Bruce Lahn has always been something of a rebel. As an undergraduate at Beijing University in the late-1980s, Lahn was a ringleader in the first wave of student prodemocracy protests. "I was fiercely opposed to the communist ideology," he says. "I just didn't want to be told what to do, especially if it didn't come with a reason." These early rallies set the stage for the huge demonstrations that would culminate in the infamous crackdown in Tiananmen Square.
Although Lahn had transferred to Harvard University by the time the government sent in the tanks, his disgust with the system helped shape his scientific career. "I had this idea that the problems with China, in addition to being social, might also have a genetic root." Indeed, all human behavior – our tendency toward violence as well as our capacity for kindness – must, to some extent, be encoded in our DNA. So Lahn decided to study human genetics. "I was attracted by the idea of understanding human behavior, especially how it relates to society, in a deeper way."
In that effort to understand human behavior, Lahn, now a Howard Hughes Medical Institute (HHMI) investigator at the University of Chicago, is searching for the genes that make the human brain unique. By scanning the sequences of some 200 brain-related genes from mice, rats, macaques, and humans, Lahn and his colleagues have turned up a handful of genes that appear to have evolved very rapidly in the human lineage. Most are involved in brain development, suggesting that bigger, better-wired brains might have given our ancestors a selective advantage. These genes, Lahn hopes, might give us a handle on what makes us human.
"Not many people start out their careers saying they're going to study the molecular basis of humanness," says Ajit Varki of the University of California, San Diego. "That's what I find interesting about Bruce: he's decided to go for it. We need more people like him in the field."
MEN IN GENES
Before pouncing on what makes humans human, Lahn focused his attention on what makes men men. As a graduate student in HHMI investigator David Page's lab at MIT, Lahn characterized a couple of dozen genes that were unique to the Y chromosome. "One day he just decided he was going to clone all the genes on the Y chromosome," says Karin Jegalian, a former lab-mate who is now a freelance writer. "He realized that with a little bit of PCR and a few sequencing machines, he could do it. And he went ahead and got it done." The feat provided insight into the evolution of the Y, which started life as a standard-issue chromosome that shrunk and became specialized to govern sperm production and the development of other male-related traits.
The experience gave Lahn an entrée into human genetics and whetted his appetite for combining molecular biology with an appreciation of evolution. "I wanted to bring evolution to bear on molecular biology and I hoped that a synergy of the two would allow me to do things that people in either camp couldn't do," he says. Take, for example, his work on the potential "humanness genes." Now that Lahn and his lab have identified genes that have undergone accelerated evolution in humans, they'll investigate how the variants unique to humans contribute to building better brains.
"We're getting to the point where we can start taking the next step to look at function – to find out how these changes do what they do," says grad student Nitzan Mekel-Bobrov.
"Tying molecular evolution to function is a big goal," says Steve Dorus of the University of Bath, Lahn's first PhD student. "But Bruce is a go-getter with boundless energy. He's very tenacious and not afraid of tackling any kind of project." Even ones that involve probing the evolutionary changes that might have helped shape human behavior.
"Bruce is very careful to stick to the science, stick to the facts," says Mekel-Bobrov, because not everyone is comfortable with comparisons between humans and other primates, particularly comparisons that involve gene sequences. "When you align the chimp sequence and the human sequence you're immediately struck by the similarity between the two: base after base, the sequences are the same. It can be very jarring," he says. "If we're so similar, what is it that makes us special?"
IT'S IN OUR MINDS
To Lahn's mind, the brain seemed a good place to start. At the time, says Lahn, "the human was sequenced, the mouse was being sequenced, the rat was beginning to be sequenced, and monkey wasn't even on the drawing board. Given that we were just one small lab, we couldn't sequence the whole genome of any species." So he targeted the brain; a move Varki likens to the outlaw Willie Sutton saying that he robbed banks because "that's where the money is."
i"Bruce is going for the brain; he's going where the action is and finding things out. And that's great," says Varki. But Varki cautions that evolutionary changes don't occur in isolation and that a narrow focus on the brain, perhaps the most complex and difficult organ to probe, might cause the researchers to overlook clues to our humanness that are more accessible. For example, Varki notes, the tissue that shows the most obvious difference between humans and chimps actually falls just below the shoulders: the breast. In female chimps the breasts do not become very noticeable until the animal is pregnant. "It may be that the genes that are involved in that difference in the breast are the same ones that are responsible for some of the differences in brain development," he postulates.
So far, Lahn's approach appears to be paying off. Over the past year, he and his team have described their findings on human brain evolution in a flurry of papers in
"These projects are large: no single person could do any of them," says Jerry Wyckoff of the University of Missouri, Kansas City, a former postdoc. Most require the expertise of molecular biologists, geneticists, bioinformaticists, and even anthropologists. Fortunately, Lahn has been able to gather this variety of talents under one roof. "The thing that Bruce is really good at – his special talent, his mutant skill – is finding good people," says Wyckoff. "Bruce has great ideas. But without the people to play out those ideas, he wouldn't get very far. He's able to assemble the resources and people to take his ideas and run with them. It's why he's a successful scientist."
OTHER 'CRAZY' IDEAS
Chasing down candidate humanness genes is not Lahn's only big idea. He also maintains an active research program on stem cell biology. Just as Lahn wishes to understand what makes humans human, he also hopes to unravel why stem cells are stem cells. "Why are they capable of many different fates, whereas differentiated cells are stuck with their particular characteristics?" he muses. Lahn is conducting some of this research in China, in a stem cell center that he founded at Sun Yat-sen University. "There, it's easier to access materials, eggs, embryos, and fetal tissue. And we can do certain manipulations that would be hard to do here," he says. "The idea is to leverage the advantages, both in terms of social permissiveness and the cost of certain reagents."
At Sun Yat-sen University's Center for Stem Cell Biology and Tissue Engineering, Lahn and his colleagues are working to derive human and primate stem cell lines from embryos and fetuses with a variety of genetic backgrounds. Like many researchers, Lahn hopes to learn how to coax stem cells to differentiate into specific cell types, perhaps for eventual use therapeutically to replenish or repair tissues in patients with blood disorders or neurodegenerative disease.
For Lahn, returning to China is more than a convenience. It's his way of doing something to make China a better place – more like the place he was thinking about when he hung those first rally posters in the halls of Beijing University. "I believe the way to develop China is not to overthrow the communist government. The costs of that, in terms of violence and the ensuing chaos, may actually be too high a price to pay," he says. "Instead I want to help China develop scientifically, by promoting the exchange of information, the exchange of people, the flow of ideas. And I'd like to pursue research directions that will put China on the map [and] make China a leader in the world instead of having the country play a me-too, catch-up role," Lahn explains.
"I also have a number of more crazy ideas," he adds: growing human organs in monkeys, for example. "People talk of stem cell biology as if someday we'll be able to grow organs in a Petri dish," notes Lahn. "That's never going to happen. Certainly not in my lifetime." The way he sees it, the best way to grow an organ, particularly a complex organ such as heart or liver, would be to implant stem cells into a suitable host and then allow those cells to form the desired tissue in vivo, in the animal. For instance, to produce a liver that's suitable for transplant, Lahn imagines first generating a transgenic monkey whose own liver development fails early on. Researchers could then seed that animal with human stem cells that could take root and give rise to a liver that's almost entirely human. Lahn and his colleagues are currently investigating whether stem cells from one type of rodent can survive and differentiate in another.
"He's been talking about this stuff since graduate school," says Jegalian: stem cell biology and what makes us human. "At the time it sounded pretty kooky. But it's cool that he's still thinking about it, has published papers on it, and is even going back to China to do it."
Of course Lahn hasn't entirely abandoned the rebellious ways he first expressed in China. "I will probably continue to work on problems that are off the beaten path [and] approach science in a way that's less conventional in the hopes of finding something that's a little more exciting, that might bring major insights or upset conventions," he says. "I guess I still have a little bit of revolutionary spirit in me – even though now I'm more of an evolutionary guy."