The Way the Spirit Comes to the Bones As I made my way down a hairpin road, a sage-brush-studded wall of sand to my right, I felt keenly aware of my own life. I could feel the steep slope in my legs. After a series of tight turns, the wall swung away, revealing a long, desolate beach. It ran northward, a corridor of coast between high, slumping cliffs and the sea. Out over the Pacific, the sun hid behind clouds, a sky-wide bank of white. Earlier that day, in my hotel room, my phone had informed me the sky was cloudy and the temperature was in the low seventies. My brain responded to that information by choosing a light, long-sleeved shirt for my walk to the beach. And now my brain was updating its decision without cc'ing my conscious self. Nerves sprinkled throughout my skin sensed the humidity and temperature of the layer of air encasing my body. Voltage spikes traveled from the nerve endings along long branches known as dendrites until they reached the cores of the nerves, called the somas. From there, new signals raced onward along long, cable-shaped extensions called axons. The axons reached my spine and traveled up toward my head. From neuron to neuron, the signals from the outside world made their way into my brain and finally to a nub of neurons deep inside my skull. Those neurons combined the Morse code readout from across my body to generate new, different signals. They carried commands instead of sensations. The new voltage spikes left my brain along outward-bound axons, through my brain stem and down my spinal cord, until they reached millions of glands in my skin. There, they created electric charges in twisted tubes that wrung water out of the surrounding cells. Sweat ran down my back. My conscious self was annoyed with the brain that generated it. One of the few shirts I had brought with me was now drenched in salt water.. I could not actually sense the trill of voltage spikes that shuttled information from skin to brain. I didn't feel a surge of blood in the center of my head as the heat-regulating part of my brain swung into action. In the moment, by the sea, I simply felt myself sweating. I felt annoyed. I felt alive. As I felt aware of my own life, I also recognized other lives on the beach. A man walked lazily south, carrying a white-and-blue surfboard. Far to the north, a paraglider launched off from the top of the cliffs. The corkscrewing of the yellow paraglider wing spoke of intentions that arose in some human's brain and produced signals to hands gripping brake handles. Along with human life, I could see feathered life as well. Sandpipers skittered along the surf. Their seed-sized brains sensed the flash of incoming waves and the cold foam around their legs, contracting muscles to keep their bodies upright, to scuttle to higher ground, to poke the sand for buried snails. The snails didn't quite have brains but rather fretworks of nerves that produced signals of their own for slowly, relentlessly burying their bodies into the earth. I contemplated the thousands of other subterranean nervous systems inside the mud dragons and the Pismo clams and other creatures buried below my feet. Out in the ocean, down the underwater canyon, other brains were swimming, carried along inside the buoyant bodies of leopard sharks and stingrays while the nerve nets of jellyfish drifted by. After a few minutes of walking along the water, I stopped and looked down. A gigantic neuron, six feet long, lay on the sand. Most of it was made up of a glistening, caramel-colored axon. It curved gently like a heavily insulated electric cable. At one end it swelled into a bulb-shaped soma, which was crowned in turn by branches of dendrites. It could have been all that survived from a kraken that died in a battle with a pod of killer whales somewhere between here and Hawaii. This fantastical neuron was, in fact, a stalk of elk kelp. It had washed up from an underwater forest a mile out to sea. What I had imagined to be an axon was the kelp's stipe, a trunk that not long ago anchored the organism to the ocean floor. What looked like a neuron's soma was in reality a gas-bloated bladder that kept the kelp upright in the ocean currents. The branching dendrites were the elk kelp's antlers, on which long blades had once grown. And the blades acted like the leaves of plants, catching what little sunlight filtered down through the seawater and fueling the growth of the elk kelps to heights that rivaled the palm trees that crowned the cliffs behind me. The kelp had the kind of complexity that marks living things. But as I looked down at it, I could not say whether this particular kelp was still alive. I couldn't ask it how its day was going. It had no heartbeat I could check, no lungs to lift and lower a chest. But the kelp still glistened, its surfaces intact. Even if it could no longer capture sunlight, its cells might still be carrying on, using up its remaining fuel to repair its genes and membranes. At some point, maybe today or next week, its death would become certain. But along the way, it would also become a part of life on land. Microbes would feast on its tough cuticles. Beach hoppers and kelp flies would follow, nibbling on its tender tissues. These wrack-feasting creatures would themselves become food for the sandpipers and terns. Plants would be fertilized by the kelp's nitrogen soaking into the ground. And a sweaty human being, his brain packed with thoughts of brains on this beach, would carry away in his neurons a memory of the kelp's neuron-like body. The next morning I walked along the tops of the cliffs. North Torrey Pines Road cut north through La Jolla, California, alongside groves of looming tower cranes. With a stream of rush-hour traffic flowing by me, it was hard to remember the ribbon of wild coast tucked away close by. I crossed a eucalyptus-lined parking lot to get to the Sanford Consortium for Regenerative Medicine, a complex of glassed-in labs and offices. Once inside, I found my way to a third-floor laboratory, and there I met a scientist named Cleber Trujillo-Brazilian-born, with a close-cropped beard. Together we suited up in blue gloves and smocks. Trujillo led me to a windowless room banked with refrigerators, incubators, and microscopes. He extended his blue 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 a hundred pale globes floated, each the size of a housefly head. 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 the 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 emigrated to the United States and became a professor at the University of California at 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 tem to develp 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. Muotri realized that he could use these neurons to study brain disorders that arose from mutation. 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 each other. He compared them to the neurons he grew from skin samples taken 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. 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. 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, known as organoids. They made lung organoids, liver organoids, heart organoids, and-in 2013-brain organoids. Researchers coaxed reprogrammed cells to become the rogenitor 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. 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. No longer did the researchers have to patiently coax the organoids to grow. The clumps of cells spontaneously pulled away from each other 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 organoids that would grow to hundreds of thousands of cells. Their creations stayed alive for weeks, then months, then years. "The most incredible thing is that they build themselves," Muotri told me. On the day I visited Muotri's lab, he was checking in on some organoids he had sent into space. He sat in his office, a glass box perched out on a balcony next to the lab. Muotri had a gentle, relaxed manner, as if he might at any moment take off early from work, scoop up the scarred surfboard leaning against the wall by his desk, and head for the water. But today he was focused on the most extravagant of his many experiments. Outside his window, the paragliders were taking flight in the distance. He paid them no mind. Aboard the International Space Station, 250 miles above Muotri's head, hundreds of his brain organoids were sitting inside a metal box. He wanted to know how they were faring. For years astronauts aboard the space station had run experiments to see how cells grow in low Earth orbit. As they free-fell around the planet, the cells no longer experienced the same tug of gravity that has pulled on all life on Earth for the past 4 billion years. Strange things happen in microgravity, it turned out. In some experiments, the cells grew faster than they would on the ground. They sometimes became bigger. Muotri was curious to see if his organoids would grow into larger clusters in space and perhaps become more like our own brains. When they won approval from NASA, Muotri, Trujillo, and their colleagues began collaborating with engineers to build a home for organoids in space. They designed an incubator that could nurture the organoids, keeping the conditions right for their development. A few weeks before I visited the lab, Muotri had poured a fresh batch of miniature brains into a vial, which he put in a backpack. Standing in the security line at San Diego International Airport, he had no idea what he'd say if anyone asked what was in the tube. These are a thousand miniature brains I've grown in my lab, and I'm about to put them into space. Apparently, organoids don't grab that kind of attention. Muotri managed to board his flight without getting questioned. When he got to Florida, he handed the tube over to the engineers for a flight aboard a supply rocket. A few days later Muotri watched the SpaceX Falcon 9 rise from the earth. When the payload arrived at the space station, the astronauts grabbed the box loaded with organoids and plugged it into a bay. There it sat for a month. When the experiment was over, the astronauts would dunk the organoids in alcohol. They would die, but their life would be frozen at the moment of death. Once they fell back into the Pacific, were fished out, and were delivered to Muotri's lab, he'd be able to inspect their cells and see which genes they had used in space. Excerpted from Life's Edge: The Search for What It Means to Be Alive by Carl Zimmer All rights reserved by the original copyright owners. Excerpts are provided for display purposes only and may not be reproduced, reprinted or distributed without the written permission of the publisher.
