Jerusalem Scientists Successfully Produced Genetically Engineered Synapses – A First Step That Could Lead to Repairing Damaged Brains

C. elegans – fortunately referred to in a short version because its C. stands for Caenorhabditis – is a free-living transparent nematodeworm just about one millimeter in length whose home is the soil. It was made famous in 1963 by molecular biologist Sydney Brenner, who suggested that it be researched, primarily in the field of development of the neurons (nerve cells in the brain). Brenner chose the worm because it was more complicated than other well-understood organisms such as bacteria, yet still simple enough to study in depth. He also co-discovered messenger RNA, which is the basis of two effective COVID-19 vaccines.

During the last half-century, the tiny worm has since been extensively used as a model organism for research into human disease and became the first multicellular organism to have its whole genome sequenced, even though it lacked both a circulatory and a respiratory system. C. elegans is still widely used in biology today, with some 15,000 scientific papers published in the past decade that include a reference to the worm.  

Born in South Africa, he moved to the University of Oxford in the United Kingdom and later crossed the Atlantic Ocean to establish the Molecular Sciences Institute in Berkeley, California, and work at the Salk Institute. For this work, he shared the 2002 Nobel Prize in Physiology or Medicine with two other biologists. 

Now, researchers at the Hebrew University of Jerusalem (HUJI) have successfully produced genetically engineered synapses to bypass neural damage – a step that they regard as a first step to what one day could allow scientists to genetically repair damaged brains. 

The team, led by Dr. Ithai Rabinowitch, a neurobiologist at HUJI’s Faculty of Medicine, applied the genetically engineered bypass to repair a failed odor-response in the worms due to neuronal loss.  With the synthetic bypass network in place, the worms successfully responded to the odor stimuli, a behavior that was reduced in the absence of the genetically engineered “fix.” The study, published in the journal Cell Systems was jointly led by Dr. Jihong Bai of the Fred Hutchinson Cancer Research Center in Seattle, Washington.

 

“Neuronal loss can considerably diminish neural circuit function, impairing normal behavior by disrupting information flow in the circuit. Here, we use genetically engineered electrical synapses to reroute the flow of information in a C. elegans damaged chemosensory circuit in order to restore organism behavior,” they wrote. “…Our analysis suggests that these additional electrical synapses help restore circuit function by amplifying weakened neuronal signals in the damaged circuit.”

 

“While this is a discovery that has so far been limited to a tiny worm, it opens the door for potential applications that may be relevant down the road to humans,” said Rabinowitch said.  “At present, various approaches are used for addressing human brain damage, including brain-computer interfaces that are based on external electronics rerouting information flow between intact brain regions.  This research indicates a new potential route for addressing brain damage – whether caused by direct physical trauma or stroke or other neurological disease – through genetically engineered changes in brain connectivity that can serve as biological neural bypasses.” He added that the next steps will involve deeper testing of the broader biological impact of genetically inserted neuronal connections and also applying the approach to other neural circuits and other organisms.

 

“In studying this tiny worm, we were able to advance our theory in an organism that has only several hundred neurons as opposed to the tens of billions of neurons in the human brain,” he concluded. “Our great hope is that as this study advances and is applied more broadly in the worm’s nervous system and in other organisms, we will one day be looking at genetic therapies based on synthetic brain rewiring as possible treatments for devastating brain disease and damage.”


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