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Book asks: Do genes cause mental defect?

'Mood Genes: Hunting for Origins of Mania and Depression'

By Samuel H. Barondes

Web posted on: Friday, October 23, 1998 2:38:25 PM EDT

We know that many physical characteristics are determined by genes. But do genes also affect mental characteristics, such as the way we feel? Can abnormalities in specific genes lead to mental disorders? And, if so, can these genes actually be identified and their discovery put to use in prevention and treatment?



Michael's Family

That ... inbred cause of Melancholy is our temperature (temperament), in whole or part, which we receive from our parents ... it being a hereditary disease; ... such as the temperature of the father is, such is the son's, and look what disease the father had when he begot him, his son will have after him... And that which is more to be wondered at, it skips in some families the father, and goes to the son, or takes every other, and sometimes every third in a lineal descent, and doth not always produce the same, but some like, and a symbolizing disease. -- Robert Burton, The Anatomy of Melancholy (1621)

When Michael was in kindergarten his mother, Flora, was overwhelmed by her first attack of mania. Then twenty-four years old, Flora had just published her first novel to great critical acclaim. In light of this early success, her exuberance initially seemed understandable. But instead of coming down to earth, Flora kept getting more and more excited. At a party in her honor, she startled the guests by dancing on the table and stripping off her clothes.

A few restless, sleepless days later, this brilliant and elegant young woman had become so agitated and disheveled that she was admitted to a psychiatric hospital. Her diagnosis, confirmed by several specialists, was manic-depressive illness, a remarkably common mental disorder that affects about one in a hundred men and women. Because this was in 1941, before tranquilizers and lithium had been developed as treatments for manic behavior, it took more than a month of hospitalization and large doses or sedatives to help calm her down, All that Michael remembers of this period is that he was very upset by her long absence.

In the years that followed, Flora was hospitalized many more times for flagrant manic episodes. Usually when they began she felt a growing sense of confidence and optimism, such as we may all experience when our lives seem to be going particularly well. But as the episodes developed, pleasant excitement was replaced by growing irritability, frequently accompanied by heavy drinking. Her mind began racing too quickly to be productive, and her work became garbled and useless. She often complained that people were stealing her ideas, that she was not properly valued by the critics, that she should have won a major literary prize. During one of these episodes she had a highly publicized affair with a well-known actor, which precipitated her divorce from Michael's father, Jacob.

Sometimes, after days of hyperactivity, Flora crashed into a deep depression--a common pattern in people with manic-depressive illness. Then she stayed in bed all day and paced all night, blamed herself for everything, stopped eating, looked despondent and unkempt. During one depressed period she told her psychiatrist that she was saving up sleeping pills to kill herself. Because antidepressants and mood-stabilizing drugs were still not available, shock treatments were given. After four or five of these her depression began to dear.

In addition to the serious breakdowns, Flora had dozens of others that didn't result in her admission to the hospital. Often they began for no apparent reason; but some, like her initial attack, were preceded by a significant professional success. One memorable episode, which made the gossip columns, began immediately after she had sold a two-part story to a major magazine. When the check came, she bought nine dresses, most of them tight and skimpy, all of them red. Every night she went out with friends, wearing a new red dress. She said this was her red period because her story was being read. She thought this pun was hilarious and she danced around, laughing, whenever she repeated it. She was high as a kite.

But red dresses were only one small part of this particular period of mania, which waxed and waned over several months. It occurred at a time when Flora's work was going particularly well. That summer, writing at least fifteen hours a day, she produced almost three hundred typed pages in three weeks, the core of one of her most successful novels.

Because of such bursts of creative energy, Flora considered mania -- "my gemlike flame" -- mostly a blessing. Although it was generally accompanied by profligate spending and sexual promiscuity that often brought her near to disaster, Flora was nevertheless very good at damage control. Michael was also a big help in smoothing things over. Beginning in his teens he had become an expert in soothing the ruffled feelings of those friends she offended while manic. They were willing to overlook her periods of grandiosity and irritability because when well she was so friendly and open and generous. Besides, she was a fascinating character -- the life of the party -- and such a brilliant writer.

I first learned about Michael's family in 1978, while attending a conference about new methods for studying brain function. Michael, who shared his mother's brilliance and eloquence, was one of a handful of molecular biologists and geneticists who were invited to spend a week teaching the rest of us, mainly neuroscientists, how to analyze DNA using the new techniques they were developing. To promote conversations between people from these different fields, the organizers of the conference had brought us together in an isolated mountain hotel and had selected pairs of us to share the small number of available rooms. Michael and I were assigned as roommates.

Once Michael found out that I was a psychiatrist it didn't take him long to tell me about the mental illness in his family. He was at the time particularly worried about Flora because she was back in the hospital, having precipitately stopped taking the lithium that she had, by then, been on for many years. But as he related her story it soon became clear that his concerns had been amplified because of his uncle Max.

Max, Flora's older brother and her only sibling, was in many ways her opposite: short, fair, and ungainly while she was tall, dark, and impeccably groomed; easygoing and the butt of his own jokes, while Flora tended to take herself more seriously. One of the few things they had in common was a facility with words, which in Max's case led him to become a writer of lyrics for popular songs and commercials.

Max also shared Flora's devotion to Michael. Unmarried and a loner, Max doted on his only nephew. When Jacob moved to another city after he and Flora were divorced, Max became Michael's surrogate father. In contrast to Flora, whose love for Michael was sometimes obscured by her unpredictability and whom Michael regarded from childhood as "my darling crazy mother," Max was always solid and reliable. Until the winter day in Michael's senior year in high school when Max, then thirty-eight years old, first tried to kill himself.

There was no apparent reason for Max's desperate action. The only unusual thing Michael could remember about the period leading up to it was that Max, who lived only blocks away and who usually dropped by almost daily, had not visited as much. Then, early one morning, Max went to the garage of his house, turned on his car's engine, and waited to die. Miraculously, a passing neighbor heard the car, found Max, and called an ambulance. Because Max was still threatening to kill himself after a week in the hospital, he was given several shock treatments, and his mood greatly improved. He also started psychotherapy, which he continued for many years, eventually going on to psychoanalysis five times a week, which he found very helpful.

But the insight he gained from this treatment didn't spare Max from more bouts of depression. Nor did a drug called imipramine -- the grandparent of contemporary antidepressants such as Prozac -- which Max began to take in the early 1960s, not long after its discovery. On two later occasions he again needed hospitalization, when self-loathing and the danger of suicide returned. But interspersed between bouts of depression were whole years when Max was quite normal. And he never became manic like his sister.

Yet the similarity between Max's and Flora's depressive episodes troubled Michael deeply. Even though Max's diagnosis was major depression, which lacks the manic episodes of Flora's illness (and affects at least five times as many people) several psychiatrists had told Michael that repeated attacks of such severe depression might really be an alternative form of the same illness Flora had. Michael's next questions were inescapable: Did the fact that two close relatives had serious mood disorders mean that others in his family would also be affected? What were the chances that he himself would eventually be stricken? Or his teenage children, Jerry and Charlotte?

Over the years Michael had learned that experts disagreed not only about the relationship between Max's and Flora's patterns of symptoms, but also about the origins of such illnesses. On one side was the view that prevailed through that period, the 1970s, that mood disorders were caused primarily by childhood traumas and parental styles. So finding that both Flora and Max had serious mood disorders was hardly surprising: their parents must have raised them both in a particular way that led to this outcome. Furthermore, proper child rearing should prevent the transmission of the problem to the next generation. But there were also a few psychiatrists who vehemently disagreed. To them the same finding meant instead that the shared mood disorders were mainly a reflection of shared genes. Though life events could certainly trigger mood disorders, having a particular genetic predisposition was, in their view, indispensable. And even though good upbringing might help prevent the development of such disorders, the vulnerability would be passed down with the genes.

To Michael both arguments seemed plausible. Already convinced of the importance of upbringing, he and his wife, Marcia, did their best to provide their children with what they believed was an ideal mixture of expectations and support. But would careful nurturing offer them any protection from a mood disorder that was primarily genetic? And if genes were really the main cause of Flora's and Max's disturbances, what were the chances that these same genes had been passed on -- via Michael -- to Jerry? Or Charlotte? Or both?

At the time I had this conversation with Michael, early in 1978, the main ideas about the inheritance of human diseases had not changed much since the start of the century. It was then that the British physician Archibald Garrod was doing his pioneering work on the inheritance of a rare form of arthritis called alkaptonuria (abbreviated AKU) which sometimes affected siblings -- the first clue that AKU is hereditary. Although Michael and I only mentioned it in passing, our shared understanding or AKU played an important role in our discussion of his family.

People with AKU have one distinctive characteristic: brown urine. The color is imparted by a pigment, discovered in 1859, named alkapton. The prefix "alk" reflects the observation that formation of the pigment is accelerated by alkali. So if the urine of a person with AKU is acidic (which urine generally is), it will have a fairly normal color. One test for AKU is to add alkali to the urine to accelerate formation of alkapton.

Although the genetic defect responsible for AKU is present at birth, the condition can go undetected. After all, slightly brownish urine is easily overlooked. Sometimes the tipoff is the intensification of stains in washed diapers, which comes about when alkaline soaps cause formation of alkapton. But bleach can obscure this chemical reaction. And there is no known harm to the infant if the diagnosis is missed.

Some harm does come from AKU, but not until middle age. By then a great deal of pigment has been deposited in body tissues, especially joint cartilage. The blackening of the joints is associated with the development of arthritis of the hips, shoulders, and spine. Pigment also accumulates at more visible sites. Middle-aged people with AKU may have gray ears and black patches in the whites of their eyes -- not desirable features, but hardly life-threatening or disabling.

Awareness of the AKU story helped frame in two ways the issues that Michael and I discussed. First AKU is a good example of the insidious nature of many genetic disorders, which may not become manifest until late in life. Although often noticed in infancy became of the colored urine, AKU may escape detection or be dismissed as a minor oddity until arthritis develops around the age of fifty. In the same way, Flora's not showing obvious signs of a mood disorder until she was twenty-four and Max's not developing a serious depression until he was even older are consistent with the possibility that their symptoms are attributable to a genetic predisposition that had been latent until then.

The second intriguing feature of AKU is that its hereditary nature was heralded by brown urine -- a very distinctive and easily measurable feature. Were there such an obvious tipoff to the nature of an inherited abnormality underlying manic-depression, no one would be arguing about whether or not genes played a role in this disorder. On the other hand, were alkapton colorless rather than brown, the very existence of AKU might still not have been discovered, let alone its genetic origin. There are, after all, millions of middle-aged people with mild arthritis of unknown cause, and many families in which more than one member is affected. So the AKU cases, a minute fraction of the total (AKU affects only a few people per million, might still be lumped together with these others, their cause still obscure. It is the distinctive pigment in the urine that was the essential factor in separating out AKU from other forms of arthritis; and it is the pigment that eventually pointed the way to the role of an abnormal gene in AKU.

Because urine has provided clues to the fundamental nature of many hereditary diseases, including common ones such as diabetes, there was a long period--from the 1940s through the 1980s -- when psychiatrists collected it by the tankload. Even though unusual concentrations of chemicals in the urine could reflect external influences, such as dietary differences, still it seemed possible that people with mental disorders just might be excreting substances that would point to a cause. But despite enormous effort, no one has ever found an equivalent of alkapton for this or any other common mental disorder. The only good thing that came from the search for an abnormality in the urine of patients with manic-depressive illness was John Cade's accidental 1948 discovery (which I will return to later) that lithium is useful in the treatment of mania.

Had an "alkapton" been discovered for manic-depression, it would have been expected to lead eventually to an understanding of the biological basis of the disorder and thus to effective ways to prevent its development. Were this the case, Michael and his wife could decide whether or when they should have their children tested. If they did, and the results were positive, they could decide whether and when to institute the recommended preventative psychological or pharmacological measures. But in the absence of such a test, there was simply nothing to be done. All we could do was hope that if specific genes really played a part in Flora's and Max's mood disorders, they had not been transmitted to Michael's children.

A few years after our meeting Michael called to tell me our hope was in vain. His son, Jerry, a college sophomore, had been hospitalized because of a pattern of behavior much like Flora's.

Jerry, then eighteen, had been everything his parents had wished for. A prodigious student in high school, he was also a star of the track team, outgoing and popular, with the dark good looks and confident bearing of both his father and his paternal grandmother. Accepted at an excellent college, Jerry quickly and successfully responded to its tough academic demands. In his sophomore year he decided to major in psychology and computer sciences, and met his first serious girlfriend, Lorraine. When Jerry came home for winter break he seemed happy and optimistic.

Soon after he returned to school, however, Jerry became obsessed with a research project on dating he had undertaken as part of a course in social psychology. He had received permission to create a questionnaire to study predictors of a successful first date and to administer the survey to several hundred members of his class. He would pair the respondents up on dates based on the answers and then assess the results. But when his closest friend, Bob, read the questionnaire and found that it mainly concerned personal sexual experiences, he urged Jerry to tone it down and prepare a revision.

The revision was worse, really bizarre. The original four-page questionnaire was now five times as long. Many of the inappropriate sexual questions had become flagrant obscenity. Alarmed, Bob showed it to Lorraine. When she agreed that it was completely out of line, they tried to persuade Jerry to drop the whole project before he got into serious trouble.

They had not bargained on Jerry's response. As they voiced their reservations, he became increasingly agitated and angry. They were pitifully conservative, he told them; the questionnaire would revolutionize dating services and would make him as rich and famous as Playboy had made Hugh Hefner. But even as he countered their arguments, Jerry acknowledged how tired and nervous he felt. Then he started to cry.

Convinced that Jerry needed professional help, his friends managed to get him to the student health service. Once there he was seen by two psychiatrists -- a young resident from a nearby teaching hospital and Dr. R., a senior member of the faculty. With them, all he would talk about was the questionnaire, explaining gleefully how he would become the national tsar of the dating business, then expand to women's lingerie. When they expressed skepticism he became angry. Pressed for details, he started hinting that many of the ideas had come to him from a female voice that he sometimes heard speaking to him in his head.

When Dr. R. called Michael, he said that Jerry had a serious problem and needed to be hospitalized. He was not sure of the diagnosis, but it was dangerous to let him return home.

During his first meeting with Jerry, Dr. R. had concluded that Jerry was probably suffering from manic-depressive illness (or, in the new terminology of the time, "bipolar disorder"). For even though no single feature of his behavior was sufficient to clinch the matter, Jerry's combination of symptoms -- elevated mood, grandiosity, decreased need for sleep, agitation, sexual preoccupation, irritability, and poor judgment--together pointed to this diagnosis. Furthermore, Jerry's wild conduct was not a minor behavioral aberration: it was serious and sustained enough to interfere with his schoolwork and his relationships.

Jerry's report of having heard voices was especially troublesome. Though not unusual in people with manic-depression, auditory hallucinations are particularly characteristic of another mental illness' -- schizophrenia -- which is generally even more disabling. Like manic-depressive illness, schizophrenia frequently strikes in late adolescence or early adulthood, so this possibility had to be taken very seriously. But Jerry's pattern of behavior, particularly his clear signs of elevated mood, were in marked contrast to the detachment and withdrawal commonly seen in schizophrenia. As Dr. R. went through a formal checklist of symptoms, manic-depressive illness fit best.

Before settling on this diagnosis, Dr. R. felt that other possibilities had to be excluded. Jerry's urine was checked for signs of drug use, since cocaine, amphetamine, and other drugs may produce a similar pattern of behavior. He was also tested for a number of general medical conditions, such as hyperactivity of the thyroid gland, the effects of which can sometimes be mistaken for manic-depressive illness. When these tests were all found to be negative, Dr. R. was convinced. Further confirmation came when Michael told him about Flora and Max. Manic-depressive illness and schizophrenia tend to run in different families.

Although the diagnosis of manic-depressive illness implies lifelong vulnerability to attacks, there was also good news. Jerry recovered very quickly. Within two weeks his behavior seemed normal. Jerry had been started on lithium pills as soon as all the medical tests were done, but improvement was evident even before the effect of the drug was to be expected. Instead of leading Dr. R. to reevaluate the diagnosis, Jerry's rapid recovery served as confirmatory evidence. Rapid and complete recovery from manic episodes is, fortunately, common--even without medication.

Because of this quick improvement, Jerry was back attending classes within ten days of his hospitalization. For the first few nights he continued to sleep in the hospital, but a week later he had returned to his apartment. Nevertheless, Dr. R. continued the treatment with lithium, because it not only relieves acute manic episodes but also prevents new attacks. It can also be effective in preventing episodes of severe depression that Jerry, like Flora, would likely be prone to in the future. This tendency to swing between the poles of mania and depression is, indeed, the basis for the diagnostic terms "manic-depressive illness" and "bipolar disorder."

In the year after Jerry's manic episode, Michael and I had many conversations about the nature of the mental illness in his family. For him it was useful to have found a colleague who knew something about the affliction that constantly threatened his mother, his uncle, and his son. For me, these talks began to take on a professional significance. I had treated many patients with serious mood disorders and hoped that new tools would eventually be developed with which to investigate their biological roots. My conversations with Michael about new ways of examining human DNA helped me realize that the time was near when that hope might be fulfilled.

This hope had first been kindled when I was an undergraduate at Columbia in the early 1950s by a teacher, Murray Jarvik, whose research on LSD led me to the startling realization that simple chemicals can control complicated mental processes. And though it had begun to fizzle when I moved on to Columbia's medical school (where I learned how little was then known about the brain), it was reignited by my training with Gordon Tomkins at the National Institutes of Health (NIH) in Bethesda, Maryland, which I began in 1960 -- just in time to participate in the first flowering of the new field of molecular biology.

So new, in fact, that it had only been seven years earlier, in 1953, that Francis Crick and James Watson had established the structure of deoxyribonucleic acid, or DNA--the genetic material. Starting with the knowledge that DNA is made up of long strands of four simple chemical building blocks called bases (whose names -- adenine, guanine, cytosine, and thymine -- are abbreviated A, G, C, and T), Watson and Crick had the brilliant insight that they come together as pairs (called base pairs) -- T pairing with A and C pairing with G --resulting in two perfectly paired strands, the famous double helix. And from that monumental contribution there soon developed what I will call (adopting a phrase first used in 1957 by Crick) the Central Dogma, which has guided biology ever since.

The crux of the Central Dogma is that the structure of a DNA molecule encodes information that can be used by the body only after it has been translated into another type of molecule called a protein. To this end the huge chains of DNA (which are, in many cases, more than one hundred million base pairs long) are divided into segments (usually tens of thousands of base pairs long), each of which constitutes a unit of information--a gene. The function of each gene is to send out a molecular "messenger," called messenger RNA, that eventually determines the structure and the ongoing manufacture of a particular protein, a working element of the body that controls a particular function (such as a step in the digestion of food).

At the time I started at the NIH, Gordon -- himself a physician-scientist -- was one of a small number of people who were thinking about the long-range medical implications of the Central Dogma. Brilliant, imaginative, and infectiously enthusiastic, he quickly persuaded me that this new approach would, as it developed, make possible a direct attack on all sorts of seemingly inscrutable biological processes, including those involved in mental illness. For just as the functioning of the intestines to digest food depends on the right balance of specific intestinal proteins (each controlled by a specific gene), so too does the functioning of the brain to process ideas and feelings depend on the right balance of specific brain proteins (each controlled by a specific gene). And just as an abnormality in the amount or composition of a single intestinal protein (such as a deficiency in a protein called lactase) can lead to an intestinal illness (lactose intolerance), so might an abnormality in the amount or composition of a brain protein (such as a protein involved in the manufacture of serotonin, a vital brain chemical) lead to alterations in mental activity that we call mental illness.

Before Gordon explained the Central Dogma, I had no idea that the revolution in biology that was going on around me would be applicable to mental disorders; afterward, its relevance to the control of brain chemistry made its potential applicability seem obvious. While Gordon recognized that we were, at the time, a long way from explaining the details of brain functioning in terms of the actions of the tens of thousands of different proteins which it makes use of, he was convinced that the Central Dogma had defined a path of systematic and cumulative research that would, step by step, lead us to that goal. So great, in his view, was the power of this revolution that, no matter how hard the problem, "anything is possible."

While at the NIH, I also had the good fortune to live through a dazzling verification of Gordon's optimism. This came by way of an apprenticeship (arranged by Gordon) with another young scientist, Marshall Nirenberg. As shy as Gordon was outgoing, and as sharply focused as Gordon was broad, Marshall was working on what seemed at the time a hopelessly difficult problem--the nature of the code used to translate the information in the arrangement of the four bases in a particular messenger RNA into the arrangement of the twenty amino acids that are used to make a particular protein. But by making use of a battery of different artificial messenger RNAs, each manufactured in a test tube, this genetic code was -- to everyone's amazement -- completely deciphered in Nirenberg's laboratory in just a few years. In a stunning series of experiments it was shown that a specific series of three bases (for example, GAA or GGC) -- called a codon -- is the instruction for the addition of a particular amino acid (for example, glutamic acid or glycine, respectively) at a particular place in the growing string of amino acids that, when completed, constitutes a protein. Even "molecular punctuation"--where to begin and end the translation of a string of bases -- was eventually attributed to specific codons.

Having been at the right place at the right time, I therefore had the heady experience of being catapulted from total naivete into charter membership in what the newspapers would soon call "The Code of Life Team." In fact, Marshall's work proved so successful that in 1968 he was on his way to Stockholm to receive a Nobel prize. And the genetic code that he deciphered now occupies the same honored place on the inside cover of many textbooks of biology that the periodic table of the elements occupies in many textbooks of chemistry. Although deciphering the code is only one step on the long road to understanding the molecular basis of biological functions--including those at work in the brain--it was indispensable for all subsequent research.

Convinced by this exciting series of events that, as Gordon had assured me, anything was really possible, I went on to three years of clinical training in psychiatry, in the hope of identifying an aspect of mental illness that I could address with these seemingly omnipotent tools. Then, coming down to earth, and recognizing that, for the moment, we were still too many steps away from being able to address the molecular aspects of these complicated disorders, I decided to bide my time by sticking to more accessible aspects of brain biology. Which brought me to the conference where I first met Michael.

At the time of the conference, late in 1978, NIH's investment in training physicians in biomedical science had begun to bear fruit in many fields, making even difficult problems such as the biological basis of mental illnesses increasingly accessible. Then, shortly after Jerry's hospitalization, the discovery of new tools for chopping up the strands of human DNA led to a conceptual breakthrough: a revolutionary new method for developing a map of all human genes. With such a map the vast uncharted regions of human DNA could be systematically examined in greater and greater detail, making possible the hunt for specific genetic variations that play a role in a particular inherited disease. As Michael and I continued our discussions, we became increasingly excited about the possibility that this approach might be applicable in elucidating and eventually alleviating the manic-depressive illness in his family.

Assuming, of course, that genes played an important role in mood disorders such as manic-depression and major depression, a hypothesis suggested but far from proved by many family histories, including Michael's. Stimulated by our conversations, and interested to explore further this assumption within his own family, Michael became curious about the possibility that other relatives, such as Flora's parents, might also have shown some signs of this disease.

Copyright 1998 Samuel H. Barondes. All rights reserved.
ISBN: 0-7167-2943-1

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