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Neurons From People With Autism Grow Differently, Scientists Find

“Whomever said being on the Asperger’s scale was a disorder?”  :/ “I imagine it’s quite orderly for some… it’s everyone else who’s got the fucking disorder!” 😀

Seriously… I know researchers and autism ‘experts’ that quietly believe it may be the next stage of human evolution (these aren’t spiritual pseudoscientists)

It doesn’t need curing or treating… the rest of world should learn to adapt to those on the spectrum! (even if it is sometimes pretty severe)

Nerve Cells In People With Autism Develop Faster And Grow Larger, Study Finds

In a “very exciting finding”, researchers at California’s Salk Institute have discovered a difference between the way nerve cells develop in people who have autism spectrum disorder (ASD) and those who don’t. The researchers hope their study will contribute to a better understanding of why ASD develops, helping to create better diagnostic techniques and treatments.
ASD is a disability that impacts how people communicate and interpret the feelings and behaviors of others, as well as how they experience the world around them. Most commonly diagnosed in children, particularly boys, it impacts one in every 59 kids in the US. There is currently no cure and the exact cause or causes of the condition are still unclear – both genetics and hyperconnectivity within the brain are believed to play a role.
“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred,” said Simon Schafer, a postdoctoral fellow at the Salk Institute, in a statement. “A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development.”
To look at how nerve cells, aka neurons, develop in people with ASD, the researchers took skin cell samples from eight people with ASD and five people without the condition and transformed them into pluripotent stem cells. These are stem cells with the ability to turn into any type of cell in the body. By exposing the cells to certain chemicals, the team could then direct them to develop into neurons.
They then used molecular “snapshots” to look at genetic activity in the cells at different developmental stages by analyzing their RNA (a molecule mainly involved in protein production that can contain genetic information). They took a look at the cells at five different points and found something interesting early on in their development.

ASDSalkInstituteStemCells.jpg
A two-dimensional culture of cortical neurons, stained in red and green, grown from induced pluripotent stem cells created from volunteers’ skin cells.

Neurons From People With Autism Grow Differently, Scientists Find

Researchers announced this week that they may have helped illuminate another small piece of the puzzle that is autism spectrum disorder (ASD), a developmental disorder that can impact social communication and behavior.
In a paper published in the journal Nature Neuroscience, an international team of neuroscientists described a process that used participants’ skin cells to eventually grow neurons in petri dishes. Their observations of the neurons’ growth could help unravel some of the mysteries about early brain development in ASD.

The group, led by Fred Gage at the Salk Institute in La Jolla, California, collected skin cells from eight volunteers diagnosed with ASD and five non-diagnosed volunteers who acted as the control group. Then, using technology that was announced in 2006, the team rolled back the developmental clock. They converted those skin cells into what are called induced pluripotent stem cells, which have the power to mature into any type of cell in the body. In this case, Gage and his team guided the cells’ development (which played out in petri dishes containing so-called growth culture) using specific chemical factors so that they’d end up as neurons.
As they watched the cells grow, the researchers tracked which genes were expressed — or switched on and used to create things like proteins — and when. They found that cells created from participants with ASD expressed some genes earlier than cells from the control group. Past research has linked those genes with an increased risk of ASD. Additionally, neurons spawned from the cells of participants with ASD sprouted more complex branches and grew faster than control cells. Understanding how those developmental changes affect the brain as a while could lead to a better understanding of the neurology behind ASD.
“Although our work only examined cells in cultures,” says Gage in a press release, “it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD. We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders.”

Stem cells used to trace autism back to the formation of neurons

Gene-activity changes come before any visible differences in neurons.

While autism is a spectrum of disorders, it’s clear that the more significant cases involve physical differences in the brain’s nerve cells. Several studies have reported an excess in connections among neurons in the brains of people with autism. But when does this happen? Changes in neural connections are key components of learning and memory, and they can happen at any point in life; major reorganizations in connectivity occur from before birth up to the late teens.
Anecdotal reports of autism’s symptoms often suggest an onset between one and two years old. But a new study places the critical point extremely early in embryo development—at a point before there are any mature nerve cells whatsoever.
A series of challenges
Figuring out how autism starts is complicated. To begin with, it’s a spectrum that might include more than one disorder. You also can’t know in advance who’s going to develop it, so you can only look at it retrospectively, after the problems are apparent. Finally, the human brain is simply not something you can ethically do invasive experiments on.
The new work relies on techniques that weren’t available just a few decades ago. We now know how to take skin cells and convert them to stem cells. We’re able to direct stem cells to develop along the lineages that contribute to brain development. And we can structure that development in three dimensions to produce a miniature version of the mature tissue, termed an organoid. Combined, these approaches allow us to study the development of autism using nothing more than a small skin sample from autistic individuals.
For the new research, a large international team obtained skin cells from eight autistic people and five controls. These were converted into stem cells and then induced to develop along a pathway that leads to brain-like neurons. This pathway includes an intermediate step, called a neural stem cell, in which the cells are committed to developing as nerve cells but haven’t adopted a mature, specialized nerve cell identity (mature cells belong to distinct populations, like serotonin-producing dentate gyrus cells, etc.). As had been seen in past studies, the mature nerve cells derived from autistic individuals created very complex patterns of branching axons compared to control cells.
At five different time points during the development of these cells, the researchers separated out the nerve cells or nerve-cells-to-be. Then they obtained all the RNA from the cells, which provides a window into gene activity. Next, the researchers performed a computational analysis to identify groups of genes that were active at specific steps. This identified three distinct groups of genes (which they termed “modules”) that defined distinct stages of the developmental process. You can think of these stages as pre-neuron, neural stem cell, and maturing neuron.
Accelerated development
When these modules were compared in cells from autistic individuals and controls, there weren’t many differences in the two that marked later stages of development. The earliest active module, however, appeared to be active on an accelerated schedule in the cells that came from autistic individuals. In other words, while normal cells might reach a given stage of gene activity at day four, those from autistic patients might reach that at day two. This accelerated pace was also apparent in the physical changes the cells undergo as they mature.
The earliest two modules also contain a number of genes that had previously been identified as enhancing the risk of autism. And expression of some of these genes at early stages in the process could mimic the progression of autism, accelerating the developmental process.
The timing of all of this suggested to the authors that the problems in these autistic individuals came from the process of forming neural stem cells. This sets the stage for problems in everything that comes after it.
To test this idea, the authors came up with a clever solution. People have identified a way to bypass the neural stem cell stage of the process and force stem cells to develop directly into neurons. (Surprisingly, all this takes is the expression of a single gene.) If the specification of neural stem cells is where things go wrong, then skipping it entirely might rescue the problems. And, in fact, it does. The complexity of neural branching was similar in the experimental and control cells when neurons were generated using this approach.
We haven’t “solved” autism
It’s important to emphasize that this research doesn’t mean we’ve “solved” autism in any way. The participants in this study were selected as having a single symptom that clearly placed them on the autism spectrum; it’s not clear whether these results will apply to those who are on the spectrum due to other symptoms. And there’s a big difference between knowing something goes wrong during neural stem cell generation and knowing what, exactly, has gone wrong. So there’s still a lot of work to do here.
But the results do indicate that, at least in some individuals with autism, problems start extremely early. In humans, neural stem cells are specified before three weeks into the pregnancy—a point when many people aren’t even aware or certain they’re pregnant. Depending on how general this is, that may mean that interventions at the earliest stages of autism—either by directly addressing the problem or by limiting any environmental influences that promote autism—is pretty unlikely.
While this is an impressive body of work on its own, what’s really striking is how it puts together so many techniques that are relatively recent developments. These include the use of stem cells to study diseases that are otherwise difficult to address experimentally, the ability to do large-scale RNA sequencing, and the algorithms that let us analyze this data—all are relatively recent developments. Biology is filled with incremental developments, and it’s only when you stop to consider what had to happen before research like this was even possible that the rate of progress can be appreciated.

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