Scientists at ISTA use brain organoids to understand how a mutated gene affects brain development. Study published in Cell Reports

Using specific protein markers, it is possible to observe structural details of organoids (yellow and red) as well as all the organoid cells in blue and green. CREDIT © Novarino group/ISTA

Several hundred genes are associated with autism spectrum disorders. Some patients are only mildly affected, while others have severe disabilities. In addition to characteristic symptoms like difficulties in social interaction and communication with other people, as well as repetitive-stereotypic behaviors, patients with mutations of the gene CHD8 oftentimes have intellectual disabilities and macrocephaly – an unusually large brain. How CHD8 causes these symptoms has long been unclear.

Tiny artificial brains

Since CHD8 mutations affect the brain at a very early stage of its development, it has proven difficult for scientists to get the full picture. Over the past years, many researchers therefore used mice as model organisms to better understand what is going on. “But mice with a CHD8 mutation barely showed the symptoms human patients are showing. The effects in mice are not comparable to humans. We needed some kind of human model,” Professor Gaia Novarino explains.

Bárbara Oliveira , author CREDIT © Bárbara Oliveira/ISTA

Together with collaborators from the Italian Human Technopole institute, the European Institute of Oncology, and the University of Milan, as well as the Allen Institute for Brain Science, USA, Novarino and her team at ISTA turned to organoids. These simplified miniature versions of organs are made from stem cells, which have the ability to become almost every other type of cell. By creating the right circumstances and giving the proper input at just the right time, the scientists were able to mimic developmental processes to create basic versions of brain tissue the size of lentils. “Organoids are the only way you can study human brain development at such an early phase,” says Bárbara Oliveira, postdoc in the Novarino group and one of the authors of the study.

CHD8 mutations disrupt balance of neuron production

In petri dishes the team created brain organoids with and without mutations of the gene CHD8. “After some time, we could see by eye that the mutant organoids were much bigger. That was the first evidence that the model works,” her colleague and co-author, PhD student Christoph Dotter, describes. Like patients with a CHD8 mutation, the organoids were showing signs of brain overgrowth.

Getting an overview of all the cell types in the organoids, the team notices something very early on: The mutant organoids started to produce a specific type of neurons, inhibitory neurons, much earlier than the control group. So called excitatory neurons, however, were produced later. Furthermore, the mutant organoids produced much more proliferating cells that later on produce a larger amount of this kind of neurons. Over all, the scientists concluded, this leads to them being significantly bigger than the organoids without CHD8 mutations correlating with patient’s macrocephaly.

Professor Gaia Novarino at ISTA CREDIT © Peter Rigaud/ISTA

Starting to understand our brain

Like previous studies by the Novarino group, their recent study shows just how important time is when studying autism. “Looking at different time points gives us the information that what you see in the end might not be the full picture of how the brain of a patient developed – much more might have happened before,” says Novarino. “We still have a limited understanding of how different trajectories affect functions of the brain.” To one day help patients with a CHD8 mutation, the basics of brain development need to be better understood. By reproducing genetic and clinical features from ASD patients in brain organoids, the Novarino group was able to make an important contribution.

At day 50, it is possible to notice the overgrowth of mutant organoids when compare to the control group. CREDIT © Novarino group/ISTA

Some kids with autism may have a genetic defect that affects the muscles, according to research.

The study looked at 37 children with autism who were evaluated for mitochondrial disease, which causes muscle weakness and prevents a child from being able to participate in physical activities and sports. Mitochondrial disease occurs when genetic mutations affect the mitochondria, or the part of the cell that releases energy.

A total of 24 of the children, or 65 percent, had defects in the process by which cells produce and synthesize energy in the muscles, or oxidative phosphorylation defects in the skeletal muscles.

“Most children with autism spectrum disorders do not have recognizable abnormalities when you look at genetic tests, imaging, and metabolic tests,” said study author John Shoffner, MD, owner of Medical Neurogenetics, LLC in Atlanta, GA, and member of the American Academy of Neurology. “But a subset of these children does have significant defects in this area. Identifying this defect is important for understanding how genes that produce autism spectrum disorders impact the function of the mitochondria.”

Findings published in advance of World Autism Day (Saturday 2 April) reveal there are fundamental similarities between autistic and non-autistic people in mental processing.

The brain processes information using two systems; System 1 for quicker intuitive judgements, and System 2 for slower rational thinking. These systems are thought to work differently in autistic people, underlying the difficulties they may experience in everyday life and the workplace.

Yet, a landmark study from the universities of Bath, Cardiff, Manchester, and King’s College London reports that these fundamental psychological systems are not impaired in autistic people as once thought. In the largest study of its kind, which involved over 1000 people, the researchers tested the link between autism and ‘quick’ intuitive and ‘slow’ rational thinking.

In three experiments, they analysed the link between autistic personality traits and thinking style. In the fourth, they compared 200 autistic and over 200 non-autistic people. Overall, their results showed that autistic people think as quickly and as rationally as non-autistic people.

The researchers conclude that certain, fundamental mental processes are more similar between autistic and non-autistic people than previously thought. In light of these findings, they call for a shift in the way that society thinks about autism as a mental processing disorder.

They also recommend that it might be important to redesign educational, clinical, and workplace support for autistic people and their families. Support should be much more targeted, instead of assuming that autistic people all have mental processing difficulties, they say.

The research team argue that the requirement to make ‘reasonable adjustments’ in education and commercial organisations, underpinned by the Equality Act, such as allowing extra time in exams and extending deadlines, is not an evidence-based way to support neurodivergent people.

Instead, more fundamental changes might be required, such as changing social and sensory environments and making them more equitable for autistic people to thrive.

Dr Punit Shah, Associate Professor of Psychology at the University of Bath and the GW4 Neurodevelopmental Neurodiversity Network, explained: “There is a tradition of investigating mental difficulties in autism. While this can be important for developing clinical interventions, there is also a need to understand psychological similarities between different groups.

“The University of Bath is doing ground-breaking work on this, showing that there is often more that unites than divides us, and our new neurodiversity research is another step in this direction.

“Many employers and organisations assume that neurodiversity is simply about celebrating differences between people. But a comprehensive approach to neurodiversity must understand and celebrate similarities between ‘neurodivergent’ and ‘neurotypical’ people, too. Not only will our research feed into and improve the design of clinical and educational interventions for autism, it may help to break down stereotypes about how autistic people think and behave, moving us closer towards an evidence-based approach to neurodiversity.”

Dr Shah added: “If we continue telling autistic people and wider society that autistic people ‘think differently’ – however well-intentioned it might be – that will lead to stereotyping and self-stereotyping, such that autistic people become restricted to thinking in certain ways and therefore doing certain jobs. Our research doesn’t support this idea and, instead, indicates that autistic people often think in a way that is very similar to non-autistic people and they should not be constrained to certain tasks in educational and workplace settings.”

Commenting on the research, Charlotte Valuer, Chair of the Institute of Neurodiversity, said: “This is very interesting research which aligns with much of our work at the Institute of Neurodiversity (ION). We are indeed more alike than different and having research to show that is important. There are so many misconceptions out there and they are best addressed through research which will also help and underpin the work autism self advocates do. ION’s purpose is to help us prosper equally to everyone else. Part of that is helpin

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