News this Week

Science  25 May 2012:
Vol. 336, Issue 6084, pp. 964

You are currently viewing the .

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

  1. Around the World

    1 - London
    British Team Cancels Geoengineering Experiment
    2 - New Delhi
    Hope for Reversal of Tiger Reserves Research Ban
    3 - Rome
    Supervolcano Drilling Plan Gets Green Light
    4 - Ontario, Canada
    Experimental Lakes on the Cutting Block
    5 - Harpenden, U.K.
    Intruder Arrested at GM Field Trial
    6 - Washington, D.C.
    Prostate Cancer Test a Failure


    British Team Cancels Geoengineering Experiment

    A U.K. project examining the feasibility of geoengineering Earth's climate to reduce global warming will no longer involve the Stratospheric Particle Injection for Climate Engineering (SPICE) project. The project was to investigate whether aerosols, such as sulfate particles, could be injected into Earth's stratosphere to scatter sunlight back into space, thereby stalling global warming. But following concerns that researchers on the SPICE project could have a commercial interest in its success, planners canceled the project on 16 May.

    SPICE scientists were hoping to test an aerosol delivery system later this year: A balloon that would carry aloft a kilometer-long pipe that would release 150 liters of water (a substitute for sulfates).

    Project leader Matthew Watson of the University of Bristol said in a 16 May statement that the cancellation of the test was partly due to concerns that the pipe-delivery technology was the subject of a U.K. patent application before the project began. Efforts are now underway to make sure the intention of the patent application is to protect intellectual property and not to pave the way for commercial gain, he added.

    New Delhi

    Hope for Reversal of Tiger Reserves Research Ban


    Field biologists seeking research permits to work in the tiger reserves of Karnataka in southern India may be getting a reprieve. Over the last 2 years, then–chief wildlife warden Brij Kishore Singh has denied permits to about 40 researchers, suggesting that the habitats were to be left “inviolate” (Science, 23 March, p. 1429). But new warden Dipak Sarmah, who took charge on 2 May, says he plans to issue some permits—although, he warns, “there will have to be some rationing.” Ecologist Raman Sukumar of the Indian Institute of Science in Bangalore says he is hopeful after resubmitting his papers 17 May to study human-elephant conflict in the Nagarahole National Park tiger reserve because Sarmah, he says, gave him “a patient hearing.”

    Last week, at an international meeting of the Global Tiger Forum in New Delhi, India's environment minister, Jayanthi Natarajan, reiterated that researchers were welcome and that the federal government had “not imposed any ban on wildlife research.” India is home to about half of the world's 3200 wild tigers, which remain endangered due to poaching and habitat loss.


    Supervolcano Drilling Plan Gets Green Light

    Part of Campi Flegrei caldera


    A project to drill 500 meters into the heart of a “supervolcano” in southern Italy got the go-ahead on 17 May, despite claims that the drilling would put the population of Naples at risk for small earthquakes or an explosion.

    The Campi Flegrei Deep Drilling Project was set up by an international collaboration of scientists to assess the risks posed by the Campi Flegrei caldera, a geological formation just a few kilometers west of Naples. Researchers will place sensors inside the wells to study the region's “bradyseisms,” the rising and falling of Earth's surface resulting from the movement of magma inside a caldera, and determine whether they are connected to volcanic eruptions.

    Originally scheduled for 2009, the plan was put on hold by then-mayor Rosa Russo Iervolino after scientists expressed concerns that the drilling might cause earthquakes or an explosion if it releases high-pressure supercritical fluids that then come into contact with magma.

    Collaboration member Ulrich Harms of the German Research Centre for Geosciences in Potsdam said at the time that if the drilling is done in a controlled way, “there is no risk to the public.”

    Ontario, Canada

    Experimental Lakes on the Cutting Block

    A wave of budget cuts to Canada's Department of Fisheries and Oceans, in which 330 DFO scientists and professionals have been warned their positions might disappear or change, is now engulfing a unique research area in Ontario. The Canadian government's announcement on 17 May that it would close the Experimental Lakes Area (ELA), composed of 58 small lakes and their drainage basins, has set off alarms in the environmental science community.

    Canadian researchers have experimented with the whole-lake laboratories in Ontario since the 1960s, exploring impacts of phosphorus, acid rain, and metal contaminants to natural ecosystems. Recent projects there include the Mercury Experiment to Assess Atmospheric Loadings in Canada and the United States (METAALICUS), a partnership with researchers from the U.S. Geological Survey to explore mercury methylation and uptake in fish in real-world settings (Science, 28 November 2008, p. 1316).

    ELA is “a one-of-a-kind place” to perform whole-ecosystem experiments, says one researcher who has worked on the METAALICUS project, and closing it would be “devastating to Canadian scientists and those around the world.” Scientists and others are mustering to protest. In a 17 May press release, a scientists' union, the Professional Institute of the Public Service of Canada, labels the proposed ELA closure and other cuts to DFO as hits to science-based decision-making by the federal government.

    Harpenden, U.K.

    Intruder Arrested at GM Field Trial


    A protester was arrested the morning of 20 May after attempting to break into a field trial of genetically modified wheat (below) at Rothamsted Research, an agricultural research station in Harpenden, U.K. The attack damaged fences and some of the “buffer zone” crops surrounding the experimental wheat, but damaged “less than 0.1%” of the test crop, says Darren Hughes, head of communications at Rothamsted.

    Take the Flour Back, a group of activists that has invited the public to a day of protest at the site on 27 May, has said it has no connection to yesterday's incident. According to an e-mailed statement, the group's Eleanor Baylis says: “We have no information about this incident, but are relieved if the quantity of GM pollen released from the trial has been reduced.” The group said it plans to go ahead with its protest plans for next weekend, which include destroying the experimental plot. Scientists involved in the trial have issued a public plea to the protesters to allow the trial to proceed. Both sides debated the issue last week on a leading BBC news program.

    Washington, D.C.

    Prostate Cancer Test a Failure

    The U.S. Preventive Services Task Force, an independent group that advises the U.S. government, trashed a popular blood test for prostate cancer risk on 21 May, saying its use is doing more harm than good.

    Measuring levels of prostate-specific antigen (PSA) in circulation is unnecessary for healthy men, regardless of age, the panel concludes. The test has prevented few deaths—at best 1 in 1000 men screened—but for every 1000 men screened, the subsequent medical treatment leaves one with a blood clot, two with treatment-related heart attacks, and up to 40 with impotence or urinary incontinence.

    Sushil S. Lacy, a professor of urology at the University of Nebraska Medical Center in Omaha and president of the American Urological Association, called the announcement a “disservice to American men.”

    Similar concerns about the government oversight of medical practice arose in 2009 when the same task force (but with different members) downgraded the value of mammography as a way of preventing death from breast cancer. Like those guidelines, the prostate cancer recommendations may be debated in Congress.

  2. Random Sample

    Dueling Over a Mongolian Dinosaur


    An Asian relative of the titanic Tyrannosaurus sparked a tussle this weekend. Questions surrounding the origin of a nearly complete Tarbosaurus skeleton, auctioned off on 20 May in New York City, touched off a protest by the Mongolian government. Tarbosaurus specimens are found in only Mongolia, which prohibits removal of vertebrate fossils from the country. Officials with Heritage Auctions, the Texas-based company responsible for the sale, said the 2.5-meter-tall, 7-meter-long specimen came from a seller in the United Kingdom who stated in writing that he had legal ownership. On 19 May, lawyers for the Mongolian government obtained a temporary restraining order from a district court judge in Dallas, Texas, to halt the sale pending confirmation of the fossil's origin. But Heritage Auctions President Greg Rohan says the restraining order was directed at the wrong corporation and thus was not enforceable. So the company went ahead with the auction. However, Heritage Auctions won't accept payment or release the fossil to the buyer until the legal issues are resolved. For now, Tarbosaurus still resides in New York City.

    Something Old and Something New


    The storage rooms of the University of Cambridge's Museum of Archaeology and Anthropology contain thousands of methodically labeled artifacts of human history in the British Isles and around the world. With funding from Arts Council England, the museum closed temporarily to delve into its collections and find new ways to describe complex migration and trading routes through Cambridgeshire, as well as human history back to the Paleolithic.


    The museum's light, airy displays, which reopen today, paint rich portraits: Several iron Viking spears confirm that people's reputation as fierce warriors, but they are juxtaposed with a whalebone ironing board (left) in the same showcase, creating an image of the Vikings' softer domestic side. A 1700-year-old coffin made from rock quarried 40 miles north of Cambridge, with a lead inner case, demonstrates the Roman commitment to preserving their dead. From the oldest, a 1.8-million-year-old stone tool from Tanzania, to the newest, a carving completed last week by George Nuku in traditional Maori style but applied to Perspex rather than wood, the museum's collection “make[s] it possible for the audience to imagine stories” about daily life across the ages, says museum Director Nicholas Thomas. “Archaeology,” Thomas says, “is not just about science, it's also about imagination.”

    Curator Mark Elliott says he also wanted to remind viewers of the archaeological research process by displaying a few of the museum's hundreds of drawers of samples, filled with treasures and discoveries such as cutlery and personal adornments.

    By the Numbers

    86% Percentage of 258 major fish stocks reviewed by the National Oceanic and Atmospheric Administration that are not being overfished, according to a 14 May report.

    15% Percentage of U.S. teenagers who have prediabetes or diabetes, according to a study published online 21 May by Pediatrics and based on data spanning from 1999 to 2008.


    Join us Thursday, 31 May, at 3 p.m. EDT for a live chat on geoengineering.

  3. Newsmakers

    Three Q's



    Electrical engineer L. Rafael Reif was voted president of the Massachusetts Institute of Technology (MIT) in Cambridge on 16 May. A faculty member for 32 years, the Venezuelan native assumes his post on 2 July. Reif replaces neuroscientist Susan Hockfield, who has been MIT's president since 2004.

    Q:Why do you want this job?

    I view MIT as my home, my extended family. So the opportunity to be sort of head of the household is something that I really want to do.

    Q:Despite gains by MIT's female science and engineering faculty, there are perceptions that some hold their positions due to gender rather than expertise. How do you combat those perceptions?

    I think people here respect each other for what they have achieved. But I don't doubt that that perception exists at other places. The way to address that is just to do what we do: hire the best people we can find regardless of sex. If we keep hiring the best people we find, they will succeed in society, and that's all we expect them to do.

    Q:MIT and Harvard University recently announced that they would offer free online courses. Why open up your classrooms like this?

    The driving force for doing this is to improve the way we educate on campus. In the future, [a] particular course will be a combination of something you learn online, plus something you do in the classroom. It doesn't cost us anything to share [our online material] with the world.

  4. Evolutionary Biology

    An Evolutionary Theory of Dentistry

    1. Ann Gibbons

    Why are our teeth so rotten? Biologists point to a mismatch between our diets and lifestyles and those of our ancestors.

    Healthy bite.

    This ancient Egyptian had healthier teeth and jaws than most living humans.


    DURHAM, NORTH CAROLINA—Remember the Coca-Cola jingle that went, “I'd like to buy the world a Coke and keep it company”? Well, it worked. And here's what happens when everyone can buy a soda every day in a small town on the northern tip of Mexico's Yucatán Peninsula: Young adults in the town of Dzilam González had three times as many cavities as those who live in a poorer, more isolated village nearby where people can't afford soft drinks every day, according to a new study. In the poorer village, people eat a traditional diet of maize tortillas at every meal. The richer village has a pizzeria in its central square, shops with ads for soft drinks, dentists' offices—and significantly more tooth decay in people aged 20 to 30, according to a new study by Elma Vega Lizama and Andrea Cucina of the Autonomous University of Yucatán in Mérida, Mexico.

    Not-so-sweet tooth.

    This German jaw from the 16th to 18th century shows the perils of a poor diet in tooth loss, cavities, and gum disease.


    Cucina presented the study of these two Maya villages at a recent meeting* here. The work offers an elegant demonstration of the message that emerged at the meeting: Human teeth, jaws, and mouths are not adapted in a healthy way to the diet of modern industrial society. We evolved to thrive on coarse seeds, nuts, tubers, fruit, and meat. In our skeletons, too, our evolutionary history leaves us prone to medical problems (see sidebar, p. 974). But when it comes to our mouths, the mismatch between our adaptations and our environment causes the dental cavities, over-crowding of teeth, overbite, and gum disease that run rampant today.

    The Maya of the two villages are before-and-after images of a population undergoing the so-called nutrition transition in which people switch from a traditional subsistence diet to an Industrial Age diet of refined sugars and processed foods. At the meeting, an unusual mix of paleoanthropologists, archaeologists, dental researchers, and food scientists explored what is known about the diets and dental health of ancient humans, and how that information might be useful to dentists today. “How does our oral environment today differ from those in which our teeth evolved?” asked co-organizer Peter Ungar of the University of Arkansas (UA), Fayetteville. “Can an understanding of this discordance inform clinical research and ultimately dental and orthodontic practice?”

    When the ancients smiled

    The meeting began with grim slides of primates with terrible teeth and swollen gums, demonstrating that humans aren't the only ones with toothache. “Trauma, dysplasia, hypoplasia, arthritis, cysts—it's all there in animals,” says anatomist Christopher Dean of University College London (UCL). “These are usual in wild animals in the last decades of their life, as part of the aging process.” But tooth decay and gum disease get worse with a soft, sugar-rich diet in captivity.

    Cavities and periodontal disease used to be diseases of aging in humans, too. In fossils of ancient humans, “you can count the number of cases of dental caries [cavities] on one hand,” says UCL bioarchaeologist Simon Hillson. Researchers, such as Ungar, who have examined thousands of fossilized human ancestors estimate that cavities appear in fewer than 2% of teeth from earlier than 20,000 years ago. Traditional foragers, such as Australian aboriginals in the 1940s, still had beautiful teeth, with cavities in only the very old. (Other foragers with diets rich in plant carbohydrates, which are sugars, are an exception.) Gum disease and malocclusion—problems in the way the upper and lower teeth fit together, such as overbite—are also surprisingly rare in prehistoric teeth, says Robert Corruccini of Southern Illinois University in Carbondale, who reviewed 20 years of research on cross-cultural differences in occlusion.

    This clean bill of dental health began to deteriorate, however, as farming started to take root as early as 13,000 years ago in the Middle East and later in other parts of the world. Roughly 9% of Neolithic people—the first farmers—had cavities, as they began to consume cereal grains rich in carbohydrates, Ungar says. Even so, many millennia elapsed before dietary changes resulted in serious oral damage. For example, the skeletons of 93 commoners excavated at Amarna, Egypt, who apparently died between about 1330 B.C.E. and 1350 B.C.E., had surprisingly good teeth, says UA anthropologist Jerome Rose. These Egyptians ate more carbohydrates than hunter-gatherers did, in the form of coarse bread, but they also ate so much grit and fiber that the surfaces of their teeth—including any cavities—wore down rapidly. “The wear was fast enough to erase decay until late in life when decay showed up between teeth,” Rose says.

    The Egyptians' coarse diet also had a positive impact on jaw development. Chewing stresses stimulate growth of alveolar bone, the thin layer of bone surrounding the roots of teeth, which causes children's lower jaws to grow more robust and longer, with little overbite or malocclusion. As a result, when the ancient Egyptians closed their jaws, their upper and lower incisors (the four front teeth) met in an edge-to-edge bite, with good spacing between the teeth in their robust faces. People today, who eat softer foods, have a “scissors configuration” bite, in which the upper incisors protrude over the lower incisors, because the lower jaw is smaller than the upper one.

    Perils of a sweet tooth

    In Europe, less than 10% of individuals had cavities until Alexander the Great brought sugar to Greece in the 4th century B.C.E., according to earlier studies, says pediatric dentist Kevin Boyd of Children's Memorial Hospital in Chicago, Illinois. Cavities increased first in Greece, then Rome; their incidence also rose throughout Europe in the Middle Ages. But the biggest spike was from 1800 to 1850, when Britain took control of the West Indies and imported far more sugar than previously. Sugar helped fuel the Industrial Revolution, which was a transition from an agriculture-based economy to a machine-based economy. In 1874, the British reduced the tax on sugar, and it became available to all social classes. “In London, mostly 1800 onwards, they have absolutely dreadful teeth,” Hillson says.

    The damage caused by refined sugar is well known: It alters the optimum pH of 5.4 in the mouth, making saliva more acidic. That saliva, as well as acid produced by bacteria in plaque, dissolves minerals in the enamel, causing cavities. By the middle of the 20th century, between 50% and 90% of the population in Europe and the United States had cavities. This improved in the 1970s when water was fluoridated. But for the first time in 40 years, the U.S. Centers for Disease Control and Prevention recently noted an increase in cavities in children aged 2 to 5 years. Dentists blame snacking and sugars in juice and sodas.

    In the latter half of the 20th century, over-crowding of teeth and malocclusion became rampant. Today, nine in 10 adolescents in the United States have some malocclusion, and half could benefit from orthodontic treatment, Corruccini says. Impaction of the third molars, or wisdom teeth, occurs 10 times more frequently in people eating an Industrial Age diet than in hunter-gatherers. “Our jaws are underdeveloped because softened, highly processed foods do not provide the chewing stresses needed to stimulate normal growth of the jaw during childhood,” Corruccini says.

    Following the old ways.

    Maya in the Yucatán of Mexico who still eat a traditional diet have fewer cavities.


    As researchers at the workshop reviewed the data, it became clear that the biggest challenge for our teeth wasn't the initial transition to agriculture, as many researchers had once thought. It was the Industrial Revolution and then, in the 1980s, another marked increase in refined sugars in processed foods, such as high fructose corn syrup in sodas. “Caries and malocclusion is not a Neolithic problem, but an industrial problem,” Boyd says.

    After establishing the complexity of the problem, the researchers began to consider solutions. “If we remove carbohydrates from the diet, do we have less disease? Is this something I should be recommending to my patients?” asked dentist John Sorrentino of Hopewell Junction, New York.

    The answer, it appears, is not simple, other than the obvious advice to cut back on refined sugars. The role of starch in causing cavities is not well known and needs study, Hillson says. Boyd suggested that consuming sugars with more fiber, such as fructose in fruit, lessens the damage because the sugars are absorbed more slowly in the gut, rather than rapidly in the mouth. But our ancestors consumed a variety of diets, so the solution may not be as simple as trying to recreate a hunter-gatherer's diet. “There was not a single oral environment to which our teeth and jaws evolved—there is no single caveman diet,” Ungar says. “Still, we need to acknowledge that our ancestors did not have their teeth bathed in milkshake.”

    Further research is needed on how sugar affects the balance of species of bacteria in the mouth, such as Streptococcus strains, which are linked to cavities in humans. These complex communities of bacteria mix with minerals from saliva and immune cells to form plaque on the teeth. Our immune systems react to the bacteria, causing gum disease. “Normally, young kids are more resistant to the effects of plaque than adults,” Dean says. But with more sugars in the diet, plaque-forming bacteria may flourish, which may trigger a bigger immune response and inflammatory reaction. That, in turn, can lead to a higher risk of systemic diseases such as cardiovascular disease and diabetes. But the response to plaque varies: “Everyone's mouth is its own ecological field,” Dean says.

    As for malocclusion and jaw disorders, Corruccini noted that a “fringe” branch of evolutionary dentistry has emerged in which children do mouth exercises and wear devices that put stronger force on their growing jaws. Ungar admitted feeding beef jerky to his own children to boost chewing stresses on their developing jaws, but he says the jury is still out on those methods to reduce overbite. “An understanding of this discordance [between traditional and modern diets and lifestyles] can inform clinical research and, ultimately, dental and orthodontic practice,” Ungar says.

    For now, one thing is perfectly clear: Our teeth have not evolved a defense against sodas. “People should understand that evolution is not as fast as the cultural changes we're seeing,” Cucina says.

    • * “Evolution of Human Teeth and Jaws: Implications for Dentistry and Orthodontics,” National Evolutionary Synthesis Center, 28–30 March, Durham, North Carolina.

  5. Evolutionary Biology

    The Burdens of Being a Biped

    1. Elizabeth Pennisi

    A number of musculoskeletal issues are rooted in our evolutionary history, in particular to the switch to walking upright more than 7 million years ago.

    Just as many dental problems are rooted in our evolutionary history (see main text, p. 973), a number of musculoskeletal issues are also traceable to our past, in particular to the switch to walking upright more than 7 million years ago. “We've taken a body that was adapted to being horizontal to the ground and made it erect,” says Bruce Latimer, a comparative anatomist at Case Western Reserve University in Cleveland, Ohio. “We've had to change nearly every bone in the body, and as a consequence, there are many things that humans suffer from that no other animal does.”

    Shifting from a four-legged support system to a two-legged one put extra stress on the legs and vertebrae. Adaptations in the feet, knees, hips, pelvis, and spine accommodate these forces, but at a cost. Imperfect evolution and constraints on how our bodies could change have left us with vertebrae that break more easily, weaker bones, and feet prone to heel spurs and sprained ankles. Our relatively inactive lifestyles and longer life span only exacerbate our orthopedic imperfections. A brief tour of the body reveals a number of design flaws, the legacy of our past.

    Walking can be a pain.

    Bipedalism leaves the human body vulnerable to a range of problems, just a few of which are pinpointed here.


    Spine. Back pain is the leading health complaint in the United States. In dogs, horses, and even chimpanzees, the backbone is a series of vertebrae neatly stacked and evenly spaced to form a relatively stiff, gently curving beam. Not so with the human spine, which is highly flexible and can even bend backward. Yet this flexibility creates wear and tear on joint surfaces and predisposes us to osteoarthritis.

    Furthermore, evolution has left our spines with an S-shaped curve, which is necessary to keep the upper body centered over the hips. Thus the lower spine curves toward the belly button, causing a hollow in the back and bringing the torso upright. To keep the head centered, the thoracic vertebrae in the chest curve in the other direction. “Spinal curvatures cause a lot of problems in humans that other animals don't have,” particularly slipped disks and broken vertebrae, says Carol Ward, an anatomist at the University of Missouri, Columbia.

    One type of break, called spondylolysis, affects about 6% of the U.S. population and is a leading cause of lower-back pain in teenage athletes. In this condition, the neural arch—a triangle of bone that surrounds the spinal cord—detaches from the rest of its vertebra, allowing the spine to slip forward relative to the back of the pelvis, pinching nerves and causing pain.

    Ward, Latimer, and their colleagues surveyed thousands of human skeletons in the 1990s and determined that the problem lies in inadequate spacing between the joints connecting the vertebrae. If the lower vertebrae are too crowded, the bone is chronically pinched, eventually causing it to dissolve and the neural arch to separate. “When people don't have that correct spacing, they tend to get spondylolysis,” Ward says. X-rays can reveal vulnerability to this condition, Latimer notes, and children with narrow vertebral spacing should avoid gymnastics, swimming butterfly stroke, and other sports that involve excessive back arching.

    Feet. To cope with the added load on just two feet, the foot evolved a shock-absorbing arch by bringing what was a grasping big toe into line with the other toes. When that arch fails to form fully, as in people with flat feet, fatigue fractures can result. And when the big toe's tendon gets misaligned from improper shoes, bunions develop. Latimer blames heel spurs, plantar fasciitis, hammer toes, shin splints, chronically sprained ankles, and even varicose veins on our erect posture.

    Fragile bones. The added load on two feet also caused knee and hip joints to expand, creating more surface area to absorb foot-fall forces. But the joints—and vertebrae as well—evolved to be bigger by enlarging the spongy, inner bone and thinning the hard, outer bone. As a result, human bones are less dense than those of other primates, a team led by mechanical engineer Christopher Hernandez of Cornell University, who studies osteoporosis, reported on 19 October 2011 in PLoS ONE.

    Bone builds mass during childhood—more so if stressed with exercise—then loses mass during adulthood. With humans having ever longer life spans, bones, particularly vertebrae, may become fragile and break spontaneously. Apes lose bone mass as they age as well, but they don't suffer fractures because their bones are so much denser to begin with. Humans could have more apelike bones if they got more exercise as youths, as early humans did, Ward says. “If we treated our skeletons the way they were designed to be treated, they would serve us better later in life.”

    Bipedality leaves its mark in other parts of our bodies, too, for example in the difficulty of childbirth and in our vulnerability to rotator cuff injuries of the shoulder. Understanding these connections can suggest preventive measures, as in the case of spondylolysis, notes Latimer, who urges such understanding even if there's no immediate biomedical application. He helped organize a series of workshops through the National Evolutionary Synthesis Center to come up with evolutionary medicine curricula about musculoskeletal disorders. “If you don't understand the evolutionary background,” he says, “you are treating the symptoms without understanding the underlying cause.”

  6. The Biology of Genomes

    Single-Cell Sequencing Tackles Basic and Biomedical Questions

    1. Elizabeth Pennisi

    At the meeting, four groups described new insights derived from sequencing DNA from individual human cells.

    One at a time.

    By sequencing single sperm cells, researchers are pinning down recombination rates.


    Over the past couple of decades, researchers have sequenced thousands of genomes from numerous species. In virtually every case, the deciphered DNA was extracted from millions of cells and pooled. The result has been a wealth of data, but, says Joel Hirschhorn, a geneticist at the Broad Institute in Cambridge, Massachusetts, “there are a lot of phenomena where there's a lot of cell-to-cell variability that won't be apparent when you look across populations of cells.” That may be about to change.

    At the meeting, four groups described new insights into how genomes generate diversity and what makes specific tumors resistant to treatment—all derived from sequencing DNA from individual human cells. Their reports sparked a lot of excitement about the potential of single-cell sequencing. “We're just starting to scratch the surface,” Hirschhorn says.

    Because the cell is the basic unit of biology, researchers are increasingly trying to isolate, study, and compare them individually (Science, 7 January 2011, p. 24). The DNA work has mostly involved sequencing the relatively simple genomes of single-cell microbes; the much larger and more complex genomes of human cells have been a bigger challenge. But the cost of sequencing has plummeted to the point at which it is becoming practical to decipher the 3-billion-base genome from single cells and compare sequences from cell to cell.

    For Adam Auton, a statistical geneticist at Albert Einstein College of Medicine in New York City, single-cell sequencing provides a window on recombination, the process by which matching chromosomes exchange pieces of their DNA during cell division. Recombination helps generate genetic diversity by putting various versions of genes together in new combinations. It is also a cell's method of weeding out DNA gone bad.

    Researchers have long sought a way to determine the amount of recombination that occurs in humans, and they have come up with several indirect ways to measure it in families or in populations. Sequencing and comparing the genomes of individual sperm cells allows for a direct and much more systematic investigation of the phenomenon, Auton says.

    So when China's sequencing powerhouse, the Beijing Genomics Institute, told Auton it had sequenced 167 individual sperm from a healthy 50-year-old Asian male, he was eager to see the data. His initial analysis highlighted how difficult it is to isolate a single cell and reliably copy its DNA for sequencing. The researchers found that several of the sequences represented DNA from multiple cells; only 40 passed muster. By comparing each sperm's DNA with that obtained from a blood sample, Auton and his colleagues detected nearly 1000 recombination events, or about 24.5 per sperm cell, a number that agrees with estimates from indirect methods. Recombination occurs unevenly across the chromosomes, with “hot spots” representing places with elevated recombination rates. For the most part, the hot spots Auton's team identified coincided with where researchers had seen them in other studies. However, there was also a spike of recombination on chromosome 15, Auton reported at the meeting.

    Lab on a chip.

    This microfluidics device isolates single cells and copies their DNA.


    Stephen Quake of Stanford University in Palo Alto, California, has been developing single-cell techniques using a so-called lab on a chip. Samples pass through a series of tiny channels and valves to isolate single cells from which DNA is extracted and copied thousands of times to get enough for sequencing. Quake reported that he had solved many of the technical issues. He sequenced his first human single cells last year, and now he is using the technology to study recombination and assess mutation rates in sperm cells.

    He determined the recombination rate from a study of 100 sperm, finding many new recombination hot spots and a rate that was on par with what indirect methods have found. Then he sequenced eight sperm to a greater degree, enough to determine the mutation rate. He found that rate to be 30 mutations per billion bases, a bit higher than what others have found, he reported at the meeting.

    Timour Baslan, a graduate student at Cold Spring Harbor Laboratory in New York, has been using single-cell technology to study cancer cells. With Nicholas Navin, a molecular geneticist now at MD Anderson Cancer Center in Houston, Texas, his laboratory developed what it calls single-nucleus sequencing to profile tumors. They have used it to follow the evolution of cancers, tracking different subpopulations of cells as they become more common over time and spread. Baslan and his colleagues now add genetic barcodes to individual cells before sequencing, which allows them to pool samples for sequencing and still be able to identify sequences from individual cells in the mix, a cost-saving measure.

    To date, Baslan reported, they have applied the approach to a dozen breast cancer patients, sampling their tumor cells before and after treatment. Each patient reacted differently. In one tumor, the proportion of one type of cancer cell increased after therapy, indicating that the drug used was effective against part, but not all, of the tumor. In another patient, they saw a major rearrangement on the X chromosome and extra copies of a gene for a protein that would enable the tumor to counteract the effects of the drug. The chromosomes of a third patient's tumor cells were shattered by the therapy. The method “is routine for us now,” and he can readily profile hundreds of single cells, Baslan said. He plans to incorporate microfluidics devices to streamline the approach even further. The goal is to understand tumor evolution and get a sense of which cancer cells will respond to the various treatments.

    Meanwhile, Navin has continued to refine single-nucleus sequencing. By picking out cells that have just doubled their chromosomes in preparation for cell division and cutting down on the number of copying and processing steps, he needs only a few nanograms of DNA instead of a few micrograms. At the meeting, he reported that he had found variation in a breast cancer cell line that profiling showed to be homogeneous. “As you bring the magnifying glass closer, you detect more variation at the level of the base pair,” he pointed out.

    Navin found a similar trend when he sequenced four tumor cells from a more complex tumor, an invasive breast cancer. The sequence of a million-cell sample of the tumor uncovered six mutations, all in known cancer genes. The single-cell sequencing revealed an additional 30 mutations in each cell that were not detected in the larger sample, he reported. When he looked at 100 other cells from the same tumor, he found many of these mutations at very low frequencies. “This diversity is probably driving the cancer,” he said. He also found the same mutations when he sequenced just the exons.

    Geneticist Elaine Ostrander of the National Human Genome Research Institute in Bethesda, Maryland, calls the prospect of analyzing individual cancer cells “unbelievably exciting” as a “promising and elegant” way to pin down what's happening in a tumor. But others are more circumspect. “It will be hard to get these kinds of data, because [you] will have to sequence a lot of cells,” says Elaine Mardis, co-director of the Genome Institute at Washington University in St. Louis in Missouri.

    While researchers agree that single-cell sequencing may not yet have a high enough throughput to be practical for cancer assessments, “it can't be overemphasized how fast the technology is advancing,” Auton says. “As the technology matures, we'll see some quite revolutionary things coming out.”

  7. The Biology of Genomes

    HDL Itself Does Not Prevent Heart Attacks

    1. Elizabeth Pennisi

    A new genetic analysis presented at the meeting shows that while high HDL might correlate with a healthier heart, it's not itself responsible for lowering heart attack risks.

    If you are hoping to lower your risk of a heart attack simply by raising your levels of “good” cholesterol—high-density lipoproteins (HDLs)—you may be disappointed. Although epidemiological studies point to HDLs as protective against heart disease, a new genetic analysis shows that while high HDL might correlate with a healthier heart, it's not itself responsible for lowering heart attack risks.

    Helpful how?

    The heart-health benefits of red wine and fish oil may not come from raising HDLs.


    To establish the role of HDL in protecting against heart attacks, Benjamin Voight, a human geneticist at the University of Pennsylvania, and his colleagues at the Broad Institute in Cambridge, Massachusetts, performed what's called a Mendelian randomization study, using records of 170,000 people who participated in existing studies. For this trial—done on a computer—he examined whether people who have a version of a gene that confers high HDL levels had fewer heart attacks than those who have versions of the gene that don't raise HDL.

    For one study, he and his colleagues focused on a mutation in the endothelial lipase gene, whose protein is involved in cholesterol metabolism. The mutation increases HDL by about 5.4 milligrams per deciliter, about 10%. About 2.6% of people have this mutation. Working with data from 51,000 people, 4200 of whom had had heart attacks, he determined whether those with the mutation had fewer heart attacks than those with other versions of the gene. Based on the epidemiological evidence, the risk of heart attack should have decreased by 13% in those carrying the mutation, but “carriers versus noncarriers had absolutely no difference in risk,” he reported at the meeting. “Epidemiological correlation doesn't tell you causality.”

    In a related study, Voight looked at 14 mutations in several genes associated with higher HDL levels. For a group of about 54,000 people, 12,000 of whom had had heart attacks, he summed the number of HDL-raising mutations and checked to see if those with higher mutation scores had lower heart disease risk. They did not, he reported at the meeting and in the 16 May issue of The Lancet.

    In contrast, when he looked at people with mutations predisposing them to high levels of LDLs—“bad cholesterol”—those people did have more heart attacks. “With LDL it's very clear: LDL really does look like it's causal,” says Andrew Clark, a geneticist at Cornell University.

    Drug companies have been trying to develop drugs that raise HDL. But, Voight says, “we should think very carefully about how we plan an intervention around HDL. It might not work as advertised.”

    Ewan Birney, a bioinformaticist at the European Bioinformatics Institute in Hinxton, U.K., is very impressed with the approach Voight took in determining whether high HDL protects against heart attacks. “It's an incredibly powerful tool,” he says. Mendelian randomization is a technique that's been around for about 10 years, but it is only now starting to be used because the approach requires data on thousands of people. Now that researchers have genotyped large cohorts of people with various diseases, the approach could be useful for studying ties to other conditions. “It's a way of teasing apart a hypothesis that's not true,” Birney says.