Eileen Malaspina dreamed of becoming a physician. But in 1971, during her senior year in high school, her grades began to deteriorate. She became increasingly withdrawn and complained that the neighbors were talking about her. After graduation she entered not the college to which she had won a scholarship but a hospital. Diagnosed with schizo-affective disorder, a devastating mix of mania, depression, and psychosis, she never made it to medical school. But her only sister, Dolores, did. Now a psychiatrist at Columbia University and the New York State Psychiatric Institute, Dolores Malaspina applied to study medicine with one aim: to understand the illness that afflicts her younger sister.
"At the time, people had the idea that schizophrenia was somehow a disease caused by how a family raised someone," Malaspina says. "It was thought that there was a style of parenting called the 'schizophrenogenic mother,' that a mother who raised a child and gave her mixed messages— they called them 'schisms and skews'— could induce this type of illness. That led to a tremendous amount of guilt and confusion."
Today schizophrenia is believed to be solely a disease of the brain. But in an ironic twist, Malaspina's quest for understanding— one that has taken her from her small office overlooking the Hudson River to a vast medical archive in Jerusalem— has led her right back to a parent. Only this time it's the father. Malaspina has found that about a quarter of all schizophrenics may owe their symptoms to spontaneous mutations in paternal sperm. And the older the father, the more likely his sperm is to carry such mutations.
Malaspina consulted a national registry of mental illness maintained by the State of Israel since 1950. At the time, isolated reports suggested that the youngest children in families have the highest risk of developing schizophrenia, but the reason for the trend was unclear. After poring over the medical records of more than 87,000 people born in Jerusalem between 1964 and 1976— 658 of whom had been diagnosed with schizophrenia or closely related psychoses— Malaspina reached a startling conclusion. Whereas one out of every 121 children born to men in their late twenties had developed schizophrenia by the age of 34, one of every 47 children born to men age 50 to 54 developed the disease. In other words, after age 50, a man's risk of having schizophrenic offspring seems to be more than twice that of a man who reproduces in his late twenties.
Malaspina's results were so surprising that some of her colleagues found them hard to digest. "Reproductive scientists in my department said 'It can't be,'" she recalls. Yet she had hit upon a phenomenon that geneticists had recognized for decades: Older fathers are far more likely than younger men to have children with genetic disorders. According to geneticist James Crow of the University of Wisconsin at Madison, paternal age is the source of genetic diseases caused by new dominant mutations. (Only one copy of a dominant mutant gene is necessary to induce disease.) Among the diseases more likely to occur in children with older fathers are achondroplasia (which causes dwarfism), progeria (premature aging), Marfan's syndrome (a connective tissue disorder), a predisposition toward a certain type of skin cancer, and some congenital heart defects. All are triggered by simple deletions or substitutions of one DNA base— unlike Down's syndrome, which is caused by the doubling of an entire chromosome and is usually inherited from the mother.
Why should mutations increase as fathers age? The answer lies in the life history of the sperm. By the time a man is 40, each of his sperm cell precursors, called spermatogonia, has divided approximately 660 times, or about 23 times a year after puberty, in order to give rise to sperm. By contrast, in a female, egg precursor cells divide only 24 times, all but one of these divisions occurring before she is born. The more replication, the greater the chance that a copying error— a mutation— will occur. To compound matters, DNA-repair enzymes become less efficient as a man ages and more frequently fail to fix a mutant sperm.
Malaspina's discovery sheds light on a mystery that has long surrounded schizophrenia: How can so disabling a disease, which appears to be at least partly genetic, persist at such high rates when its victims so rarely reproduce? Schizophrenia is common— one in every 100 people suffers from it— and it tends to run in families. Siblings of schizophrenics are 10 times as likely to get the disease, and for identical twins the risk rises to 40 to 60 percent. Yet signs of schizophrenia do not appear until late adolescence, and sometimes not until the fourth decade of life (women tend to develop symptoms later than men).
Biologists have long suspected that mutant genes pass the potential for schizophrenia from generation to generation but that they have to be turned on by something in the environment. Head injuries, maternal malnutrition, and rubella during gestation have all been found to increase a person's risk of contracting the disease. But the leading candidate for an environmental trigger was only recently discovered: a dormant retrovirus incorporated into the human genome millions of years ago. Virologist Robert Yolken of Johns Hopkins School of Medicine found the retrovirus after examining the spinal fluid of 35 schizophrenics. In 29 percent of those who had recently developed symptoms, and in 7 percent of chronic cases, the retrovirus was active and generating RNA, the template for proteins. Yolken found no such signs in people free of schizophrenia.
Yolken believes that the retrovirus itself has to be triggered by yet another infection: a herpes virus. But Malaspina thinks the mechanism may be even stranger. Last year researchers at the Genetics Institute Inc. in Massachusetts announced that a gene carried by Yolken's retrovirus may play an integral role in building the human placenta. The protein for which the gene codes, called syncytin, both prompts placental cells to knit together to nourish a fetus and enables the virus to fuse with the cells it infects. The source of schizophrenia, in other words, may lie far back in fetal development, perhaps in faulty neuronal wiring. "It could be that it's a neurodevelopmental disease," Malaspina says, "in which a flawed gene derails the normal development of brain neurons."
The story is far from over. It's not clear, for instance, how a single mutant gene— even one involved in building the brain— can unleash the elaborate symptoms of schizophrenia. Contrary to popular belief, schizophrenics don't have "split personalities," and they're rarely violent. But they do suffer from delusions, disordered thinking, and hearing voices, as well as extreme apathy and a profound inability to feel pleasure or motivation. Malaspina has tremendous hope that her research will lead to greater understanding of a misunderstood disease as well as hope for her own family. Last year her sister— who did, eventually, graduate from college— got married at the age of 46. Her husband, too, has schizophrenia. As for Dolores Malaspina: "I'm poised to write a book. It will be called Sister, Psychiatrist, Scientist, Friend."
The National Institute of Mental Health has general information about schizophrenia: www.nimh.nih.gov/ publicat/ schizoph.htm.
