ALL STEM CELLS

The quest to learn if our brain's mutations affect mental health

Is the mosaic phenomenon of the brain related to "mental health"?

The relationship between the genetic mosaic phenomenon in the brain and psychiatric disorders such as autism, schizophrenia, and Alzheimer's disease is becoming clear. Dr. McConnell has spent more than 20 years in this field of research since he was a very poor graduate student.

 

He was 29 when Mike McConnell decided what to spend his career on. I was motivated to get a PhD, but I didn't have a sentence. McConnell learned in his biology class that immune cells in the body constantly rearrange their DNA to create properly shaped receptors that bind to invasive pathogens, thereby protecting humans from pathogens. .. When he completed his master's degree in immunology at Virginia Tech in Virginia in the late 1990s, he enthusiastically talked about the mechanism of immunology while drinking beer with his roommate. "Suddenly, this idea came to me," recalls Dr. McConnell. If gene rearrangement helps the immune system function, where else can it occur? What about the brain? He thought, "Isn't it amazing if genes have been rearranged in neurons?"

At that time, most scientists assumed that cells of the normal nervous system had the same genome. However, when McConnell examined the scientific literature, he found that he was not the only one pursuing this question. Dr. Jerold Chun, a neuroscientist at the University of California, San Diego (UCSD), was already working on this subject. McConnell wrote to Dr. Chun and asked him to join Dr. Chun's lab on the west coast. However, there was only one problem. McConnell couldn't afford to go to San Diego.

McConnell was a "poor graduate student who didn't eat or eat" and didn't have the money to repair the dark blue 1966 Ford Mustang. Since I went to college for the first time in my family, there weren't many messengers and connections available. "No one was able to help with the cost of moving," he recalls. Dr. Chun offered $ 1000 to help McConnell repair a broken car, cross the country, and begin testing his hypothesis.

McConnell used a special stain to stain the chromosomes of mouse embryos and adult mouse neurons. He hoped to find diversity in neurons with gene rearrangements similar to those found in immune cells, rather than the exact copy of the gene as most researchers predicted. .. But instead, they discovered brain cells with the wrong number of chromosomes in quick succession.

This was a surprise. When cells divide and replicate DNA for daughter cells, copies of the gene can be accidentally added or lost. This was considered to be a very detrimental error, unlike intrachromosomal rearrangements that are beneficial to the immune system. It was not thought that neurons could tolerate such major changes in genetic material. However, McConnell discovered a series of abnormal neurons with extra or missing chromosomes, forcing him to reconsider his scientific assumptions. "We took this crazy idea seriously," says Dr. McConnell. Stevens Leen, a postdoctoral fellow in the same lab, analyzed the data because he had the expertise to culture neurons in his research.

A study by Leen and McConnell et al.'S team, published in 2001, showed that the central nervous system of developing mouse embryos contained imperfect copies of genes. On average, about one-third of the neurons in each mouse embryo were found to have lost or had extra chromosomes. The result was known as "gene mosaic". Many of these cells did not survive, but some survived into the brains of adult mice. McConnell and Dr. Chun wondered what such a genetic mosaic meant. Perhaps in humans, it may cause neuropathy and even mental illness. In any case, the mistaken conventional notion of genetically identical brain cells was an early clue in solving the mystery.

 

At that time, scientists trying to understand the biological consequences of mental illness were looking for mutations in genes that occurred primarily near the moment of conception and thereby reflected in all human cells. However, intriguing clues have emerged that a single gene may be the cause of a particular disease. For example, in 1970, a Scottish teenager with strange behavior was found to have a broken genetic region. And it turned out that his relatives with mental illness had the same anomaly. It took 30 years to identify this error, which researchers named "DISC1 (disrupted-in-schizophreni)".

Although about 1000 research papers have been published so far, there is still much debate about whether DISC1 (or any other single gene) is involved in schizophrenia. Several other genes have also been scrutinized for possible causes, and one study of the entire human genome found that mutations increase the risk of schizophrenia in more than 120 different locations. It has been pointed out. However, even with such extensive searches for "schizophrenia genes," a single gene or mutation studied so far is considered the definitive cause of schizophrenia, including DISC1. It doesn't seem to have as much of an impact.

In fact, scientists have had a hard time finding the specific genes that cause most brain disorders, such as autism and Alzheimer's disease. Unlike problems in other parts of the human body, "most of the symptoms of brain damage are not associated with identifiable genes," said the Sanford Burnham Prebys Medical Research, now in La Jolla, California. Professor Chun, who works at the Sanford Burnham Prebys Medical Discovery Institute, says.

However, McConnell et al.'S work showed a different idea. What if it wasn't a single defective gene or a set of genes that was always causing cognitive problems? What if the cause is due to genetic differences between cells?

This interpretation seemed unreasonable, but more researchers began to take it seriously. Scientists already knew that 85 to 100 billion neurons in the brain would work in concert to some extent. However, I wanted to know what the risks exist if some of these cells may have different genes than other brain cells.

 

Breaking away from the established theory

Dr. McConnell, now 51, has spent most of his career answering this question. He has a short beard that looks like a professor, wears square glasses, and speaks a little like a surfer. However, it also has fierceness. A little like Hollywood star Liam Neeson's youth, his eyes are melancholy and his forehead is wrinkled. After earning a PhD from UCSD, McConnell packed up again and moved to Boston to become a postdoctoral fellow at Harvard Medical School. But I wasn't calm. I didn't like the cold climate, so I wanted to go back to California and review the data I found there about genetic differences in the brain. "I thought the mosaic phenomenon was the most interesting thing I could tackle. I really missed San Diego after spending a winter in Boston," said Dr. McConnell in his ears with brown hair. I recalled while flowing behind.

So Dr. McConnell began contacting Dr. Rusty Gauge, a neuroscientist at the Salk Institute in San Diego. Dr. Gauge was also interested in genetic diversity, but was best known for his counter-arguments to other scientific dogma. For a long time it was thought that adults would never make new neurons, but in the late 1990s, Dr. Gauge detailed evidence of new cell birth in a brain region called the hippocampus ...

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