By David N. Leff

Once upon a time, a few million years ago, a tribe of ancestral humans came down with a retroviral infection similar to AIDS or leukemia. Somehow, the genome of this virus got incorporated into that Homo sapiens' own DNA sequences, where it survives to this day.

Now, virologists and psychiatrists are sharing an infectious-agent hunch that that long-dormant retroviral gene has come back to life, and may be guilty of such modern brain disorders as schizophrenia and multiple sclerosis.

"Until recently, in the 1960s," research psychiatrist E. Fuller Torrey recalled, "schizophrenia was thought to be caused by your mother looking at you cross-eyed. This was back in the old Freudian psychoanalytic days," he explained, "when domineering mothers were thought to be destructive to their children's psychosexual development."

Torrey is executive director of the Stanley Foundation Research Program in Bethesda, Md., which fosters and funds schizophrenia research.

"Since the 1960s, and especially in the '70s and '80s," he continued, "there have been two major lines of research. One is that schizophrenia is a genetic disease, the other that it's caused by neurotransmitter - neurochemical - abnormalities in the brain. In fact, the infectious hypothesis is not inconsistent with either.

"We know there is a genetic predisposition to many, if not most, infectious agents," Torrey went on. "And we also know that many of these agents do affect neurotransmitters. So, for example, if you say that schizophrenia is a disease of dopamine receptors, we'll buy that, because many of these agents also affect the dopamine system."

Torrey is co-senior author of an article in today's Proceedings of the National Academy of Sciences (PNAS), dated April 10, 2001. Its title: "Retroviral RNA identified in the cerebrospinal fluids and brains of individuals with schizophrenia." His co-senior author is virologist Robert Yolken, at the Johns Hopkins School of Medicine in Baltimore.

Not By Viruses Alone . . .

"We've been very careful not to say that retroviruses cause schizophrenia," Torrey told BioWorld Today. "What we are saying is that there's clearly an activation of the retroviruses in the central nervous system, measured by the brain tissue, and in the cerebrospinal fluid [CSF], and that the disorder could be caused by any of two or three pathways.

"First of all, schizophrenia and manic depressive illness are very common diseases. On any given day, about eight of every thousand people will be affected with one of these. Lifetime incidence of schizophrenia is one in 100. Its main hallmarks are hearing voices, hallucinations, delusional thinking, inability to think logically. These are the people who occupy the largest number of beds remaining in the state mental hospitals. They account for about a third of the homeless population, and some 10 percent of the people who wind up in jails because of their illness. Their offenses are usually misdemeanors - for example, dining and dashing. That is," he explained, "going to a restaurant, not paying for a meal."

The co-authors took CSF samples from 35 new-onset schizophrenia patients in their 20s, plus 20 chronic cases who had been ill for one to 37 years. They also obtained post-mortem brain tissue specimens from five individuals whose illness had lasted eight to 32 years.

Their PNAS paper reports detecting the molecular "footprint" of a retrovirus in the CSF from 29 percent of the subjects with acute schizophrenia, and 7 percent with a chronic form of the disease. This genomic trace was absent in the brains and CSF of all controls who did not have schizophrenia.

"While our report doesn't explain why the retrovirus becomes active in the first place," Yolken observed, "it presents clues as to what may happen when it does become activated. Our ultimate hope," he went on, "is that we can interfere with the retrovirus by preventing its activation. If we can do that, it may give doctors another method of treating schizophrenia."

Torrey concurred: "I think this not only points toward additional lines of research, but also toward some possible modes of treatment. And in terms of the biotech industry, it's something we are starting to discuss with them."

In An Ideal World - Vaccines

"If you can figure out what that viral or other infectious pathway is in the brain," he pointed out, "what that cascade is that leads to the symptoms of schizophrenia, presumably you can interfere with it - finding better medications. Also, in an ideal world, if it's an infectious agent that lends itself to immunization, you could conceivably think about vaccines down the line.

"We have just started within the last three months," Torrey allowed, "to deal with individual biotech companies, and will be having further discussions certainly in the next few months. So the object would be to try and develop drugs that target some of these hypothetical pathways that we think are involved in the development of the disease. Therefore, we are adding $10 [million] or $15 million in new money to our annual $21 million support for new treatment approaches."

A neighboring paper in the same April 10 issue of PNAS strikes a different note on the same theme of schizophrenia's etiology. Its title: "Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia." Its senior author is neuropathologist Allen Fienberg at The Rockefeller University in New York.

The most notable finding, his article states, is "the differentiation of myelination-related genes, suggesting a disruption in oligodendrocyte function in schizophrenia." Oligodendrocytes are brain cells that sheath neuronal axons in myelin, which enhances nerve conduction.

Axonal demyelination, as Torrey notes, is a hallmark of multiple sclerosis, which, along with schizophrenia, is also suspected of retroviral activation etiology.

Fienberg's study reported that five genes linked to formation of myelin sheaths tended to be turned off in schizophrenia. Using DNA microarray chips, his co-authors assayed the activation status of several thousand genes at once, and compared it in a dozen schizophrenic patients with 12 nonschizophrenic individuals. They also scoped post-mortem analysis of brain cells implicated in the disease pathology.

Of 89 genes specifically activated in schizophrenia, Fienberg reported, only those involved in demyelination were downregulated. The paper suggests that the disease impairs the function of oligodendrocytes.

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