Jim was 20 when it hit. He ran across the field with his suitcase, feet hardly touching the ground, joy in his heart and not a care in the world, off on a vacation to Florida.
When it happened to Elizabeth, she was 18. She bought three roomfuls of yarn, more than she could possibly use up in a lifetime. John bought a fancy new car with extra chrome and whitewalls. He was 23.
Altogether these events do not seem that much out of the ordinary. Lots of people travel to Florida, and lots of people buy cars or other
extravagances.
The difference is when they happen among the Old Order Amish in Lancaster County, Pa., people who live simple lives and drive horse-drawn buggies. Then these grandiose actions are dead giveaways to the first episodes of manic behavior, the out-of-control hyper side of manic-depressive illness.
Jim, who was caught by relatives before he reached the bus station, was leaving behind a new wife and baby, unplowed fields, untended cows and countless other chores. John and Elizabeth didn`t have the money to pay for their purchases, which had to be returned.
Because these people stand out like sore thumbs in a genetically isolated population, their stories helped lead to one of the most profound discoveries in the mental health field: the first solid evidence that a common psychiatric illness can be genetically inherited.
The discovery is one of the latest benefits of the recent revolution in brain research that is unraveling many mysteries of mankind`s most complex organ.
Using the powerful new technology that has created the science of molecular biology and opened the door to genetic engineering, scientists probed the chromosomes of the Amish patients to locate genetic markers associated with manic-depressive illness. People in the Amish community who inherit the markers also inherit the disease-causing gene that has not yet been mapped, thereby greatly increasing their risk of getting the disease.
The discovery, made last year, was stunning, and it has turned psychiatry upside-down.
”Who would have believed even three years ago that this new technology
(which has produced breakthroughs in molecular biology) can be applied to a common psychiatric condition,” said Dr. Janice Egeland, a University of Miami psychiatrist whose work with the Amish for nearly three decades led to the breakthrough. ”Many people were saying it`s premature, you can`t do this, it`s not time yet for recombinant DNA (genetic engineering) in psychiatry.”
Rapid advances in molecular biology are opening a breathtaking new chapter in which scientists may be able to uncover much of the biological basis of mental illness.
It seems clear already that the distinction between neurological diseases and psychiatric disorders is crumbling. In the past, a disorder was considered neurological if doctors could find pathological changes in the brain, upon autopsy. Alzheimer`s disease, for example, is only definitively diagnosed after an autopsy, which reveals damaged brain cells. Psychiatric problems previously were thought to be character flaws because pathologists could find nothing wrong. The brain looked perfectly normal.
It now turns out that the biological markers are there, after all, in psychiatric illnesses. They were merely too small to be seen until recently, when science brought the genetic code into focus.
”What is amazing is the number of diseases for which genetic factors may play a role,” said Dr. Herbert Pardes, chief of psychiatry at Columbia University. ”These include panic disorders, schizophrenia, affective disorders (such as depression and manic-depressive illness), Alzheimer`s disease, Huntington`s disease, learning disabilities and even suicide.”
A genetic marker (a known gene that usually codes for a minor genetic disorder) signifies the presence of an abnormal gene nearby that is causing the disease. The next big step is isolating the errant gene itself. Finding out what it is doing wrong to brain chemistry may yield new ways to diagnose, correct, cure and even prevent mental problems.
Furthermore, different genes may cause similar problems, researchers are finding. Manic-depressive illness now has been linked to separate genetic markers on two different chromosomes in widely separated but isolated populations.
The findings support the growing concept that mental disorders are not single diseases, as has long been thought, but a variety of diseases, many of which have similar symptoms.
”These discoveries represent an enormous step forward in our understanding of psychiatric disorders,” said Pardes, who is also vice president of the American Psychiatric Association.
The change is fundamental. The new insights indicate that genes may lie at the base of mental illness either because they are abnormal or because they are missing. In either case, brain chemistry is messed up.
In some disorders, such as Huntington`s disease, one gene may be able to cause mental dysfunction by itself. Huntington`s symptoms, which usually occur between ages 35 and 50, are marked by loss of muscle control and mental deterioration. In other disorders, probably most, a gene or a number of genes, may increase a person`s vulnerability to a specific problem.
A person may be perfectly fine until something from the environment affects the gene. It could be a virus, an environmental toxin or a
psychological stress that acts on the abnormal gene to evoke the faulty chemistry and the ensuing symptoms of mental disease. This idea is similar to the ”two hit” theory of cancer, in which a cancer gene gets turned on by similar insults.
Finding out what those second ”hits” are could open the possibility of preventing some mental problems. People with vulnerable genes may be taught to avoid the triggering agents. Public prevention programs could be designed along the lines of those for heart disease, which stress low-fat diets and exercise.
”Molecular genetics is likely to have a massive impact on psychiatry,”
Pardes said. ”As we learn more about peoples` genetic endowment, we will learn about how they differentially respond to environmental influences. We`ll learn more about the diseases and how to better treat them.”
The new knowledge comes with its ethical entanglements. Physicians may eventually be able to diagnose many more genetically linked mental disorders in unborn babies. In some cases, where the disease is devastating, parents may opt to have the fetus aborted.
What would be the ethical course if a couple decided to abort a fetus because it might develop depression at age 35 or manic-depressive disease at 18? How would a person`s employment and insurance benefits be affected by genetic susceptibility to a mental disorder?
Healthy people who carry the defective genes can also be identified. Obviously this information will be useful for couples who are planning families, but it may cause considerable harm if it falls into the wrong hands. The rapid advances in molecular biology that are forcing some of these ethical issues to the forefront also threaten to deflate some of psychiatry`s long-held beliefs.
”Psychiatry in the past 20 or 30 years has been like a religion in the sense that we have certain strong schools and belief systems that are predicated not so much on factual information but on pseudofactual
information,” said Dr. Steve Paul, chief of the clinical neuroscience branch at the National Institute of Mental Health in Bethesda, Md.
Psychoanalytic thought, for example, is tremendously perceptive, but scientists have problems knowing whether it`s true, he said. Manic-depressive disease for a long time was thought to be caused by bad parenting, and panic attacks were believed to result from castration anxiety, he said.
”Well hell, it may be a lousy gene,” Paul said. ”We`ve got to throw all that stuff out the window. We`re moving from our religious preoccupations to scientific preoccupations.”
Trying to ease the growing identity crisis in psychiatry, Pardes, in a major address at the American Psychiatric Association meeting last May in Chicago, said: ”All of this promises a time of enormous and exciting change in the field. But it is important for all of us to learn and integrate this knowledge explosion and to use it to enhance our field rather than feeling threatened by these developments.”
For victims of mental disorders, which affect 1 of 5 Americans, the new findings will mean a liberation from the old notion of blaming the patient or his family for the disease.
”The real message is that we`re looking at this illness in a new way,”
Egeland said. ”Publicly and professionally we are acknowledging that there is a biological basis. It`s a medical problem. It`s treatable. So don`t be embarrassed with this as a diagnosis. It`s called a mental condition, but it`s a mood and energy disorder, and it needs to be treated just as diabetes would be treated with insulin.”
One to 2 million Americans suffer from manic-depressive illness, and the vast majority have never been diagnosed. The manic state is marked by bursts of energy, extravagant actions, expansive thoughts and intense activity. This mood alternates with incapacitating depression. The first symptoms usually appear between ages 15 and 35.
One young Amish man struck by his first manic episode concoted a scheme to help humanity. He thought he had invented a way to end the gasoline shortage by adding manure to gas tanks.
Manic-depressive illness, which occurs in the Amish at the same rate it does in the general population, is fascinating to scientists for another reason.
Some think the gene that causes it may be associated with creativity. Studies have shown that an unusual number of artists, writers and famous people probably had some degree of manic-depressive illness. Maybe it`s an experiment of nature that has gone somewhat awry, an evolutionary genetic modification that improves creativity but at the same time removes the control over mood swings.
”Perhaps nature had wanted it to be this way, but maybe something went wrong,” said Dr. Miron Baron of the New York State Psychiatric Institute and Columbia-Presbyterian Medical Center. ”Instead of generating something that would be only constructive, we have to pay a price, and the price is the persistence of manic-depressive illness in the population.”
Manic-depressives tend to be very attractive, energetic, productive, creative people who may be using part of their illness, the submanic phase, to be productive, said Dr. Richard J. Wyatt, a neurochemist at the National Institute of Mental Health. Somewhere between the mood swings of mania and depression there may be a period of creative energy, he suggested.
Many patients are reluctant to take medications that control the violent mood shifts because they are afraid also of losing what they consider their creative impulse.
”Do you want to get rid of that gene or do you want to control it in some way?” Wyatt asked. ”If getting rid of the gene means you`re losing the Handels, Schumanns, Berliozes and other people who contribute enormously to our society, then you might not want to get rid of it so quickly. You might want to control it.”
A major reason that the Amish, who guard their privacy, agreed to cooperate in the study was that they saw the dramatic benefit medications had on restoring normal behavior. Between 70 and 80 percent of the cases can be effectively treated with lithium or monamine oxidase inhibitors and antidepressants.
The Amish population is an ideal laboratory for genetics studies because of its restricted gene pool. The more than 12,000 members are descended from 50 couples who emigrated from Germany between 1720 and 1750. They have large families and keep extensive genealogic records. There is virtually no crime or violence and almost no use of drugs or alcohol, which can conceal psychiatric symptoms. So when a member of the Amish sect does become violent or commits a crime, he stands out immediately.
In the general population, manic symptoms often go unrecognized. When Uncle Harry gets in one of his moods, for instance, he may go out and buy Cadillacs for everyone or jet around the world. His relatives may think he`s a little eccentric, not realizing he may be a manic-depressive.
In fact, it was the Amish who got Egeland interested in the disease. Decades ago they had noticed something psychiatrists sometimes overlooked:
Many mental disorders tend to occur in certain families. They called it ”Siss im blut”: ”It`s in the blood.”
By taking blood samples from all 81 members of one Amish clan that had 14 cases of manic-depressive illness, Egeland and her colleagues were able to find the genetic markers for the disorder.
Every cell of an individual contains all the genes or DNA
(deoxyribonucleic acid) that he inherited from his parents.
DNA is packaged as a set of 23 chromosomes from each parent. They code for about 100,000 genes, about half of which are active in the brain. Geneticists hope to identify all the chemicals in the genetic code by the end of the century, an accomplishment that is expected to hasten the identification of individual genes.
A person`s genes dictate his chemical makeup, from the color of his hair to his susceptibility to various diseases.
Techniques developed by molecular biologists in the last 10 years use enzymes to chemically snip off pieces of DNA. The pieces from someone with a mental disorder can be compared to pieces of DNA from a normal person.
By looking at the pieces of DNA from the manic-depressives, scientists can identify specific patterns of genes that only they inherit. These genes often also produce minor genetic disorders-such as color blindness or anemia- and are inherited along with genes that cause serious disorders, thereby serving as markers.
James Gusella, a neurogeneticist at Massachusetts General Hospital, was the first to show the awesome power of this method. The turning point came in 1983, when he found genetic markers on Chromosome 4 for Huntington`s disease. That was followed in his laboratory by the discovery of a marker on Chromosome 21 for Alzheimer`s disease, and a marker on Chromosome 17 for neurofibromatosis, sometimes called the ”Elephant Man`s disease.”
”I think people in my area probably always had the view that there was a genetic link to mental illness,” Gusella said. ”But now we have the tools to dissect it.”
The first genetic markers were linked to neurological disorders. The first genetic marker associated with a psychiatric illness came from Egeland`s blood samples.
Geneticists David Housman of the Massachusetts Institute of Technology and Daniela Gerhard, now at Washington University, found two genetic markers on Chromosome 11 for manic-depressive disease in the Amish group. The genetic markers were genes that were already known, one that directs the production of insulin and another that codes for an oncogene, a gene that can cause a normal cell to turn cancerous.
The implication is that someone who inherits these markers, and presumably the disease gene, has a 70 percent to 80 percent chance of getting manic-depressive disease, Housman said. In many cases the markers themselves are defective genes that cause minor genetic disorders, like color blindness. Although the actual disease gene has not yet been identified, scientists are zeroing in on a gene found near the tip of Chromosome 11. This gene makes the enzyme tyrosine hydroxylase, which is essential in the formation of dopamine, a neurotransmitter implicated in other mental disorders.
”If the level of production of dopamine were altered in an individual because of a genetic difference in the makeup of their tyrosine hydroxylase, then you might get a vulnerability under some circumstances to bipolar (manic- depressive) illness,” Housman said.
Scientists are hard at work trying to find these disease genes that lie tantalizingly close to the marker genes. Genetic engineering techniques allow them to ”walk” along a chromosome, plucking out and identifying individual genes, but it is time-consuming work. When they do find a faulty gene, they can try to figure out what it is doing wrong that is causing the disease, and, they hope, prevent or correct it.
”That`s the goal of genetic research,” Gusella said. ”We want to isolate the gene so we know what the defect is, what protein (which is made from the gene) is defective and what its normal function is. We want to know what`s going wrong with it so we can be rational about trying to design something to intervene.”
For some diseases the cure may be relatively simple. Phenylketonuria
(PKU), which causes mental retardation in infants, is such a success. PKU babies inherited a genetic defect that didn`t allow them to make an enzyme that broke down phenylalanine, an amino acid found in common foods. Consequently, amino acids accumulated in brain cells and destroyed them.
Now infants are screened routinely for this inborn error. Those with PKU are put on special diets during childhood that eliminates foods containing phenylalanine, thereby preventing retardation. Researchers hope other mental disorders can be similarly prevented.
”That`s probably the most significant aspect of this type of work,”
Housman said. ”If you can understand the underlying pathology, then the development of rational therapeutic intervention is more likely.”
A second set of genetic markers linked to manic-depressive illness was reported about a month after the Amish findings. The team of researchers, led by Columbia`s Baron, found their markers, which code for color vision and a form of anemia, on the X, or sex, chromosome. (The inheritance of two X chromosomes means the baby will be female. An X and Y chromosome means it will be male.)
The markers, which were found among genetically isolated families in Israel, may represent a common form of the disorder, according to the investigators. The National Institute of Mental Health has awarded the team a major grant to study a large group of manic-depressives in this country and elsewhere to look for other markers for the disease.
”Once we are able to identify the genes themselves, then it will be fairly straightforward to identify the people at risk of developing the disease,” Baron said.
As with the Amish group, not all the Israelis who inherited the X-linked form of the disorder developed the disease. The markers indicated an 80 percent probability of getting the illness.
Scientists want to find out why all of those with the markers didn`t become sick. Perhaps they were protected by certain factors that could be used to prevent the disease occurring in others who carry the defective gene. On the other hand, those who came down with the disease may have been exposed to certain environmental factors that triggered the disease gene.
Scientists also are looking for errant genes in Alzheimer`s disease, a disorder causing brain deterioration that affects an estimated 2.5 million Americans.
Dr. Charles A. Marotta of Harvard University and Massachusetts General Hospital discovered that the frozen brains of people who died of Alzheimer`s disease held an apparent clue to the cause of the disease. Contrary to what everyone expected, Marrota found that their brain cells still contained RNA
(ribonucleic acid).
RNA is basically a mirror image of DNA. Genes, or DNA, make RNA, which directs construction of proteins that genes are coded for. RNA serves as a messenger from the DNA to a protein assembly factory inside a cell.
By working backward, Marotta and his colleagues are able to use the RNA to make synthetic copies of the genes that coded them. One is a gene for the amyloid protein that is found in abundance in a substance called senile plaque in Alzheimer`s victim`s brains.
Although proteins normally are supposed to be redigested when they are no longer needed, part of the amyloid protein appears to solidify and get stuck in brain cells, forming the senile plaque, Marrota said.
”Our hypothesis is that in the very aged brain and in Alzheimer`s disease a segment of the amyloid protein gets cut out,” he explained. ”The remaining protein has unusual properties in that it self-aggregates, becomes insoluable, precipitates inside the brain and contributes to the death of cells.”
Marrota plans to insert the part of the amyloid gene that makes insoluable protein into cells to see if they produce senile plaques. If they do, then they may serve as a method to screen for chemicals that prevent plaque formation.
”What we`re hoping is that by using these esoteric molecular genetic techniques we can develop a method to find new drugs that can at least treat one aspect of this disease,” he said.
