News this Week

Science  28 Feb 2014:
Vol. 343, Issue 6174, pp. 954

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  1. Around the World

    1 - Beijing
    Crackdown on Southern Chinese Research Graft Widens
    2 - Washington, D.C.
    New Website Tracks Forests in Near-Real Time
    3 - Paris
    Europe to Launch Hunt for Earth-Like Planets


    Crackdown on Southern Chinese Research Graft Widens


    Guangzhou, capital of Guangdong province.


    A corruption probe in one of China's wealthiest provinces has so far snared more than 50 scientists and research administrators. On 14 February, a government website for Guangdong province revealed that the provincial science bureau's former deputy director, Wang Kewei, was under investigation for violating antigraft regulations. The bureau's director, Li Xinghua, was removed from his post and stripped of Communist Party membership last month. And 21 employees of the science department of Foshan city were also charged in December with skimming money from government R&D subsidies intended for local companies.

    Guangdong spent nearly $4 billion on science and technology in 2012—a disproportionately large share of the roughly $36 billion in provincial government spending overall. "I think the current national leadership is very serious about corruption," says Cao Cong, an expert on Chinese science policy at the University of Nottingham in the United Kingdom. "They really want to crack down."

    Washington, D.C.

    New Website Tracks Forests in Near-Real Time

    Scientists, policymakers, and the public have a powerful new tool to study and monitor forests online. Global Forest Watch, launched last week by the World Resources Institute, allows users to access deforestation alerts updated monthly, locate current fires, and track forest loss or growth anywhere in the world.

    Underpinning the interactive website are two powerful new data sets based on satellite imaging. The first, with a geographical resolution of 500 meters, has already helped chimp conservationists confirm deforestation events as they occur. The second, highlighted in a paper last fall (Science, 15 November 2013, p. 850), offers an annual snapshot of global forests at 30-meter resolution. "In itself, more transparency doesn't lead to stopping deforestation," says Steve Schwartzman, of the Environmental Defense Fund in Washington, D.C., "but this is a terrific step."


    Europe to Launch Hunt for Earth-Like Planets


    The European Space Agency last week added a new mission to its "Cosmic Vision 2015–2025" program: a search for habitable planets outside our solar system. Of about 1000 known exoplanets, only a few dozen are rocky, as opposed to gaseous, and none of these have conditions that would allow liquid water on their surfaces. The PLAnetary Transits and Oscillations of stars (PLATO) mission, to launch in 2024, will try to find more planets that occupy the so-called habitable zone around sunlike stars by measuring the dimming of the light from a star as a planet passes in front of it.

    Other space-based observatories have used this technique to search for exoplanets, but to do so have had to monitor very faint stars. That makes it hard to determine an exoplanet's mass, and thereby decide if it is rocky or gaseous. PLATO will use 34 small telescopes to widen its field of view and monitor large numbers of bright, relatively nearby stars for up to 3 years at a time.

  2. Newsmakers

    Three Q's


    Last week, one of two research physicists in the U.S. House of Representatives announced he won't run for re election this fall. Representative Rush Holt (D–NJ), 65, isn't saying what he'll do next. But his passion for science-based policies still burns brightly.

    Q:How has the level of scientific discourse changed since you first came to Congress in 1999?

    R.H.:It has not gotten better, let's put it that way. There are still people who read popular science articles, and most members of Congress say they value science and respect scientists. But I don't see more scientific thinking—evidence-based, critical thinking.

    Q:Why would a scientist want to run for Congress?

    R.H.:We need all kinds, especially people who can analyze problems and not be bamboozled by technical talk. And scientists bring a skill set that can be useful.

    Q:What would it take to regain bipartisan support for science-related legislation?

    R.H.:It will take more people who have an allegiance to evidence. And what I'm saying is that many [current members] do not. That's what would have to change.

    Revered Primatologist Dies


    Primatologist and conservationist Alison Jolly, who suggested that social behavior drove the evolution of intelligence, died on 6 February in England at age 76.

    American-born Jolly, who studied the lemurs of Madagascar, was the first to report in the 1960s that females are dominant in some primates. This discovery "upended virtually all standing hypotheses about primate social behavior … and didn't go down easily at the time," says Anne Yoder, director of the Duke Lemur Center in Durham, North Carolina. Then, in a seminal Science paper (Science, 29 July 1966, p. 501), Jolly proposed that complex social interactions, rather than the need for sophisticated tools, drove the evolution of primate intelligence. This is now a leading theory. "[H]er insights transformed our understanding," wrote anthropologist Alison Richard of Yale University in an obituary. Jolly "never described herself as a feminist," Richard wrote, but "lived a life that led and supported feminism."

  3. Random Sample

    Science by the Eyeful


    The digital age may offer new ways to make data more eye-catching, but the effort to turn scientific research into a visual story is centuries old. The British Library in London is honoring that effort in a new exhibit called Beautiful Science: Picturing Data, Inspiring Insight. The exhibit draws on the library's collections to showcase artful displays of science through the ages, focusing on the themes of weather, evolution, and public health.


    The oldest piece on view is a 1617 illustration of the ancient Greek classifications of life forms, the Great Chain of Being, in which the goddess of wisdom stands atop a hierarchy of animals, plants, and minerals. The newest work, Martin Krzywinski's Circles of Life, relies on DNA sequencing data to illustrate our relationship to other species using colorful links between the top and bottom halves of the circles—each representing genes arrayed on a chromosome. The exhibit opened last week and will run through 26 May.

  4. Welcome to Beringia

    1. Heather Pringle

    A flurry of studies suggests that instead of being simply a bridge from Asia to the Americas, Beringia may have beckoned the ancestors of the first Americans to linger.

    The land time forgot.

    Even during an ice age, Beringia had few glaciers and greenery enough for large game.


    One summer day during the height of the last ice age, a small herd of elk moved through a now-vanished region of lowland above the Arctic Circle, nosing about small woody shrubs like crowberry and Labrador tea. Far to the west lay glacier-capped mountains, and along the plains between, horses, mammoths, and caribou wandered through patches of wildflowers—violet asters, yellow tansies, red burnets. The large animals and other game made good eating for roaming cave lions and cave hyena, as well as this landscape's top predator, humans.

    This vision of a land dotted with elk, blooming with wildflowers, and sprinkled with shrubs for firewood is a far cry from traditional views of the ice age north. For decades, researchers considered Beringia—the now partly submerged landmass that once stretched from Siberia's Verkhoyansk Mountains to northern Canada's Mackenzie River (see map)—as chiefly a highway. It served as a "land bridge" that large mammals, as well as the ancestors of the first Americans, hurried across on their way from Asia to a new continent.

    Now, a flurry of studies, including analyses of seafloor sediments and ancient DNA from plants and animals, are painting a surprising picture of this lost world. They suggest that Beringia, twice the size of Texas, could have been more welcoming than expected during the Last Glacial Maximum (LGM), a period of intensely cold temperatures from about 17,000 to 28,000 years ago. The research "really expands our knowledge of the ecology of Beringia," says archaeologist Michael Waters of Texas A&M University, College Station. And it fits well with one idea about the peopling of the New World, namely that the ancestors of the first Americans holed up in Beringia for 10,000 years during the LGM before continuing into North America.

    The findings are far from conclusive, and direct evidence for a long-term human presence in Beringia is scarce. But the results highlight an urgent need to get archaeological teams searching this now partly submerged and remote region, Waters says. "What I'd sure like to see is the archaeological Manhattan Project of Beringia," he says.

    Big chill, big pause

    Ancient Beringia is lost to us in more ways than one. The mammoths, woolly rhinos, and most other megafauna have vanished, along with most of the glacial-era vegetation that sustained them. And the central Beringian lowlands were drowned some 10,500 years ago, when melting ice raised sea level by about 120 meters. Areas that remain above water are often difficult to reach except by helicopter, so whole chunks of Beringia are terra incognita to archaeologists.

    Some of the most compelling hints of a human presence in Beringia have come from the genes of people living thousands of miles away. Back in 2007, for example, researchers led by molecular anthropologist Erika Tamm of the Estonian Biocentre in Tartu analyzed mitochondrial DNA from 601 Native Americans and 3764 Asians from geographically diverse populations. The team identified three subclades—C1b, C1c, and C1d—that were widely distributed in Native American groups, but absent in Asians. This pattern, plus a chronology based on mutation rates, strongly suggested that the ancestors of the first Americans were isolated from their Asian kin some 25,000 years ago, diversifying into the C subclades before they entered the Americas some 15,000 years ago.

    Standing still.

    One model suggests that people and game were isolated in Beringia for thousands of years before migrating to the Americas.

    After analyzing how the genetic signals are distributed geographically, Tamm and her colleagues concluded that the most likely place for this isolation was Beringia. If the ancestors of the Native Americans toughed it out there during the LGM, they would have been well positioned to swiftly people the New World when the cold period ended. Several other analyses of mitochondrial and nuclear DNA have supported this "Beringian standstill" model.

    Archaeological evidence for this scenario remains scarce, but some clues come from the Yana RHS locality at 71°N latitude in Beringia's far west in Siberia. This locality, the earliest known in Beringia at 32,000 years old, brimmed with carved ivory ornaments and bone tools such as sewing needles (Science, 2 January 2004, p. 52), suggesting a culture well adapted to life in the Arctic interior. Yana's broad-based hunters and foragers appear to have brought down diverse game including steppe bison, reindeer, horses, polar foxes, and birds.

    After Yana, the archaeological record in Beringia goes dark. The next site doesn't pop up until 14,400 years ago, at Swan Point, Alaska. Like Yana's occupants, the earliest Alaskans were broad-based hunter-gatherers, targeting everything from horses to hares.

    Given the spotty archaeological record, most archaeologists remained skeptical that people occupied northern Beringia throughout the brutally cold LGM. Most of the region escaped glaciation because of its largely arid climate, but winters averaged about 8°C colder than today. "Beringia seemed the last place on Earth that you would put a large population during one of the coldest periods in history," says archaeologist John Hoffecker of the University of Colorado, Boulder.

    Light my fire.

    Woody plants in Beringia's shrub tundra may have supplied firewood and tools for humans.


    In search of new clues, a team led by molecular biologists Meirav Meiri of Tel Aviv University and Ian Barnes of the Natural History Museum in London examined another Asian immigrant that passed through Beringia on its way to the New World: the elk, or wapiti (Cervus elaphus canadensis). Previous studies had suggested that these temperate and boreal forest dwellers first appeared in Alaska about 15,000 years ago, roughly the same time that humans seem to have arrived. Meiri and Barnes hypothesized that as temperatures rose, the elk swiftly barreled across Beringia and into the Americas.

    To test the idea, they collected 113 bone, antler, and teeth samples from ancient elk in museums and 74 specimens from modern elk across North America and Asia. After dating and sequencing most of the samples, they found what Barnes calls an "astonishing" picture, very different from what they had expected, as reported in the 7 February issue of the Proceedings of the Royal Society B.

    The radiocarbon dates and locality data indicate that elk had pushed into northwestern Beringia by at least 50,000 years ago, but didn't advance into North America until 15,200 years ago. Barnes and colleagues were so surprised that they analyzed hydrogen and oxygen isotopes from the Siberian specimens to double-check the locality data supplied by the museums. (The water and food the elk ingested influenced the isotopes in their bones, and can be used to trace the latitude where the animals lived.) The results confirmed the samples' Arctic origins. The researchers also used DNA data to estimate elk population size, which apparently declined during the LGM. But there was no sign that the population had been wiped out and later replaced.

    If the elk stood still in Beringia, perhaps humans did, too. The elk data suggest that humans could have been present in northwestern Beringia "much earlier and longer than we thought," Barnes says. Elk and humans may have migrated into the Americas together, he adds. Some of the oldest known artifacts in North America—13,000-year-old rods buried with Clovis tools and human bones at the Anzick site in Montana—are made from elk antler (Science, 14 February, p. 716). (The rods are even older than the bones at the site, suggesting that the artifacts were heirlooms when buried.)

    The elk findings are "an elegant piece of research," says archaeologist Greg Hare of the Yukon Government in Whitehorse, who was not a member of the team. Hare thinks both elk and humans could have survived in parts of Beringia during the LGM "as long as they had enough to eat."

    Arctic refuge

    The humans could have eaten the elk and any other game. But what were elk and other large herbivores eating? Previous pollen studies of Beringia's vegetation revealed mostly grasses. But grasses make more pollen than other types of plants do, so pollen studies may give a biased view.

    To get a more complete picture, an international team led by geneticist Eske Willerslev of the University of Copenhagen used a new technique: They extracted bulk DNA from 18 Beringian permafrost sites and used primers to fish out and sequence fragments of ancient DNA from plants. As they reported in Nature this month, their samples spanned the past 50,000 years and came from Beringia and other parts of the Eurasian Arctic. To find out what the megafauna ate, the team also sequenced the gut contents and coprolites of woolly mammoths, woolly rhinoceros, a horse, and a bison.

    The data held "a number of surprises," Willerslev says. Broad-leafed herbaceous plants called forbs, including species of thyme, vetch, and anemone, dominated the samples, even during the LGM. More than 60% of the DNA in the giant mammals' guts and poop was from forbs, and these flowering plants may have helped the megafauna survive. Forbs are rich in protein, and "promote easy digestion, so maybe the megafauna were [choosing] the forbs," says Yukon government paleontologist Grant Zazula in Whitehorse, a member of the team.

    Willerslev's samples came from areas of Beringia still on dry land. But pollen from what is now the sea floor suggests that different vegetation may have cloaked the lowlands, which would have been slightly warmer and moister than other areas. Pollen from a sediment core drilled near the coast of the central Beringian lowland shows that some trees and shrubs—including spruce, birch, and alder—survived the LGM, as graduate student Rachel Westbrook of the University of Alaska, Fairbanks, and colleagues reported at a 2012 meeting of the Geological Society of America. Pollen, plant, and insect records from other seafloor cores suggest a similar picture.

    Early adapters.

    Denizens of temperate and boreal forests today, elk survived ice age cold in Beringia.


    The now-drowned part of central Beringia was likely covered with shrub tundra—a form of tundra dominated by small woody plants and sprinkled with other vegetation including forbs—according to a Perspective by Hoffecker and colleagues on page 979 of this issue. Hoffecker adds that the woody shrubs, including dwarf birch, dwarf willow, and crowberry, could have been sources of valuable firewood for Beringian hunter-gatherers, helping them survive the ice age cold. Archaeological evidence shows that later indigenous peoples of both Alaska and Northeast Asia often fed their fires with fresh bone, which burns hot and fast, but they also added small quantities of wood. The wood makes the bone easier to ignite and the flames last longer, as shown in experiments reported in 2001 by archaeologist Isabelle Théry-Parisot of CNRS, the French national research agency.

    Arctic toolkit.

    Humans made bone tools as early as 32,000 years ago at Yana RHS in Siberia.


    There's no data on whether elk lived in the now-submerged Beringian lowlands, but Hoffecker suspects they might have, noting that wapiti are versatile grazers and browsers. With game to hunt and fuel for fires, "central Beringia could have been a magnet for people during that intense cold period," he says. He, too, thinks Beringia is the most plausible location for the geneticists' standstill model. It "not only gives people the resources to survive, but it's a place that was isolated from everywhere else during the Last Glacial Maximum," he says. Pollen records show that the shrub tundra expanded eastward into Alaska and the Yukon after about 16,000 years ago. Both elk and people could have followed the shifting vegetation into the New World.

    Barnes sees a slightly different story in the elk data. Rather than central Beringia being a magnet that caused species to linger, he thinks it was the site of some kind of ecological barrier that kept elk and possibly people in western Beringia—and out of the Americas—during the LGM. "It seems that the land bridge is closed for business before 15,000 years ago, and that humans were affected as well," he says.

    Finding out whether central Beringia was refuge or barrier and searching northeastern Siberia's wilderness for traces of ice age Beringian hunters will require a multidisciplinary approach. "Right now we have three stories that have been developing independently in the fields of archaeology, genetics, and paleoecology," says Hoffecker, who's organizing an interdisciplinary workshop on the Beringian standstill to be held in Colorado in the fall. "Now we have to bring the stories together."

  5. Can Down Syndrome Be Treated?

    1. Emily Underwood

    People with Down syndrome are signing up for trials of several drugs aimed at helping their cognitive impairment, even as researchers explore more radical ideas to "cure" the genetic disorder.

    Treatment plan.

    Brian Skotko (left) hopes to help people with Down syndrome, such as Kayla Flinkstrom (right), live independently.


    Brian Skotko remembers clearly when he first became an advocate for people with Down syndrome. It was on the playground in grade school, listening to his classmates use the R-word.

    "Someone would just casually say, ‘I'm such a retard,’ or ‘You're such a retard,’" he says. Even at that young age, Skotko found himself speaking up for his younger sister Kristin, who has the typical constellation of physical features and intellectual disability caused by having a third copy of chromosome 21. "I got to see firsthand what it's like to grow up with an extra chromosome," he says. "I learned along the way that some of the struggles are not defined by your chromosomes, but by the community that you live in."

    Over time, brotherly concern also developed into an intellectual curiosity about the cause of his sister's disorder, and Skotko became a medical geneticist. Now co-directing the Down Syndrome Program at Massachusetts General Hospital in Boston, he hopes to overturn one of the most entrenched assumptions about the disorder: that its cognitive symptoms are too complex and permanent to treat pharmaceutically.

    This spring, Skotko's clinic and others around the world are running two major trials of drugs that may alleviate some of the intellectual impairments in people with Down syndrome. One targets a chemical compound that is elevated in the blood in both Down syndrome and Alzheimer's disease, and may somehow harm the brain. The other takes aim at an inhibitory neurotransmitter system that may put a brake on brain activity in people with Down syndrome. Both trials face some unusual challenges, including recruiting enough people with Down syndrome and gaining their informed consent. But if the drugs work, they could give these individuals—who increasingly survive into middle age thanks to improved treatments for the syndrome's physical symptoms—a better chance at an independent life, Skotko says.

    Even as these trials move forward, a number of labs are pursuing a more radical option: addressing Down syndrome at its root. One line of work aims to steer fetal brain development back onto a more typical path; another would address the genetic cause of Down syndrome by inactivating the extra copy of chromosome 21. Although the prospect of treating Down syndrome at an early age, or even in the womb, is still far off, "this is an achievable goal," says Diana Bianchi, an expert on fetal genetic conditions at Tufts University, Boston.

    Early origins

    In 1946, popular pediatrician Benjamin Spock declared that all babies with Down syndrome should be immediately institutionalized because "if [the infant] merely exists at a level that is hardly human, it is much better for the other children and the parents to have him cared for elsewhere." The statement encapsulated a belief about the disorder that remained entrenched for decades: that Down syndrome is an immutable condition with little prospect of improvement or integration into society.

    In most cases, Down syndrome occurs when the two copies of chromosome 21, the smallest human chromosome, don't separate properly during the formation of sperm or eggs or during their union. Once fertilized, the egg ends up with three, rather than two, copies in each cell. As a result of the extra chromosome, scientists believe, the developing fetus receives an extra dose of the products of hundreds of genes, altering the delicate balance of proteins and other chemicals in the body.

    At the time of Spock's recommendation, most children with Down syndrome died before their teenage years from one of the myriad health problems that frequently accompany the disorder, such as congenital heart defects, immune deficiencies, and leukemia. Today, many people with the disorder live into their 60s, but these strides toward better physical health—largely the indirect result of medical advances ranging from antibiotics to heart valve replacement surgery—have greatly outpaced progress toward treating the impairments in IQ, speech, learning, and memory.

    The most dramatic changes in how people with Down syndrome are treated since Spock's era have not been medical, but social, says geneticist and cell biologist Robert Schoen of the nonprofit organization Research Down Syndrome in Chicago, Illinois. Now that people with Down syndrome have secured some basic rights—to attend school; to be employed; to be protected from abuse and discrimination—treatment is coming to the forefront, Schoen suggests. "I think this current generation of parents is looking for the next step beyond acceptance and inclusion."

    That statement rings true for Elaine Chaisson, mother of Brian, a 22-year-old with Down syndrome in Massachusetts. Brian, who is also legally blind, was the first teenager with significant mental and physical disabilities allowed to attend his local public high school. Getting the extra help he needed was exhausting, and it wasn't easy for him socially, she says. Other students "tried to break him," she says, "but he rose to the occasion."

    When they heard about the drug trials at Skotko's Down syndrome clinic at Massachusetts General Hospital, the Chaissons leapt at the opportunity to enroll. Brian is one of roughly 24 patients taking part in the smaller of the two, testing a compound called ELND005, or scyllo-inositol, originally intended for Alzheimer's disease. Researchers had noticed in animal and cell studies that ELND005, a sugar alcohol derived from plants such as the coconut palm, breaks up the β-amyloid plaques that accumulate in the brains of Alzheimer's patients. Further testing by the Dublin-based biotechnology company Elan, now part of Perrigo Co., then revealed that it also lowers levels of myo-inositol, a chemical associated with plaque formation and cognitive impairment.

    People with Down syndrome have unusually high levels of myo-inositol in their brains, particularly in the hippocampus, a region vital to memory and learning. By the time they reach their 40s, roughly 75% have also developed Alzheimer's-like plaques and dementia, presumably because they get an extra dose of the amyloid precursor protein gene on chromosome 21. Although ELND005 isn't intended to reverse abnormalities in brain development typical of Down syndrome, Elan proposes that by reducing myo-inositol, the drug will help neurons communicate more effectively and prevent the sticky plaques from forming.

    The current study will measure only the drug's short-term effects on Brian's learning, memory, and language abilities, but the Chaissons hope that it will also help their son avoid dementia in later life. Although he is "still struggling" with some aspects of the trial, such as having his blood drawn, the choice to join was ultimately her son's, Chaisson says. "Brian knows he has problems and just wants those things not to be there."

    Skotko hopes that the drugs he's testing will indeed help clear some of the cognitive obstacles Brian faces. He acknowledges having some mixed feelings about the trials, however. One lesson he's learned from his sister, and from surveying hundreds of people with Down syndrome, is that the vast majority are happy with their lives, who they are, and how they look. "People with Down syndrome are achieving success in school and employment, and are very satisfied with their lives," he says.

    Informed consent

    Decorating the walls of Mary Ellen McDonough's office is a lively collection of snapshots. Each smiling face has the almond-shaped eyes, flattened noses, small ears, and slightly protruding tongues that are telltale physical signs of Down syndrome. In one photo, a young man sits on the bed of an MRI scanner and gives the camera a celebratory two thumbs-up. McDonough, Skotko's clinical trial coordinator, explains that he had just had his brain scanned—a mandatory baseline before beginning the Elan trial—and had been so anxious about being rolled inside the machine's claustrophobia-inducing cylindrical gullet that he had to be sedated.

    Reassuring patients is only one of the challenges McDonough faces. After realizing that a 21-page, single-spaced legal consent document is inappropriate for people with Down syndrome, she devised a simplified, illustrated version. "A drug company called Elan has a new medicine," reads one caption next to an image of a pillbox. "We want to test how well it works. We need to know how people's bodies react to the new medicine." A "thumbs-up" and a "thumb-down" symbol on another page reads: "You can say YES, or you can say NO."

    Although the form mentions the possibility of dizziness, headache, sleepiness, and muscle pain, McDonough says she avoids talking too much about risks with the participants, as they sometimes become frightened and confused. Instead, she saves in-depth discussions of potential side effects for guardians and parents, who in most cases must give consent as well. Because the drug trials require a great deal of time and commitment—clinic visits at least once per week for 10 weeks for the Elan trial—Down syndrome researchers need participants and families "to understand and to trust," she says.

    Although Chaisson's family is particularly interested in the Elan trial because of their fear of Alzheimer's disease, Brian's mother also hopes to enroll her son in the second, much larger trial, which will begin in the next few months. The phase II trial, sponsored by Swiss pharmaceutical company Hoffmann-La Roche, will recruit 180 young adults and adolescents with Down syndrome at sites all over the world, including 33 from Skotko's clinic.

    The trial will test a compound called RG1662 that targets memory def icits thought to stem from an imbalance of inhibitory and excitatory activity in the brain. In the early 2000s, neuroscientist William Mobley, then at Stanford University in Palo Alto, California, and several other researchers noticed that mice bred with third copies of genes similar to those tripled in Down syndrome showed an excess of inhibitory brain activity. The inhibition seemed to encumber the rodents' ability to learn. Stanford neuroscientist Craig Garner likens it to driving with the parking brake on. The problem seemed especially pronounced in the hippocampus, where memories are processed and stored.

    Mobley wondered if it was possible to release that brake by blocking the activity of GABA, the brain's primary inhibitory neurotransmitter. He applied picrotoxin, a poisonous crystalline plant compound that prevents GABA from binding to a class of receptors called GABAA, to living slices of brain taken from the hippocampi of Down syndrome mice. The compound normalized electrical brain activity in the tissue, but was too dangerous to use as a drug because it causes seizures. Garner began administering other, safer GABA-blocking drugs to Down syndrome mice. In 2007, he and colleagues reported that several compounds, including PTZ, a circulatory and respiratory stimulant, largely reversed the rodents' memory and learning deficits. Once used to treat memory disorders, the Food and Drug Administration (FDA) took PTZ off the market in 1982 due to concerns about its efficacy and safety: Like picrotoxin, it causes seizures.

    Eerie similarity.

    Unlike a scan of a normal brain (center), those of people with Down syndrome (left) and Alzheimer's disease (far right) show similar protein plaques.


    As these discoveries unfolded, Michael Harpold, chair of the scientific advisory board for the Down Syndrome Research and Treatment Foundation, which had funded much of the laboratory work, decided to try to translate them into a safe treatment. Hoffmann-La Roche, along with several other companies, was already working to develop drugs that target GABA activity for general cognitive impairment, but not for Down syndrome. Tapping into the company's long-running focus on developmental disorders, Harpold helped persuade it to tackle the genetic disorder.

    The firm went on to develop its own drug, which selectively blocks brain receptors that contain a specific protein subunit called GABAA α5. In February 2013, it released a study in The Journal of Neuroscience showing significant reductions in the cognitive deficits in a mouse model of Down syndrome, without seizures. The company went on to demonstrate the initial clinical safety of the drug in people with and without Down syndrome with two phase I trials.

    Buoyed by such developments, Mobley, who is now at the University of California, San Diego, predicts that a pill that alleviates some of the memory and learning deficits of Down syndrome will be available within 5 years. Hoffmann-La Roche isn't the only company now pursuing drugs that target the balance of inhibitory and excitatory brain activity in Down syndrome, Harpold notes. Balance Therapeutics, a California-based company, is now recruiting participants for a phase I clinical trial of a compound commonly used in cough syrup that also has been shown to influence the GABA system.

    Neuroscientist Alberto Costa of Case Western Reserve University in Cleveland, Ohio, shares Mobley's excitement. But nearly 2 decades of searching for cognitive treatments for Down syndrome—inspired by his 19-year-old daughter, Tyche, who has the disorder—have taught him to be cautious. The recent flourishing of research into Down syndrome has produced at least 11 potentially interesting new drug leads, including nicotine, green tea extract, and various nerve growth factors, he says, but testing their efficacy and safety will be slow given the relatively low prevalence of the disorder, about one in 1000.

    For Costa's own recent trial of memantine, a drug already used to slow cognitive decline in Alzheimer's disease, it took 4 years to recruit 42 people with Down syndrome. The participants scored better on verbal memory tests when they took memantine than they did on a placebo, but the study was too small to be conclusive. Now, Costa is working with researchers in São Paulo, Brazil, to recruit 200 young adults and adolescents for a follow-up trial.

    Early intervention

    If current clinical drug trials in adults with Down syndrome don't work, it may be because the window of opportunity is already closed in adults, suggests Tufts University's Bianchi. Indeed, Costa believes that previous clinical trials of memantine in adults "completely failed" to show any benefits because the drug was likely administered too late. "You can't really revive neurons, or restore a disturbed neuronal network" if important brain structures "have basically gone away," he says.

    Once mature, the brains of people with Down syndrome are about 20% smaller than average and have fewer neurons, as well as abnormal connections between cells. Studies of rodent models of Down syndrome by Costa; Roger Reeves of Johns Hopkins University in Baltimore, Maryland; and Tarik Haydar of Boston University School of Medicine, among others, have revealed aberrations in the earliest stages of brain development. The most affected regions include the hippocampus; the prefrontal cortex, which governs higher level cognitive tasks such as planning; and the cerebellum, which coordinates movement and learning, as well as attention and language.

    The cerebellum is Reeves's personal fascination. In normal brain development, he notes, a population of neural stem cells in the cerebellum "has to divide like crazy the day after birth." In the Down syndrome mice he studies, these cells seem to miss the starting gun, he says, and the cerebellum never reaches its proper size and function.

    Last year, Reeves decided to amplify that "Go" signal. He used Sonic hedgehog, a powerful growth factor responsible for many aspects of development—we have Sonic hedgehog to thank for our symmetrical bodies and distinct fingers and toes, for example. On the day the Down syndrome mice were born, he injected the growth factor into cells in their cerebellum, and was startled to see that just one dose made the brain region develop to a normal size and at a normal pace. When the mice grew up, some of their learning deficits were also lessened, his group reported in Science Translational Medicine.

    The fact that "a single shot of a drug" at birth could correct an aspect of brain development "was a pretty satisfying and gratifying result," Reeves says. Although Mobley describes the improvements in the rodents' behavior and physiology as "modest," based on the study, "I bet there's something really significant about Sonic hedgehog signaling in Down syndrome," he says. Even subtle tweaks in the growth factor at birth or in the womb could have profound effects on development, he adds.

    Hopeful result.

    Jeanne Lawrence points to a cell in which her team has turned off a third copy of chromosome 21, leaving the two others untouched.


    There's still an enormous gap between such experiments in mice and treating a fetus diagnosed with Down syndrome, however, says cell biologist Jeanne Lawrence of the University of Massachusetts Medical School in Worcester. "Would you ever feel like you could apply this drug to a child or prenatally, based on a mouse study?"

    "If I waltzed down to the FDA and said we'd like to squirt Sonic hedgehog in some babies they'd probably just arrest me right there," Reeves acknowledges. The next step, he says, is to start exploring why neural stem cells in humans with an extra chromosome 21 are so reluctant to grow. "It would be a really neat experiment" if we could turn off the extra chromosome in those cells, he says.

    Genetic off switch

    A few hundred miles to the north of Baltimore, Lawrence is experimenting with exactly that. Last summer in Nature, to media fanfare that occasionally suggested a "cure" was at hand, she and her team unveiled a new technique for "silencing" the extra chromosome 21.

    Lawrence was trained as a genetic counselor before "falling in love" with chromosomes while working as an assistant in a lab. Her potential Down syndrome treatment involves inserting a gene called XIST into one of the copies of chromosome 21. XIST normally resides on the X chromosome and serves to shut down one of the two X chromosomes in females—both men and women get along with one X. The gene produces a long strand of RNA, which Lawrence says likely covers the chromosome in an RNA shroud, triggering proteins that block any genes from being transcribed.

    Working with pluripotent human stem cells created from people with Down syndrome, Lawrence used proteins that target specific DNA sequences to place XIST on one of the copies of chromosome 21. The added gene shut off the entire extra chromosome. Her colleague Jun Jiang, whose job is to try to coax Down syndrome stem cells into differentiating into neurons in a petri dish, says that the "silenced" cells develop normally. Rather than a scarce, neuron-poor moonscape or an unhealthy overgrowth of glial cells, which such stem cells from Down patients typically produce, Jiang sees many flourishing neural "rosettes" in her petri dishes—the early agglomerations of stem cells that ultimately turn into neurons. "Like beautiful flowers," she says.

    The XIST strategy is already a powerful tool for studying what goes wrong in Down syndrome in humans, Lawrence says. For example, because scientists can switch chromosome 21 off in some cells and not in others, this could provide a controlled model for testing drugs, such as regulators of Sonic hedgehog, that could improve neural stem cell function or differentiation, she says. Long-term, her team plans to extract neural stem cells from mouse models of Down syndrome, treat them with XIST, and transplant them back into the rodents' hippocampi to see if the cells proliferate and restore learning and memory, she says. Her lab is also planning to test strategies to deliver the XIST gene directly into neural stem cells in mice hippocampi to see if the injected gene can correct fetal brain development and later function in vivo.

    Both Lawrence and Reeves agree that the prospect of using XIST to treat Down syndrome in humans—either in utero or adulthood—is still extremely remote. Beyond the considerable technical obstacles, there are the ethical hurdles that come with a powerful genetic therapy, especially one that might be deployed in utero. "It's not clear to me how this is going to be translated into humans," Reeves says.

    That hasn't stopped the phone at Skotko's Massachusetts General Hospital Down Syndrome Program from ringing off the hook with calls from people wanting to sign up family members with Down syndrome for a trial with XIST, however. "We had a lot of untangling and explaining to do," when Lawrence's research was first published last summer, McDonough says.

    For Mary Beth Rattey, Lawrence's results generated strong emotions. "I burst into tears and had to pull over to the side of the road," when she heard about the work over the radio, the Townsend, Massachusetts, restaurant manager recalls. She, her husband Ray, and their 19-year-old daughter Genevieve, who has Down syndrome, regularly visit Lawrence's course on human genetics to talk to medical students about the disorder, so she had heard hints about the research before it was published. Even though she knows the advances will likely not benefit Genevieve, the potential for treatments that could help other families in the future is "incredible news," Rattey says. "I don't feel like I missed a boat—our life has been awesome—but for the first time, it seems like they have something to work with."