Organoids are not brains. How do they brain wave?



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LA JOLLA, California. – Two hundred and fifty miles above the head of Alysson Muotri, one thousand small spheres of brain cells were navigating in space.

The clusters, called brain organelles, had been grown a few weeks earlier in the biologist's laboratory. here at the University of California at San Diego. He and his colleagues turned the cells of human skin into stem cells and then persuaded them to grow like brain cells do in an embryo.

Organoids have grown into balls the size of a pinhead, each containing hundreds of thousands of cells in a variety of types, each type producing the same chemicals and electrical signals that these cells produce in our own brain. In JulyNASA packed the organoids on board a rocket and sent them to the International Space Station to see how they were developing in weightlessness.

Now, the organelles were stored in a metal box, fed by bags of nutritious broth. "I think they're replying like crazy at this point, and so we're going to have bigger organoids," Dr. Muotri said in a recent interview in his office overlooking the Pacific.

"People will say," Ah, it's like the brain of the premature, "she said. "No they are not."

Scientists have created the first brain organoid from human skin cells. Today, they are cultivated in laboratories all over the world, offering scientists a new window on the early stages of human brain development.

Here in the United States, researchers are using them to recreate, in miniature, hereditary brain disorders and brain infections. They are also trying to develop larger and more complex brain organelles. In a recent experiment, related scientists a cerebral organoid and a spider-like robot, so that both can exchange signals.

With the Thursday report, published in the journal Cell, the question of what could become the brain organoids becomes more and more urgent.

"Some of my colleagues say," No, these things will never be conscious, "said Dr. Muotri. "Now, I'm not so sure."

Even if one day scientists produce only organoids with little awareness of their consciousness, this could be a serious ethical problem, said Christof Koch, chief scientist and president of the Allen Brain Institute in Seattle.

"The closer we get to his goal, the more likely we are to have a brain that can feel and feel pain, agony and distress, "said Dr. Koch.

"The most incredible thing is that they are building themselves," he said. Prepared with the right conditions, the organelles assume their own development.

Today, Cleber Trujillo, a project scientist, oversees the growth of thousands of organoids in a tissue culture room of Dr. Muotri's lab. "This is where we spend half the day," he said, signaling to the banks of refrigerators, incubators and microscopes.

Brain organelles require a lot of work because to grow them, it's more to make a puff than to do a chemistry experiment. Scientists must continually replace the broth in which cells grow and keep a close eye on the cells themselves.

"We have to guide them," said Dr. Trujillo. "Otherwise, they become other things."

If everything goes as planned, the cells turn into brain organelles. They become blobs within which tunnels are formed. The so-called progenitor cells surround the tunnels and the germination cables. Other cells run through the cables and form successive rings.

They correspond to the cells of our cortex in many ways. Their surface even folds on itself.

Dr. Trujillo pulled out a translucent muffin tray and lifted it over his head. The lights above lit up hundreds of tiny, pale spheres. At two months, the cells inside each organoid retained it with a network of sticky branches.

"They like to stay in touch with each other, "said Dr. Trujillo affectionately.

Dr. David Baud, expert in zika at the University of Lausanne in Switzerland, who did not participate in the study, described this discovery as promising, difficult to achieve for mice or neurons individual. "Organoids offer the best alternative," he said.

Fabio Popes, neuroscientist at the University of Campinas in Brazil, shares the same view on organoids when it comes to studying hereditary brain disorders. Dr. Papes is working with Dr. Muotri to study a condition called Pitt-Hopkins syndrome.

It is a rare disease that prevents children from speaking and suffers from regular seizures. To understand how certain mutations cause disease, Dr. Papes cultivates organoids from skin cells donated by patients.

"For this particular disease, the mice are not good," he said. "And you obviously can not open the child's head to find out what's going on. You can go there or not go at all.

In 2016 Priscilla Negraes, a researcher in Dr. Muotri's lab, started spying on organelles. She figured out how to stick them to the bottom of a well lined with 64 electrodes. When a neuron in the organoids fires, one of the electrodes ignites.

The organoids were surprisingly noisy – and with each passing week, they became noisier. Then she noticed that the models emerged.

Most neurons would suddenly trigger into a synchronized burst – a pattern that looked remarkably like brain waves.

Dr. Negraes and her colleagues began working with brainwave experts. They discovered some similarities between organoids and the brain of premature babies. Babies and organoids both produced synchronous activity surges, followed by silent lulls.

As organoids grew up, the researchers found, the lulls have shortened. This too is a characteristic of the brains of premature babies at the age of maturity.

What makes the similarity so remarkable is that the organelles and brains of babies are so different, said Richard Gao, a graduate student at the University of California. and co-author of the new study.

"I do not think you need all the billions of brain neurons to produce these models," Gao said. "Once you have passed a critical mass, you can do it."

To learn more about brain organelles, researchers want to make them larger, 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 carve branches of neurons, helping them to mature. Researchers at Dr. Muotri's lab have persuaded microglia to crawl into brain organelles. Now scientists are following the activity of organoids as they develop.

"To be able to say what you should do, you must first say: is that's it? "We make things that were not known 10 years ago. They were not in the catalog of philosophers. "

At this stage of research, Dr. Lunshof said, the most important thing is to avoid confusing today's brain organoids with the real human brain – let alone humans. "They are in a completely different category," she said.

For the moment, these debates are of interest to some scientists: chefs capable of producing enough brain organoids to conduct experiments. Doctors Muotri and Trujillo hope to automate the process so that other scientists can manufacture many inexpensive and high quality brain organelles.

"It's our concept – plug and play," said Dr. Muotri. "We want to make farms of these organoids."

Organoids sent into space can help to make this concept a reality. The box in which they were housed is a rough prototype of a device that could someday produce organelles without human intervention.

The astronauts aboard the space station simply installed the case, turned on the power, and let it run on its own.

A recent morning, Dr. Muotri wanted to check his space organoids. Cameras inside the box take pictures every half hour, but all the pictures Dr. Muotri had seen were obscured by unexpected air bubbles.

Now, to his delight, the bubbles had disappeared from the last picture. On his computer screen, he saw half a dozen gray spheres float on a beige background.

"They are rounded and they are more or less the same size," he said. "You do not see them merging or regrouping. This is so good news.

If all this work eventually leads to mass-produced organelles, Dr. Muotri will not worry if his organo-culture skills become obsolete.

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

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