Scientists fix the gene that causes intellectual disability in men

Researchers use a cutting-edge technique to restore activity to the fragile X syndrome gene.


The fragile X syndrome is the most common form of intellectual impairment in men, affecting 1 out of 3,600 boys. Now, scientists at the Whitehead Institute used the CRISPR/Cas 9 gene editing method to restore activity to the fragile X syndrome gene in affected neurons. Their work, performed on human brain cells in a dish, paves the way for trying the technique on the brain, with the hope that it may treat a host of genetic conditions.

The syndrome can cause mild to severe intellectual disability, with symptoms like delays in talking, hyperactive behavior and anxiety. It may also result in physical features like large ears, a long face with prominent jaw and forehead, as well as flat feet. The disorder has also been linked to autism.

The Whitehead Institute for Biomedical Research, while independent of MIT, has 17 members from the MIT department of biology. The current research was led by the Institute’s founding member (and MIT professor) Rudolf Jaenisch. The team produced the first evidence that removing methylation, which are molecular tags that keep a mutant gene shut off, can reactivate the gene and restore the fragile X syndrome neurons.

A normal version of the FMR1 gene sequence, where the fragile X syndrome can develop, contains 5-55 nucleotide (CGG) repeats. Nucleotides are the basic structural units and building blocks for DNA. The scientists concluded that versions of the FMR1 sequence with over 200 nucleotide repeats can result in the syndrome’s production.

 

Demethylation at work. Credit: Cell.

The researchers hypothesized that methylation can blanket the nucleotide repeats and shut down the gene’s expression. To test this, postdoctoral researchers Shawn Liu and Hao Wu from Jaenisch’s lab developed a CRISPR/Cas9-based technique which can add or delete methylation tags from a specific stretch of the DNA. Removing the tags proved to renew the FMR1 gene expression, turning it back into a normal gene.

“These results are quite surprising—this work produced almost a full restoration of wild type expression levels of the FMR1 gene,” explained Jaenisch. “Often when scientists test therapeutic interventions, they only achieve partial restoration, so these results are substantial.”

Jaenisch’s team was able to reverse the abnormal electrical activity associated with the fragile X syndrome. Neurons rescued by this procedure were grafted into the brains of mice, with the FMR1 gene remaining active for at least three months. This promises that correcting methylation can lead to a sustained remedy for the disease.

“This work validates the approach of targeting the methylation on genes, and it will be a paradigm for scientists to follow this approach for other diseases,” said Jaenisch.

You can read the study here. 

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Researchers at the University of Colorado Boulder found that the fatty 10(Z)-hexadecenoic acid from the soil-residing bacterium Mycobacterium vaccae aids immune cells in blocking pathways that increase inflammation and the ability to combat stress.

The study's senior author and Integrative Physiology Professor Christopher Lowry described this fat as "one of the main ingredients" in the "special sauce" that causes the beneficial effects of the bacterium.

The finding goes hand in hand with the "hygiene hypothesis," initially proposed in 1989 by the British scientist David Strachan. He maintained that our generally sterile modern world prevents children from being exposed to certain microorganisms, resulting in compromised immune systems and greater incidences of asthma and allergies.

Contemporary research fine-tuned the hypothesis, finding that not interacting with so-called "old friends" or helpful microbes in the soil and the environment, rather than the ones that cause illnesses, is what's detrimental. In particular, our mental health could be at stake.

"The idea is that as humans have moved away from farms and an agricultural or hunter-gatherer existence into cities, we have lost contact with organisms that served to regulate our immune system and suppress inappropriate inflammation," explained Lowry. "That has put us at higher risk for inflammatory disease and stress-related psychiatric disorders."

University of Colorado Boulder

Christopher Lowry

This is not the first study on the subject from Lowry, who published previous work showing the connection between being exposed to healthy bacteria and mental health. He found that being raised with animals and dust in a rural environment helps children develop more stress-proof immune systems. Such kids were also likely to be less at risk for mental illnesses than people living in the city without pets.

Lowry's other work also pointed out that the soil-based bacterium Mycobacterium vaccae acts like an antidepressant when injected into rodents. It alters their behavior and has lasting anti-inflammatory effects on the brain, according to the press release from the University of Colorado Boulder. Prolonged inflammation can lead to such stress-related disorders as PTSD.

The new study from Lowry and his team identified why that worked by pinpointing the specific fatty acid responsible. They showed that when the 10(Z)-hexadecenoic acid gets into cells, it works like a lock, attaching itself to the peroxisome proliferator-activated receptor (PPAR). This allows it to block a number of key pathways responsible for inflammation. Pre-treating the cells with the acid (or lipid) made them withstand inflammation better.

Lowry thinks this understanding can lead to creating a "stress vaccine" that can be given to people in high-stress jobs, like first responders or soldiers. The vaccine can prevent the psychological effects of stress.

What's more, this friendly bacterium is not the only potentially helpful organism we can find in soil.

"This is just one strain of one species of one type of bacterium that is found in the soil but there are millions of other strains in soils," said Lowry. "We are just beginning to see the tip of the iceberg in terms of identifying the mechanisms through which they have evolved to keep us healthy. It should inspire awe in all of us."

Check out the study published in the journal Psychopharmacology.