Future Tense

What On Earth Are These Things?

An excerpt from Carl Zimmer’s new book, Life’s Edge.

An early 20th century model of a head and brain, the face looking pensive with eyes closed.
The line between cells and a brain, between living and life, is extremely blurry. David Matos on Unsplash

From Life’s Edge: The Search For What It Means To Be Alive by Carl Zimmer, published by Dutton, an imprint of Penguin Publishing Group, a division of Penguin Random House, LLC. Copyright © 2021 by Carl Zimmer.

Cleber Trujillo led me to a windowless room banked with refrigerators, incubators, and microscopes. He extended his blue-gloved hands to either side and nearly touched the walls. “This is where we spend half our day,” he said.

In that room Trujillo and a team of graduate students raised a special kind of life. He opened an incubator and picked out a clear plastic box. Raising it above his head, he had me look up at it through its base. Inside the box were six circular wells, each the width of a cookie and filled with what looked like watered-down grape juice. In each well 100 pale globes floated, each the size of a housefly head.

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Every globe was made up of hundreds of thousands of human neurons. Each had developed from a single progenitor cell. Now these globes did many of the things that our own brains do. They took up nutrients in the grape juice–colored medium to generate fuel. They kept their molecules in good repair. They fired electrical signals in wavelike unison, keeping in sync by exchanging neurotransmitters. Each of the globes—which scientists call organoids—was a distinct living thing, its cells woven together into a collective.

“They like to stay close to each other,” Trujillo said as he looked at the undersides of the wells. He sounded fond of his creations.

The lab where Trujillo worked was led by another scientist from Brazil named Alysson Muotri. After Muotri immigrated to the United States and became a professor at the University of California, San Diego, he learned how to grow neurons. He took bits of skin from people and gave them chemicals that transformed them into embryo-like cells. Dousing them with another set of chemicals, he steered them to develop into full-blown neurons. They could form flat sheets covering the bottom of petri dishes, where they could crackle with voltage spikes and trade neurotransmitters.

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Muotri realized that he could use these neurons to study brain disorders that arose from mutations. Instead of carving out a piece of gray matter from people’s heads, he could take skin samples and reprogram them into neurons. For his first study, he grew neurons from people with a hereditary form of autism called Rett syndrome. Its symptoms include intellectual disability and the loss of motor control. Muotri’s neurons spread their kelp-like branches across petri dishes and made contact with one another. He compared them with the neurons he grew from skin samples taken from people without Rett syndrome. Some differences leaped out. Most noticeably, the Rett neurons grew fewer connections. It’s possible that the key to Rett syndrome is a sparse neural network, which changes the way signals travel around the brain.

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But Muotri knew very well that a flat sheet of neurons is a far cry from a brain. The three pounds of thinking matter in our heads are a kind of living cathedral, if a cathedral were built by its own stones. Brains arise from a few progenitor cells that crawl into what will become an embryo’s head. They gather together to form a pocket-shaped mass and then multiply. As the mass grows, it extends long, cable-like growths out in all directions, toward the forming walls of the skull. Other cells emerge from the progenitor mass and climb up these cables. Different cells stop at different points along the way and begin growing outward. They become organized into a stack of layers, known as the cerebral cortex.

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This outer rind of the human brain is where we carry out much of the thinking that makes us uniquely human—where we make sense of words, read inner lives on people’s faces, draw on the past, and plan for the distant future. All the cells that we use for these thoughts arise in a particular three-dimensional space in our heads, awash in a complex sea of signals.

Fortunately for Muotri, scientists came up with new recipes to coax reprogrammed cells to multiply into miniature organs. They made lung organoids, liver organoids, heart organoids, and—in 2013—brain organoids. Researchers coaxed reprogrammed cells to become the progenitor cells for brains. Provided with the right signals, those cells then multiplied into thousands of neurons. Muotri recognized that brain organoids would profoundly change his research. A disease like Rett syndrome starts reworking the cerebral cortex from the earliest stages in the brain’s development. For scientists like Muotri, those changes happened inside a black box. Now he could grow brain organoids in plain view.

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Together, Muotri and Trujillo followed the recipes that other scientists laid down for making organoids. Then they began creating recipes of their own to make a cerebral cortex. It was a struggle to find the blend of chemicals that could coax the brain cells onto the right developmental path. The cells often died along the way, tearing open and spilling out their molecular guts. Eventually the scientists found the correct balance. They discovered to their surprise that once the cells set off in the right direction, they took over their own development.

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No longer did the researchers have to patiently coax the organoids to grow. The clumps of cells spontaneously pulled away from one another to form a hollow tube. They sprouted cables that branched out from the tube, and other cells traveled along the cables to form layers. The organoids even grew folds on their outer surface, an echo of our own wrinkled brains. Muotri and Trujillo could now make cortex organoids that would grow to hundreds of thousands of cells. Their creations stayed alive for weeks, then months, then years.

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“The most incredible thing is that they build themselves,” Muotri told me.

Meanwhile, Cleber Trujillo’s wife, Priscilla Negraes, began listening to the chatter going on between the organoid cells.

When a brain organoid reaches a few weeks in age, its neurons become mature enough to generate spikes of voltage. Those spikes can travel down an axon and trigger neighboring neurons to fire as well. Negraes and her colleagues created an eavesdropping device that could pick up the crackle. At the bottom of miniature wells, they placed eight-by-eight grids of electrodes. They filled the wells with broth and rested an organoid atop each array.

On her computer, the readout from the electrodes formed a grid of 64 circles. Whenever one of the electrodes detected a firing neuron, its circle swelled, turning from yellow to red. Week after week the circles reddened and swelled more often, but there was no pattern Negraes could see to the bursts. The cells in the organoids spontaneously fired on their own from time to time, creating neurological static.

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But as the organoids got more mature, Negraes thought she saw some order emerge. Sometimes a few of the circles would all suddenly swell red together. Eventually all 64 electrodes registered signals at once. And then Negraes began to see them turn on and off in what looked like waves.

Was Negraes seeing actual brain waves developing in the organoids? She wished that she could compare the patterns she was seeing in her wells with the developing brains of human fetuses. But scientists had yet to figure out how to detect their electrical activity in the womb. The closest that anyone had managed was to study babies born premature, putting miniature EEG caps on their orange-sized heads.

Negraes and her colleagues enlisted a University of California, San Diego, neuroscientist named Bradley Voytek and his graduate student Richard Gao to compare organoids to premature babies. The earliest-born babies, with the least developed brains, produced sparse bursts of brain waves separated by long spells of disorganized firing. The babies that were born closer to term had shorter lulls, their bursts of brain waves growing longer and more organized. Organoids displayed some of the same trends as they got older. When a young organoid first began making waves, they came in sparse bursts. But as the organoid developed over months, they grew longer and better organized, their lulls growing smaller.

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This unsettling discovery did not mean that Negraes and her colleagues had created baby brains. For one thing, a human infant’s brain is 100,000 times bigger than the biggest organoids. For another, the scientists only mimicked one part of the brain—the cerebral cortex. A working human brain has many other parts: a cerebellum, a thalamus, a substantia nigra, and on and on. Some of its parts take in smells. Others handle sight. Still others make sense of different kinds of input. Some parts of the brain encode memories; some jolt it with fear or joy.

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Still, the scientists were unsettled. And they had every reason to suspect that, with more research, brain organoids might become more brain-like. A blood supply might let them grow bigger. Researchers might connect a cerebral cortex organoid to a retinal organoid that could sense light. They might link it to motor neurons that could send signals to muscle cells. Muotri even dabbled with the idea of linking an organoid to a robot.

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What might happen then? When Muotri started growing organoids, he assumed they could never become conscious. “Now I’m more unsure,” he confessed.

So were bioethicists and philosophers. They began gathering to talk about brain organoids and how to think about them. I called one—a Harvard researcher named Jeantine Lunshof—to get her opinion.

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Lunshof wasn’t too worried about Muotri accidentally creating conscious creatures in a dish. Brain organoids were so small and simple that they still fell far below that threshold. What concerned her was a simple question: What on earth are these things?

“In order to say what you should do with it, you first have to say, ‘What is it?’” Lunshof explained to me. “We’re making things that were not known ten years ago. They were not in the catalog of philosophers.”

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In La Jolla, Lunshof’s question came to my mind as Trujillo showed me his latest batch of organoids.

“This is just a mass of cells,” he said, pointing to one of his wells. “It does not get close to a human brain. But we have the tools to make a more complex mini-brain.”

“So you feel OK with this,” I said, groping for the right words, “because obviously it’s not a human brain—”

“Human cells!” Trujillo clarified.

“So they’re alive,” I half said, half asked.

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“Yes,” Trujillo replied. “And they’re human.”

“But they’re not a human being?”

“Yes,” he said.

“But where would you start to approach that line?” I asked.

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Trujillo had me imagine an organoid rigged up to an electrode.

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“You can do a pattern of electrical shocks,” he said.

Trujillo was sitting in front of a microscope as we talked. He extended two of his fingers and rapped them on the counter, producing galloping beats.

Ba-bap, ba-bap, ba-bap.

He suspended his hand over the counter. “And then we stop.”

After a few seconds Trujillo brought down his fingers again.

Ba-bap, ba-bap, ba-bap.

“And then the thing fires,” he said. In response to the incoming signal, the organoid uses its neurons to create a matching signal of its own. “That’s a bit more concerning. It’s learning something.”

The cover of Life's Edge by Carl Zimmer shows multicolored blobs.
Dutton

Future Tense is a partnership of Slate, New America, and Arizona State University that examines emerging technologies, public policy, and society.

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