Oct. 20, 2000 -- In a midsize Midwestern town, four elderly sisters are living out their remaining years in a way that might be called unremarkable. But the sisters, known as the Genains, are far from typical: Born in 1930, they are among the oldest living quadruplets, and they are all identical.
And the uniqueness of the Genains does not stop there, for all four of the sisters developed schizophrenia, a disease said to afflict only 1% of the total population. For this reason, they have been the object of intense scrutiny, beginning in the 1950s, by researchers hoping to discern clues about the cause and course of their illness.
Study of the Genains has taught researchers much about schizophrenia. But it has also taught them how much is still to be learned about "the interaction" of contributing factors that may lead to the disease, says Allan Mirsky, PhD, author of a recent report in Schizophrenia Bulletin that follows up on the Genains' progress through the years.
In his report, Mirsky and colleagues conducted psychological tests of the Genains at age 66, and compared them to similar tests conducted earlier in life. The results showed stable or even improved performance in thought functions over time, supporting the notion that schizophrenia is not a degenerative illness, as many physicians believe it to be. Mirsky is chief of the section on clinical and experimental neuropsychology in the laboratory of brain and cognition in the intramural research program at the National Institutes of Mental Health.
Mirsky says that what stands out about the Genains is not the remarkable and terrible serendipity of their common disease -- but the significant differences in the course of their illness, and its effect on their lives. One sister, known as Myra, has worked, married, and raised a family despite her illness. Another sister, Hester, never completed high school and has never been able to function independently outside a home or institution. Two other sisters, Nora and Iris, fared somewhat better than Hester but have never married or had a substantial career.
It is an observation that has profound meaning for researchers. And despite much consensus in the field, there remains wide disagreement about how to explain the different outcomes of people who have schizophrenia, Mirsky and other experts tell WebMD.
Mirsky says that because they have exactly the same genetic makeup, the Genains are confirmation of the widely acknowledged fact that genes are necessary to "predispose" an individual to schizophrenia. But he believes the sisters' experience also points to the fact that a host of other variables -- including the treatment they received at the hands of their parents -- can have a role in the different courses their disease has taken.
He notes that the Genains' father was a harsh and brutal man who treated Myra and Nora preferentially, expecting more of them and thereby hastening their intellectual and emotional development. In contrast, he was cruel and hostile to Hester and Iris, Mirsky reports.
Mirsky says the observation shows that while such psychosocial trauma cannot cause schizophrenia, it may account for the different course the disease takes in different people. "You can make the condition worse by mistreatment," he says. "You can't make someone schizophrenic, but you can make them worse. The genetic endowment can be modified by environmental experience."
E. Fuller Torrey, MD, executive director of the Stanley Foundation for Research Programs in Bethesda, MD, who reviewed the recent follow-up report on the Genains, said it confirms that the clinical course of illness varies from individual to individual. The Stanley Foundation is a nonprofit organization supporting research on schizophrenia and bipolar disorder.
While Torrey acknowledges the role of genes in predisposing an individual to schizophrenia, he believes they are not necessarily decisive. "We all agree there are genes involved," he tells WebMD. "The strength of that involvement is what we argue about."
Like Mirsky, Torrey acknowledges that some other factor -- he calls it "Factor X" -- must interact with the genetic predisposition to cause schizophrenia. But if there is disagreement about the strength of the role of genes, there is also no complete consensus on what Factor X might be, Torrey says.
Torrey does not believe that psychosocial trauma -- of the kind suffered by some of the Genains -- is a contributing factor in schizophrenia. "There is no data to support that at all, except on a theoretical basis," Torrey says.
Rather, he believes the important interactive factor is "almost certainly biological," and not related to their psychological makeup, or experiences. Specifically, he believes the genetic predisposition is probably complicated by a biological insult that occurs before the child is born, resulting in a neurological deficit causing the symptoms of schizophrenia.
Richard Wyatt, MD, chief of the neuropsychiatry branch at the National Institute of Mental Health, who also reviewed the report, says Mirsky's follow-up, and the entire history of Genains research, has an important lesson for doctors, researchers, and patients and their families. "It tells us that you can have clones of the disease but have different manifestations according to the different ways the genetic vulnerability meets the environment," Wyatt tells WebMD. "What it doesn't tell us is where the deviation occurs."
Regarding the effects of psychosocial trauma on the sisters, Wyatt says he can't disprove its relationship to the course of schizophrenia. "But I don't have much faith in it," he says.
Wyatt, like Torrey, believes the weight of research is leaning toward something harmful occurring when the child is in the womb, in combination with a genetic vulnerability. Specifically, he cites evidence of infection in the second trimester of pregnancy -- a critical period when important structures of the brain are formed.
Ultimately, schizophrenia may prove to result from an extraordinarily complex interaction of genes, biology and environment, continuously over time, says Irving Gottesman, PhD, the Sherrell J. Aston professor of psychology at the University of Virginia in Charlottesville.
The follow-up study of the Genains "continues the tradition in schizophrenia research of demonstrating that it is inaccurate to push for an exclusive genetic, biological or environmental point of view as being sufficient to account for what we see in schizophrenia generally, or in the Genains in particular."
For this reason, study of the four sisters may carry lessons beyond understanding schizophrenia. The factors that contribute to the disease -- genes, biology, psychosocial factors and the random events of life itself -- are what also contribute to normal development and personality, he says.
Genains research contributes to "an enlightened view of how genes and environmental factors are continuously interacting to make all of us what we are," says Gottesman.
The Genain sisters, scrutinized by researchers the world over, have become four unique individuals living out the seventh decade of remarkably difficult lives. Scientists have been at pains to guard their privacy and confidentiality, while relishing the opportunity they provide for a glimpse into the varying course of a dread disease, Mirsky says.
"They are still of interest, and I get calls from geneticists all over the world wanting a blood sample," Mirsky says. "The story of the Genains is not over."