Recent USC graduate Megginson Hollister remembers being devastated at age 12, when her older sister was diagnosed with schizophrenia.

"She was my idol - a beautiful, artistic and intelligent teenager," Hollister recalled. "I couldn't understand why she got sick."

The desire to find answers helped to motivate Hollister to complete first a B.A. and later a Ph.D. in psychology at USC.

Hollister's dedication paid off earlier this year when a major psychiatric journal published research inspired by her sister's illness. The study, which appeared in the January issue of The Archives of General Psychiatry, established for the first time a link between trauma from fetal blood incompatibility and the later onset of schizophrenia.

The study, which Hollister conducted as her doctoral dissertation, found that women with the incompatibility were twice as likely as others to have children who later developed schizophrenia.

Hollister's sister, Annick, had a different blood type than her mother, Patsy - now an Orange County mental health advocate. Meanwhile, Hollister, her mother and her older brother shared the same blood type.

Psychology professor Sarnoff Mednick, who advised Hollister on her dissertation, said that it is very rare for a researcher's personal experiences to have such direct bearing on his or her findings.

"Meggin wanted to do this months before I said OK," said Mednick, a co-author of the study. "It was just too much of a long shot. But she was very dedicated to the hypothesis, and I think her personal resolve carried the project along."

A renowned researcher in schizophrenia, Mednick said the findings add to an expanding body of research that shows a link between pregnancy complications and a propensity for mental illness.

In 1988, Mednick published a landmark study that demonstrated a higher-than-normal rate of schizophrenia among children whose mothers contracted influenza in the second trimester of pregnancy. Researchers had long known that complications in delivery put babies at risk for developing a range of illness, including mental illnesses. But Mednick's study for the first time established a link between illness during pregnancy and an increased risk for schizophrenia - mental illness characterized by bizarre behavior, delusions and hallucinations.

Since that time, a wide range of events during pregnancy - some of which are quite ordinary and harmless on their own - have been shown to increase a child's risk of developing schizophrenia. Exposure during pregnancy to colds, viruses, stress, radiation and even cats - which can carry a virus that causes toxoplasmosis - have been linked (at least theoretically) to increased rates of the disorder once thought to be triggered primarily by such environmental stresses as a dysfunctional family.

"We used to think that the mammalian pregnancy was pretty well protected, as compared, say, with fish, which dump their eggs into the ocean," Mednick said. "But that perception conflicts with a growing body of literature that we at USC have helped to originate. We're finding that some obstetrical complications may predispose people to mental illnesses."

This latest study involves the Rhesus factor. In Caucasians, 85 percent of women are born Rh-positive, which means they have a protein on the surface of their red blood cells, explained Hollister, who received her doctorate in August. The remaining 15 percent tests negative for the protein; they are Rh-negative. (The rate is 7 percent among African Americans; virtually all Asians and Native Americans are Rh-positive). Whenever Rh-negative blood comes into contact with Rh-positive blood, the immune system produces antibodies to fight this protein, which the body perceives as an intruder. With each successive contact, the amount of the antibodies increase.

Trouble starts brewing when the Rh factor enters the Rh-negative mother's circulatory system during the delivery of a baby (or abortion or miscarriage of a fetus) that has inherited the Rh factor from its father. Antibodies begin to build that can later attack the infant's oxygen-carrying red blood cells, Hollister said.

Hollister studied 1,867 male children born between 1959 and 1961 to Danish women. Mednick has long tracked this sample for his schizophrenia research. (Scandinavian nations are particularly suited to genetic studies because their populations are homogeneous and because they keep excellent records.)

Hollister found a schizophrenia rate of 2.1 percent in male children with this blood incompatibility. By contrast, the disease occurred in only 0.8 percent of Rh-compatible births.

Furthermore, she found that the incidence of schizophrenia rises with each Rh-incompatible birth. For example, it climbs to 2.9 percent for third-born children.

The researchers stress that they don't believe the blood incompatibility in itself puts children at risk for schizophrenia. They believe a well-known fetal disease caused by Rh-incompatibility is the likely culprit.

This condition, called hemolytic disease, can cause hypoxia - a shortage of oxygen - in the fetus. One region of the brain that is vulnerable to hypoxia is the hippocampus, Hollister said. Hemolytic disease can also result in the buildup in the fetus of bilirubin - same substance that causes jaundice. Bilirubin is flushed from the fetus' body by the mother's system, but newborns lack the enzyme for this cleansing process. Once a baby is born, the toxin builds up and must be removed by blood transfusion. Bilirubin is toxic to certain regions of the brain, including the basal ganglia. Researchers have observed brain abnormalities in the hippocampus and basal ganglia of schizophrenics, she said.

"Schizophrenia is such a complex illness that there isn't going to be a simple answer," said Hollister, now a postdoctoral fellow at the University of Pennsylvania. "But I hope that the steps I make may bring us closer to an understanding of its causes and any possible cures."

Interestingly, a drug that fights the development of Rh antibodies in women became widely available in 1968 - seven years after the birth of the last child in the Danish sample.

Doctors administer the vaccine at 28 weeks of pregnancy to Rh-negative women and, again, within 72 hours of birth. Doses are also supposed to be administered after an amniocentesis, bleeding during pregnancy, miscarriages and abortions. In the cases of undetected miscarriages and other glitches, the vaccine does not get administered and Rh-negative women will develop the antibodies that can lead to hemolytic disease in future pregnancies. Still, the Rh-immune globulin has dramatically reduced hemolytic disease, Hollister said.

"If Rh-incompatibility is indeed a risk for schizophrenia, we should see a reduction in the instance of schizophrenia from use of the vaccine," Hollister said.

Even if the threat of complications from hemolytic disease has been dramatically reduced, Hollister's research is valuable, according to Mednick.

"This is a model for how an auto-immune - or allo-immune - system might be responsible for disturbances in the development of the brain," Mednick said. (Auto-immunities act against one's own body, whereas allo-immunities attack cells similar to one's own in the body of another.)

Ironically, it's an idea that had occurred to Hollister's family.

"Over the years, we talked about possible reasons for Annick's illness, and the topic of Rh-incompatibility came up," Hollister said. "My mother even asked one psychiatrist whether the incompatibility could have played a role. He said he'd never heard of it, and he seemed skeptical."

Hollister remembered those discussions when she started to study Rh-incompatibility in her second year of graduate school.

"The more I learned about hemolytic disease, the more it seemed to fit," she said.

Her instinct and tenacity led to a research finding with important implications for the link between brain development and the auto-immune system.