Geneticists have studied the DNA of schizophrenics and made a sensational discovery. For the first time, a picture of how madness is embedded in the human brain has been captured.
Jonathan Stanley was on the run for three days. Without money, food, and sleep, he wandered the streets of New York, being chased by secret CIA agents. At one point he entered the deli, where he tore off all his clothes. The store owner called the police.
There are many mentally ill people in New York, but the case of this college student in the late XNUMXs went down in the history of psychiatry. It happened thanks to Jonathan’s father, Ted Stanley. He was deeply shocked when informed of the whole affair, arrived at the scene and saw his son in a straitjacket. How did imaginary agents take over his mind? Why was the boy convinced that he had telepathic abilities? And what can you do about it? Ever since the son became psychotic, the father was unable to break free from these questions.
Ted Stanley was a rich man. He made a fortune of a billion from selling collector’s coins, commemorative stamps and other memorabilia. This money, he decided now, should be used to investigate the biological causes of insanity. Stanley donated a total of $ 825 million to the Broad Institute in Cambridge, near Boston. It was one of the greatest sums a single citizen had ever donated to science.
Ted Stanley died on January 4 at the age of 84. Had he lived three weeks longer, the Stanley Center for Psychiatric Research he had founded at the Broad Institute would have triumphed. Steven Hyman, head of the center, announced that a discovery has been made here that marks the “beginning of a new era” in terms of schizophrenia. “For the first time,” he said, “we see light at the end of the long tunnel of ignorance.”
“It was worth it,” says Steven McCarroll, smiling broadly. The Broad Institute researcher leads a team that recently published sensational research results in the journal Nature. They confirm McCarroll’s belief that he did the right thing by deciding to investigate the genetic causes of schizophrenia, although many advised him against it.
Schizophrenia has always been considered a disease that is particularly difficult to study by genetic means. It is a formidable, disturbing mental disorder that embeds itself in the brain in the form of intrusive thought and then takes over the mind step by step. It often appears during the difficult process of finding one’s own identity during adolescence. He uses hallucinatory voices to gain control over the sick person’s psyche. At the same time, it makes his own thoughts flatter and reduces his ability to perceive complex relationships. And all of this would be the result of a few typos in DNA? Critics of this concept are more vehemently than in the case of other diseases to defend themselves against the, in their opinion, too mechanistic search for causes in biology.
Added to this is the fact that geneticists have not provided any logical explanations so far. Research on twins has shown that schizophrenia is largely hereditary. However, all attempts to identify risky genes have been unsuccessful for a long time. Schizophrenia seemed too complex for the methods of genetics. “The researchers were already close to giving up,” says Steven McCarroll.
During his studies, he says, he also learned simple Mendelian principles. Recessive and dominant, pure and mixed – according to Mendel, nature is subject to strictly defined laws. – The reality, however, is not so simple – says the scientist. Mendel’s world is not what we live in today.
Rare inherited conditions are governed by laws formulated by a XNUMXth-century geneticist. On the other hand, great endemic diseases are complex in nature, they arise as a result of the action of many genes, and the diet, the action of harmful substances, mental stress and many other environmental factors also play a role here. Extracting specific genes from this chaos seems an almost hopeless task.
But McCarroll knew a way by which geneticists could master this complexity: the magic of large numbers. If nothing unusual can be found in the genome of a thousand schizophrenics, the genetic makeup of ten or one hundred thousand patients should be analyzed. The researcher and his large team, backed by millions of Ted Stanley, set about combing the DNA of more than 150 volunteers, 37 of whom had been diagnosed with schizophrenia.
Only with such a large number of respondents revealed the genes responsible for the disease. However, there were a few of them, but a total of 108 turned out to be suspects. How were geneticists to recognize any meaningful pattern in this interplay of so many factors? The problem so far has turned into its opposite: instead of the lack of a suspect gene, so many have now had to be dealt with.
However, the head of the research team was not afraid of these difficulties. He decided to first analyze the one of 108 fragments of the genome that showed the strongest correlation with schizophrenia. It is located on the sixth chromosome, the region most known to geneticists. There are tons of genes crammed in here, most of which have something to do with the immune system. McCarroll wanted to know if this indicated any deeper connection.
Schizophrenia researchers have often assumed that it may be the result of an infection. Some suspected herpesviruses or bornaviruses as the culprit, others blamed pet-borne toxoplasmosis. – You will not believe how many concerned parents have already called us – says the geneticist, showing an article in the magazine “The Atlantic”. Its title is “How Your Cat Drives You Mad”.
The trail that McCarroll and his team followed did not lead them to any germs, however, but precisely to where insanity unfolds its effects: the brain. But first, researchers had to pick out the immune system that is involved in the development of schizophrenia from an opaque chaos of genes that influence the immune system. It’s called C4, and immunologists know it well. Its function is to recognize disease cells. It then summons specialized cells, so-called phagocytes, which immediately engulf the suspect. This is the “Eat me!” Signal Says Beth Stevens.
The neurobiologist conducts her research a few hundred meters from McCarroll’s laboratory at Boston Children’s Hospital. There she made a discovery that made Steven McCarroll, when he found out about it, put into a state of utmost excitement. She found that molecules such as C4, in addition to removing garbage, play an additional role in the human body, and more precisely in the brain: they are involved in connecting nerve cells with each other.
The way they work in the immune and nervous systems is surprisingly similar. Also in the brain, C4 serves as an inducer that transmits the message: “Eat me!”, Except that here it marks not all nerve cells, but only contact sites, synapses, as destined to be destroyed. Eliminating them is a process of the utmost importance. Many neural circuits in the brain are created in such a way that the nerve cells initially form a network by any means, and then all unnecessary synapses are pruned.
In an article published in Nature, geneticist McCarroll and brain researcher Stevens combine their findings. This creates a picture that shows the process of developing schizophrenia in a completely new light.
Much speculation remains, but the idea itself is impressive: Disease occurs when synaptic pruning gets out of hand. If too many of them find the C4 gene unnecessary, the phagocytes will cut off too many neural cables. This explains why schizophrenia affects perception, thinking, and the emotional world in such a comprehensive way. In the brain lacking important synaptic connections, intellectual processes are disrupted
This picture is also completed by anatomical observations. Psychiatrists have long wondered why the cerebral cortex of schizophrenics is often thinner in some places than in healthy people. It appears that it is not the number of neurons that is reduced, but their connections, which fits perfectly with the hypothesis that schizophrenia is caused by the destruction of an excessive number of synapses.
The defect of the cerebral cortex in the frontal lobe is particularly characteristic, a phenomenon that occurs in the typical course of schizophrenia. The first psychotic episodes usually appear in adolescence, when the neural circuits in the frontal lobes are still maturing. This region of the brain is responsible for planning and self-control, where memory, perception and emotions come together. Some believe that there is a neural correlate of morality in this place. And it is in this area, so crucial for the development of the personality, that the loss of synapses is particularly pronounced in schizophrenics.
(…) The geneticist McCarroll believes that schizophrenia is a byproduct of evolution – the specificity of Homo sapiens is that synaptic pruning continues into adolescence or even longer. It is possible that this is what makes a person particularly susceptible to mental disorders. Seen from this perspective, this disease would be the price Homo sapiens has to pay for late maturation of the frontal lobe of its brain.
Steven Hyman, head of the Stanley Center for Psychiatric Research, is exploring another direction. He is interested in whether synapse thinning in the brain of schizophrenics begins early in the disease. Perhaps – he supposes – there are also characteristic thinning connections in the area responsible for vision. This could help you recognize your risk of getting sick before you have psychotic seizures. Psychiatrists would be grateful as they are still looking for convincing methods to diagnose schizophrenia early.
“This is, of course, just guesswork, of course,” emphasizes Hyman. The importance of synaptic destruction in the course of the disease has not yet been elucidated. “We’re only at the very beginning,” says Eric Lander, founder of the Broad Institute. Research into schizophrenia has now reached a point where cancer researchers were in the early XNUMXs. It was then that the first genes responsible for the development of this disease were discovered, and scientists began to have an idea of how a cancerous tumor arises. More than thirty years have passed since then, and still millions of people worldwide are dying from cancer. No one is currently able to say whether it will go faster with schizophrenia, Lander believes. ‘We have to be quite clear: it may take decades for the results of the current research to lead to the development of new drugs.
Nevertheless, the current discovery is of great importance. “This is the first time a biological mechanism has been discovered and we can now work on it,” Lander says. The pharmaceutical industry is currently looking for nothing more urgently than molecular targets that its strategists can direct their attention to. The development of psychotropic drugs has been stagnant for fifty years. The pills prescribed by psychiatrists today may have fewer side effects than those from the XNUMXs, but they are not any more effective. And the corporations are running out of imagination more and more. Novartis, Pfizer, Sanofi and Merck have largely withdrawn from developing new psychiatric drugs – because they simply lack molecular targets.
Steven Hyman has no illusions. – A company that has once decided to leave this field will not be able to be brought back so quickly.
Nevertheless, it intends to seek the interest of the industry. He owes it to Ted Stanley. He clearly linked his donation with the task of financially supporting the development of new drugs so that people like his son could be better helped.
Researcher Steven McCarroll is already seeing interest from the pharmaceutical industry starting to grow. “Everyone invites me to lectures to learn more about our research,” he says. He himself prefers to stay in the laboratory and explore the mysteries of the human genome further. – I am pleased with the interest of corporations, so that I do not have to set up a start-up right away.