Secrets of the Brain. Van Wedeen strokes his half- gray beard and leans toward his computer screen, scrolling through a cascade of files. We’re sitting in a windowless library, surrounded by speckled boxes of old letters, curling issues of scientific journals, and an old slide projector that no one has gotten around to throwing out.“It’ll take me a moment to locate your brain,” he says. On a hard drive Wedeen has stored hundreds of brains—exquisitely detailed 3- D images from monkeys, rats, and humans, including me.
Wedeen has offered to take me on a journey through my own head.“We’ll hit all the tourist spots,” he promises, smiling. This is my second trip to the Martinos Center for Biomedical Imaging, located in a former ship- rope factory on Boston Harbor.
The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain.
The first time, a few weeks ago, I offered myself as a neuroscientific guinea pig to Wedeen and his colleagues. In a scanning room I lay down on a slab, the back of my head resting in an open plastic box. A radiologist lowered a white plastic helmet over my face. I looked up at him through two eyeholes as he screwed the helmet tight, so that the 9. As the slab glided into the cylindrical maw of the scanner, I thought of The Man in the Iron Mask.
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The magnets that now surrounded me began to rumble and beep. For an hour I lay still, eyes closed, and tried to keep myself calm with my own thoughts. It wasn’t easy. To squeeze as much resolution as possible out of the scanner, Wedeen and his colleagues had designed the device with barely enough room for a person of my build to fit inside. To tamp down the panic, I breathed smoothly and transported myself to places in my memory, at one point recalling how I had once walked my nine- year- old daughter to school through piles of blizzard snow.
As I lay there, I reflected on the fact that all of these thoughts and emotions were the creation of the three- pound loaf of flesh that was under scrutiny: my fear, carried by electrical impulses converging in an almond- shaped chunk of tissue in my brain called the amygdala, and the calming response to it, marshaled in regions of my frontal cortex. My memory of my walk with my daughter was coordinated by a seahorse- shaped fold of neurons called the hippocampus, which reactivated a vast web of links throughout my brain that had first fired when I had clambered over the snowbanks and formed those memories. I was submitting to this procedure as part of my cross- country reporting to chronicle one of the great scientific revolutions of our times: the stunning advances in understanding the workings of the human brain. Some neuroscientists are zooming in on the fine structure of individual nerve cells, or neurons. Others are charting the biochemistry of the brain, surveying how our billions of neurons produce and employ thousands of different kinds of proteins.
Still others, Wedeen among them, are creating in unprecedented detail representations of the brain’s wiring: the network of some 1. In an announcement last spring President Barack Obama said that the large- scale project aimed to speed up the mapping of our neural circuitry, “giving scientists the tools they need to get a dynamic picture of the brain in action.”As they see the brain in action, neuroscientists can also see its flaws.
They are starting to identify differences in the structure of ordinary brains and brains of people with disorders such as schizophrenia, autism, and Alzheimer’s disease. As they map the brain in greater detail, they may learn how to diagnose disorders by their effect on anatomy, and perhaps even understand how those disorders arise. On my return trip to his lab Wedeen finally locates the image from my session in the scanner.
My brain appears on his screen. His technique, called diffusion spectrum imaging, translates radio signals given off by the white matter into a high- resolution atlas of that neurological Internet. His scanner maps bundles of nerve fibers that form hundreds of thousands of pathways carrying information from one part of my brain to another. Wedeen paints each path a rainbow of colors, so that my brain appears as an explosion of colorful fur, like a psychedelic Persian cat. Wedeen focuses in on particular pathways, showing me some of the circuitry important to language and other kinds of thought. Then he pares away most of the pathways in my brain, so that I can more easily see how they’re organized.
As he increases the magnification, something astonishing takes shape before me. In spite of the dizzying complexity of the circuits, they all intersect at right angles, like the lines on a sheet of graph paper.“It’s all grids,” says Wedeen.
When Wedeen first unveiled the grid structure of the brain, in 2. But Wedeen is more convinced than ever that the pattern is meaningful. Wherever he looks—in the brains of humans, monkeys, rats—he finds the grid. He notes that the earliest nervous systems in Cambrian worms were simple grids—just a pair of nerve cords running from head to tail, with runglike links between them.
In our own lineage the nerves at the head end exploded into billions but still retained that gridlike structure. It’s possible that our thoughts run like streetcars along these white matter tracks as signals travel from one region of the brain to another.“There’s zero chance that there are not principles lurking in this,” says Wedeen, peering intently at the image of my brain. In the ancient world physicians believed that the brain was made of phlegm. Aristotle looked on it as a refrigerator, cooling off the fiery heart. From his time through the Renaissance, anatomists declared with great authority that our perceptions, emotions, reasoning, and actions were all the result of “animal spirits”—mysterious, unknowable vapors that swirled through cavities in our head and traveled through our bodies.
The scientific revolution in the 1. The British physician Thomas Willis recognized that the custardlike tissue of the brain was where our mental world existed. To understand how it worked, he dissected brains of sheep, dogs, and expired patients, producing the first accurate maps of the organ. It would take another century for researchers to grasp that the brain is an electric organ. Instead of animal spirits, voltage spikes travel through it and out into the body’s nervous system. Still, even in the 1.
The Italian physician Camillo Golgi argued that the brain was a seamless connected web. Building on Golgi’s research, the Spanish scientist Santiago Ram. Cajal recognized what Golgi did not: that each neuron is a distinct cell, separate from every other one. A neuron sends signals down tendrils known as axons.
A tiny gap separates the ends of axons from the receiving ends of neurons, called dendrites. Scientists would later discover that axons dump a cocktail of chemicals into the gap to trigger a signal in the neighboring neuron. Jeff Lichtman, a neuroscientist, is the current Ram.
Instead of making pen- and- ink drawings of neurons stained by hand, he and his colleagues are creating extremely detailed three- dimensional images of neurons, revealing every bump and stalk branching from them. By burrowing down to the fine structure of individual nerve cells, they may finally get answers to some of the most basic questions about the nature of the brain. Each neuron has on average 1. Is there some order to their connections to other neurons, or are they random? Do they prefer linking to one type of neuron over others?
To produce the images, Lichtman and his colleagues load pieces of preserved mouse brain into a neuroanatomical version of a deli meat slicer, which pares off layers of tissue, each less than a thousandth the thickness of a strand of human hair. The scientists use an electron microscope to take a picture of each cross section, then use a computer to order them into a stack.
Slowly a three- dimensional image takes shape—one that the scientists can explore as if they were in a submarine traveling through an underwater kelp forest.“Everything is revealed,” says Lichtman. The only problem is the sheer enormity of “everything.” So far the largest volume of a mouse’s brain that Lichtman and his colleagues have managed to re- create is about the size of a grain of salt.
Its data alone total a hundred terabytes, the amount of data in about 2. Once the scientists have gathered this information, the really hard work begins: looking for the rules that organize the brain’s seeming chaos.
Recently Lichtman’s postdoctoral researcher Narayanan Kasthuri set out to analyze every detail in a cylinder of mouse brain tissue measuring just a thousand cubic microns—a volume 1/1. He selected a region surrounding a short segment of a single axon, seeking to identify every neuron that passed through it.
That minuscule patch of brain turned out to be like a barrel of seething snakes. Kasthuri found a thousand axons and about 8. Lichtman and Kasthuri discovered that every neuron made nearly all its connections with just one other one, scrupulously avoiding a connection with almost all the other neurons packed tightly around it. Even as they scale up the technology, he and his colleagues will need another two years to complete a scan of all 7.
I ask about scanning an entire human brain, which contains a thousand times more neurons than a mouse’s.“I don’t dwell on that,” he says, with a laugh. His imaged neurons are hollow models; real neurons are crammed with living DNA, proteins, and other molecules.
Each type of neuron uses a distinct set of genes to build the molecular machinery it needs to do its own job. Light- sensitive neurons in the eyes produce photon- catching proteins, for example, and neurons in a region called the substantia nigra produce dopamine, crucial to our sense of reward. The geography of proteins and other chemicals is essential to understanding how the brain works—and how it goes awry. In Parkinson’s disease the substantia nigra neurons produce less dopamine than normal, for reasons that aren’t yet clear.