I pick up and examine each slice, and Dr. Herman points to its folds and creases and the borders marked by different tones of pinkish gray or white. These delineate subregions of the brain, the gray, neuron-rich areas and the white connecting fibers that run between them. Depending on where a given slice is, a particular specimen may include parts of the hippocampus, the amygdala, or some other structures inside the brain.
We quickly place each slice on a glass plate and immerse it in a mixture of dry ice and a volatile chemical called isopentane—a slurry with a very low temperature of minus 86°C. The semiliquid mixture steams and bubbles violently as we slide the tissue into it, and the slice freezes instantly, turning in seconds from bloody pink to frosted white. This procedure preserves the anatomy of the slice, preventing cell membranes from bursting open as they would during a slower freezing process. We promptly fish it out with forceps and place it in a plastic bag that we seal shut and label with a printed barcode. The preservation process is now complete.
If this brain initially resembled an ordinary piece of meat, it now looks like a stack of cold cuts in a grocery store’s deli case. As if to reinforce that impression, white-coated technicians arrive to ferry the cut-up samples to our laboratory’s deep freezer. There the specimens will sit, cold and silent, until they can be employed in our endless quest to discover the brain’s secrets.
Human brains are exquisitely complex, but we can learn a great deal about them by studying creatures with brains vastly simpler than our own, as I found out early in my scientific career.
Thirty years before I became the leader of the brain bank at NIMH, I was a young research scientist at the Institute of Psychiatry and Neurology in Warsaw with a master’s degree in chemistry and a PhD in medical sciences with a focus on the brain and nervous system. In the mid-1980s, I was working on clinical trials of drugs manufactured by Western companies to treat schizophrenia and living in a small apartment in Warsaw with Mirek, my then boyfriend, and my two young children from my first marriage.
In August of 1988, our lives were upended. That month, at the invitation of a German pharmaceutical company, I attended the International Congress of Neuropsychopharmacology in Munich. I was to present a poster on certain antipsychotic drugs designed to reduce the severity of hallucinations and psychosis, the most distressing symptoms of schizophrenia. I had no way of knowing that my focus was soon to shift from treating this terrible disease to hunting for its underlying causes.
I arrived in Munich with no more than twenty dollars in my pocket—an entire month’s salary—and was immediately dazzled by the opulence of West Germany. But my culture shock paled in comparison to the thrill I experienced when, at the conference, I was approached by Dr. Daniel R. Weinberger, an NIMH psychiatrist who was world-renowned for his studies on schizophrenia. No sooner had we met than Dr. Weinberger offhandedly suggested I come work as a postdoc in his lab.
I could hardly believe my luck. NIH was the most prestigious medical institution in the world, and its mental-health division was at the forefront of global research on the very illnesses that I’d devoted my career to studying. I’d never dared to dream that I might someday end up at NIMH myself.
A few days later, I returned to Poland and proudly announced to Mirek and my children that we were going to America! They were just as excited as I was. Poland at the time was looking bleaker and more unstable than ever, and many of its unhappy citizens dreamed of the freedom that the West offered. And everyone knew that American society was the freest of them all.
I arrived in the United States ahead of my family, in the spring of 1989, just as Poland was tipping toward democracy and threatening to bring the rest of the Soviet bloc down. The day after my arrival, Dr. Weinberger—who would be my boss for the next twenty-three years—drove me to the NIH campus and introduced me to Dr. George Jaskiw, a psychiatry fellow from Canada. Dr. Jaskiw became an enthusiastic mentor to me, and together we began to explore the mysteries of the same disease—schizophrenia—that I had studied in drug trials in Warsaw.
Dr. Jaskiw and I worked on rats because their brains are similar to human brains in their structure, although not nearly as sophisticated, and because rats display complex behaviors, such as working memory, cognition, and social behaviors, that are useful in understanding humans. We first focused on creating slight defects in the hippocampi of living rats because robust research data at that time suggested that the hippocampi in humans with schizophrenia were structurally abnormal and therefore did not function correctly. To disrupt the connections between the hippocampus and the prefrontal cortex in the brains of newborn rats, we injected minute amounts of neurotoxins into the hippocampus. In this way, we created brains with faulty wiring between these two areas critical in schizophrenia. We wanted to see how different our neurologically altered rats would be from normal animals and, especially, how they would behave when they grew up.
I’d never sliced into any creature, living or dead, but I was delighted to be part of this work. We threw ourselves into the experiments with the crazed abandon of knowledge-hungry scientists. Once, when I needed a quiet area to conduct our rat-behavior experiments, I placed my rats in their testing cages on the floor of the men’s restroom, taped up a sign that said EXPERIMENT IN PROGRESS! DO NOT ENTER, and locked the door. I was determined to learn and succeed. Dr. Jaskiw taught me neuroanatomy and neurochemistry, rat physiology, and the best techniques for brain dissection. Together we operated on and tested thousands of rats.
After eighteen months, and much to my dismay, Dr. Jaskiw left NIH for another career opportunity. Without him, my work became much more challenging. At times, I wept with frustration as I tried to recognize tiny structures in rodent brains, use our lab’s finicky slicing machines, and catch escaped rats as they hid under the cabinets, hissing and baring their razor-sharp teeth.
As painful as Dr. Jaskiw’s departure was, it forced me into independence—and led to the most significant discovery of my career. Just as we had expected, this scientific breakthrough concerned the frontal cortex, the same brain region whose critical importance I would come to understand on a deeply personal level when, ironically, my own began to break down.
Schizophrenia is a devastating illness that has plagued humans for many thousands of years. Today, it affects about 1 percent of the population worldwide—over seventy million people, including more than three million in the United States and over seven million in Europe. Schizophrenia can affect individuals in any area and from any culture or social class. Symptoms vary from person to person, as does responsiveness to treatment. Many patients suffer from delusions, hallucinations, and full-blown psychosis—the symptoms you see exhibited, for example, by people wandering the streets talking to themselves. Many patients with schizophrenia show cognitive deficits and are unable to make decisions and think logically. The deficits may particularly affect working memory, which helps prioritize and execute the tasks of life. A significant number are depressed and have trouble displaying emotions.
Until quite recently, psychiatrists believed that schizophrenia was a psychological illness caused by stress and upbringing, particularly by the influence of a “schizophrenogenic mother” who did not provide her child with enough maternal warmth and care. Today, this theory has been soundly discredited. Schizophrenia, we now know, is a disease caused by abnormal brain structure and function, just as heart disease is a product of faulty arteries. The difference is that we don’t yet have a “brain fingerprint” for schizophrenia.
In the 1940s and 1950s, doctors suspected (correctly) that the frontal cortex was involved in mental illnesses, including schizophrenia. They began treating such illnesses, at times, with a frontal lobotomy—a horribly invasive type of brain surgery that involves cutting at least some of the connections within the prefrontal cortex or from the prefrontal cortex to other parts of the brain. Controversial from the start, lobotomies robbed some patients of their personalities and intellects. (These appalling effects did not st
op the Swedish Academy from awarding António Egas Moniz, the neurologist who developed the procedure, a Nobel Prize in 1949.)
The advent of antipsychotic drugs in the mid-1950s, which alleviated at least some psychotic symptoms in most patients, helped sideline this crude and brutal “cure.” But that pharmaceutical breakthrough came too late for many people. Between 1946 and 1956, an estimated sixty to eighty thousand lobotomies were performed worldwide.
Since the mid-1990s, the focus of research in mental illness has shifted from psychological studies, which analyze behaviors, to genetics and the study of chemicals in the brain (DNA, RNA, and proteins). This allows us to search for inherited genes, mutated genes, aberrantly structured proteins, or dysfunctional pathways that are associated with an increased risk for mental illness. The hope is that, by using precisely targeted therapies that activate or inhibit certain molecules, we can bring these disrupted pathways back to normal.
Still, for the most part, scientists’ understanding of the causes of schizophrenia (as well as of other mental disorders) remains woefully inadequate. Abnormalities in perhaps hundreds or even thousands of genes may be required in order for schizophrenia to manifest itself in a particular person. And because of the great variability among the individual genetic makeups of people afflicted with schizophrenia, it is impossible at this time to predict whether any given individual carries enough risk variants to make him or her ill.
The experiments I conducted in the 1990s on rodents provided clear evidence that abnormal behaviors in rats and, by extension, in humans, may be triggered by subtle brain insults that result in lasting cognitive deficits. The rats whose brains we altered demonstrated difficulties in spatial recognition, including finding their way through mazes that contained savory rewards. Compared to normal rats, they also showed a lack of interest in novel places and objects, and they didn’t interact as much with their peers. We concluded that in humans, as in our rats, slight brain defects may be initiated by a variety of factors that compromise the function of the developing brain, leaving it permanently “out of whack.” Those factors in humans might include maternal malnutrition or viral infections and perhaps many other influences in combination with defective genes that alter molecular pathways and the wiring within and between brain regions. Our findings clearly implicated the frontal cortex as an essential site for the development of schizophrenia, just as Dr. Weinberger and my NIMH colleagues hypothesized in the late 1980s.
Our discoveries gained enormous interest around the world and became known as the neonatal hippocampal lesion model of schizophrenia or, for short, the Lipska model. Drs. Jaskiw and Weinberger and I first described our findings in a paper published in 1993 in Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology. Since then, the Lipska model has been described in hundreds of scientific publications, replicated in many laboratories around the world, and applied to other research areas, including electrophysiology, genetics, and cognition. It has also provided a framework for designing new drugs that might offer benefits for treatment of cognitive deficits in schizophrenia. In 1996, our model was awarded a U.S. patent for screening and developing novel antipsychotic treatments.
In 2002, I became director of the molecular biology lab at the NIMH, where I continued to study chemical and genetic differences in brains of people with mental illness. The subsequent decade was a busy and fruitful one for me, despite my own serious encounters with illness: breast cancer in 2009, and melanoma—the deadliest form of skin cancer—in 2011. I was convinced I’d beaten them both, and I kept my eyes fixed on the future. Like almost everyone at NIMH, I was enthusiastic about the incredible promise of genetic studies for unlocking the secrets of diseases like schizophrenia. Knowing where genes are located, how they work, and how they send information into cells and tissues would dramatically advance every scientific field, including the study of mental illness. And, indeed, mental-health researchers were beginning to discover thousands of risk-carrying genes in people with various mental illnesses.
In 2013, I am named director of the brain bank, and I quickly settle into this exciting new phase of my career. My work with rat and human brains has long since given me widespread recognition among my colleagues. Indeed, it’s what put me on the path that, twenty years after my first paper on the subject, has landed me in charge of so many precious human samples.
Despite multiple discoveries in mental-health research, scientists don’t yet completely understand what isn’t working in the brains of people with mental illness, and determining how to fix it will likely take many decades and require tenacious dedication from every researcher involved.
And so, despite my brushes with cancer, I work hard, publishing scores of scientific articles and sharing my findings with hundreds of other investigators as we all tackle questions about abnormal genes and the problems they create.
A naturally high-energy person, I bike twenty miles to my office, work all day, then cycle back to our quiet house in the suburbs. Every night at dinner, Mirek and I sit on our elevated back porch as if we are on the deck of a ship sailing through a green sea of woods and grass. We revel in the many birds around us: huge woodpeckers with red caps, tiny house wrens building nests in our flowerpots, colorful hummingbirds feeding on our red impatiens. We feel exceedingly content with life.
Everything seems to be going right—but very soon, I will begin to wonder whether the rats from my early experiments are exacting their revenge on me. Because the same brain structure that I sabotaged in thousands of rodents will begin to malfunction, spectacularly, in my own brain. The cause will not be a neurotoxin injected into my hippocampus that damages my frontal cortex. It will be something far more prosaic, and far more familiar: cancer.
2
The Vanishing Hand
At the beginning of January 2015, roughly two and a half years after handling my first human brain, I decide to fulfill a dream I’ve held for years: to compete in an Ironman Triathlon. Though I’ve completed several Olympic-distance triathlons, I’ve never tried anything as challenging as an Ironman, which is 140.6 miles of combined swimming, running, and cycling. But it’s now or never, my last reasonable chance before I’m too old. I plan to train with a coach and compete this summer or fall in a half Ironman, with three stages that cover a combined distance of 70.3 miles. If that goes well, I will attempt a full Ironman the following year, when I’m at the ripe old age of sixty-five.
It’s going to demand incredible effort, but I feel ready and the time feels right. Mirek and our two children, who followed me from Poland some twenty-six years ago, have long since settled into our new home, making wonderful lives for themselves in America just as I have. They, too, are successful and happy. Mirek is a computer engineer in a large software company; Kasia is an endocrinologist at the Yale School of Medicine, where she focuses on diabetes; and Witek is a neuroscientist in the Brain Modulation Lab at the University of Pittsburgh. Both of my children are in happy relationships, and Kasia and her husband, Jake, have two young sons, our beloved grandsons, Lucian and Sebastian, who are growing up rapidly. Mirek and I are celebrating thirty years of a good marriage.
With my family happy and my career going so well, I can devote more time to my hobbies, especially sports. I’m obsessed with developing lean, powerful muscles, not only to feel healthy and strong but because I like looking healthy and strong too. I’m in excellent shape and eager to become even more athletic as I prepare for my greatest physical challenge yet.
In the first days of the new year, I hire a coach and start preparations for the half Ironman. I buy my dream bike, a white carbon-fiber Cannondale Evo road bike with high-end components: eleven-speed Ultegra and deep carbon wheels. Since swimming is my slowest event, I decide to concentrate over the winter on my swimming technique. Several times a week, I get up before dawn and go to a nearby pool to swim eighty to a hundred laps—about two to three thousand yards—before heading to work.
On a
Thursday morning toward the end of January, as I pull myself from the pool after one of my first training sessions, I suddenly feel dizzy.
I must have overtrained or run out of calories, I tell myself.
I’m looking forward to a productive and upbeat day. Tomorrow morning, I’m leaving for a conference on brain research in Montana, where I’m meeting Witek and his girlfriend, Cheyenne, for work and skiing, and I’m excited about the trip. But as I drive to work, I have a strange feeling that something’s off. My driving feels shaky, although I can’t tell what’s wrong.
At my office, I sit down and begin to eat a bowl of steel-cut oatmeal I brought from home. I reach out to switch on my computer.
My stomach clenches.
My right hand is gone.
I can’t see it. It’s disappeared.
I move my hand toward the left.
There it is! It’s back!
But when I slide it back to the lower-right quadrant of the computer keyboard, it vanishes again. I repeat my movements and the same thing happens. Whenever I place my hand in the lower-right quadrant of my field of vision, it disappears completely, as if it were cut off at the wrist.
Nearly paralyzed with fear, I try again and again to recapture my disappearing right hand. But once it enters that part of my visual field, it’s gone. It’s like a freaky magic trick, mesmerizing, frightening, and totally inexplicable—except . . .
Brain tumor.
I immediately try to push the thought from my mind.
No, I think. That can’t be it. This cannot be happening.
I was sure that I beat stage 3 breast cancer in 2009 and stage 1B melanoma three years ago. But breast cancer and melanoma often metastasize to the brain. I know that a brain tumor in the occipital lobe, the area at the back of the brain that controls vision, is the most likely explanation for this bizarre vision loss. And I know that any brain tumor indicating metastasis—the spread of cancer cells—is horrifying news.
The Neuroscientist Who Lost Her Mind Page 3