NORTH CAROLINALate last month, in a former Block-buster Video store in tiny Kenans-ville, North Carolina, an insulated cardboard box awaited a placenta. Collected after a nearby birth the night before, the placenta would be shipped to the University of Rochester Medical Center, home of the central histological lab for the US National Children’s Study. There, pathologists would catalogue the placenta’s weight, size and shape; note any abnormal features; fix it in formalin and embed it in paraffin; then make slides and tissue blocks to preserve it for future use by research-ers studying major childhood ail-ments from asthma to obesity.
Many more specimens may soon be coming from rural Duplin County, North Carolina. Over the next several years, investigators in this land of hog farms and cotton fields hope to enrol half the new pregnancies in what is arguably the most ambitious study ever of how the environment affects children’s health.
Authorized by Congress in 2000, the study has ramped up only recently, with funding rising from US$69 million in 2007 to $180 million this year (see graph). It aims to study more than 100,000 children at 105 locations around the country, following them from before birth to age 21. Its 28 proposed hypoth-eses intend to explore, among other things, whether prenatal infection is a risk factor for autism; how media exposure influences neu-rological, cognitive and social development; and how recurrent, low-level pesticide expo-sure might affect cognitive skills.
The study is now enrolling patients at seven ‘vanguard’ centres, including the one in Duplin County. But just as it is getting off the ground, it is running into political tumult. In August, angry senators on the Senate appropriations committee declared that the National Insti-tutes of Health (NIH), the study’s principal overseer, had committed a “serious breach of trust” by withholding from Congress news that estimates of the study’s cost — initially around $3 billion over 25 years — had grown to as much as $7 billion. Among other things, officials at the NIH’s National Institute of Child
Health and Human Development (NICHD) had failed to include estimates of the indirect costs routinely paid to institutions.
Until the NIH provides “the most up to date information possible”, the senators wrote, they would reserve a decision on how many dollars — “if any” — they would allocate to the study in 2010. (The number will be settled during upcoming negotiations between appropriators in the Senate and the House of Representatives; lawmakers in the latter have agreed to fund the study at $194 million in 2010.)
In the staid parlance of Capitol Hill reports, the words “breach of trust” landed with the impact of a hand grenade. “I have never seen report language referring to anything that the
NIH has ever done as a ‘serious breach of trust’. I think that is tell-ing,” says a seasoned observer of biomedical politics in Washington DC who asked not to be named.
The NIH had already responded by shaking up its staff, removing study director Peter Scheidt in July. By early October, NICHD direc-tor Duane Alexander was out of his job, too. (Alexander, now at the NIH’s Fogarty International Center, has said that he was already considering leaving the director’s job after 23 years.)
The NICHD’s new acting director, Susan Shurin, says that “we obvi-ously take the Senate’s concerns very seriously.” Some of the 28 hypotheses will “probably” be dropped, she says; “we are going to be managing to a budget.” The NIH’s deputy director Raynard Kington says that when a pilot phase finishes in spring 2010,
the agency will embark on a “rigorous evalua-tion” to determine the study’s future trajectory.
The Senate rebuke was far from the study’s first labour pain. In the mid-2000s, the White House under George W. Bush had repeatedly zeroed out its budget — with the support of the NIH’s then-director Elias Zerhouni, who argued that its long-term costs were prohibi-tive. But members of Congress, many of whom had potential study locations in their districts, repeatedly reinserted the funding.
Power of the peopleStudy leaders say that big is the way to go with this study — that the power of 100,000 par-ticipants and the extensive amount of infor-mation they will provide, from house-dust samples to parental toenail clippings, will produce a data bank that detectives of dis-ease causation can mine for decades to come. Other major longitudinal studies, such as the Framingham Heart Study, have provided this kind of trove — but for adults, notes Barbara Entwisle, director of the Carolina Population Center in Chapel Hill and the principal inves-tigator at the Duplin County centre. “All of the recent science shows the importance of what happens early on in people’s lives for health all the way through their lives,” she says. “This is the future of our country.”
US politicians, once supportive of a massive research project on childhood health, are now criticizing it.
Children’s study fights to survive
A study of 100,000 US children should provide insights on how the environment affects their health.
‘BAD GENES’ WIN LIGHTER SENTENCE FOR MURDERERJail term cut after genetic tests.go.nature.com/zpUfSg
Results are just beginning to arrive for the 1000 Genomes Project, a genomic study of human diversity. However, an international group is already planning something even more ambitious — a 10,000 genomes project. The initiative, called Genome 10K, aims to tackle thousands of vertebrate species.
Project members write this week in the Journal of Heredity that the effort will provide an unprecedented look at the genomic mechanisms for generating diversity in a group of animals with different lifestyles and adaptations.
“We see this stunning diversity of forms in vertebrates, from manatees to anteaters,”
says David Haussler of the University of California, Santa Cruz, one of the three masterminds behind the project, which involves 68 scientists from five continents. “What continually strikes me is the unbelievable malleability and adaptability of the vertebrate genome,” he says, “and we have an enormous amount to learn about the genetic roots of that.”
Haussler, Stephen O’Brien of the National Cancer Institute in Frederick, Maryland, and Oliver Ryder, director of genetics at the San Diego Zoo’s Institute for Conservation Research in Escondido, California, decided to organize the project after realizing that one of the major obstacles to non-human sequencing projects has been collecting and organizing specimens. After an April meeting in Santa Cruz to bring in other scientists, the team now has a database of samples from more than 16,000 species from 50 institutions. The scientists are also planning a pilot project to sample portions of the genomes of a small subset of these species.
The group is looking for funding for the main phase of the project, which could cost anywhere from US$10 million to $100 million, depending on the costs to process and sequence each sample. The team anticipates that sequencing costs will drop below $10,000 per genome within a few years, making it feasible to sequence the entire genomes of 10,000 vertebrates within this budget.
However, analysing all the data will be an enormous challenge, because it is still not easy to assemble new genomes from the short readouts of DNA delivered by current sequencing technologies.
Other scientists say that the project sounds exciting, but question the decision to sequence so deeply solely among vertebrates.
David Maddison, who studies beetle phylogeny at Oregon State University in Corvallis, points out that, so far, only one beetle species has had its genome sequenced, despite there being about six times as many beetle species as there are vertebrates.
“My biggest concern is that if one were to decide where our funds
should go — to 10,000 vertebrates or more generally scattered across organismal diversity — I would very strongly argue for the latter,” says Maddison, who conceived the Tree of Life project, a web-based catalogue of biodiversity.
O’Brien agrees that invertebrate-genome sequencing is “a valuable area that should also be considered for whole-genome-sequence assessment”. Other scientists are already planning a large invertebrate sequencing project.
Indeed, O’Brien expects Genome 10K to be the first study in what he anticipates will be a larger shift toward using sequencing technology to study biodiversity. He compares it to the culture shift that accompanied the invention of the printing press, which was first used to print the Bible and then for broader purposes.
“If the Human Genome Project is the Bible,” he says, “then the [Genome 10K] is a library that gets filled up with other books.” ■
Erika Check Hayden
10,000 genomes to comeIn 2004, after long and controversial consultations, study leaders adopted a household-based sampling strategy, a costly and labour-intensive decision meaning that participants from the 105 far-flung study locations will be more representative of the broad population than, say, those recruited from health facilities and doctor’s offices, a more common approach.
In May 2008, in a 140-page report, the National Research Council and the Institute of Medicine praised the study’s household-based sampling approach, as well as the statistical power rendered by its 100,000 participants. But it also identified a laundry list of weaknesses in the study’s design. The first was the absence of a pilot phase; because the vanguard centres’ data were to be part of the final data set, investigators would be less likely to experiment with methods and change things that weren’t working. That concern is being addressed, says Shurin, by turning the vanguard centres into long-term development platforms for the main study’s methodology and feasibility, and not, as initially intended, folding them into the main study. Study leaders have also pushed back the launch of the study’s main phase until late 2011, giving investigators time to tweak the methodology according to what’s learned at the vanguard centres.
Despite the rough waters, advocates remain passionate about the study’s poten-tial, arguing that it is an investment that will more than pay for itself. Leonardo Trasande, a study investigator at the Mount Sinai School of Medicine in New York, notes that just six of the conditions the study explores — asthma, autism, diabetes, injury, obesity and schizo-phrenia — cost the United States at least $650 billion a year (L. Trasande and P. J. Landri-gan Environ. Health Persp. 112, A789–A790; 2004). “If the study identifies preventive interventions that can reduce those annual costs by even 1%, [a $3-billion] study repays itself twofold in one year,” he says.
Meanwhile, Duplin County continues to enrol participants. While recruiters work church dinners and organize soccer tour-naments, data collectors recently finished enumerating 10,800 households — roughly half of those in the county — aiming to locate reproductive-age women.
“I have two daughters. Both have asthma. I have lived this,” says Entwisle. “But the scientific reason for my involvement has to do with the fact that there are so many questions that need answers. This design is exactly what needs to be done to begin to develop some of those answers.” ■
