The “mini-brains” Pruning peas helps us study incurable neurological diseases

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In recent years, neuroscientists have improved a lot in early growth of the human brain in the laboratory. Today, these “mini-brains” are becoming complex enough that we can study neurological diseases in their early stages.

Gray spots, known as brain organoids, are not capable of consciousness, but they can tell us about the structure, diversity, and interactions of cells in parts of the developing brain.

Researchers compare brain organoids to the structure of a fetal brain after about a dozen weeks of growth. Small spots can’t think, but they can send tendrils to a muscle and cause contractions. They can’t smell, but they can develop rudimentary eye structures.

Reaching even this simple level of development takes scientists much longer than nature itself. In order for a human’s stem cells to proliferate by the millions and become something that looks like a “mini-brain”, you have to bathe it in the right cocktail of molecules to turn the genes on or off at the right time.

Maintaining them is not easy either. Brain organoids derived from stem cells of people with Parkinson’s disease have been cultivated for about 30 days. For Alzheimer’s disease, they have been cultivated for 84 days.

Cambridge researchers have now developed a mini-brain the size of a pea to study amyotrophic lateral sclerosis (ALS) for almost a year, which is a huge step forward.

ALS, which often overlaps with frontotemporal dementia (ALS / FTD), is a currently incurable neurodegenerative disease that results in rapid cognitive decline and paralysis. Because neurological symptoms don’t appear until later in life, scientists know very little how it starts.

Enter the lab-grown mini-brain using stem cells from patients with ALS / FTD.

One of the big obstacles to the growth of brain-like clumps in a dish is that as the organoid grows, the cells in the middle deprive themselves of nutrients and cease to be useful models.

To get around this problem, some researchers began a few years ago to cut up organoids before bathing them in culture, keeping their models alive longer and for better study.

Cambridge researchers did this with their first SLA / FTD model. In unpublished work, the team claims to have cultivated their organoids for a total of 340 days.

Everything published so far is 240 days, but during that time the authors observed changes in two types of brain cells. These changes included cellular stress, damage to cellular DNA, and changes in the way the cell’s DNA was ultimately transcribed into proteins.

The destructive changes appeared to impact C9 neurons and another type of neural cell – called astroglia – both of which help manage muscle movement and mental capacity in the real human brain.

“While these initial disruptions were subtle, we were surprised at how early changes have occurred in our human model of SLA / FTD,” said the neurologist András Lakatos of the University of Cambridge.

“This study and other recent studies suggest that damage can start to accumulate as soon as we are born. We will need more research to understand if this is really the case, or if this process is advanced in organoids by artificial conditions in the dish. “

One of the most interesting findings of the ALS / FTD model was that a drug known as GSK2606414f, or GSK for short, could partially suppress some of the neural changes that seemed to occur early in cortical development, including clumping of toxic proteins, cellular stress and loss of nerve cells.

Already, the authors say, similar drugs better suited to humans are being tested in clinical trials for neurodegenerative diseases. The team hopes their technique for growing organoid models of neurological diseases will help identify other potential drug targets in the future.

“We currently do not have very effective options for treating ALS / FTD, and while there is still a lot of work to be done after our discovery, it at least offers hope that it may be possible. ultimately to prevent or slow down the disease process, ” Explain Lakatos.

“It may also be possible in the future to be able to take cells from a patient’s skin, reprogram them to develop their ‘mini brain’ and test which unique combination of drugs is best for their disease. “

We’re still a long way from that reality, but looking back, neuroscientists have accomplished a lot in just a few years.

The study was published in Neuroscience of nature.


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