By David N. Leff

The very term schizophrenia has had multiple meanings, ever since the psychiatric disease got its name nearly a century ago. Based on his clinical studies of 647 mentally disturbed patients, the preeminent Swiss psychiatrist Eugen Bleuler (1857-1939) in 1911 invoked the Greek word skizein meaning "split" to describe schizophrenia as a "split personality." (Interestingly, the word "science" derives from the same Sanskrit root: In Latin, "scire" , means "to separate things from one another.")

Modern psychiatric science is split by two explanations for the root cause of schizophrenia: Nature (genetic) versus nurture (environmental). Both camps regard "split personality" as an outdated oversimplification.

During World War II, Hitler's minions carried out the dictator's diktat that schizophrenics, like Jews, were to be separated from human society. Tens of thousands of these mentally impaired individuals were gassed to death by the Nazis.

Today, observed Canadian research geneticist Kathleen Hodgkinson, "the prevalence of schizophrenia, at one percent of the global population, has been pretty general across all ethnicities and socioeconomic backgrounds."

As for the nature-nurture question, she opined, "the consistent finding over the whole of the past century has been that genetics plays a significant role in the etiology of schizophrenia. And nothing else has been consistently shown to be a causative agent. There is almost certainly an environmental component to that."

Hodgkinson, a research genetic counselor at the Health Science Center in St. John's, Newfoundland, is engaged in an ongoing, Canada-wide hunt for a schizophrenia susceptibility gene. She is co-author of a progress report in the current issue of Science, dated April 28, 2000, and titled: "Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22." Its senior author is research psychiatrist and neuroscientist Anne Bassett, at the University of Toronto.

The paper's overall finding, Hodgkinson said, "is that we have significant evidence that a major susceptibility locus exists on chromosome 1. The majority of the 22 families in this study did appear to be linked to that location. If they weren't, we wouldn't have found it." She continued: "We decided to publish these interim results at this time, because we thought it important to get the finding out and share it with the general scientific population."

It All Began With Ostensible Chromosome 5

"The genesis of the project," Hodgkinson told BioWorld Today, "was Dr. Bassett's baby, in effect from very early on. It began when she was involved in the late 1980s with the publication in the Lancet of a study of a family in which an uncle and a nephew both were schizophrenic, and had an apparent genomic abnormality at chromosome 5. She thus became very interested in the genetics of schizophrenia and the possibility of being able to locate the gene or genes that might predispose certain people to developing the disease.

"Of course, genetics has always utilized chromosome abnormalities for locating genes," Hodgkinson observed. "If someone has such a genomic anomaly that you can see, that pinpoints the way to a gene location. But sadly," she continued, "that wasn't the case for the chromosome 5 story, which turned out to be unfounded.

"But I think the excitement related to that finding was the genesis for Bassett, and the possibility that in a complex disorder like schizophrenia there was a potential at some point to be able to pinpoint the susceptibility genes. At that point, she began collecting families with schizophrenia from all over Canada."

Hodgkinson signed on to this familial phase of the project in 1993. To date, it includes 22 families, numbering 288 members with schizophrenia.

"Because schizophrenia is considered so genetically complex," she pointed out, "and because many teams all over the world have been collecting large numbers of nuclear families and individuals with the disease, it is difficult to find susceptibility genes. Although we have this very good data set, in terms of absolute numbers of course it isn't very large compared to a lot of other teams working in the area."

As the person largely responsible for locating, contacting, drawing blood for DNA analysis, and keeping in close touch with the families, Hodgkinson attributes the soundness of their data to the almost family-style relationship with these cohorts. "I have always been amazed," she recounted, "at how good people with schizophrenia are. Obviously, if they are very sick and symptomatic, we don't interview them.

"But quite often," she said, "a lot of the newer antipsychotic drugs have been so beneficial for individuals, that over the years, people who were just too sick to be interviewed have subsequently come forward to participate."

The blood samples she and her colleagues collected were sent to New Jersey for the gene-mapping phase of the project. This is in the hands of the Science paper's lead author, neuroscientist and psychiatrist Linda Brzustowicz, at the Rutgers University-Newark campus. "We have identified a major gene effect conferring susceptibility to schizophrenia," she said. "This goes a long way to demonstrating a very strong genetic component to the disorder - at least in the family groups studied.

"While drugs to better control schizophrenia, based on this finding, appear at least a decade away," Brzustowicz predicted, "a blood-based screening test for genetic susceptibility to schizophrenia might be possible in a year or less."

Hoping To Ring Gene's Doorbell

She added that, based on statistical validity testing of the linkage data obtained, "this study provides evidence for a linkage that is at least 100 times stronger than any other study published to date. The next step," Brzustowicz said, "will be to pinpoint what gene on chromosome 1 causes schizophrenia. That is, now that the genomic neighborhood is known, to find its specific address."

Bassett puts that search this way: "If we compare the human genome to a map of the world, and gene localizing to finding the neighborhood the gene lives in, previous studies have been able to say that there may be a gene in North America, maybe even in Canada. Our study," she said, "tells us that there is a gene predisposing to schizophrenia in the neighborhood of downtown Toronto, and that we should be able to pinpoint its exact location in the next step of our research."

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