The Invisible Made Visible
By Claire Jeantheau
For a long time, they sat in the dark, listening. Researchers, including Clay Reid ’78, investigating electrical activity in the brain could only perceive the sounds of neurons clicking, each noise representing a signal transmitted to another part of the body. Then, in the early 2000s, a new technique called cellular-resolution imaging allowed them to take images up to half a millimeter deep inside of living tissue to suddenly, strikingly illuminate the firing of neurons.
Clay is still enraptured describing the sight, his face alight just as the pixelated bursts must have been on the display screen: “It was the most exciting thing ever, after living inside—not even Plato’s cave—inside Plato’s cave with a blindfold. It was like watching the light panel on one of those ancient computers.”
Moments of revelation like this, Clay knows, don’t come every day; as a Senior Investigator at the Allen Institute in Seattle, Washington, understanding often arrives piece by piece. But with the help of a dedicated team and advances in technology, those pieces are adding up to an unprecedented view of the brain’s inner workings.
A “Fundamental Problem”
Clay has always been fascinated by philosophy, his time at Commonwealth capped by a tight-knit seminar that covered Hume, Kant, and Hegel. Until very recently, the structure of the organ involved in producing such thought was a mystery in itself.
Human brains are made up of gray matter (where neuronal bodies live) and white matter (composed of axons that connect neurons from one brain area to another and to muscles, nerves, and organs). Many of the axons are myelinated, surrounded by a material that dramatically speeds the transmission of messages sent throughout the brain. Historically, only a few millimeters of myelinated axons could be traced within human brains; we know now that there are more than 100,000 kilometers of them. That’s almost one-third of the distance of traveling from the earth to the moon—a feat, one might note, we accomplished before we mapped the brain.
For neuroscience researchers, a complete understanding of the structure of the brain and its network of connections would be a discovery as thrilling as space exploration. But research is motivated by pragmatic considerations, too. “There are numerous degenerations that, on a human level, cause great suffering,” Clay says, disorders like Alzheimer’s and Parkinson’sthat impair memory and mobility, and could be more effectively treated with a complete understanding of neural networks.
Clay was drawn to complex problems like this as a Yale undergraduate but unsure which direction his study would take; he deliberated whether to pursue a career as a physicist or mathematician. When he approached a mentor in the philosophy department, the professor pointed him towards the pioneering work of scientists David Hubel and Torsten Wiesel on how the brain’s visual system processes information. Clay resolved to follow their path.
“There isn’t a more fundamental problem, I think, than the workings of the brain, and certainly none more fundamental than the human cerebral cortex,” Clay asserts. “What does it do? How does it do it? I think the wiring [of neurons] makes it do it…so what is the wiring?”
The Horizon of Possibility
Along with Hubel and Wiesel’s research, a prescient 1979 Scientific American article by Francis Crick also struck Clay in college; to this day, he can still quote it nearly word-for-word. In “Thinking About the Brain,” the geneticist states that in neuroscience research, “it is no use asking for the impossible, such as, say, the exact wiring diagram for a cubic millimeter of brain tissue and the way all its neurons are firing.” Impossible, that is, until recently.
“That’s the exact experiment that we’ve been trying to do for a long time and finally did for the first time five years ago” at the Allen Institute, with help from collaborators at Princeton and Baylor College of Medicine, Clay says. “We’re not yet ata complete wiring diagram…but it’s kind of fun to realize that something in the back of your brain percolated for thirty-five to forty years, and we’ve made a pretty good stab at it.”
Between 1979 and 2024, those deceptively simple questions—What does the human brain do? How does it do it?—drove Clay to earn an M.D. at Cornell University Medical College and a Ph.D. at The Rockefeller University, where he eventually collaborated with Wiesel. Before joining the Allen Institute, he returned to Massachusetts, working down the hall from Hubel as a Professor of Neurobiology at Harvard Medical School. Like the pair of scholars that first guided his research, Clay has a particular interest in understanding how neurons in the brain’s visual system transmit information. “It’s not terrifically different from a camera, except neurons are slightly more finicky than individual camera sensors” when they take in light, he explains.
Visual technologies like cameras have been critical in Clay’s work, too. After the “magical” discovery of cellular-resolution imaging, “we got greedy,” he says with a laugh. “If we could see the neurons, why don’t we see the connections, too?” The smallest diaxons in the gray matter are a tenth of the wavelength of light; when using light microscopy, those bonds are too small to see. So researchers turned to electron microscopy, where resolution on a nanometer scale enabled them to see hundreds of thousands of connections in finely cut segments of brain tissue.
At the Allen Institute, Clay’s team and their collaborators at Princeton used tools like 3-D computer modeling and machine learning to map the brain’s wiring, drawing from billions of data points collected from electron microscopy.
Making Progress Together
With research advances inching across several decades, it can be difficult to convey victories to those outside the lab—especially if they lack the visual allure of the outputs of cellular-resolution imaging. “When you try to do science that is potentially encyclopedic” like mapping the brain, Clay notes, “people tend to think that if the current state of the art is not yet encyclopedic, in some sense, you’re failing.” He recounts the common critiques: “‘Didn’t you set out to do X? You’ve only answered a few questions so far. Why haven’t you done something yet?’” When Clay writes research grants, he works to show that incremental successes are successes nonetheless.
Clay values the network of fellow researchers, at the Allen Institute and beyond, who share his experience, the same sort of conviviality that marked his years at 151 Comm. Ave. “I just loved Commonwealth,” he says. “We all talked to each other. There were extremely high standards but in a playful, non-punitive way.” He credits teachers Polly and Charles Chatfield and Judith Siporin for showing him the composition fundamentals he still uses when communicating with others through grant-writing. (His one-sentence summary of that education: “If you can’t write a paragraph that someone enjoys reading, why bother?”)
Today, Clay aims to cultivate a similar “family” atmosphere amongst his team of scientists and regularly teams up with experts across anatomy, biology, and other fields of study. “No single lab can learn one percent of what one could learn from the new large data sets,” he says. Clay envisions a future for neuroscientific study that mirrors the Human Genome Project, with computational scientists from different disciplinary branches and institutions receiving grant-funded training and joining together to share conclusions.
“Be brave,” Clay advises the researchers-in-training who will one day step into those efforts. “It’s hard to be a scientist, and it can be all drudgery or you can keep trying new things. It’s fabulous to try out new ideas that start out as fairly harebrained but can eventually yield really exciting science.”
Were the twenty years he spent waiting in the dark for a breakthrough drudgery? Clay smiles. “If you’re getting somewhere,” he says, “it’s not.”
Claire Jeantheau served as Commonwealth’s Communications Coordinator before becoming the Marketing Manager for the American Exchange Project. This article originally appeared in the summer 2024 edition of CM, Commonwealth's alumni/ae magazine.