Science / Medicine : Cornering the Genes That Cause Mental Illness : In a new era of psychiatric research, scientists hope to isolate the genes that predispose people to severe mental disorders like schizophrenia or manic depression.
In Sweden and Scotland, England and Israel, the United States and Belgium, scientific sleuths are hot on the trail of some wily genetic culprits.
The scientists are cooly slicing up microscopic segments of deoxyribonucleic acid, or DNA, which carries the genes that contain the human chemical blueprint. Somewhere along the delicate strands of DNA they hope to corner genes that critically influence the appearance of manic depression and schizophrenia, severe psychiatric disorders that afflict millions of people around the world.
These DNA studies “usher in a new era of of psychiatric research” that promises to reveal the physiological basis of severe mental disorders, says Darrel A. Regier, director of the division of clinical research at the National Institute of Mental Health in Bethesda, Md. If genes predisposing some people to schizophrenia or manic depression are found, researchers will be able to study more precisely how current drug treatments work and develop better drugs.
But in true scientific fashion, as the DNA detectives turn up new clues, the enormous complexity of their task becomes more apparent.
The international search owes its existence to advanced techniques of molecular biology. Substances called “restriction enzymes” are applied to DNA isolated from members of families extending across several generations. The enzymes make cuts at recognizable sites along the 23 pairs of slender chromosomes making up DNA. In this way, chance variations or “markers” are picked up, such as a deletion or addition of a segment of DNA. If the same marker occurs predominantly in family members with a particular disease, researchers assume a gene crucial to the disease lies somewhere along the genetic variation.
Genetic markers for manic depression have been found on two chromosomes. This supports the contention of many scientists that manic depression, characterized by recurring bouts of deep depression and overactivity mixed with euphoria, is not a single entity but a group of related disorders.
Two years ago, scientists found a genetic marker for manic depression on chromosome 11 in members of Pennsylvania’s Amish population. Shortly thereafter, studies of families in Jerusalem and Belgium found several markers in the same area of the X chromosome. Chromosomes are identified by number except for the sex chromosomes; there are two X chromosomes in the female, and one X and one Y in the male.
Pinning down a specific gene is an arduous task, however. The Amish researchers were initially heartened by the proximity of their chromosome 11 marker to a gene for tyrosine hydroxylase, a substance that helps form a chemical messenger in the brain thought to be involved in manic depression. But Yale University researchers now find the tyrosine hydroxylase gene is farther away from the genetic marker than had first been thought and is probably not involved in manic depression.
In ongoing studies of the Amish, Yale’s David L. Pauls and his co-workers hope to develop markers accurate enough to flank the chromosome 11 gene. Only then can its code be deciphered.
The search for genes predisposing their bearers to schizophrenia is perhaps even more daunting. There is no universally accepted definition of schizophrenia. The term refers to a group of disorders with such symptoms as hallucinations, delusions, confused thinking, inappropriate emotions and the deterioration of the ability to take care of one’s basic needs. Contrary to popular notions, schizophrenia is not a split personality.
Several months ago, scientists led by Hugh Gurling of the University of London, England, reported two genetic markers on chromosome 5 are linked to schizophrenia in seven Icelandic and English families. But another research team, directed by Kenneth K. Kidd of Yale, found the same DNA region is unrelated to schizophrenia in several generations of a Swedish family.
The location of potential chromosome 5 markers “is the most important genetic finding on schizophrenia I’ve seen in recent years,” says Elliot S. Gershon, a psychiatrist with the National Institute of Mental Health. Nevertheless, preliminary results of his own studies of four families with a large number of schizophrenic members find no evidence for a predisposition gene in the same area. Similar work is under way at the University of Edinburgh, Scotland, and the University of Utah in Salt Lake City.
The most likely reason for the different findings, according to Kidd, is that a number of genes are involved in the expression of schizophrenia. Even in the Icelandic and English families, he notes, there is about a 30% chance that someone with a chromosome 5 variation will not develop schizophrenia.
Genetic work does not rule out the appearance of nongenetic forms of schizophrenia or the importance of environmental influences on those genetically predisposed to the disorder, Gurling says. Further evidence for the importance of environment as well as heredity comes from studies of identical twins. If one twin is schizophrenic, the other has a 50% chance of developing the disorder. This is a much higher rate than for the general population, but it “points to powerful nongenetic factors,” says Eric S. Lander of Harvard University.
While one in 100 people suffer from schizophrenia, research indicates about one in 10 relatives of schizophrenics have the disorder. Manic depression also affects around 1% of the population, but one in five relatives of manic depressives have manic depression or severe depression without mania.
Gurling estimates it will take at least five years to isolate the chromosome 5 “predisposition gene,” but hazards no guess as to its biological functions.
Until then, his study still has important implications. Because most forms of schizophrenia described by psychiatrists were represented in the Icelandic and English families, Gurling explains, there is now evidence for a common genetic origin in the majority of schizophrenics. Further genetic studies may “pave the way” to splitting schizophrenia into distinct diseases, according to Lander.
Yet there are limitations to the scientific paving genetic studies are capable of, Kidd says. For instance, the researchers rely on families in which schizophrenia affects as many as one in three individuals, although most schizophrenics have far fewer schizophrenic relatives. Thus, the chromosome 5 variation may merely illustrate a rare genetic predisposition to this mental disorder.
“One major factor will influence the future of this work,” Kidd says, “and that’s locating additional large families with enough schizophrenic members to further test the chromosome 5 findings.”
It will also be important to identify people with the genetic markers early in their lives and follow them into adulthood to see who develops schizophrenia. Such time- and money-consuming studies are essential if scientists are to discover genetic and environmental influences on psychiatric illnesses.
While schizophrenics think and behave in unusual ways, their intelligence is normal, Kidd points out. Large areas of the brain must be unaffected by the disorder, he says.
“How can a gene perturb brain function just a little bit, but in a critical way?” he asks. “We have no good idea how a genetic abnormality contributes to something as complex as schizophrenia.”
If work goes ahead on a controversial proposal to draw up the entire human genetic blueprint, some answers to Kidd’s query may eventually come to light. The availability of a complete map of these chemical sequences, which contain 3 billion bits of genetic information and as many as 100,000 distinct genes, will greatly aid in the search for genes responsible for “a thousand diseases,” says biologist Robert A. Weinberg of the Massachusetts Institute of Technology.
But even if, for example, investigators uncover the chemical sequence of a protein in a DNA sequence linked to manic depression or schizophrenia, “a laboratory can still struggle for a decade or more just trying to learn what that protein does,” Weinberg says. And even then scientific understanding is limited, he adds, because a single protein operates within a complex, interacting network of other proteins to determine cell function.
Whether researchers disentangle the DNA of families with a preponderance of psychiatric disorders or map the entire human genetic text, the results constitute an important but small step forward. “After all of this,” Weinberg says, “we shall still only have scratched the surface of life.”
