doctoral students.”
Subsequent molecular-genetic studies have indeed shown that the genes implicated in schizophrenia psychosis and bipolar psychosis are in fact overlapping. But, he stresses, “We also know that [the predisposing genes of] people with bipolar illness who are not psychotic are different from those who are. So the very, very impressive thing we’ve learned is that in psychosis there is a shared genetic component, across schizophrenia and bipolar disorder.”
Multiple causes, multiple manifestations
As strongly today as the first day he went on hospital rounds as a young psychiatrist, Dr. Tsuang wants to know why a devastating illness like schizophrenia occurs. Being a scientist, he wants to know precisely why; yet ever since his thesis research, he has appreciated all too well that such yearnings for clarity are not destined to be easily satisfied. He has conducted many studies over the years that collectively place a bold underline beneath the technical term “heterogeneity,” which in shorthand calls our attention to the important differences within and between different mental illnesses.
On the one hand, he and his colleagues are certain that there is a strong heritability factor in schizophrenia. But this alone tells us much less than we would like, for schizophrenia and other serious neuropsychiatric illnesses are both causally and clinically plural. As Dr. Tsuang has written, two or more causes can independently induce the same clinical syndrome. It is equally true that a single set of biological causes can lead to more than one clinical syndrome—that is, manifestations of illness that appear to be different.
How do we make sense of this tangle of heterogeneity? Does it not doom the quest for reliable diagnostic tools to analyze young people whom we fear are at high risk of becoming schizophrenic? Doesn’t it imperil even simpler diagnostic tasks such as determining that while patient A has schizophrenia, patient B actually has the psychotic form of bipolar depression?
Taking risks – with high reward
One focus of his attention over the last several years has been comparing the activity levels of certain genes in people who have—and also, importantly, in people who do not have—psychotic disorders. “This kind of work was unthinkable before the Human Genome Project,” Dr. Tsuang points out. To appreciate his approach, though, one has to grasp that even technological advances such as gene chips, microarrays and gene sequences, which make it possible for scientists to measure which genes in a particular cell are active and which are not active at a given moment in time, do not directly reveal anything about the cause of an illness. This is true regardless of whether the genes being measured are from a sample taken from a cancer patient or a person with schizophrenia.
“What excites me today is measuring mRNA (messenger RNA), the chemical message sent by active genes to cells, instructing them to manufacture proteins. No gene or set of genes directly causes any illness. It’s the messages they send, or don’t send, to the cellular machinery that affects biological function,” Dr. Tsuang clarifies. “The wonderful thing we can do today that we couldn’t do years ago is called genomics—we can study many genes at one time. In one-gene studies, which we used to do, you open a window. In genomics, it’s as if you are opening all the windows, and studying all the genes at once.”
Just as Dr. Tsuang went against conventional wisdom when he challenged the “one-gene” theory of schizophrenia advanced by his graduate school mentor, so today he is happy to perform studies that some colleagues think will fail. A vivid example concerns the mRNA sampling that so captivates him. In cancer or heart disease, the RNA messages of active genes can be readily sampled in peripheral blood—the blood that circulates through one’s veins and which is sampled in common blood tests. Illnesses seated in the brain pose a special problem, however, due to what scientists call the blood-brain barrier. The expression of genes in brain cells is much harder to measure, since direct sampling of brain tissue is not an ethical option in living human patients. One way around this is to develop models of human brain illnesses in mammals—in rats, for instance. But there is a much less complex alternative, which Dr. Tsuang has taken risks to explore.
Why not closely study ordinary, peripheral blood samples from a population of people with schizophrenia, and compare it with blood samples from healthy “control” subjects? “I felt that if nobody is doing it, why can’t I just take a risk? If I don’t find anything, that’s fine. But what if I do find something? It’s worth a try. So we did pilot studies.”
Pilot studies are an important means by which scientists at the cutting edge can try out unproven ideas—provided they can get them funded. In fact, Dr. Tsuang says, “My NARSAD istinguished Investigator grant supported pilot research on schizotaxia—an observed tendency of some people to suffer some of the negative and cognitive symptoms of schizophrenia, but without the psychotic dimension. This is one of the grant types that NARSAD is famous for—they enable a proven scientist to take risks on a project that has a high potential payoff. I’m very grateful to the organization, as are many of my colleagues in brain research.”
Several years ago, Dr. Tsuang and colleagues undertook a pilot study to see if there might be markers for schizophrenia or psychosis lurking in ordinary blood samples. “Lo and behold! When we carefully examined the mRNA profiles of a small sample of people with schizophrenia and affective disorder, and compared them with controls, we found that we could indeed differentiate them based on markers in the blood,” he reports.
Dr. Tsuang most values being able to measure markers of gene activity in people before they “convert” to psychosis, and then, in those who do convert, measure it again after their conversion. “Which genes are up-regulated or abnormally active in those with early symptoms? Which genes are down-regulated? We compare converted patients with their baseline. From that data we can zero in on those genes that are changed in expression, and look into what their biological function is.” This is the long-sought connecting link between abnormal gene expression and manifestations of illness in specific patients: How is the biology of the brain affected? How is the brain—its billions of nerve cells, the circuits they form, the neurotransmitters that relay messages between them—changed?
Shedding light on the gene-environment linkage
Once the role of genetics is better understood in a given set of patients, the question for Dr. Tsuang becomes, “What is going on in people who do have the malfunctioning genes, but who do not have the illness? This can also tell us a great deal—what scientists call the ‘penetrance’ of a given susceptibility gene.” He believes in such cases it will be fruitful to examine on a comparative basis the environmental exposures of those who became ill vs. those who stayed well. “When I was at Harvard, I studied conditions within the uterus, when a person’s brain is still developing, and the way in which those conditions might affect illness in the child who emerges. We’ve published many papers on the possible impact of viral infection, trauma, drug intoxication—all during pregnancy, which predisposes those people with the susceptibility gene to develop schizophrenia in the future.”
Yet this is only one way of studying the genetics-environment linkage. “A very exciting new concept involves the millions upon millions of microorganisms that colonize our bodies,” Dr. Tsuang says. “We are particularly interested in the effects of the interaction with our own genes and genes from these micro-organisms in our bodies. We suspect these gene interactions may result in not only harmful but also protective effects against human illness.” Because the cost of sequencing the full genomes of individuals is now approaching affordability—it is expected to reach $1,000 within several years—it becomes possible to contemplate sequencing a person’s DNA and that of the organisms that live in his or her body. This, of course, would be just a preliminary step on what would likely be a long pathway of discovery.
These are the pathways that pioneering researchers will be taking in the coming years, as they seek to make real the advances about which Ming Tsuang is optimistic. “You ask me what excites me, what I find exciting about research today? These are some of the things, none of which we could contemplate when NARSAD was first founded, about a quarter-century ago. But beyond the technology that is making this promising work feasible, we have to always remember why we are doing it—how we can help patients with schizophrenia and their relatives identify schizophrenic psychosis before onset and to plan for early intervention, aiming toward prevention.”
Ming T. Tsuang, M.D., Ph.D., D.Sc.
Foundation Scientific Council Member and 2010 Lieber Prizewinner for Outstanding Research on Schizophrenia Research
Behavioral Genomics Endowed Chair
and University Professor, University of California;
Director, Harvard Institute of Psychiatric Epidemiology and Genetics
Harvard Medical School and Harvard School of Public Health