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Organoids are not brains. How do brainwaves make?



SAN DIEGO – Two hundred and fifty miles above Alysson Muotri's head, a thousand small small spheres of brain cells floated through space.

Clusters called brain organoids were grown several weeks earlier in the biologist's laboratory here at the University of California, San Diego . He and his colleagues transformed human skin cells into stem cells, and then coaxed them to develop, as brain cells do in an embryo.

Organoids have grown into balls the size of a pin, each containing hundreds of thousands of cells in various types, each producing the same chemical and electrical signals as those cells in ours. brain. In July NASA packed the organoids aboard a rocket and sent them to the International Space Station to see how they evolve at zero gravity.

The organoids were now stored in a metal box filled with bags of nutrient broth. "I think at this point they are playing like crazy and that is why we will have bigger organoids," Dr. Muotri said in a recent interview in his office overlooking the Pacific.

"People will say, 'Ah, they're like the brains of premature babies,'" she said. "No, they are not."

It's only been six years since scientists created the first brain organoid of human skin cells. They are now being grown in laboratories around the world, offering scientists a new window into the earliest stages of human brain development.

Here in the USA, researchers use them to recreate in miniature inherited brain disorders and brain infections. They also try to grow larger, more complex brain organoids. In a recent experiment scientists linked a brain organoid and a spider-shaped robot for the two to exchange signals.

With a report on Thursday published in Cell magazine, the question of what brain organoids

"There are some colleagues of mine who say, 'No, these things will never be realized,'" says Dr. Muotri. "I'm not so sure now."

Even if scientists produce only minimally self-aware organoids someday, that could be a serious ethical concern, said Christoph Koch, principal scientist and president of the Alan Brain Institute in Seattle.

"The closer we get to our goal the more likely he is to get m brain capable of feeling and feeling pain, agony and distress, "says Dr. Koch.

"The most amazing thing is that they build themselves," he said. Primed with the right conditions, organoids take on their own development.

Today, Clube Trujillo, a project scientist, monitors the growth of thousands of organoids in a tissue culture room in Dr. Muotri's laboratory. "We spend half our day here," he said, pointing to banks for refrigerators, incubators and microscopes.

Brain organoids require so much labor because growing them is more like making a souffle than conducting a chemistry experiment. Scientists need to constantly replace the broth in which cells grow and monitor the cells themselves closely.

"We must guide them," says Dr. Trujillo. "Otherwise, they become other things."

If everything goes according to plan, the cells turn into brain organoids. They become spots within which tunnels form. The so-called progeny cells bypass the tunnels and penetrate the cables. Other cells crawl down the cables and form successive rings.

In many respects, they correspond to the cells in our cortex. Their surface even folds on itself.

Dr. Trujillo pulled out a translucent muffin tray and lifted it above his head. The lights above her head illuminated hundreds of tiny pale spheres. For two months the cells in each organoid held it together with a network of sticky clones.

"They like to keep in touch with each other," said Dr. Trujillo kindly.

p. David Baud, a Zika expert at the University of Lausanne in Switzerland who did not participate in the study, called it a promising discovery – one that would be difficult to do in mice or individual neurons. "Organoids offer the best alternative," he says.

Fabio Papes, a neurologist at Campinas University in Brazil, feels the same way with organoids when it comes to studying hereditary brain disorders. Dr. Paps is collaborating with Dr. Moutree to investigate a disease called Pitt-Hopkins Syndrome.

This is a rare condition that prevents children from speaking and suffering from regular seizures. To understand how certain mutations cause the disease, Dr. Papes grows organoids from skin cells donated by patients.

"Mice are not useful for this particular disease," he said. "And you obviously can't open your child's head to know what's going on. We can go this route or not walk at all. ”

In 2016, Priscilla Negri then a scientist on the project at Dr. Muotri's laboratory began tapping into the organoids. She figured out how to glue them to the bottom of a well that was lined with 64 electrodes. When a neuron in the organoids ignites, one of the electrodes will light up.

The organoids turn out to be surprisingly noisy – and with each passing week they become noisier. Then she noticed that models were emerging.

Most of the neurons will suddenly start firing into a synchronized crash – a model that looked remarkably like brain waves.

Dr. Negro and her colleagues began working with brainwave experts, and they found some similarities between organoids and the brains of premature infants. Babies and organoids produce bursts of synchronized activity, followed by a quiet lull.

As the organoids grow researchers find that the silences are shortening. This is also characteristic of the brains of premature babies as they mature.

What makes this resemblance so remarkable is that organoids and baby brains are so different, said Richard Gao, a graduate student at U.C.S.D. and co-author of the new study.

"I don't think you need all the billions of neurons in your brain to produce these models," Mr. Gao said. "Once you pass a critical mass, it can do that."

To learn more from brain organoids, researchers want to make them bigger, more complex, and more durable. Immune cells, surprisingly, can make this possible.

Immune cells called microglia do not only fight pathogens. In the developing brain, they sculpt branches of neurons, helping them to mature. Researchers at Dr. Muotri's lab have caused microglia to crawl inside brain organoids. Now scientists are tracking the activity of organoids as they develop.

"To say what you have to do with it, you first have to say, 'What is this ?'" She said. "We do things that were not known 10 years ago. They were not in the catalog of philosophers. "

At this stage of research, Dr. Lunshoff said, the most important thing is to avoid confusing today's brain organoids with real human brains – not to mention humans. "They are in a completely different category," she argues.

So far, this debate is relevant to several scientists: chefs who can reliably make enough brain organoids to perform experiments. But Dr. Muothi and Dr. Trujillo are hoping to automate the process so that other scientists can make very cheap, high-quality brain organoids.

"This is our concept – plug and play," says Dr. Muotri. "We want to farm off these organoids."

Organoids sent into space can help make this concept a reality. The box they housed is a rough prototype of a device that can someday produce organoids without human intervention.

Astronauts aboard the space station simply installed the box, turned on the power, and left it to work on its own.

Recently, in the morning, Dr. Muotri wanted to check his cosmic organoids. The cameras inside the box take pictures every half hour, but all the pictures that Dr. Muotri had seen were obscured by unexpected air bubbles.

Now, to his delight, the bubbles had disappeared from the latest image. On the computer monitor, he saw half a dozen gray spheres floating on a beige background.

"They are rounded and they are more or less the same size," he said. "You don't see them merging or uniting together. That is good news. “

If all this work eventually led to mass-produced brain organoids, Dr. Muotri would not mind if his organoid-growing skills were aged.

"I think we can use our brains for something nobler," he said.


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