This is part of IEEE Spectrum's SPECIAL REPORT: THE SINGULARITY

PHOTO: Timothy Archibald

What do fruit-fly brains have in common with microchips? That's not the setup for a bad joke; it's David Adler's life. Under Adler's ultra sophisticated electron beam microscopes, advanced microprocessors with transistors far smaller than red blood cells have been reduced to their wiring diagrams. Now the noggin of the humble Drosophila melanogaster is next, as Adler is being courted by researchers at a neurobiology wing of the Howard Hughes Medical Institute to help them reverse engineer the human brain. They're starting small, with the fruit fly.

Located in the green, rolling hills of Ashburn, in northern Virginia, the campus, known as Janelia Farm, has been described as a kind of Bell Labs for neuro-biology. Its task is solving what Adler calls the most important question in science: How exactly does the human brain do what it does? Lots of people are trying to answer this question, and there's a growing impetus toward using high- definition brain scans to find out how the brain works.

“In a hundred years I'd like to know how human consciousness works,” says Janelia director Gerry Rubin. “The 10‑ or 20-year goal is to understand the fruit- fly brain.” It's this difference between consciousness and brain that has neuro-science researchers stymied. The simplest system stores and processes information the same way the most complex system does; a primitive computer from 1986 works a lot like a supercomputer. Similarly, Rubin suspects that the human brain and the fruit-fly brain are separated only by degrees of complexity: “Just because it's much more advanced doesn't mean the basic wiring rules are different.” Right now, Janelia is working on a circuit diagram of the fruit-fly brain.

To that end, Rubin has stocked the Janelia campus with a collection of neuro-scientists, biologists, physicists, engineers, and computer scientists. The process resembles that of reverse engineering a microprocessor. It starts with a full-scale, three-dimensional wiring diagram of the fly's brain, in which the density of neurons is substantially higher—“but not infinitely higher,” insists Adler—than the wiring in a high-end IC. “If we can get a circuit diagram of the human brain,” says Adler, “then we can understand what causes a lot of neurological disorders—depression, epilepsy, maybe even Alzheimer's.”

Like an IC, the fruit-fly brain is subjected to logic and optical testing to derive its circuit diagram. With one approach, called neuronal electro physiology, researchers can record the electrical activity of neurons. “But the fly brain is even more complicated than an integrated circuit,” says engineer and group leader Eric Betzig. “With an IC, you know that every transistor fires the same—it's either on or off. But the neurons in the brain don't necessarily do that—they fire sometimes 20, sometimes 80, sometimes 100 percent.” So in addition to logic testing, the researchers also need to do imaging, and that's where Adler and his amazing microscope come in.

A standard scanning electron microscope (SEM) images at about 10 million pixels per second. For comparison, a high- definition TV screen runs at 30 million pixels per second. In 2005, the Pentagon gave funding to California-based KLA‑Tencor Corp., where Adler was then working, to invent a microscope that could operate at 1 billion pixels per second to verify circuit patterns on defense chips. Shortly after that, Janelia lured Harald Hess, a former colleague of Adler's, to the campus to direct its applied physics and instrumentation group. When the Janelia team started looking into imaging, Hess called Adler. When he found out what Janelia was working on, Adler says, “it blew my mind.” Hess wasn't interested in a microscope that could image at a paltry billion pixels per second. He wanted one that could process 10 billion per second.

To image the fruit-fly brain, the researchers use what they all refer to, gruesomely, as a “deli slicer”—the machine shaves 50-nanometer slices off the top of the infinitesimal fruit-fly brain “like slices of prosciutto,” says Betzig. (The same technique is used to reverse engineer microchips.) Then an electron microscope takes images of the brain slices, and these images are stacked carefully to form a 3‑D virtual wiring diagram.

Slice, image, slice, image. Easy, right? Wrong.

Compared with an IC, even a tiny fruit-fly brain is a mess. One major bottleneck is the sample preparation: the brains must be sliced into perfectly even slivers before they're imaged. Right now, that slice-and-image routine takes a whopping 10 months. The real time-waster isn't the actual imaging—it's the time it takes for each slice of brain to settle into place. Any movement, however slight, will make that hard-won image blurry. The fly brain is only about 300 micrometers on a side, but imaging one, even at 10 billion pixels per second, would take a whole day. You're trying to image everything down to about 5 nm—about one-hundredth the size of what a regular lab microscope can resolve.

The storage requirements for the raw data alone are staggering: Adler estimates that scientists could rack up about a petabyte—that's 1000 terabytes—of data for every day of imaging. Bear in mind that 1000 terabytes is for one fruit fly, with its sorry speck of a brain, and the biggest hard drive you can buy from a commercial vendor today holds only one terabyte of data. To get any good data, you'd have to compare hundreds of fruit-fly brains. Imaging hundreds of them at the speed and resolution of Adler's technology would require a warehouse. “If nothing else,” he says, “you're going to run out of space.”

Anyone over 30 remembers when a gigabyte of storage in one place was laughably sci-fi. It won't be long before a 10-PB hard drive is as boring as today's 100-GB hard drives. But this project doesn't have as its goal merely collecting data; it is trying to establish the exact connections among the neurons and synapses of the tiny creature's brain. And therein lies the big challenge. Each slice holds billions of pixels, and once every slice has been imaged, scientists have to piece them all back together to generate a 3-D wiring diagram. Adler compares the scale of the undertaking to trying to put together a real-time traffic map of North America from high-resolution satellite photos. “Now imagine that the United States is paved coast-to coast as densely as New York City,” he says. At the resolution necessary to see individual synapses, the data glut is crippling. “You have to turn that data glut into a wiring diagram that doesn't take up 1000 hard drives,” says Adler.