For the past 20 or so years, we have tried to understand the biological processes that are responsible for this most profound abnormality of mental illnesses we call schizophrenia. Our work has mainly concentrated on characterizing the illness's basic biology. Early on, we focused primarily on studying the brain. And, much more recently, we've become involved in trying to characterize the biology of genetic susceptibility to schizophrenia because the tools now exist to do this.

So, as with much of science, we're always asking questions about basic biological processes that would be responsible for this condition and the emergence of this condition. But the tools that were available to answer these basic questions have changed. Now, basic genetic tools as well as basic neurobiological tools are involved. In schizophrenia, the neurobiological tools for studying the illness primarily involve brain imaging. This allows us to explore the biology of the living brain. Regarding genetic tools, we identify biological characteristics associated with risk for the illness in families with a history of schizophrenia and we use genomics to identify the genes associated with these biological characteristics.

  How did you become interested in schizophrenia research?

That's a complicated thing. The answer really is that I found, from the time of my early training in medicine, neuroscience to be a particularly exciting, challenging, and endlessly fascinating area of medicine. Schizophrenia is this engaging riddle and it's such a profound impairment. It soon became very difficult to not have that be my top research priority.

  What were the greatest challenges in performing your work?

The greatest challenges still exist basically, which is to get to the bottom of the biology of this illness. There are many levels of challenges. At a political level, there have always been challenges because studying schizophrenia has always been a backwater of neuroscience and there have been challenges in engaging more traditional neuroscientists in this effort.

There are methodological issues, because patients with mental illness pose unique challenges to clinical researchers. In part that's because of the nature of the illness in that the portions or functions of the brain affected in schizophrenics are functions that can often intervene in a negative way with all efforts to study it. For example, patients can't participate in experiments the way normal individuals do and this creates confounded understanding of the data. This has been especially problematic in the area of neuroimaging. It's relatively easy to demonstrate differences in neuroimaging data between patients with schizophrenia and normal controls, but difficult to attribute the differences to pathological biology rather than abnormal behavior.

There's always challenges in having adequate funding to do the work. It's not inexpensive.

And then the scientific challenge has been particularly acute in that we don't know exactly what the right questions are. In the area of genetics, we're probably stuck in an anachronistic view that mental illnesses are defined at the biological level the way we define them clinically, and there's no reason to assume that's the case. We study schizophrenia but we have no valid definition of what it is at a biological level.

  What would you like to convey to the general public about your work?

That schizophrenia is an extremely profound, complex disease that involves many, many levels of human function, experience, and biology. This is a disorder of human perception, cognition, and behavior, and the complexities of the processes that contribute to those kinds of abnormalities are enormous.

The other message is that we've made enormous progress. We now have information on the schizophrenic brain that we didn’t have a generation ago. We have the tools to identify the genes that account for the genetic risk for the illness. And we have better treatments than ever—and these continue to improve.

In our group, we have now characterized what we believe is the first genetic mechanism for any mental disorder and have identified a genetic effect that seems to account for biological risk of schizophrenia.

There's been a huge amount of progress made in chipping away at this massive edifice, at this multi-faceted structure that we call schizophrenia.

  If you performed your research again, or published your papers again, what, if anything, would you do differently and why?

Anytime we've discovered a new way to do things we've always done it that way. The process of research is evolving. We always update methods. We always ask new questions when we have new information.

  What are the implications of your work for the future of your field or neighboring fields?

I think the main implications right now for our work is that we have probably identified a gene that contributes to the variance in an important biological factor that predisposes a person to schizophrenia. This factor involves the function of the frontal cortex, which is the part of the brain that governs one's ability to sequentially perform a series of actions to guide behavior based on memory and the instincts to reason logically.

  How rapidly has the state of knowledge about your field evolved in the past decade, and what were the key discoveries that furthered the advancement of the field?

Very, very rapidly. We've learned a great deal about the basic neuroscience of executive cognition, working memory, and frontal lobe function, that is making decisions and using information to guide behaviors.

Schizophrenics have a lot of problems using information to guide behavior. They don't act on a necessarily rational assessment of the world around them. This leads to bad judgment, misinterpretation of stimuli, and a misinterpretation of environmental events and circumstances.

  What is your prediction for the state of our knowledge about your field 10 years from now?

I think that we will have found several genes that account for liability to manifest the illness. I think that we will understand a great deal about the molecular regulation of frontal lobe function as it relates to schizophrenia. And I think that there will be new treatments based on these insights. (0.5 to 1 percent of the population is considered a schizophrenic depending exactly how the diagnosis is made.)

  What lessons would you draw from your work to pass on to the next generation of researchers?

Research is an endlessly fascinating, exciting pursuit. The combination of mental health, basic neuroscience, genetics, and behavior research is an area ripe for study. There are so many unanswered questions. At least for the next generation of researchers, this would be an area to go into that really needs people.

Dr. Daniel R. Weinberger
National Institute of Mental Health
Clinical Brain Disorders Branch
Bethesda, MD, USA