The Troubled Helix

Seated in a chair, with quick access to escape through the back door of the conference room, Jim Watson was twitching, peering, scanning, squinting, and yawning. His fingers, linked together on the top of his head, were tapping restlessly, and he alternately was paying avid, if fleeting, attention to the data being presented, snatching a look at his New York Times, and drifting off into his own version of planetary wanderings. Jim is not good at looking interested when he is bored, and it was impossible to know if he really was thinking about the science at hand—the genetics and molecular biology of manic-depressive illness—or was instead mulling about politics, gossip, love, potential financial donors for Cold Spring Harbor Laboratory, architecture, tennis, or whatever other heated and passionate enthusiasm occupied his mind and heart at the moment. An intense and exceedingly blunt man, he is not someone who tends to bring out the dispassionate side of people. For myself, I find him fascinating and very wonderful. Jim is genuinely independent and, in an increasingly bland world, a true zebra among horses. While it could be argued that it is relatively easy to be independent and unpredictable if you have won the Nobel Prize for your contributions to discovering the structure of life, it is also clear that the same underlying temperament—intense, competitive, imaginative, and iconoclastic—helped propel his initial pursuit for the structure of DNA.

Jim’s palpably high energy level is also very appealing; his pace, whether intellectual or physical, can be exhausting, and trying to keep up with him, in discussions across the dinner table or walking the grounds of Cold Spring Harbor, is no mean task. His wife maintains she can tell whether or not Jim is in the house simply by the amount of energy she feels in the air. But however interesting he is as a person, Jim is first and foremost a scientific leader: director until only very recently of one of the foremost molecular biology laboratories in the world, Cold Spring Harbor Laboratory, and the first director of the National Center for Human Genome Research. In the past few years, he has turned his interest toward the search for the genes responsible for manic-depressive illness.

Because the scientific understanding of manic-depressive illness is so ultimately beholden to the field of molecular biology, it is a world in which I have spent an increasing amount of time. It is an exotic world, one developed around an odd assortment of plants and animals—maize, fruit flies, yeast, worms, mice, humans, puffer fish—and it contains a somewhat strange, rapidly evolving, and occasionally quite poetic language system filled with marvelous terms like “orphan clones,” “plasmids,” and “high-density cosmids”; “triple helices,” “untethered DNA,” and “kamikaze reagents”; “chromosome walking,” “gene hunters,” and “gene mappers.” It is a field clearly in pursuit of the most fundamental of understandings, a search for the biological equivalent of quarks and leptons.

The meeting where Watson was peering and twitching and yawning was focused specifically on the genetic basis of manic-depressive illness, with the intent of bringing together clinical psychiatrists, geneticists, and molecular biologists, all of whom are in one way or another actively engaged in the search for the genes responsible for manic-depressive illness, to share information about their research methods, findings, and the pedigrees of the affected families whose genetic material is being analyzed. Pedigree after pedigree was being projected onto the screen, some with relatively few ill family members, others containing large numbers of squares and circles that had been completely blackened in, indicating men or women who suffered from manic-depressive illness. Half-blackened circles and squares depicted depressive illness, and an s, cross, or slash flagged those individuals who had committed suicide. Each of these black or half-black symbols represented a life with periods of terrible suffering, yet, ironically, the more of these darkened squares and circles in a particular family, the “better” (that is, the more genetically informative and useful) the pedigree was considered to be. It seemed very likely, when I looked around the room, that among these scientists, and somewhere within these pedigrees, the location of the gene or genes responsible for manic-depressive illness was going to be found. It was a very exciting thought, because once the genes are located, early and far more accurate diagnosis is likely to follow; so, too, is more specific, safer, less problematic, and more effective treatment.

The slides went off, the curtains were pulled back, and I looked out beyond Jim Watson, past the apple trees, and remembered a trip I had taken, years ago, down the Mississippi. Mogens Schou, a Danish psychiatrist who, more than anyone, is responsible for the introduction of lithium as a treatment for manic-depressive illness, and I had decided to skip a day’s sessions of the American Psychiatric Association’s annual meeting and take advantage of being in New Orleans. The best way to do this, we decided, was to take a boat ride down the Mississippi River. It was a gorgeous day, and, after having discussed a wide variety of topics, Mogens turned to me and asked me point-blank, Why are you really studying mood disorders? I must have looked as taken aback and uncomfortable as I felt, because, changing tack, he said, “Well, why don’t I tell you why I study mood disorders?” He proceeded to tell me about all of the depression and manic-depressive illness in his family, how devastating it had been, and how, because of this, years ago, he had been desperately searching the medical literature for any new, experimental treatments. When John Cade’s article about the use of lithium in acute mania first appeared in 1949, in an obscure Australian medical journal, Mogens pounced on it and began almost immediately the rigorous clinical trials necessary to establish the efficacy and safety of the drug. He talked with ease about his family history of mental illness and emphasized that it had been this strongly personal motivation that had driven virtually all of his research. He made it clear to me that he suspected my involvement in clinical research about manic-depressive illness was likewise personally motivated.

Feeling a bit trapped, but also relieved, I decided to be honest about my own and my family’s history, and soon the two of us were drawing our pedigrees on the backs of table napkins. I was amazed at how many of my squares and circles were darkened, or darkened with a question mark placed underneath (I knew, for instance, that my great-uncle had spent virtually all of his adult life in an asylum, but I didn’t know what his diagnosis had been). Manic-depressive illness occurred repeatedly, throughout the three generations I had knowledge of, on my father’s side of the family; asterisks, representing suicide attempts, showed up like a starfield. My mother’s side of the family, in comparison, was squeaky clean. It would not have taken a very astute observer of human nature to figure out that my parents are terribly different, but here was one very concrete example of their differences—and, quite literally, in black and white. Mogens, who had been sketching out his own family tree, took one look over my shoulder at the number of affected members in mine and promptly, laughingly, conceded the “battle of the black boxes.” He noted that the circle representing me was solid black and had an asterisk next to it—how remarkable to be able to reduce one’s suicide attempt to a simple symbol!—so we talked for a long time about my illness, lithium, its side effects, and my suicide attempt.

Talking with Mogens was extremely helpful, in part because he aggressively encouraged me to use my own experiences in my research, writing, and teaching, and in part because it was very important to me to be able to talk with a senior professor who not only had some knowledge of what I had been through, but who had used his own experiences to make a profound difference in the lives of hundreds of thousands of people. Including my own. No matter what struggles I had had with lithium, it was painfully clear to me that without it I would have been long dead or on the back wards of a state hospital. I was one of many who owed their lives to the black circles and squares in Schou’s family tree.

The fact that manic-depressive illness is a genetic disease brings with it, not surprisingly, very complicated and often difficult emotions. At one extreme is the terrible shame and guilt one can be made to feel. Many years ago, when I was living in Los Angeles, I went to a physician recommended to me by a colleague. After examining me, and after finding out that I had been on lithium for many years, he asked me an extended series of questions about my psychiatric history. He also asked me whether or not I planned to have children. Having generally been treated with intelligence and compassion by my various doctors up to that point, I had no reason to be anything but direct about my extensive history of mania and depression, although I also made it clear that I was, in the vernacular, a “good lithium responder.” I told him that I very much wanted to have children, which immediately led to his asking me what I planned to do about taking lithium during pregnancy. I started to tell him that it seemed obvious to me that the dangers of my illness far outweighed any potential problems that lithium might cause a developing fetus, and that I therefore would choose to stay on lithium. Before I finished, however, he broke in to ask me if I knew that manic-depressive illness was a genetic disease. Stifling for the moment an urge to remind him that I had spent my entire professional life studying manic-depressive illness and that, in any event, I wasn’t entirely stupid, I said, “Yes, of course.” At that point, in an icy and imperious voice that I can hear to this day, he stated—as though it were God’s truth, which he no doubt felt that it was—“You shouldn’t have children. You have manic-depressive illness.”

I felt sick, unbelievably and utterly sick, and deeply humiliated. Determined to resist being provoked into what would, without question, be interpreted as irrational behavior, I asked him if his concerns about my having children stemmed from the fact that, because of my illness, he thought I would be an inadequate mother or simply that he thought it was best to avoid bringing another manic-depressive into the world. Ignoring or missing my sarcasm, he replied, “Both.” I asked him to leave the room, put on the rest of my clothes, knocked on his office door, told him to go to hell, and left. I walked across the street to my car, sat down, shaking, and sobbed until I was exhausted. Brutality takes many forms, and what he had done was not only brutal but unprofessional and uninformed. It did the kind of lasting damage that only something that cuts so quick and deep to the heart can do.

Oddly enough, it had never occurred to me not to have children simply because I had manic-depressive illness. Even in my blackest depressions, I never regretted having been born. It is true that I had wanted to die, but that is peculiarly different from regretting having been born. Overwhelmingly, I was enormously glad to have been born, grateful for life, and I couldn’t imagine not wanting to pass on life to someone else. All things considered, I had had a marvelous—albeit turbulent and occasionally awful—existence. Of course, I had had serious concerns: How could one not? Would I, for example, be able to take care of my children properly? What would happen to them if I got severely depressed? Much more frightening still, what would happen to them if I got manic, if my judgment became impaired, if I became violent or uncontrollable? How would it be to have to watch my own children struggle with depression, hopelessness, despair, or insanity if they themselves became ill? Would I watch them too hawkishly for symptoms or mistake their normal reactions to life as signs of illness? All of these were things I had thought about a thousand times, but never, not once, had I questioned having children. And despite the cold-bloodedness of the doctor who examined me and who told me I shouldn’t, I would have delighted in having a houseful of children, as David and I once had planned. But it just didn’t work out that way: David died, and Richard—the only man since David’s death that I wanted to have children with—already had three from a previous marriage.

Not having children of my own is the single most intolerable regret of my life. I do, however, and very fortunately, have two nephews and a niece—each wonderful and quite remarkable in his or her own way—and I enjoy, beyond description, my relationships with them. Being an aunt is an extraordinarily pleasurable sort of thing, especially if your nephews and niece are reflective, independent, thoughtful, droll, smart, and imaginative people. It is impossible not to find their company delightful. My nephews, whose interests, like those of their father, have leaned toward the study of mathematics and economics, are quiet, witty, freethinking, gentle souled, and charming young men. My niece, considerably younger, is now eleven and, having already won a national writing award, is very determined to become a writer. One often finds her curled up in a chair, scribbling away, asking about words or people, tending to her many and various animals, or leaping mouth first into a family discussion to defend her point of view. She is fiery, sensitive, original, and disconcertingly able to hold her own against a very vociferously articulate pack of older brothers, parents, and sundry other adults. I cannot imagine the awful gap that would exist in my life without these three children.

Now and again, despite my strong commitment to the scientific efforts that are being made to track down the genes for manic-depressive illness, I have concerns about what finding the genes might actually mean. Clearly, if better and earlier diagnosis and more specific, less troublesome treatments result from the ongoing genetic research, then the benefits to individuals who have manic-depressive illness, to their families, and to society will be extraordinary. It is, in fact, only a matter of time until these benefits will be available. But what are the dangers in prenatal diagnostic testing? Will prospective parents choose to abort fetuses that carry the genes for manic-depressive illness, even though it is a treatable disease? (Interestingly, a recent study done at Johns Hopkins, which asked manic-depressive patients and their spouses whether or not they would abort an affected fetus, found that very few said that they would.) Do we risk making the world a blander, more homogenized place if we get rid of the genes for manic-depressive illness—an admittedly impossibly complicated scientific problem? What are the risks to the risk takers, those restless individuals who join with others in society to propel the arts, business, politics, and science? Are manic-depressives, like spotted owls and clouded leopards, in danger of becoming an “endangered species”?

These are very difficult ethical issues, particularly because manic-depressive illness can confer advantages on both the individual and society. The disease, in both its severe and less severe forms, appears to convey its advantages not only through its relationship to the artistic temperament and imagination, but through its influence on many eminent scientists, as well as business, religious, military, and political leaders. Subtler effects—such as those on personality, thinking style, and energy—are also involved because it is a common illness with a wide range of temperamental, behavioral, and cognitive expression. The situation is yet further complicated by the fact that additional genetic, biochemical, and environmental factors (such as exposure to prolonged or significant changes in light, pronounced sleep reduction, childbirth, drug or alcohol use) may be at least in part responsible for both the illness and the cognitive and temperamental characteristics associated with great achievement. These scientific and ethical issues are real ones; fortunately, they are being actively considered by the federal government’s Genome Project and other groups of scientists and ethicists. But they are immensely troubling problems and will remain so for many years to come.

Science remains quite remarkable in its ability to raise new problems even as it solves old ones. It moves quickly, often beautifully, and as it moves it brings high expectations in its wake.

Sitting on one of the hard, uncomfortable chairs that are so characteristic of medical conferences, I was semi-oblivious to the world. My mind was on hold after having been lulled into a mild hypnotic state by the click, click, click of the changing of slides in a carousel. My eyes were open, but my brain was swaying gently in its hammock, tucked away in the far back reaches of my skull. It was dark and stuffy in the room, but beautiful and snowing outside. A group of my colleagues and I were in the Colorado Rockies, and anyone with any sense at all was skiing; yet there were more than a hundred doctors in the room, and the slides were going click, click, click. I caught myself thinking, for the hundredth time, that being crazy doesn’t necessarily mean being stupid, and what on earth was I doing indoors instead of being out on the slopes? Suddenly, my ears perked up. A flat, numbingly objective voice was mumbling something about giving an “update on structural brain abnormalities in bipolar illness.” My structurally abnormal brain came to attention, and a chill shot down my spine. The mumbling continued: “In the bipolar patients we have studied, there is a significantly increased number of small areas of focal signal hyperintensities [areas of increased water concentration] suggestive of abnormal tissue. These are what neurologists sometimes refer to as ‘unidentified bright objects,’ or UBOs.” The audience laughed appreciatively.

I, who could ill afford any more loss of brain tissue—God knows what little chunks of gray matter had crossed the River Styx after my nearly lethal lithium overdose—laughed with somewhat less than total enthusiasm. The speaker went on, “The medical significance of these UBOs is unclear, but we know that they are associated with other conditions, such as Alzheimer’s, multiple sclerosis, and multi-infarct dementias.” I was right; I should have gone skiing. Against my better judgment, I pointed my head in the direction of the screen. The slides were riveting, and, as always, I was captivated by the unbelievable detail of the structure of the brain that was revealed by the newest versions of MRI techniques. There is a beauty and an intuitive appeal to the brain-scanning methods, especially the high-resolution MRI pictures and the gorgeous multicolored scans from the PET studies. With PET, for example, a depressed brain will show up in cold, brain-inactive deep blues, dark purples, and hunter greens; the same brain when hypomanic, however, is lit up like a Christmas tree, with vivid patches of bright reds and yellows and oranges. Never has the color and structure of science so completely captured the cold inward deadness of depression or the vibrant, active engagement of mania.

There is a wonderful kind of excitement in modern neuroscience, a romantic, moon-walk sense of exploring and setting out for new frontiers. The science is elegant, the scientists dismayingly young, and the pace of discovery absolutely staggering. Like the molecular biologists, the brain-scanners are generally well aware of the extraordinary frontiers they are crossing, and it would take a mind that is on empty, or a heart made of stone, to be unmoved by their collective ventures and enthusiasms.

I was, in spite of myself, caught up by the science, wondering whether these hyperintensities were the cause or the effect of illness, whether they became more pronounced over time, where in the brain they localized, whether they were related to the problems in spatial orientation and facial recognition that I and many other manic-depressives experience, and whether children who were at risk for manic-depressive illness, because one or both of their parents had the disease, would show these brain abnormalities even before they became ill. The clinical side of my mind began to mull about the visual advantages of these and other imaging findings in convincing some of my more literary and skeptical patients that (a) there is a brain, (b) their moods are related to their brains, and (c) there may be specific brain-damaging effects of going off their medications. These speculations kept me distracted for a while, as changing gears from the personal side of having manic-depressive illness to the professional role of studying and treating it often does. But, invariably, the personal interest and concerns returned.

When I got back to Johns Hopkins, where I was now teaching, I buttonholed neurology colleagues and grilled my associates who were doing the MRI studies. I scurried off to the library to read up on what was known; it is, after all, one thing to believe intellectually that this disease is in your brain; it is quite another thing to actually see it. Even the titles of some of the articles were a bit ungluing: “Basal Ganglia Volumes and White Matter Hyperintensities in Patients with Bipolar Disorder,” “Structural Brain Abnormalities in Bipolar Affective Disorder: Ventricular Enlargement and Focal Signal Hyperintensities,” “Subcortical Abnormalities Detected in Bipolar Affective Disorders, Using Magnetic Resonance Imaging”; on and on they went. I sat down to read. One study found that “Of the 32 scans of the patients with bipolar disorder, 11 (34.4%) showed hyperintensities, while only one scan (3.2%) from the normal comparison group contained such abnormalities.”

After an inward snort about “normal comparison group,” I read on and found that, as usual in new fields of clinical medicine, there were far more questions than answers, and it was unclear what any of these findings really meant: they could be due to problems in measurement, they could be explained by dietary or treatment history, they could be due to something totally unrelated to manic-depressive illness; there could be any number of other explanations. The odds were very strong, however, that the UBOs meant something. In a strange way, though, after reading through a long series of studies, I ended up more reassured and less frightened. The very fact that the science was moving so quickly had a way of generating hope, and, if the changes in the brain structure did turn out to be meaningful, I was glad that first-class researchers were studying them. Without science, there would be no such hope. No hope at all.

And, whatever else, it certainly gave new meaning to the concept of losing one’s mind.