By Carl Zimmer
Photograph by Robert Clark
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
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 96
miniature antennas it contained would be close enough to my brain to
pick up the radio waves it was about to emit. As the slab glided into
the cylindrical maw of the scanner, I thought of
The Man in the Iron Mask.
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 100,000 miles of nerve fibers,
called white matter, that connects the various components of the mind,
giving rise to everything we think, feel, and perceive. The U.S.
government is throwing its weight behind this research through the Brain
Research through Advancing Innovative Neurotechnologies (BRAIN)
Initiative. 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
2012, some scientists were skeptical, wondering if he’d uncovered only
part of a much more tangled anatomy. 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. “We’re
just not yet in a position to see the simplicity.”
Scientists are learning so much about the brain now that
it’s easy to forget that for much of history we had no idea at all how
it worked or even what it was. 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 17th century began to change
that. 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 19th century scientists knew little about the paths those spikes
followed. The Italian physician Camillo Golgi argued that the brain was a
seamless connected web. Building on Golgi’s research, the Spanish
scientist Santiago Ramón y Cajal tested new ways of staining individual
neurons to trace their tangled branches. 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 Ramón y
Cajal Professor of Arts and Sciences at Harvard, carrying Cajal’s
project into the 21st century. 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 10,000 synapses. 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 25,000
high-definition movies.
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 1/100,000 the
size of a grain of salt. 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 80 dendrites,
each making about 600 connections with other neurons inside the
cylinder. “It’s a wake-up call to how much more complicated brains are
than the way we think about them,” says Lichtman.
Complicated, but not random. 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. “They seem to care who they’re connected to,”
Lichtman says.
Lichtman can’t say yet whether this fastidious pattern is a
general rule or a feature of just the tiny area of mouse brain he
sampled. Even as they scale up the technology, he and his colleagues
will need another two years to complete a scan of all 70 million neurons
in a mouse. 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. “It’s too painful.”
When and if Lichtman completes his three-dimensional
portrait of the brain, it will reveal much—but it will still be only an
exquisitely detailed sculpture. 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. Alzheimer’s disease
scatters tangles of protein through the brain, although scientists have
yet to firmly settle on how those tangles give rise to the devastating
dementia the disease causes.
A map of the brain’s molecular machinery called the Allen Brain
Atlas has been generated at the Allen Institute for Brain Science in
Seattle, founded ten years ago with funds from Microsoft co-founder Paul
Allen. Using the brains of recently deceased people, donated by their
families, researchers there use a high-resolution magnetic resonance
imaging (MRI) scan of each brain as a three-dimensional road map, then
slice it into microscopically thin sections that are mounted on glass
slides. They then douse the sections with chemicals that reveal the
presence of active genes harbored in the neurons.
So far the researchers have mapped the brains of six people,
charting the activity of 20,000 protein-coding genes at 700 sites within
each brain. It’s a colossal amount of data, and they’ve only begun to
make sense of it. The scientists estimate that 84 percent of all the
genes in our DNA become active somewhere in the adult brain. (A simpler
organ like the heart or pancreas requires far fewer genes to work.) In
each of the 700 sites the scientists studied, the neurons switch on a
distinct collection of genes. In a preliminary survey of two regions of
the brain, the scientists compared a thousand genes that were already
known to be important for neuron function. From one person to the next,
the areas of the brain where each of those genes was active were
practically identical. It looks as if the brain has a finely grained
genetic landscape, with special combinations of genes carrying out tasks
in different locations. The secret to many diseases of the brain may be
hiding in that landscape, as certain genes shut down or switch on
abnormally.
All the information from the Allen Brain Atlas is posted online,
where other scientists can navigate through the data with custom-made
software. Already they’re making new discoveries. A team of Brazilian
scientists, for instance, has used it to study a devastating brain
disorder called Fahr’s disease, which calcifies regions deep inside the
brain, leading to dementia. Some cases of Fahr’s disease had already
been linked to a mutation in the gene
SLC20A2. In the atlas the scientists found that
SLC20A2
is most active in precisely the regions that are targeted by the
disease. They also found a network of other genes that is most active in
the same areas, and now they’re trying to find out whether they’re
involved in Fahr’s disease as well.
Of all the new ways of visualizing the brain, perhaps the
most remarkable is one invented by Stanford neuroscientist and
psychiatrist Karl Deisseroth and his colleagues. To see the brain, they
begin by making it disappear.
On my visit to Deisseroth’s lab, undergraduate Jenelle Wallace led
me to a bench where half a dozen beakers rested in a plastic-foam base.
She pulled one out and pointed to a grape-size mouse brain resting at
the bottom. I didn’t look at the brain so much as through it. It was
nearly as transparent as a glass marble.
Needless to say, a normal human or mouse brain is decidedly
opaque, its cells swathed in fat and other compounds that block light.
That’s why Cajal had to dye neurons in order to see them and why
Lichtman’s group and the Allen Institute scientists slice the brain into
thin sections to gain access to its inner depths. The advantage of a
transparent brain is that it allows us to peer into its workings while
the organ is still intact. Along with postdoctoral researcher Kwanghun
Chung, Deisseroth came up with a recipe to replace the light-scattering
compounds in the brain with transparent molecules. After making a mouse
brain transparent in this way, they can then douse the brain with
glowing chemical labels that latch on to only certain proteins or trace a
specific pathway connecting neurons in distant regions of the brain.
The scientists can then wash out one set of chemicals and add another
that reveals the location and structure of a different type of neuron—in
effect untangling the Gordian knot of neural circuits one by one.
“You
don’t have to take it apart to show the wiring,” says Deisseroth.
It’s not easy to dazzle neuroscientists, but Deisseroth’s method,
dubbed CLARITY, has left his colleagues awestruck. “It’s pretty badass,”
says Christof Koch, the chief scientific officer at the Allen
Institute. Wedeen has called the research “spectacular ... unlike
anything else in the field.”
Because of our shared evolutionary heritage, a clarified mouse
brain can reveal a great deal about human brain function. But
Deisseroth’s ultimate goal is to perform the same transformation with a
human brain—a far more difficult task, not least because a human brain
is 3,000 times as large as that of a mouse.
A CLARITY picture showing the location of just one type of protein
in just one human brain would create a monstrous heap of data—about two
petabytes, or the equivalent of several hundred thousand high-def
movies. Deisseroth anticipates that CLARITY may someday help the sort of
people he treats in his psychiatric practice, by revealing hidden
features of disorders like autism and depression. But for now he’s
keeping those hopes in check.
“We have so far to go before we can affect treatments that I tell
people, Don’t even think about that yet,” he says. “It’s just a voyage
of discovery for now.”
As revealing as a transparent brain may prove to be, it
will still be dead. Scientists need different tools to explore the
terrain of living brains. The scanners Wedeen uses to trace white matter
patterns can, with different programming, record the brain in action.
Functional magnetic resonance imaging (fMRI) pinpoints regions of the
brain recruited during a mental task. Over the past couple of decades
fMRI has helped reveal networks involved in all manner of thought
processes, from recognizing faces to enjoying a cup of coffee to
remembering a traumatic event.
It’s easy to be dazzled by fMRI images, which festoon the brain
with rainbow blobs. But it’s important to bear in mind that those images
are actually quite coarse. The most powerful scanners can record
activity only down to the scale of a cubic millimeter—a sesame seed’s
worth of tissue. Within that space, hundreds of thousands of neurons are
firing in synchronized patterns, trading signals. How those signals
give rise to the larger patterns revealed by fMRI remains mysterious.
“There are ridiculously simple questions about the cortex that we
can’t answer at all,” says Clay Reid, a former colleague of Jeff
Lichtman’s at Harvard who moved to the Allen Institute in 2012.
Reid has come to Seattle hoping to answer some of those questions
with a grand series of experiments he and his colleagues call MindScope.
Their goal is to understand how a large number of neurons carry out a
complex task.
The function Reid and his colleagues have chosen to decipher is
vision. Scientists have been investigating how we see for decades, but
they’ve been able to study it only piecemeal. A neuroscientist might
place an electrode in the region of a mouse’s brain involved in visual
perception and then note whether nearby neurons fire when the animal
sees a particular image.
This approach has allowed scientists to map regions of the visual
brain that specialize in different tasks, such as detecting the edges of
an object or perceiving brightness. But scientists haven’t been able to
see all those regions work together at once—to learn how the million or
so neurons in the visual regions of a mouse’s brain instantly put
information together into the image of a cat.
Reid and his colleagues are setting out to solve that problem by
engineering mice so that their visual neurons will release flashes of
light when they fire. The flashes record the neural activity when a
mouse sees a specific object, be it a cat, a snake, or an appealing
piece of cheese. The scientists can then compile the data to create
massive mathematical models of vision. If the models are accurate, the
researchers will be able to literally read the mind of a mouse.
“Our goal is to reconstruct what the mouse sees,” says Reid. “And I think we can do it.”
Reid’s research on mouse vision is another step toward
neuroscience’s ultimate goal: a comprehensive view of how this vastly
complicated organ really works—what the scientists I talked to call a
theory of the brain. Such a grand vision is still a long way off, and
for the most part, the search for it has yet to change the way doctors
treat patients. But there is one line of research—brain-machine
interfaces—where the mapping of the mind has started to change people’s
lives.
When she was 43 years old, Cathy Hutchinson suffered a massive
stroke, leaving her unable to move or speak. Lying in her bed in
Massachusetts General Hospital, she gradually figured out that her
doctors didn’t know if she was brain-dead or still aware. Her sister
asked Hutchinson if she could understand her. She managed to answer by
moving her eyes up on command.
“It gave me such a relief,” Hutchinson tells me 17 years later, “because everybody talked about me as if I was dying.”
It is a chilly winter day at her home in eastern Massachusetts,
and she’s sitting in a wheelchair in the middle of the living room,
dressed in a dark green jogging suit and sneakers. Still almost
completely paralyzed and unable to speak, she communicates by looking at
letters arrayed on a computer monitor bolted to her wheelchair, a
camera tracking the movement of a tiny metal disk attached to the center
of her eyeglasses.
Near the top of the brain is a region called the motor cortex,
where we generate commands to move our muscles. For more than a century
we’ve known that each part of the cortex corresponds to a particular
area of the body. When people like Hutchinson become paralyzed, the
motor cortex often remains intact, but it can’t communicate with the
rest of the body, because its connections have been destroyed. John
Donoghue, a neuroscientist at Brown University, wanted to find a way to
help people with paralysis by tapping into the signals from their motor
cortex. Perhaps they could eventually learn to type on a computer or
operate a machine merely with their thoughts. Donoghue spent years
developing an implant and testing the device on monkeys. Once he and his
colleagues knew it was safe, they were ready to start working with
human patients.
One of them was Hutchinson. In 2005 surgeons at Rhode Island
Hospital drilled a hole the size of a poker chip in her skull and
inserted the sensor for Donoghue’s device. About the size of a ladybug,
the sensor contained a hundred miniature needles, which, pressing into
Hutchinson’s motor cortex, recorded the signals from nearby neurons. A
set of wires anchored to this device passed through the hole in her
skull and led to a metal connector sitting on her scalp.
After her surgery had healed, the Brown University researchers
plugged Hutchinson’s implant into a cable that relayed signal patterns
from her brain to a cart of computers they wheeled into her room. As a
first step, the scientists trained the computers to recognize signals in
her motor cortex and use them to move a computer cursor around a
screen. This was achieved the first time she tried because they had
learned how to translate patterns of brain activity into movements. Two
years later they coupled a robotic arm to the computers, refining a
program that could interpret Hutchinson’s brain signals to move the arm
forward and back, to raise it up and down, and to open its robotic
fingers and squeeze them shut.
After just a few sessions Hutchinson, the computer, and the
robotic arm had become a team. “It felt natural,” she tells me. So
natural that one day she reached out for a cinnamon latte, grabbed it,
and brought it to her lips to drink.
“Cathy’s smile when she put down that drink—that’s everything,” Donoghue says.
Today Donoghue and other scientists are building on that success,
hoping to create human-machine interfaces that will be powerful, safe,
and easy. At Duke University Miguel Nicolelis has been experimenting
with exoskeletons that strap on to the body. Signals from the brain
control each limb. Already he has gotten monkeys to control full-body
exoskeletons. If all goes well, a paraplegic wearing a simpler version
of the device will deliver the opening kick at the 2014 World Cup in
Nicolelis’s native Brazil.
“Eventually brain implants will become as common as heart implants,” says Nicolelis. “I have no doubt about that.”
When it comes to the brain, predicting the future is a tricky
game. Advances in the past have inspired giddy expectations that in many
cases have not been met. “We can’t tell a schizophrenic brain from an
autistic brain from a normal brain,” says Christof Koch. But the
research that’s going on now, he believes, is moving neuroscience to a
remarkable new stage. “I think we can begin to put the pieces together.”
