Jonah Lehrer - Scientists Map the Brain, Gene by Gene

Jonah is writing for Wired this time, but he is as interesting and informative as usual. In this article he looks at efforts to map the brain's cortex at the level of specific genes and individual neurons. More reductionism, yes, but the more we know, the more we know.

Scientists Map the Brain, Gene by Gene

By Jonah Lehrer 03.28.09

"The brain is details on top of details on top of details." — Michael Hawrylycz
Photo: David Clugston

The human brain is surprisingly bloody. I've worked in neuroscience labs, and I'm used to seeing brains that are stored in glass jars filled with formaldehyde, the preserved tissue a lifeless gray. But this brain—removed from a warm body just a few hours ago—looks bruised, its folds stained purple. Blood drips from the severed stem, forming puddles on the stainless steel table.

I'm in the dissection room of the Allen Institute for Brain Science in Seattle, and the scientist next to me is in a hurry: His specimen—this fragile cortex—is falling apart. Dying, the gray matter turns acidic and begins to eat away at itself; nucleic acids unravel, cell membranes dissolve. He takes a thin, sterilized knife and slices into the tissue with disconcerting ease. I'm reminded of Jell-O and guillotines and the meat counter at the supermarket. He saws repeatedly until the brain is reduced to a series of thin slabs, which are then photographed and rushed to a freezer. All that remains is a pool of blood, like the scene of a crime.

Behind all the gore there's a profound purpose: The scientists here are mapping the brain. And while conventional brain maps describe distinct anatomical areas, like the frontal lobes and the hippocampus—many of which were first outlined in the 19th century—the Allen Brain Atlas seeks to describe the cortex at the level of specific genes and individual neurons. Slices of tissue containing billions of brain cells will be analyzed to see which snippets of DNA are turned on in each cell.

If the institute succeeds, its maps will help scientists decipher the function of the thousands of genes that help produce the human brain. (Although the Human Genome Project was completed more than five years ago, scientists still have little idea which genes are used to make the brain, let alone where in the brain they are expressed.) For the first time, it will be possible to understand how such a complex object is assembled from a basic four-letter code.

"The maps of the brain we currently have are like those antique maps people used to draw of the New World," says Allan Jones, chief scientific officer at the Allen Institute. "We can see the crude outlines of the structure, but we have no idea what's happening on the inside." Jones is in charge of making sure the atlas gets finished. He wears starched button-up shirts and crisply pleated khakis, and he looks like the kind of guy who has a drawer full of bow ties. "Studying the brain now is like trying to navigate a vast city without any driving instructions," he says. "You don't know where you are, and you have no idea how to find what you're looking for."

Author Jonah Lehrer spoke at San Francisco's Commonwealth Club on February 19, 2009 about the black box of the human mind.

For more from FORA.tv, visit wired.com/video.

When the project is completed in 2012, at an expected cost of $55 million, its data sets will list the roughly 20,000 genes that, switched on in the exact right place at the exact right time, give rise to this self-aware tangle of neurons. And because the vast majority of mental illnesses and disorders, from schizophrenia to autism, have a significant genetic component, scientists at the institute hope that the atlas will eventually lead to new methods of diagnosis and more effective medical treatments. To map the brain is to map its afflictions.

This enterprise is unique in one other respect: scale. "People ask me why we didn't start with a more modest goal, like trying to map some small brain area," Jones says. "The point of doing the whole brain, though, is that it allows us to really develop theories about how the brain works. Sometimes, the only way to make sense of a complex system is to be systematic."

To achieve this, the Allen Institute reimagined the scientific process. There was no grand hypothesis, or even a semblance of theory. The researchers just wanted the data, and, given the amount needed, it quickly became apparent that the work couldn't be done by hand. So, shortly after the institute was founded in 2003, Jones and his team started thinking about how to industrialize the experimental process. While modern science remains, for the most part, a field of artisans—scientists performing their own experiments at their own benches—the atlas required a high-throughput model, in which everything would be done on an efficient assembly line. Thanks to a team of new laboratory robots, what would have taken a thousand technicians several years can now be accomplished in less than 20 months.

The institute can produce more than a terabyte of data per day. (In comparison, the 3 billion base pairs in the human genome can fit in a text file that's only 3 gigabytes.) And the project is just getting started.

Preparing a fresh specimen for analysis.
Photo: David Clugston

In March 2002, Paul Allen—cofounder of Microsoft and 41st-richest person in the world—brought together a dozen neuroscientists for a three-day meeting aboard his 300-foot yacht, Tatoosh, which was anchored in Nassau, Bahamas. At the time, Allen's philanthropic work consisted of an eclectic (some say frivolous) set of endeavors. There was the Experience Music Project in Seattle, a rock-and-roll museum designed by Frank Gehry; the Allen Telescope Array, 350 radio telescopes dedicated to deep-space observation and the search for extraterrestrial life; and SpaceShipOne, the first privately funded plane developed to put a human in space. But Allen was eager to start something new: a project involving neuroscience. He was excited by the sheer uncharted mystery of the mind—one of the last, great scientific frontiers—hoping a single large-scale endeavor could transform the field.

"I first got interested in the brain through computers," Allen says. "There's a long history of artificial intelligence programs that try to mimic what the brain is doing, but they've all fallen short. Here's this incredible computer, a really astonishing piece of engineering, and we have no idea how it works."

Over several days, Allen asked the neuroscientists to imagine a way to move their field forward dramatically. "I wanted them to think big," he says. "Like the Human Genome Project, only for the brain." Some advocated focusing on a single disease, like Alzheimer's. Others argued for more investment in brain imaging technology. But a consensus emerged that what neuroscience most needed was a map, a vast atlas of gene expression that would reconcile the field's disparate experimental approaches. It's not that scientists don't know a lot about the brain—it's that they have no idea how it all fits together.

Today, you can measure the electrical activity of individual neurons, which involves plunging a microelectrode into the tissue and hoping to find an interesting cell. You can image the brain in an fMRI machine and isolate the areas that are active during certain types of mental activity. Or you can use the tools of molecular biology and study specific kinase enzymes, synaptic proteins, or RNA splices.

The problem with this multiplicity of techniques is that they fail to explain how the brain's essential elements—the wet stuff, the genetic text, the electric loom of cells—conspire to create a sentient piece of matter. Allen decided that what neuroscience needed was a tool to help get beyond these obsolete boundaries. "It became apparent to me that there were lots of scientists studying their own little area of brain, pursuing these very specific questions," he says. "But I wanted to develop something that would focus on making these crosscutting connections, so that everybody in the field could benefit."

Say, for instance, someone is investigating the anatomy of autism. The scientist has done an fMRI study that reveals abnormalities in a cortical area in autistic subjects—a bit of brain is not functioning properly—and this might help explain the symptoms of the disease. But now what? The problem has been isolated, but at a very abstract level. The research has hit a dead end.

Meanwhile, another scientist is looking at autism from a very different perspective, conducting large-scale genetic studies that identify a few of the fragments of DNA associated with the disease. (Autism is one of the most heritable psychiatric disorders.) The problem with these efforts is that they often highlight obscure genes that haven't been studied. Nobody knows what these genes do, or whether they're even expressed in the brain. As a result, the research stalls and it remains completely unclear how this genetic defect might lead to the particular problems seen in the fMRIs.

But now imagine that this scientist has access to the Allen atlas. By looking at the map, he should be able to quickly see whether any of the genes known to be associated with autism—several have already been identified—are expressed in the brain areas that appear abnormal in the fMRI scans. This means that the disease can be pinpointed at a very precise level, reduced to a few dysfunctional circuits expressing the wrong set of genes. "That's what having a huge database lets you do," Allen says. "It becomes a tool that will really accelerate the pace of research." Such a map can also help neuroscientists better target their genetic searches. Instead of looking at every gene expressed in the brain—according to the institute's research, that may include nearly 80 percent of the human genome—they can focus only on those that are present in the relevant brain areas.

Then there's the mystery of the developing brain. How does something so complex manage to build itself? The Allen Institute is also measuring genetic expression in the mouse brain, from embryo to adult, to explore how the orchestra of genes is switched on and off in different areas during development. Which snippets of DNA transform the hippocampus into a center of long-term memory? Which make the amygdala a warehouse of fear and anxiety? "One of the things I've come to appreciate about the brain is the importance of location," Allen says. "It's not just a set of interchangeable parts that you can swap in and out. These brain areas are all so distinct, and for reasons we can finally begin to understand."

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Tags: brain, Psychology, genetics, Wired, Jonah Lehrer, Scientists Map the Brain, Gene by Gene, Allen Institute for Brain Science, cortex, genes, neurons