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A Theory of Schizophrenia, Viruses and Pregnancy
Millions of years ago, viruses hitched a ride on the primate genome.
What a long, strange trip it's been.
By Lone Frank

Featured Article.

With one percent of the world's population suffering from schizophrenia, there is a rush among researchers to identify the inherited component of this complex and still mysterious disease. Despite many promising studies, no schizophrenia susceptibility genes have been found. Now, a group of American scientists and their Danish collaborators are taking a different approach. Although still probing the human genome, the team is studying viruses that first invaded our lives millions of years ago and are still causing trouble.

"As the first study of its kind, this investigation could be very important," says Robert Yolken, who heads the Stanley Division of Neurovirology at Johns Hopkins Medical School, in Baltimore. Yolken believes that schizophrenia may be linked to so-called endogenous retroviruses.

These poorly understood bugs are intriguing. Unlike all other viruses, they do not infect their host; rather, they are inherited as part of the human genome—each of us has several classes of viral DNA sequences in every cell. The sequences may have multiplied and become a part of our genetic heritage after hitching a ride on the primate genome millions of years ago. Today, the viral sequences comprise about half of one percent of all human DNA.

The hypothesis: Infections during pregnancy activate dormant viruses, disrupting brain development and increasing the risk for schizophrenia later in life.

Normally, the viral sequences are harmless and lie dormant—most are relics that cannot be transcribed into proteins. But some are still intact and can be activated by various agents, such as infection by viruses or microbes. "We hypothesize that in schizophrenia endogenous retroviruses are activated by infections occurring during pregnancy," explains Yolken. "Activation leads to disturbances of fetal brain development, which pave the way for development of schizophrenia later in life."

Though Yolken's idea is still a theory, it has some support. Many studies have identified morphological changes in schizophrenic brains, ranging from enlarged ventricles to altered cell structures and protein levels in certain brain regions. There is evidence that infection during pregnancy plays a role in schizophrenia. A study begun in the 1960s involving 60,000 pregnant women found that children born to mothers infected with herpes virus are five times more likely than other children to develop schizophrenia.

"We have found antibodies to retroviral protein in these women, suggesting that endogenous activation has occurred," says Yolken. Furthermore, Håkon Karlsson, a member of Yolken's group, recently identified traces of active retrovirus in spinal fluid from a group of schizophrenics suffering their first episode of the illness. No such traces showed up in controls.

To test the connection between retroviruses, early infection and schizophrenia, the Johns Hopkins group teamed up with colleagues in Denmark. The Danish researchers bring unique resources to the study.

Clinical biochemist Bent Nørgaard Pedersen, of Statens Serum Institute, in Copenhagen, has a collection of blood samples taken from all Danish newborns since 1981 as part of the routine screening for metabolic disorders. Psychiatric epidemiologist Preben Bo Mortensen, of Århus University, offers access to Denmark's centralized psychiatric registry. The database contains information on every patient who came into contact with the country's psychiatric health care system since the sixties.

‘Much about schizophrenia is determined in and around pregnancy’

"In the registry, we have identified 600 schizophrenic patients age 14-15," says Pedersen. "By using the personal identification number (carried by every Dane), we have pulled out these patients' infant blood samples." Together with 1,200 age-matched controls, these anonymous samples are on their way to Yolken's laboratory in Baltimore. His team will look for traces of active retrovirus and infections that were present around the time of birth.

"We are especially interested in herpes, but we test for the standard battery of viruses, including cytomegalovirus, toxoplasma and rubella," says Yolken. The results will be sent back to Mortensen, whose analyses are expected to reveal possible links between infection and schizophrenia.

"Epidemiological investigations in various populations have shown us that schizophrenia is a complex disorder," says Mortensen. Both a genetic susceptibility and a considerable contribution from the environment are required for the development of the disease, and Mortensen's mining of the Danish registry has uncovered a host of environmental factors that may be involved.

"It is now clear that much about schizophrenia is determined in and around pregnancy," says Yolken. He points out that the cooperation between genes and environment is exactly what makes the endogenous retrovirus theory so appealing: "These viruses, which are also implicated in diseases such as sclerosis and arthritis, make attractive candidates for the unknown link that bridges the gap."

How this bridging happens is still largely unknown. Once activated, the otherwise benign retroviruses seem to cause great damage in their genetic neighborhood, perhaps by altering the expression of nearby genes. This is where the individual's genetic susceptibility comes into play. "While one person's genetic makeup is not affected by retro-viral activation," says Yolken, "the same activation may trigger a chain of events in another individual."

Once schizophrenia susceptibility genes are identified, the genes can be analyzed for the presence of endogenous viral sequences. Yolken is particularly hopeful that the new study may raise the prospects for treatment of schizophrenia. "If retroviral activation starts off processes leading to the development of schizophrenia, it should be possible to treat or even prevent the disease with anti-viral drugs," he says.

Herpes infection is common among schizophrenics, and many patients suffer from intermittent worsening of the disease. Yolken is interested in testing whether the standard herpes treatment can prevent such episodes. "There is also the prospect of screening pregnant women for herpes infection and treating the ones at risk," he says.

See related GNN article
»Riches of the Brain Bank

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Johnston-Wilson, N.L. et al. Disease-specific alteration in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol Psych 5, 142-149 (2000).
Karlsson, H. Detection of retroviral RNA in the CSF of individuals with schizophrenia, abstract presented at the 1999 International Congress on Schizophrenia Research. Santa Fe, NM.

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