Sunday, March 23, 2008

The Genetics of Language

Locating Language: The neural circuitry for speech and language is typically localized in the left hemisphere of the brain, along a region called the Sylvian fissure that stretches from Broca's area to Wernicke's. Researchers are searching for the genes that wire these regions and produce the uniquely human capacity for speech. Broca's area, highlighted above in green, is associated with speech and language output. Wernicke's area, highlighted in red, is associated with language comprehension.
Credit: John MacNeill

Daniel Geschwind reaches up to his office bookshelf, takes down a three-dimensional puzzle of the human brain, and begins trying to snap the plastic pieces together. A neurogeneticist at the University of California, Los Angeles, Geschwind hopes the puzzle will help him describe the parts of the brain that control speech and language. But for the life of him, he can't figure out how the left and right hemispheres attach. "I'm really bad spatially, so don't make fun of me," he pleads. "It's like I'm having a little stroke or something. I'll get it together, and then I'll figure it out."

The plastic model may have momentarily flummoxed Geschwind, but when it comes to the genes that govern the brain's development and functions, he excels at putting the pieces together. Over the past few years, he has emerged as one of the leading geneticists in a nascent field that aims to spell out which genes are related to speech and language development--and how our intelligence and communication skills evolved beyond those of our ape relatives, giving us the unique ability to speak.

Research like Geschwind's sits at the intersection of two fields: behavioral genetics and evolutionary bi­ology. Each field depends on the other to make sense of the flood of studies on the genetics of language now pouring out of labs around the world. To peer into the human brain and see how it typically stores, uses, and comprehends words, Geschwind investigates not only normal human brains but also those where the process goes awry, studying the genes of families afflicted by autism, dyslexia, schizophrenia, and other conditions that can involve speech and language disorders. This research may help make diagnosis and treatment of language-related disorders more precise, but it also has a more basic purpose. "Studying disease is really a fundamental way to understand normal function," says Geschwind. "Disease has given us extraordinary insight to understand how the brain works or might not work."

While behavioral genetics compares the genes of people with different abilities, evolutionary biology compares the genes of different species. Researchers use this data to determine what limits other species' communication skills and what expanded ours so dramatically that language became one of our defining characteristics. Geschwind's own forays into evolutionary bi­ology have led him to look at DNA in the brains of chimpanzees, monkeys, and even songbirds. "A lot of people think our lab is all over the place," he says. "It's actually pretty integrated. Language is complex, and the only way we're going to have a hit is when two or three findings point to the same place."

With the help of improved techniques for detecting DNA, as well as cutting-edge analytical tools and the genome sequences of species from humans to mice, Geschwind and other researchers have begun to tease out how we evolved the capacity for sophisticated speech. But though neuroscientists working in the postgenomic era have made a lot of progress, they have only begun to scratch the surface of how the relevant genes are collectively put into action.

FOXP2 Hunting
Despite more than a decade of effort and many tantalizing leads, neurogeneticists have so far definitively linked only a single gene to speech and language. The story of its discovery begins in 1990, when clinical geneticists at the Institute of Child Health in London first reported a speech disorder that appeared in three generations of Britons known as the KE family. The doctors took note of 15 affected members who seemed to have inherited problems with grammar, syntax, and vocabulary that were tied to poor control of facial muscles and difficulty pronouncing words. Although it seemed clear that there had to be a genetic link, researchers hunted for more than a decade before they found the gene responsible.

The big break came in 1998, when University of Oxford geneticists led by Anthony Monaco and Simon Fisher identified a distinct chunk of chromosome 7 linked to the speech and language problems found in the KE family. Yet the region held dozens of genes, and they couldn't pinpoint the one bad actor. Enter Jane Hurst, a clinical geneticist who worked at a hospital on Oxford's grounds and, coincidentally, had coauthored the first report on the KE family.

The Glimmering Promise of Gene Therapy

Its history is marred by failures, false hopes, and even death, but for a number of the most horrendous human diseases, gene therapy still holds the promise of a cure. Now, for the first time, there is reason to believe that it is actually working.

Credit: Illustration by Chris Buzelli

By the late 1960s, molecular biologists had erected an overarching explanation of how genes work--their substance, their structure, their replication, their expression, their regulation or control. Or at least they had done so in outline, for prokaryotes, the simplest single-celled organisms (which include bacteria), and for the viruses, called bacteriophages, that prey upon them. The leaders of the field were now looking to a far more difficult problem: doing it all over again for higher organisms.

What this new generation of molecular biology demanded, and what was developed in just a few years, was a set of methods for investigating and precisely manipulating the genetics of eukaryotes, including animals and plants. With reverse transcriptase, which was discovered independently by ­Howard Temin and David Baltimore in 1970, genes encoded in RNA could be read back into DNA. With Daniel Nathans's and Hamilton Smith's work on restriction enzymes, segments of DNA could be snipped out at chosen sites. In a rush, from laboratories chiefly at Stanford University, came ways to link together genetic material from disparate sources. "We will be able to combine anything with anything," one senior scientist told me at the time. "We can combine duck with orange." The initial purpose was to get at the most basic questions of cellular biology, to find out exactly what individual genes do and how they do it. Immediately, though, a shining hope dawned: that this toolbox could be carried from the laboratory to the clinic, to cure hereditary diseases caused by genetic defects. Already, some scientists were dreaming of gene therapy.

By 1970, some 1,500 genetically determined diseases had been identified in humans. Some show up in babies; others surface at puberty; a few emerge only toward the end of the victim's reproductive life. Some can be held in check by dietary restrictions, a few by drugs. But most cannot be cured or even palliated by conventional medicine. Though almost all are rare, some extremely rare, collectively they were coming to be recognized as a burdensome and costly medical problem. Many are marked by gross mental impairment. Victims of Lesch-Nyhan disease, for example, suffer severe mental retardation. They must have their arms splinted, because otherwise they bite their hands and arms. They die in childhood or early adulthood. Though scientists had traced fewer than a hundred of these human diseases to specific genetic deficiencies, they began searching for ways to cure them by safely inserting correcting genes into people suffering from them.

They were still trying nearly two decades later, when on September 29, 1999, the front page ofthe Washington Post carried the headline "Teen Dies Undergoing Experimental Gene Therapy." Jesse Gelsinger was 18, a recent high-school graduate from Arizona who had a potentially fatal genetic disease. He was one of 18 patients taking part in a trial at the University of Pennsylvania. Viruses carrying a new gene had been injected into one of the arteries supplying blood to his liver. In gene therapy, an engineered virus is often used as a "vector," delivering the desired gene to the patient's cells; in this case, however, the virus apparently triggered a series of deadly events.

The New York Times picked up the story the day after it ran in the Post. The National Institutes of Health and the U.S. Food and Drug Administration started investigations, which moved with commendable speed; more details came out. Later, the U.S. attorney general got involved. But with those first newspaper reports, gene therapy seemed dead.

Cheap, Efficient Thermoelectrics

Nanomaterials could be used for lower-emission cars and solar panels.

Efficient crystals: Researchers increased the efficiency of a commonly used thermoelectric material, bismuth antimony telluride, by grinding it into a fine powder and pressing it back together. This technique creates random crystal lattices (lines in this tunneling-electron microscope image of the material) that interrupt the flow of heat.
Credit: Zhifeng Ren, Boston College

Thermoelectric materials promise everything from clean power for cars to clean power from the sun, but making these materials widely useful has been a challenge. Now researchers at MIT and Boston College have developed an inexpensive, simple technique for achieving a 40 percent increase in the efficiency of a common thermoelectric material. Thermoelectric materials, which can convert heat into electricity and electricity into heat, hold promise for turning waste heat into power. But thermoelectric materials have not been efficient enough to move beyond niche applications. The new jump in efficiency, achieved with a relatively inexpensive material, may finally make possible such applications as solar panels that turn the sun's heat into electricity, and car exhaust pipes that use waste heat to power the radio and air conditioner.

The researchers started with bismuth antimony telluride, a thermoelectric material used in niche products such as picnic coolers and cooling car seats. Then Gang Chen, a professor of mechanical engineering at MIT; Institute Professor Mildred Dresselhaus; and Boston College physics professor Zhifeng Ren crushed it into a powder with a grain size averaging about 20 nanometers, and pressed it into discs and bars at high heat. The resulting material has a much finer crystalline lattice structure than the original material, which is made up of millimeter-scale grains. Chen and Ren's nanocomposite formulation of the material is 40 percent more efficient than the conventional form of the material at 100 °C, and it works at temperatures ranging from room temperature to 250 °C.

"Power-generation applications [for thermoelectrics] are not big now because the materials aren't good enough," says Chen. He believes that his group's more efficient version of the material will finally make such applications commercially viable.

Thermoelectric materials must be able to maintain a heat gradient, which means that they must be good conductors of electrons and good thermal insulators. When one end of a bar of thermoelectric material is heated, electrons move from the hot side to the cold, creating an electrical current. If a material conducts heat well, this current-generating temperature gradient will dissipate. Unfortunately, in most bulk materials, electrical conductivity and thermal conductivity "go hand in hand," says John Fairbanks, who heads thermoelectrics efforts in the Department of Energy's Vehicle Technologies Program.

One approach to making better thermoelectric materials has been to build nanostructured materials from the bottom up. Interfaces in these materials reflect the flow of heat without impeding electrical current. Researchers who have grown arrays of silicon nanowires, pressed silicon and germanium nanowires into millimeter-scale bars, and tested single organic molecules have had success on a small scale, but making such materials in bulk is a major hurdle.

The researchers' nanocomposite technique creates many interfaces in the material that reflect thermal vibrations, says Chen. Peidong Yang, a professor of chemistry at the University of California, Berkeley, says that the work is "a great example of how defect engineering can significantly impact on the [vibration] transfer in solids."

Ren says that it's easy to make large amounts of the nanocomposite material: "We're not talking grams; we're not talking kilograms. We can make metric tons." Because bismuth antimony telluride is already used in commercial products, Ren and Chen predict that their technique will be integrated into commercial manufacturing in several months.