After eighteen months, and much to my dismay, Dr. Jaskiw left NIH for another career opportunity. Without him, my work became much more challenging. At times, I wept with frustration as I tried to recognize tiny structures in rodent brains, use our lab’s finicky slicing machines, and catch escaped rats as they hid under the cabinets, hissing and baring their razor-sharp teeth.
As painful as Dr. Jaskiw’s departure was, it forced me into independence—and led to the most significant discovery of my career. Just as we had expected, this scientific breakthrough concerned the frontal cortex, the same brain region whose critical importance I would come to understand on a deeply personal level when, ironically, my own began to break down.
Schizophrenia is a devastating illness that has plagued humans for many thousands of years. Today, it affects about 1 percent of the population worldwide—over seventy million people, including more than three million in the United States and over seven million in Europe. Schizophrenia can affect individuals in any area and from any culture or social class. Symptoms vary from person to person, as does responsiveness to treatment. Many patients suffer from delusions, hallucinations, and full-blown psychosis—the symptoms you see exhibited, for example, by people wandering the streets talking to themselves. Many patients with schizophrenia show cognitive deficits and are unable to make decisions and think logically. The deficits may particularly affect working memory, which helps prioritize and execute the tasks of life. A significant number are depressed and have trouble displaying emotions.
Until quite recently, psychiatrists believed that schizophrenia was a psychological illness caused by stress and upbringing, particularly by the influence of a “schizophrenogenic mother” who did not provide her child with enough maternal warmth and care. Today, this theory has been soundly discredited. Schizophrenia, we now know, is a disease caused by abnormal brain structure and function, just as heart disease is a product of faulty arteries. The difference is that we don’t yet have a “brain fingerprint” for schizophrenia.
In the 1940s and 1950s, doctors suspected (correctly) that the frontal cortex was involved in mental illnesses, including schizophrenia. They began treating such illnesses, at times, with a frontal lobotomy—a horribly invasive type of brain surgery that involves cutting at least some of the connections within the prefrontal cortex or from the prefrontal cortex to other parts of the brain. Controversial from the start, lobotomies robbed some patients of their personalities and intellects. (These appalling effects did not stop the Swedish Academy from awarding António Egas Moniz, the neurologist who developed the procedure, a Nobel Prize in 1949.)
The advent of antipsychotic drugs in the mid-1950s, which alleviated at least some psychotic symptoms in most patients, helped sideline this crude and brutal “cure.” But that pharmaceutical breakthrough came too late for many people. Between 1946 and 1956, an estimated sixty to eighty thousand lobotomies were performed worldwide.
Since the mid-1990s, the focus of research in mental illness has shifted from psychological studies, which analyze behaviors, to genetics and the study of chemicals in the brain (DNA, RNA, and proteins). This allows us to search for inherited genes, mutated genes, aberrantly structured proteins, or dysfunctional pathways that are associated with an increased risk for mental illness. The hope is that, by using precisely targeted therapies that activate or inhibit certain molecules, we can bring these disrupted pathways back to normal.
Still, for the most part, scientists’ understanding of the causes of schizophrenia (as well as of other mental disorders) remains woefully inadequate. Abnormalities in perhaps hundreds or even thousands of genes may be required in order for schizophrenia to manifest itself in a particular person. And because of the great variability among the individual genetic makeups of people afflicted with schizophrenia, it is impossible at this time to predict whether any given individual carries enough risk variants to make him or her ill.
The experiments I conducted in the 1990s on rodents provided clear evidence that abnormal behaviors in rats and, by extension, in humans, may be triggered by subtle brain insults that result in lasting cognitive deficits. The rats whose brains we altered demonstrated difficulties in spatial recognition, including finding their way through mazes that contained savory rewards. Compared to normal rats, they also showed a lack of interest in novel places and objects, and they didn’t interact as much with their peers. We concluded that in humans, as in our rats, slight brain defects may be initiated by a variety of factors that compromise the function of the developing brain, leaving it permanently “out of whack.” Those factors in humans might include maternal malnutrition or viral infections and perhaps many other influences in combination with defective genes that alter molecular pathways and the wiring within and between brain regions. Our findings clearly implicated the frontal cortex as an essential site for the development of schizophrenia, just as Dr. Weinberger and my NIMH colleagues hypothesized in the late 1980s.
Our discoveries gained enormous interest around the world and became known as the neonatal hippocampal lesion model of schizophrenia or, for short, the Lipska model. Drs. Jaskiw and Weinberger and I first described our findings in a paper published in 1993 in Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology. Since then, the Lipska model has been described in hundreds of scientific publications, replicated in many laboratories around the world, and applied to other research areas, including electrophysiology, genetics, and cognition. It has also provided a framework for designing new drugs that might offer benefits for treatment of cognitive deficits in schizophrenia. In 1996, our model was awarded a U.S. patent for screening and developing novel antipsychotic treatments.
In 2002, I became director of the molecular biology lab at the NIMH, where I continued to study
