2023-05-19 20:02:26
For years, researchers have been trying to discover the mechanisms responsible for autism, but the mystery that surrounds the syndrome is preserved. Research that is the result of international collaboration, published about a week ago in the journal Cell, is now exciting the scientific community. It shows how brain cells taken from people with autism can cause inflammatory symptoms when transplanted into a new environment. “This is an interesting study because it shows that the immune system’s response to environmental changes can lead to changes in nerve cells in the brain that have been linked to autism,” explains Prof. Idan Menashe, an autism researcher at Ben Gurion University.
This is a preliminary study, in cells taken from only three people with a certain type of autism (which is also characterized by an especially large brain), yet it was published in the leading journal in the field, because it demonstrates for the first time how neurons originating from a person with autism trigger an inflammatory response in their environment. It is of great interest to the broad and multidisciplinary community of researchers of the mechanisms and origins of autism, who hope one day to develop a drug that will relieve those afflicted with the syndrome.
What happened that a human brain was transplanted into a mouse
Dr. Abed Mansour, from the Faculty of Medicine at the Hebrew University, was a partner in the study alongside Prof. Fried Geig (USA), Simon Schiffer (Germany) and other researchers. “We wanted to build a 3D model as similar as possible to the brain of an autistic person, a syndrome It has a successful animal model,” he tells Globes. “That’s why we built an organoid, a kind of small brain, based on cells we took right from people with autism.
Dr. Abd Mansour / Photo: Private photo
“They contributed skin cells to science, which underwent a process that turns them back into stem cells, then re-grows them into different types of cells: brain cells, immune system cells, blood cells and everything our little brain needed. These cells assemble themselves in a dish to create the The tiny, 3D brain. We built three appropriate models of people with autism and another three appropriate models taken from people without autism, for the purpose of control.”
The goal was to study the interaction between nerve cells and immune system cells. “The immune cells developed outside the brain and migrated to it as we had hoped, but they did not manage to fully mature. We decided to transplant the brain cells into mice, and indeed this is how they probably got what they were missing. The glial cells (immune cells – JU) both migrated to the right place and matured Fully”.
At this point the experiment actually started. “First of all, we saw that the transplanted human immune system cells were functioning. In the next step, we examined the inflammatory component in autism. We saw that the microglial cells, which developed in the brain originating from a person with autism, have a larger body and branches, a kind of spikes. These are signs that indicate inflammation and were not in the brain from which the cells were taken From a person without autism.
“Then we wanted to check who is the ‘bad boy’ here: do the neurons affect the microglia or the other way around? We rebuilt the brain again, but this time with neurons sorted from skin cells of a person with autism and microglia from people without autism. We saw that the microglia cells develop the inflammatory morphology, i.e. The neuron is the source of the problem.”
In the last step, the researchers took a mouse that had a brain transplanted from a person without autism and injected it with an inflammatory substance. “We saw that this human brain inside the mouse also begins to develop inflammation characteristics that are reminiscent of those we saw when we connected the neurons from the autistic samples to the immune system from non-autistic samples.”
What do we already know about autism?
1. Genetics: It is known that there is a hereditary component to autism. Among identical twins, the chance that one will be autistic if the other is autistic is 60%-90%, depending on which study
2. Preliminary signs: Research has shown that they can be identified by reviewing systems during pregnancy. “We saw that the more findings for problems in the ultrasound, the higher the risk of giving birth to a child with the syndrome,” says Prof. Idan Menashe
3. The structure of the brain: Autism can be characterized by dramatic changes in 11 different areas of the cortex, compared to one change in Alzheimer’s and Parkinson’s
What does all this mean?
“First of all, this is a very interesting tool for drug development. It is a mouse that is an improved model for autism because it has cells that characterize human autism. But in addition, the experiment indicates that inflammation is part of the mechanism of autism, at least in certain subtypes of the syndrome. We are not the first who tested this direction. In a study from 2005, in which the brains of people with autism were analyzed after death, signs of brain inflammation were found.”
Were you able to figure out anything about how the inflammation causes the syndrome?
“Not yet. Autism is a complex syndrome. We know that inflammation can cause damage to cells and the death of brain cells, however, some of the theories of the development of autism say that people with autism actually have too many cells.
“A previous study I was involved in, in which we also developed a suitable brain from people with autism but without immune microglia cells, showed that these cells undergo very rapid development and actually ‘jump’ a stage in development. This creates a situation where there are many cells of a certain type but lack cells of another type Unfortunately, this is the most concrete thing I can say about the development of cells in autism right now. How is it related to the inflammatory process, if at all? I don’t know.”
The genetic connection: know how to give a risk score
“There is no such thing today – the cause of autism,” says Dr. Boaz Barak, a senior lecturer at the School of Psychological Sciences and the Segol School of Neuroscience at Tel Aviv University: “The autistic continuum describes a variety of conditions that are involved in neurodevelopmental disorders, which includes a variety of sub- -Types of disorders, each of which develops for slightly different reasons and in a slightly different way. In the end, they all lead to different patterns of impairment in the social, communicative and behavioral levels. But every boy or girl on the autistic continuum is a world unto itself.”
Dr. Boaz Barak / Photo: Yonatan Barak
“If you now sit down to talk to a group of children about the autistic spectrum and their parents, the advice of one of them will not necessarily suit the other in light of the great diversity in the manifestation of autistic pathology.” Barak believes that until we divide the broad autistic spectrum into its subgroups, based on the cause of autism and investigate each of them separately, we will not understand the mechanism that has been damaged and therefore our ability to benefit will be limited. The term “autistic spectrum” is used for a reason.
However, genetics are known to play a role. “We see heredity in autism,” says Barak. “For example, in identical twins, the chance that one will be autistic if the other is autistic is 60-90%, depending on which study. If it is non-identical or fraternal twins, we are already talking about 3-10%, which definitely indicates that the source is in the genetic load .
The disconnect between biological research and cognitive research
One of the controversial issues among autism researchers is the nature of the differences in thinking patterns, that is, what are the cognitive deficits or differences that people with autism suffer from and which manifest outwardly in behavioral difficulties.
Three competing theories have previously been proposed. One theory, usually attributed to Prof. Simon Baron Cohen (cousin of the actor Sacha Baron Cohen), says that the main difference is that people with autism lack a “theory of mind”, that is, they do not know how to construct in their mind’s eye a perception of what another person is thinking. Therefore, they have difficulty reading emotions, describing and understanding their own emotions, predicting the behaviors of others, detecting lies and understanding how their behavior may hurt others.
Another theory talks about an inability to integrate information. That is, they are unable to connect details to pay. And a third theory talks about a disturbance in the executive functions, that is, in that part of the brain that tells the other parts what to do. Impairment of executive functions can affect the ability to plan ahead, follow multi-step instructions, or solve problems.
Not all autistics are equally characterized by these three differences, which is another reason why the syndrome is confusing. There also seems to be a disconnect between the cognitive research of autism and its biological research. Thus, for example, to this day no explanation has been developed as to how the brain structure unique to autistics or the processes of overexcitation and the multitude of neurons and the connections between them can lead to a lack of “theory of mind”.
The idea that noise interferes with the integration of information and executive functions seems logical, but to date this connection has not been really mapped at the biological level either.
“We also see non-inherited genetics, that is, new genetic mutations in genes that we know are predisposed to autism, which were created in the child during his development and are not found in his parents. One of the factors that increase the likelihood of developing autism is the age of the parents. Such a reason, for example, can increase the chance of developing a disorder Genetic at birth, inherited or non-inherited, that may lead to autism.”
In some cases, it is possible to identify a gene with mutations that certainly lead to a syndrome that also has autism symptoms, as in the case of Rett or Fragile X. In other cases, a certain genetic mutation increases the risk of autism, but not definitively. In other cases, it was found that several genetic changes together increased the risk of the syndrome.
“The more we can link the syndrome to a single gene, the more likely we are to see low function, visible brain differences, and also unique physical characteristics in addition to behavioral characteristics,” Menashe says. “But with some people with autism, there are no genetic differences that we know how to recognize, there are no brain and physical differences, and these are usually the people with higher functioning. Although this relationship between the ability to physically recognize autism and the level of functioning is not univalent either.
“Today we know how to take the genomic sequence of an embryo and give it a ‘risk score’. But today it is not customary to do these tests, because most of them give a score that is still not conclusive enough for a decision to be made about it.”
A study that Menashe participated in showed that it is possible to see early signs of autism in the ultrasound system review tests that are accepted in pregnancy. “We saw that the more findings there are in the ultrasound, the higher the risk of giving birth to a child with the syndrome,” he says.
What findings?
“For example, a hole in the heart, damage to the kidneys, morphological differences in the brain. In general, the more findings there are, the risk of autism increases up to 3 times.”
Over the years, a correlation has also been found between environmental influences and the prevalence of autism, “and this does not contradict the genetic aspect of the disease,” Menashe says. “It is possible that people with certain genetics have a sensitivity to certain environmental factors, and it is possible that the inflammatory factor mediates the relationship.”
The most sensitive time to the influence of the environment is probably the first two trimesters of pregnancy. The environmental factors found to increase risk are almost endless. Heavy metals, air pollution, hypertension, various viral infections, pregnancy and childbirth complications – these are just a few of them.
But not vaccines.
Menashe: “The link to vaccines has been disproved in many studies.”
Barak: “The only study that found this result, in 12 children, was revealed to be a lie and a manipulation. Since then, studies of thousands of children have not found the connection.”
Too many cells making noise
Studies from recent years have tried to establish the differences between the brain of a person with autism and the brain of a person without autism. “One of the world’s leading autism researchers, Prof. Daniel Gershwind from UCLA, showed that autism can be characterized by dramatic changes across 11 different areas of the cortex,” says Dr. Jeremy Levin, former CEO of Teva and today CEO of OVID. which develops drugs for rare brain diseases in children, including diseases with characteristics of autism. “If in Alzheimer’s or Parkinson’s we identify one change or a change in one place, in autism we see many and varied changes.”
Dr. Jeremy Levin / Photo: Yeh’ach
Could it be related to the inflammatory aspect found in the new study?
Barak: “If there is a violation of the electrical activity in the brain, for example, the increased activity of the nerve cells may lead to toxicity and an inflammatory reaction. It is possible that the inflammatory reaction is a secondary process to the damaged primary process, of abnormal activity of the nerve cells, so maybe after all anti-inflammatory drugs can help”.
Menashe: “We know that people with autism are overwhelmed by a lot of ‘noise’ from increased activity of the neurons. There are drug treatments in development, which should ease this neurological load and allow them to experience the world in a way that is a little more similar to the way we experience it, and thus communicate better “.
Who is a drug developed for?
Researchers hope that as the mechanism of autism becomes clear, it will be possible to develop drugs or treatments that will make it easier for those with the syndrome to integrate into society, but not everyone is enthusiastic about defining it as a disease and the idea that it is possible or desirable to find a cure for it.
“The cause of autism is sex,” we were told when we addressed the question to the AS forum, Israeli people on the spectrum. To put it simply: as long as people continue to be born, some of them will be autistic and this is simply a part of life and everyone has to deal with it.
The experts we spoke with agree that it probably won’t be possible and it may not even be desirable to “cure” all autistics, but it might be possible to alleviate some of them.
“When talking about a drug, it is very difficult to decide where within the whole complex of these trillions of cells we want to intervene,” says Levin. The progress should be first of all in the genetic mapping and understanding the mechanisms, and then in the delivery of the drugs to the brain, and there are companies working on all of these.”
OVID itself sought to develop a drug to treat the imbalance between stimulation and suppression of cells in Engelmann syndrome, in which a defect in a single gene leads to a variety of vulnerabilities, including autistic symptoms. Today, several other drugs with similar mechanisms are in development, and promising signs were seen in a trial conducted in patients with fragile X syndrome.
Barak points in a different direction. “We conducted a study in a mouse model of genetic autism (with all its problems) in which we implanted a genetic mutation that exists in some of the loci in autism, and we saw that the animals did indeed show typical autistic behavior. Inbar Fischer, a doctoral student in the laboratory who led the research, found increased inflammation in the brains of the animals compared to normal mice. We discovered that pressure chamber treatment reduced it and significantly improved social behavior, so this is definitely an interesting direction for further research.
“It is possible that in the mutation we studied the causes of the behavioral damage are inflammation and a problem with neural activity, and in another genetic damage the cause is different, so the treatment is also expected to be different. In any case, it can be said that the involvement of the immune system in the brain of people with autism is known, and this is an important research direction to go in , hoping to improve the quality of life of people on the continuum.”
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