Scientist of the Year: Runners-Up

John Donoghue is developing implants that connect the brain to a prosthetic limb, and Svante Pääbo is mapping the DNA of the Neanderthal.

By Kyla Dunn, Jennifer Kahn|Friday, December 01, 2006

Which scientist had the greatest impact in the past year? Mike Brown of Caltech forced astronomers to rethink what a planet is. Neil Shubin of the University of Chicago found a key fossil showing how life moved onto land. Emma Whitelaw of the Queensland Institute of Medical Research documented how heredity extends beyond genes. NASA's James Hansen bolstered the case for global warming and spoke out against government censorship. And these were just some of our finalists.

In the end we zeroed in on one researcher whose work stands out even in this illustrious company. We are pleased to announce Jay Keasling as the winner of DISCOVER's first Scientist of the Year award. Now meet the runners-up.

John Donoghue

BrainGate, the most sophisticated brain-computer interface yet tested in humans, is being developed by John Donoghue, head of the Brain Science Program at Brown University, through a company he cofounded: Cyberkinetics Neurotechnology Systems. In June 2004, quadraplegic Matthew Nagle became the first patient to receive an experimental implant in a part of his brain that controls hand and arm movement. The implant is a square silicon chip just four millimeters (about 1/6 of an inch) wide, studded with an array of 100 hair-thin electrodes. The chip sits on the surface of the brain, while the electrodes delve midway into the brain's two-millimeter-thick cortex to eavesdrop on neurons that normally signal muscles to move. A bundle of gold wires sends those signals out through a connector affixed to the top of the skull, and to an amplifier the size of a cigar box; they then travel by fiber-optic cable to a dishwasher-size cart of computers. During training sessions for BrainGate, the computer software learns to associate patterns of neural activity with the intent to move a hand in a particular direction; it can use those intentions to pilot a computer cursor or, if all goes as planned, a motorized wheelchair.

Donoghue remembers Nagle's first training session clearly. His team asked Nagle to imagine moving his arm and hand: first to the left, then to the right, to flex his wrist, or to open and close his hand. "To me it was just incredible because you could see brain cells changing their activity," Donoghue recalls. "Then I knew that everything could go forward, that the technology could actually work."

After three years of limb paralysis, it was by no means clear that Nagle's motor cortex could still signal his intentions in a meaningful way. Donoghue's work "profoundly shows that the signals in the part of the brain you'd need to operate these neuromotor prostheses exist years after a spinal cord injury," says neuroscientist Krishna Shenoy of Stanford University, who is working with the BrainGate sensor in monkeys. That finding, he says, along with the apparent safety of the implants, "has catapulted this entire field."

The eldest son of a bricklayer, Donoghue spent several years of his Arlington, Massachusetts, childhood in a wheelchair after developing a painful degenerative bone disease that ravaged his upper leg bones where they form the hip joint. It gave him some perspective, he says, "on what it means to be limited in your mobility and not able to do the things that the rest of the world is doing."

When he started his lab at Brown in 1984—after completing a doctorate there in 1979­—it was not to address mobility problems but to ask fundamental questions about the brain. How, for instance, does the brain translate intention into skilled movement? "I want to pick up my coffee cup, and my hand gets shaped and goes over there, picks it up, and grabs it. How does that happen?"

Recordings from just one, or even a few, neurons at a time in rats or monkeys weren't getting him close enough to the answer. So by 1992, he had begun looking for new technology that could detect the activity of many brain cells at once. He soon settled on a multi­electrode array­—now a component of BrainGate—developed by bioengineer Richard Normann at the University of Utah. Donoghue's original intent was basic brain research, but a powerful idea was taking shape among neuroscientists: coupling this type of sensor to an external device that could help the disabled.

In 2002 Donoghue reported that he had successfully trained monkeys to move a computer cursor using only their thoughts. Now, with FDA oversight, his team has tested BrainGate in four human patients, including Nagle. Two suffered spinal cord injury, a third was paralyzed by a stroke, and a fourth has amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). Still, kinks remain. Nagle often took two to three times as long as an able-bodied person would to move the computer cursor, and its trajectory often zigzagged wildly. Technical problems have plagued the performance of some of the implanted electrodes. Using the BrainGate system also requires a technician to recalibrate and tweak the software. But the bulky, wire-trussed equipment represents just an early stage technology. The next step is to miniaturize everything, to automate the functions currently performed by a technician, and to transmit the signals wirelessly so that nothing pokes out through the patient's head.

One of the most exciting things, Donoghue says, will be to see people who are paralyzed control their own limbs again in a very simple way. "I'm almost certain I'll never see somebody playing piano," he concedes. "But feeding themselves, doing simple tasks, I'm hoping that that's one thing that would happen." He is already taking steps in that direction. Cyberkinetics recently teamed up with bioengineer P. Hunter Peckham, director of the Functional Electrical Stimulation Center at the Louis Stokes Veterans Affairs Medical Center in Cleveland, Ohio. Peckham's team has developed a device that stimulates muscles patients can't control on their own—allowing them to use an arm, say, or extend their legs to stand up. Around 300 people are now implanted with these devices.

"I've had lunch with people with these things," Donoghue says. "You can pick up a Coke can and drink your Coke. Imagine your hand couldn't do anything, and now you can close it." Within five years, he hopes to couple that technology with BrainGate, allowing quadriplegics to move their limbs again, bypassing their damaged spinal cords entirely. In the meantime, he takes great satisfaction from seeing the effects of hope on patients like Matthew Nagle. "Think of the life that he leads and the fact that he got to be around technicians his own age. There was a lot of kinship, friendship there. That was really special."

Svante Pääbo

The genomes of humans and our closest living relatives, the chimpanzees, differ by just 1.23 percent. The difference between humans and our extinct cousins, the Neanderthals, is far smaller still: perhaps a tenth of that. Yet somewhere in that tiny gap lie the clues to what has been called "the great detective story of how we became what we are." Svante Pääbo, director of evolutionary genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, is one of the most masterful sleuths tracking down those clues. Recently he set out to sequence the complete Neanderthal genome within two years, in preparation for a side-by-side comparison with our own.

Pääbo did not begin his career with the mysteries of human evolution in mind. He was deep into medical school in his native Sweden when, in 1980, he interrupted those studies to pursue a Ph.D. in molecular genetics. The timing was fortunate; the early 1980s were a boom period for the field, thanks to a newfound ability to cut, paste, and sequence DNA. Soon after, a technology called PCR would enable scientists to pick out and amplify desired DNA while ignoring rogue elements, such as fungal and bacterial DNA.

Inspired by these advances, Pääbo—who as a teenager dreamed of becoming an Egyptologist—decided to take a look at ancient human DNA. With the help of an Egyptology professor, he obtained soft-tissue samples from several Egyptian mummies and, in 1984, coaxed scraps of human genetic material from them. His unprecedented success helped create the field of molecular paleontology. Pääbo has since plucked DNA from cave bears, mammoths, ground sloths, and even from a 5,000-year-old "ice man" found in the Italian Alps. After a decade of honing his skills, he turned to Neanderthals.

Ancient DNA is no picnic to work with. Bones rot, and the DNA in their marrow breaks down. Contamination from bacteria, fungi, and people—including well-meaning scientists who have touched the bones—is an ever-present problem. Recently, Pääbo's team had to probe some 60 different Neanderthal museum specimens to find just two containing viable material. He estimates that only 6 percent of the genetic material his team extracts from bones turns out to be Neanderthal DNA. A meticulous worker, Pääbo has been uniquely successful at producing clean results in the face of these odds.

In 1996, while a professor at the University of Munich, he and graduate student Matthias Krings recovered mitochondrial DNA from a 40,000-year-old piece of Neanderthal arm bone. An analysis of its sequence provided strong evidence that Neanderthals lie on a separate branch of the human family tree and are not our direct ancestors. It showed their evolutionary line splitting off from our own a little over 550,000 years ago, before modern humans emerged and before key changes in human brain evolution.

With new technology—developed by 454 Life Sciences Corporation of Branford, Connecticut—that vastly increases the number of short DNA segments that can be sequenced in a day, Pääbo can now go further. "Even a few years ago, I didn't imagine it would be possible to sequence the whole Neanderthal genome," he says. "This process is so cheap and efficient, it's a match made in heaven."

With the sequencing results in hand, Pääbo can make headway on exciting questions of evolution and identity. He has spent the past few years comparing chimp genes with our own, trying to reconstruct the crucial mutations responsible for our differences. In 2002 he reported that a gene known as FOXP2, which plays a role in language acquisition, produces a subtly different protein in humans than in chimps. Although the difference is small—just two amino acids—it is most likely significant, since the alteration was strongly favored by natural selection starting less than 200,000 years ago, around the time when human language took a great leap forward.

But gene sequences alone do not tell the whole story. Pääbo has also found that differences in gene expression (how active a gene is) may have played a role in creating the gap between chimp and human brains. By measuring messenger RNA in autopsied brains, he found that many genes, around 10 percent of those studied, are expressed at significantly different levels in the two species.

The challenge now is to prove that those results are meaningful. "We don't even know how gene expression changes on a day-to-day basis!" says glycobiologist Ajit Varki, who studies ape-human differences at the University of California at San Diego. "Somebody made a joke about it, but it's not really a joke: 'What was that human thinking before he died? What was that chimp thinking before he died?'" Even if a particular difference between the species is real, it does not necessarily explain our divergent cognitive abilities.

Since a rough draft of the chimp genome became available in 2005, much research has focused on human gene sequences that are missing in apes. One way to discern their function: Breed chimps that carry a uniquely human stretch of DNA and see what happens to their brains. But chimps are so similar to us that this type of experiment is considered unethical. "The dilemma, when one is interested in human-specific traits, is that there's really no animal model you can use," Pääbo says. "It's almost getting a little boring to find more genes that have been selected for, without having the connection to what they do."

So Pääbo recently began a project to breed mice laced with human-specific genes. "One could imagine, say, if you introduced genes involved with brain growth during development, that you might actually see a bigger brain or a differently structured brain," he explains. "Or you could imagine introducing genes that have to do with speech and language and seeing a change there—some motor control of the thorax." The first of these humanized mice are now being born in Germany. "It's the next big step in understanding human evolution," Pääbo says. "It's kind of futuristic."

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