Letter 1

Science and Mental Diseases

My first letter starts with mental diseases because this is where my research as a medical student began. My primary interest then was the cure of mental diseases. How did it come about that now, some forty-five years later, I am doing basic research on membranes?

Wagner-Jauregg, a famous Viennese psychiatrist who received the Nobel Prize in 1927 for his treatment of patients suffering from syphilitic general paresis dementia paralytica, said in his first lecture to medical students in Vienna: There are two kinds of psychiatrists. First there are those who came to the profession with conviction and devotion, who knew from the first semester of medical school that psychiatry was their field of interest. They are fascinated by mental diseases and not afraid to confront the violence and confusion of the mind. They want to cure psychotics and neurotics, they are psychiatrists at heart. Then there are the other types of psychiatrists who got into the field by accident, because they really didn't know what else to do. They didn't want to get up in the middle of the night to deliver babies or they happened to be offered a well-paying job in a state mental hospital. "I want you to know," said Wagner-Jauregg, "that I belong to the second category." He was very suspicious of the first category and coined the phrase that the major difference between the psychiatrists and the patients in a mental hospital is that the psychiatrists had a key.

I must confess that I belonged to the first category. I wanted to work with patients with mental disorders and I wanted to have a key — a key to the building but also a key to the understanding of the deranged mind. I was impressed with the relevance of the problem, the enormity of the economic burden to society which has to take financial responsibility for millions of mentally sick people. But most of all, I wanted to help these patients out of their nightmares.

Having been raised in Vienna to the music of psychoanalysis and the lullaby of the Oedipus complex, I turned first to the psychoanalytical approach, but I was soon plagued by doubts whether psychoses could be approached by psychoanalysis. In fact, Freud believed in the organic basis of the genesis of psychosis. He said in his book Beyond the Pleasure Principle (New York, 1924): "The shortcomings of our description would probably disappear if for the psychological terms we could substitute physiological or chemical ones." He continued: "Biology is truly a realm of limitless possibilities; we have the most surprising revelations to expect from it, and cannot conjecture what answers it will offer in some decades to the questions we have put to it. Perhaps they may be such as to overthrow the whole artificial structure of hypotheses."

In 1938, an invasion of a mass psychosis took place from Germany to Austria, and I hurriedly left for England. There I came across an article by J. H. Quastel, a brilliant British biochemist, on "Biochemistry and Mental Disorder" (in the book Perspectives in Biochemistry, Cambridge, England, 1936). I went to work with Dr. Quastel in a state mental hospital in Cardiff, Wales, on the effect of drugs on brain metabolism.

Quastel's hypothesis of mental diseases was this: The proteins of our food are digested in the body to amino acids, which are the building blocks of proteins. By splitting off one molecule of carbon dioxide, amino acids are then metabolized to toxic substances called amines. If there is something wrong with either the rate of production or the removal of these amines, brain metabolism is affected and mental disease may arise. There were two experimental facts on which this hypothesis was based. One, certain amines when given in large doses cause psychosis-like conditions. I mention three such drugs which are widely known: Mescaline, LSD, and amphetamine. LSD can precipitate a psychosis, and the chronic use of amphetamine may cause a clinical picture remarkably similar to schizophrenia. Two, Quastel found that various amines inhibit the metabolism of rat brain slices in the test tube.

Quastel's idea was that since sugar is the major food of the brain, we should look for changes in sugar metabolism induced by toxic amines. One of the experiments I did in Cardiff, with all the optimism and enthusiasm of youth, was to expose rat brains to the blood of schizophrenic patients. I reasoned that if toxic amines were present in their blood, they should inhibit the sugar metabolism of the rat brain. These experiments were doomed to failure because I knew too little about sugar metabolism and about the complexity of brain function and structure. But above all I knew too little about biogenic amines, so-called, because they are normal and biologically important ingredients of our body. Among them are potent hormones such as dopamine, adrenalin, and serotonin. As we shall see, these biogenic amines regulate our emotions and alertness. Many psychiatrists now believe that a disturbance in the function of biogenic amines in the brain is a key feature in psychosis. Amphetamine and LSD are toxic amines believed to induce psychosis by interfering with the proper function of the natural biogenic amines.

When I immigrated to the United States in 1941,1 encountered no interest in either toxic or biogenic amines, but there were funds available through the March of Dimes for research in poliomyelitis. I was happy to get a job with a salary of 12,000 dimes per year to explore the effect of polio viruses on brain metabolism. I soon discovered a defect in the utilization of sugar in the brains of mice infected with polio virus. But once again I could not proceed logically with the problem because we were lacking fundamental information on sugar metabolism.

This was a turning point in my career, for I realized that without fundamental knowledge of the biochemical processes we cannot understand diseases of either the body or the mind; we cannot design a logical approach to either their treatment or their prevention. I therefore turned to the study of basic processes of carbohydrate and energy metabolism.

Diagnosis and Classification

During the first decades of this century, psychiatrists developed the diagnosis of mental diseases — an important contribution. To make a diagnosis we need a classification, and the most useful classifications are dependent on basic studies, either biological or psychological. If we have a patient with an insulin deficiency, we treat the patient with insulin. However, if we were to call every patient with sugar in the urine a diabetic, we would find many patients who would not be helped by insulin. The trouble with most mental diseases is that we do not know their basic causes and we diagnose by symptoms and signs only. Yet the symptoms are even more vague than sugar in the urine. It is therefore remarkable that the classification of...