# News this Week

Science  03 Jun 2005:
Vol. 308, Issue 5727, pp. 1388
1. EMBRYONIC STEM CELLS

# Spotlight Shifts to Senate After Historic House Vote

1. Constance Holden

Bone cell researcher Steven Teitelbaum had a brush with history last week as the U.S. House of Representatives weighed in on one of the most dramatic scientific debates in years.

Teitelbaum was on the sidelines, clarifying issues for undecided legislators during the 4-hour debate right up until the 238-to-194 vote in favor of using federal funds to conduct research on newly derived lines of human embryonic stem (ES) cells. “It was a great day,” says the former president of the Federation of American Societies for Experimental Biology in Bethesda, Maryland. “This is what our country is all about; it was bipartisan,” he told Science. The vote, he says, was not a political contest but rather “a contest between us as a society and disease.”

Little in biomedical history can match the hot and heavy politicking that has surrounded the stem cell debate, which has evoked people's deepest concerns about suffering and disease, children, and the meaning of human life. President George W. Bush, who declared on 9 August 2001 that only ES cell lines developed before that date could be used in federally funded research, vowed before the vote to use his first veto if the measure passed, saying he opposed “the use of federal money, taxpayers' money, to promote science which destroys life.”

Despite that threat, 50 Republicans defied their party leader and voted to allow federally funded scientists to do research with human ES cells derived after 9 August 2001. The primary sponsors, representatives Michael Castle (R-DE) (see next page) and Diana DeGette (D-CO), say they'll keep pushing to turn the bill (H.R. 810) into law. And supporters in the Senate claim to have enough votes to override a presidential veto. But first they'll need the consent of Senate Majority Leader Bill Frist (R-TN) to schedule a vote on the measure.

The day of the 24 May House vote began with crowded press conferences by both supporters and opponents of H.R. 810. The Castle team featured Teitelbaum, from Washington University in St. Louis, and John Gearhart, a stem cell researcher at Johns Hopkins University in Baltimore, Maryland. The opponents countered with 21 “snowflake” babies—the products of embryos “adopted” from fertility clinics—to suggest that even 5-day-old blastocysts are individuals.

Pat White, director of federal relations for the Association of American Universities in Washington, D.C., says pro-stem cell lobbyists conducted a slick “whip” operation before the vote. Patient lobbyists, scientists, and university federal relations people were all over the House on the big day. “We wanted to be in position to have scientists answer any question that came up by any member during the day or during the debate,” says White.

Gearhart says a number of members asked him if the frozen embryos mentioned in the bill had ever been inside a womb. Teitelbaum says he thinks his conversation with Representative Jo Ann Emerson (R-MO) may have contributed to her 11th-hour decision to support the bill. Their knowledge served as a counterweight to comments from opponents such as Representative Dave Weldon (R-FL), a physician who erroneously told his supporters before the vote that adult stem cells “have been shown to be pluri-potent” and, thus, just as useful as ES cells.

The recent success by Korean scientists has moved up the likely timetable for when nuclear transfer—otherwise known as research cloning—will become a feasible research tool (Science, 20 May, p. 1096). Polls show steady increases in public support for human ES cell research. A broad range of patients, politicians, and scientists, including several leaders at the National Institutes of Health, have expressed increasing dissatisfaction with the president's policy as the limitations of existing cell lines—22 of which are available—have become clear.

By omitting any mention of nuclear transfer, the Castle bill managed to attract 201 co-signers, including several opponents of abortion. The measure is aimed solely at allowing federally funded researchers to have access to stem cell lines derived after the presidential cutoff date—provided they come, with proper donor permission, from fertilized eggs that would otherwise be discarded from fertility clinics. The bill would not allow federally funded researchers to actually generate new ES cell lines or to use lines from any embryos created solely for research.

Those restrictions didn't mollify opponents. “Yes, sir. You, too, were an embryo once!” Representative Mike Ferguson (R-NJ) cried rhetorically to the bill's supporters. House Majority Leader Tom DeLay (R-TX), who has been lying low recently amid accusations of ethics improprieties, delivered a fire-breathing speech saying that “we cannot use U.S. taxpayer dollars to destroy” embryos.

Immediately after the vote, the White House repeated the president's intention to veto the bill and broadcast his support for H.R. 2520, which encourages the collection of umbilical cord blood stem cells. That measure passed the House earlier in the day with only one dissenting vote.

The next day, Castle and DeGette ceremoniously handed a copy of their bill, topped with a red bow, to senators Arlen Specter (R-PA) and Tom Harkin (D-IA), sponsors of an identical measure (S. 471). “I've never been enthusiastic about a press conference,” says Castle, but this one was an exception.

Although the Senate has generally been more supportive than the House toward ES cell research, getting a public vote may be tougher. Specter's and Harkin's bill has been awaiting action since February, and on the day of the House vote they wrote to Frist urging him to schedule a vote on it. Frist's resistance, say insiders, is fueled not just by his opposition to human ES cell research but also by his presidential ambitions for 2008.

Specter said that an alternative strategy to winning a direct vote would be attaching it to a spending bill. He predicted that the measure would pass by more than the 2:1 margin needed to override a presidential veto (and, along the way, stave off a filibuster). Last year 58 of the body's 100 senators sent a letter to the White House asking for a less restricted stem cell policy, he said, and “20 more are in the wings.”

Overriding a veto would be a tall order in the House, however. House Rules Committee chair David Dreier (R-CA), who supported H.R. 810, last week suggested that some kind of compromise might be reached to avoid a presidential veto. But Castle says that “it would be very hard to tighten our bill” by narrowing its scope any further.

White says that the groundwork for last week's victory was laid shortly after Bush announced his policy in 2001 and that supporters now feel the momentum has shifted in their favor. And although Gearhart cautions that the House vote “is very much of a baby step,” he is hopeful that an even more decisive Senate vote will make it clear that Bush is out of step with the wishes of the American people.

2. EMBRYONIC STEM CELLS

# Moderate Republican Led the Winning Coalition

1. Constance Holden

Representative Mike Castle (R-DE) has received the lion's share of the credit for getting an up-or-down vote on his bill to expand the pool of human embryonic stem cells available to federally funded researchers. A seven-term member, he's the chair of the House subcommittee on education reform and president of the Republican Main Street Partnership, a centrist group that has championed tort reform and R&D tax credits. Stem cell researcher Steven Teitelbaum of Washington University in St. Louis, Missouri, calls him “one great guy. … He's a real person: totally unpretentious and smart as a whip.”

A former governor of Delaware, the 65-year-old Castle says he got on the stem cell bandwagon half a dozen years ago because of the large number of constituents worried about health issues. He told Science he started reading about stem cells and “realized this was probably the greatest hope extant out there” for many of them. He says he had no illusions about the chances of success in an increasingly polarized and conservative House of Representatives. “I knew we would gear up to run hard” with it.

Republican Party leaders were in no hurry to hold a vote on H.R. 810. And proponents didn't want to rock the boat during an election year. But this spring Castle and Representative Diana DeGette (D-CO) decided to make their move. In March, Castle says he sent Speaker Dennis Hastert (R-IL) a message offering a deal, saying that “we were not interested in voting for the budget until such time as we had a date for a [stem cell] vote.” After meeting with Castle's delegation, Hastert decided to schedule an up-or-down vote with no strings attached. Castle says he thinks Hastert wanted to remove the specter of the issue cropping up throughout the year in conjunction with other House bills.

Now that his hard work is starting to pay off, Castle says he plans to stick with the issue for as long as it takes. If the Senate passes the bill and the President vetoes it, “you're looking at a wasteland of 3 1/2 years,” he says. “I'm not interested in that. … [Instead] we'll do something.”

Castle knows that somewhere down the road looms the question of human cloning. The previous House twice voted to outlaw all forms of cloning, including research cloning (otherwise known as nuclear transfer), which scientists say is necessary to realize the promise of the research. Castle agrees, predicting that nuclear transfer “will at some point probably be essential.”

But that battle lies sometime in the future, he says: “I don't think we have to cross that bridge at this moment. … The moderate cause is advanced one issue at a time.”

3. DEVELOPMENTAL BIOLOGY

# Endocrine Disrupters Trigger Fertility Problems in Multiple Generations

1. Jocelyn Kaiser

A fungicide and a pesticide, both already known to be toxic to animals, have revealed a potentially even darker side: On page 1466, researchers report that the two chemicals cause fertility defects in male rats that are passed down to nearly every male in subsequent generations. No other known toxin has been shown to do that, according to the study's authors and other scientists. The startling results seem to support the controversial idea that such hormonelike chemicals, known as endocrine disrupters, could be causing population-wide reproductive problems, such as lowered sperm counts in men. But many scientists caution against drawing conclusions until other labs have confirmed the unexpected findings.

“These are remarkable observations. If they're solid and reproducible, they are going to have a large impact on how we look at these kinds of chemicals,” says Earl Gray, a toxicologist with the Environmental Protection Agency (EPA). Biologists are stumped by the apparent mechanism of the chemicals; they may alter how genes are expressed in subsequent generations, but without mutating DNA. “It's provocative. But I don't think we have a clue as to what's really happening,” says geneticist Robert Braun of the University of Washington, Seattle.

The work was led by reproductive biologist Michael Skinner of Washington State University, whose lab has been studying vinclozolin, a fungicide used in the wine industry. Vinclozolin blocks cell receptors that are normally activated by the hormone androgen. It is just one of a suite of widely used chemicals, from flame-retardants to ingredients in plastics, that can cause reproductive abnormalities in lab animals. Over the past 15 years, many scientists have come to think that these endocrine disrupters are potentially causing harmful effects, such as cancer and reproductive abnormalities, in humans, too.

It was already known that when pregnant rats are treated with relatively high doses of vinclozolin every day, their male offspring are sterile, Gray notes. But Skinner and his team found that when they injected vinclozolin into the abdomens of pregnant rats during a specific window of pregnancy—8 to 15 days into gestation—they got a different result. Although the offspring's testes appeared normal and the rodents could reproduce, their sperm count dropped 20% compared to control mice, their sperm motility was 25% to 35% lower, and the cells within the testes underwent higher rates of apoptosis—a form of cell death.

The researchers then bred these males with females born to other pregnant rats similarly treated with vinclozolin. To their surprise, more than 90% of males born from these matings had very similar reproductive abnormalities, as did similar numbers in the next two generations. To determine if the male rats inherited the defect from their fathers, they bred a second-generation vinclozolin male—its grandmother had been injected with the fungicide—with a normal female. Their male offspring again had nearly identical sperm and testes defects, whereas a vinclozolin-mother female offspring crossed with a normal male did not. The researchers got similar results when they treated rats with methoxychlor, a pesticide used as a substitute for DDT and whose metabolites include an antiandrogenic compound.

That only male offspring were affected suggested that the two compounds had caused mutations in the male cell's germ line, the cells that give rise to sperm, says Skinner. Radiation can increase the risk of cancer in multiple generations by mutating germ line cells, but it triggers such mutations in a small number of germ line cells, so that only a tiny percentage of offspring are affected. Moreover, the effect gets smaller with each generation. In contrast, the vinclozolin-induced fertility changes occurred in almost every male rat descended from a treated mother. To Skinner and his colleagues, that suggested an epigenetic mechanism might explain their data.

Although they don't mutate the DNA sequence of an animal, epigenetic changes can be inherited and affect how genes are expressed. One common epigenetic change is the attachment of methyl groups to DNA, which can shut a gene off or turn it on. Indeed, Skinner's group showed that methylation patterns in the testes of affected rats differed from those in control rats. However, they didn't rule out mutation of the animal's DNA sequence, notes epigeneticist Emma Whitelaw of the University of Sydney, Australia. The changes in methylation might simply correlate with the declining fertility, she says: “I'm not sure it's an epigenetic mark.”

“We're mostly describing a new phenomenon,” acknowledges Skinner. But he is worried nonetheless. “The hazards of environmental toxins are much more pronounced than we realized,” he asserts.

Still, according to EPA, the doses used in the experiment were much higher than the exposure levels allowed for people, and Gray says this single study won't change regulations for vinclozolin and similar antiandrogens. For now, “it's going to be very important for other people to look at this,” he says. Adds Braun, “It baffles me.”

4. GENETICS

# Spliced Gene Determines Objects of Flies' Desire

1. Greg Miller

The male fruit fly is a winged Casanova. He pursues lady flies with a repertoire of song, dance, and well-placed licks that many find impossible to resist. Now, by creating genetically engineered female flies that mimic the male courtship display, researchers have taken important steps toward understanding the biological basis of this complex, instinctive behavior.

In a pair of papers in the 3 June issue of Cell, Barry Dickson and colleagues at the Institute of Molecular Biotechnology in Vienna, Austria, report that a gene called fruitless (fru) sets up the fly brain to produce male courtship behavior in Drosophila melanogaster. Female flies altered to use the fru gene to make proteins normally made only by males woo other females much as males do. Additional experiments by Dickson's team identify a circuit of neurons in the fly brain that appears to mediate such courtship behavior and sexual orientation.

“I think it's quite remarkable,” says Catherine Dulac, a neuroscientist at Harvard University. The work convincingly demonstrates that a single gene can regulate a complex sequence of behaviors, she notes. The team's “very elegant experiments” represent “a start toward understanding how an innate behavior is laid down in a nervous system,” says Edward Kravitz, a Harvard neuroethologist.

In the 1960s, scientists discovered that male flies with a mutated fru gene become sexually indiscriminate—courting males as well as females. Then, in the mid-1990s, two teams reported that the fru gene operates differently in males and females; the cells of each sex read the gene in distinct ways, splicing together different mRNA transcripts. In males, these transcripts produce up to three distinct proteins, whereas the female mRNAs seem to lead to none. The DNA sequence of fru suggests that it encodes proteins that regulate the expression of other genes—but no one knows what those genes might be.

Scientists have hypothesized that male fru proteins are necessary and sufficient for male courting behavior, but Dickson's paper is the first to show that directly, says Daisuke Yamamoto of Tohoku University in Sendai, Japan, who led one of the teams that discovered the splicing difference.

The key was making very minor modifications to the region of fru that is spliced differently in males and females, forcing female flies, for example, to splice the gene as males normally do. Although the sexual anatomy of these females appeared to be entirely normal, their behavior was dramatically altered. They courted other female flies, using all steps of the male courtship ritual, short of attempting copulation. Yet, male flies altered to splice fru as females do barely courted at all. Dickson hypothesizes that “behavioral switch genes” like fru provide a way to hard-wire adaptive behaviors into the brain so that an animal can perform them instinctively. Still, he and others caution against extrapolating the results to sexual behavior in humans. “Clearly, we are vastly more complicated creatures than flies, and our common experience tells us that our sexual interests are not irreversibly set by our genes,” Dickson says.

To investigate how fru programs the courtship routine into the fly brain, Dickson's team engineered additional fly strains. In one, a genetic marker identified all of the neurons in male flies that normally express the male-specific mRNAs of fru. Many of the labeled neurons appeared to form a circuit. Key elements of this circuit are olfactory neurons that may be specialized for pheromone detection. Inactivating these cells abolished courtship behavior in male flies, Dickson's team found. Somewhat puzzlingly, the researchers also found a similar circuit of neurons in female flies. This suggests to Dickson that courtship behavior depends not on anatomical differences between the male and female brain but rather on how this circuit functions.

Kravitz suspects that fru may also be involved in other instinctive behaviors that differ between the sexes—a possibility he will be investigating with a visiting postdoc from the Dickson lab. “We're pretty sure these same genes are involved in whether flies fight like males or females,” he says. If so, fru may turn out to make male fruit flies fighters as well as lovers.

5. BIOCHEMISTRY

# Protein That Mimics DNA Helps Tuberculosis Bacteria Resist Antibiotics

1. Dan Ferber

If imitation is the sincerest form of flattery, nature just paid DNA a big compliment. A novel protein that helps the tuberculosis bacterium resist antibiotics shares an uncanny resemblance to DNA, researchers report on page 1480. This resistance protein represents an entirely new way for bacteria to ward off antibiotics; it is also the first of a class of proteins that may play a key role in regulating bacterial growth. “It's a fascinating way to become resistant,” says biochemist Gerry Wright of McMaster University in Hamilton, Canada. “This is really quite new and cool.”

Biochemist John Blanchard of Albert Einstein College of Medicine in New York City and his colleagues happened on the protein while probing for new mechanisms of tuberculosis antibiotic resistance. Working on Mycobacterium smegmatis, a cousin of M. tuberculosis, co-author Howard Takiff, now at the Venezuelan Institute of Scientific Investigations in Caracas, isolated a gene that helped the bacterium to withstand fluoroquinolone antibiotics. Dubbed mfpA, the gene, also found in the tuberculosis bacterium, encoded an unusual protein composed almost entirely of end-to-end repeats of five amino acid segments ending in leucine or phenylalanine.

Blanchard's postdocs Subray Hegde and Matthew Vetting then spent more than 2 years trying to purify and crystallize enough MfpA protein to determine its atomic structure. The researchers ultimately found that the five amino acid repeats in the sequence coil around in a rod-shaped, right-handed helix just about the width of DNA. One side of the protein has a strong negative charge, also like DNA. “It's so rare when you look at a structure, and the function of the protein just jumps out at you,” Blanchard says.

From the protein's structure, the team could deduce how it confers fluoroquinolone resistance. It's long been known that cells compact long lengths of DNA by twisting the entire double helix, much as a phone cord folds up on itself when it's twisted too tight. The enzyme that performs that reaction in bacteria, gyrase, grabs hold of two segments of DNA, cuts one, passes the other through, and then reseals the cut segment. Fluoroquinolones bind to that gyrase-DNA complex, tricking the bacterial enzyme into chopping but not resealing the DNA, which kills the microbe.

Computer modeling showed that the MfpA protein could lie across the saddle-shaped active site of gyrase, just as DNA is thought to do. In test-tube experiments, the researchers showed that MfpA blocks gyrase's ability to twist and untwist DNA. By binding to gyrase in DNA's place, MfpA apparently deprives fluoroquinolones of their target; the drugs bind to gyrase-DNA complexes rather than to just the enzyme. MfpA's inhibition of gyrase function probably slows the bacteria down, but it's better than being killed by fluoroquinolones, Blanchard says.

This is the first antibiotic-resistance protein that protects the target of the antibiotic by binding to it rather than, say, by degrading the drug, says Wright. Still, MfpA's public health impact is unclear. Fluoroquinolone-resistant tuberculosis strains isolated from people don't seem to depend on MfpA; they have mutations in gyrase itself.

It may be possible to turn the tables on bacteria by engineering MfpA to kill germs rather than protect them, researchers note. MfpA inhibits gyrase, which a bacterium needs in the long run to replicate its DNA and proliferate. “If I'm a clever chemist and I could build a small molecule that looks like that, then I have a new class of antibiotics,” Wright says.

Fluoroquinolones are a relatively recent invention, so what is mfpA doing in bacteria in the first place? Related genes have been found in numerous bacteria, fruit flies, mice, and humans. Blanchard speculates that DNA-mimicking proteins could provide a general mechanism to regulate proteins that bind DNA. “The biology is extraordinarily rich and completely unknown,” he says. “Who knows where it's going.”

6. PUBLIC HEALTH

# Europe's New Disease Investigator Faces an Uphill Start

1. Martin Enserink

PARIS—Europe finally has a watchdog for infectious diseases, but it is only beginning to sniff out its territory. Public health experts applaud the inauguration of the new European Centre for Disease Prevention and Control (ECDC) in Stockholm last week. Many say, however, that the new E.U. agency, led by Hungarian health administrator Zsuzsanna Jakab, will have to overcome formidable obstacles to become a significant player in Europe's fractured public health structure.

Working from a temporary site—the agency will move to the Karolinska Institute's campus later—Jakab has been hiring researchers and technical staff since March. Their key task: to develop a Europe-wide system of disease surveillance, risk assessment, and early warning. They will also advise countries on public health issues.

There's broad agreement that coordination is needed. Currently, information about the spread of diseases flows through a myriad of networks at institutes across the continent, but no central agency collects and analyzes the data. ECDC “is a sign that we understand the importance of surveillance,” says Tamsin Rose, secretary-general of the European Public Health Association in Brussels.

Public health is traditionally an area of authority that countries are loath to relinquish. ECDC will have to build scientific credibility—“it can't be seen as an annex of bureaucrats in Brussels,” says Marc Sprenger, who chairs the ECDC management board—even though doing so will be a challenge with a staff of about 100 and a $29 million budget by 2007. (By comparison, the$7 billion U.S. Centers for Disease Control and Prevention employs over 9000.) The agency will not have its own labs; instead, it will gather data by coordinating work across Europe, Jakab says: “We won't go around taking blood or urine samples.”

It will be vital to get good, specialized labs as partners, says virologist Albert Osterhaus of Erasmus Medical Center in Rotterdam, the Netherlands. But ECDC will have to avoid duplicating structures such as the global influenza network to coordinated by the World Health Organization. “Nobody is interested in yet more meetings,” says Osterhaus.

Because ECDC will have no labs, it may have difficulty recruiting top-notch scientists, notes Ragnar Norrby, director of the Swedish Institute for Infectious Disease Control, who helped lure the new center to Stockholm. Norrby has proposed that some ECDC staff use facilities at his own institute or at Karolinska. Jakab says she's interested in the idea. But interest in ECDC jobs has been healthy so far, Sprenger says.

Jakab has a symbolic role, too: She is the first national from one of the 10 states that joined the E.U. in 2004 to head an agency. Norrby says she is efficient and diplomatic—traits that should help her put ECDC on the map quickly. And she will need to do just that: The agency faces a review in 2007 that will determine whether it is succeeding and will continue to grow.

7. EVOLUTION POLITICS

# Is Holland Becoming the Kansas of Europe?

1. Martin Enserink

AMSTERDAM—Well, not quite Kansas—after all, this is the country that legalized euthanasia and invented gay marriage. But when science and education minister Maria van der Hoeven recently announced plans to stimulate an academic debate about “intelligent design” (ID)—the movement that believes only the existence of a creator can explain the astonishing complexity of the living world—she triggered an uproar not unlike that raging in the sunflower state.

Prominent biologists have denounced Van der Hoeven, a member of the Christian-Democratic Party and a Catholic, for blurring the line between church and state. Last week, she faced a barrage of hostile questions in the House of Representatives of the Dutch Parliament, where she was compared to the Kansas school board members who want to introduce ID in the classroom. “Does she want to go back to the Dark Ages?” the usually sober daily NRC Handelsblad lamented in an editorial. The minister has called the issue a “storm in a teacup” and claims she has been misunderstood.

Van der Hoeven's plan came to light in March, after she had what she called a “fascinating conversation” with Cees Dekker, a renowned nanophysicist at Delft University of Technology who believes that the idea of design in nature is “almost inescapable.” ID could be a tool to promote dialogue between the religions, Van der Hoeven wrote in her Web log that week: “What unites Muslims, Jews, and Christians is the notion that there is a creator. … If we succeed in connecting scientists from different religions, it might even be applied in schools and lessons. A few of my civil servants will talk further with Dekker about how to shape this debate.”

Except for a plan to hold a hearing about evolution and religion at her department in the fall, Van der Hoeven has issued few details about what she has in mind; instead, she has mostly been defending herself. In Parliament last week, the minister said she isn't a supporter of ID and isn't planning to impose or ban anything. But she insisted that she has the right and the duty to stimulate debates. (Van der Hoeven declined to be interviewed.)

That doesn't convince the scientists who have scolded her. “It's not a minister's job to get involved in biology,” says biochemist Piet Borst, a former director of the Netherlands Cancer Institute. Vigilance is important, he adds: “Even in Holland, there are plenty of people ready to castrate Darwin.” Borst has declined an invitation to the hearing, as has geneticist Ronald Plasterk, who heads the Hubrecht Laboratory in Utrecht. “I think Kansas has made us all a bit more sensitive,” says Plasterk.

Dekker says he's puzzled by the outcry but chalks it up to a “Pavlov reaction” to ID. “Many scientists associate it with conservative Christians, Kansas, and George Bush—so it has to be bad,” he says. He hopes the debate will get more serious after the impending publication of a collection of 22 essays about ID and related themes, most of them by Dutch scientists, which he has co-edited. Van der Hoeven has agreed to receive the first copy of the book at a ceremony in The Hague next week.

Meanwhile, Van der Hoeven's initiative is welcomed in the real Kansas. Says managing director John Calvert of the Intelligent Design Network in Shawnee Mission: “I think it's a dynamite idea.”

8. U.S. FUSION RESEARCH

# With Domestic Program at Issue, House Votes to Hold Up Funding for ITER

1. Eli Kintisch

The Department of Energy (DOE) has jousted with Congress for years over how to fund the U.S. share of the International Thermonuclear Experimental Reactor (ITER). Now some key members of Congress want to take the project hostage until the White House lays out a funding plan that covers both ITER and domestic fusion research.

Although the 2006 budget proposed by the White House would increase fusion research spending by 17%, to $291 million, it gouges U.S. projects while pledging$50 million for the nascent ITER. Last week, the House of Representatives restored the domestic money as part of a $3.7 billion budget for DOE's Office of Science. But it held up the 2006 ITER funds until March 2007, 5 months after the start of the fiscal year, and threatened to cut the funds in future spending bills. An amendment went a step further, preventing the United States from agreeing to join the$5 billion plasma reactor effort until that date.

## How well have you explained to the public what it got from doubling NIH's budget?

I think we've made enormous progress. You go to Congress, I travel around the country—the Roadmap, I'm amazed, actually, about how people get it. … This year, we're one of two agencies that did not get a cut [in the president's budget]. And as meager as the [0.7%] increase is, it came in the context of a 2% decrease in domestic spending.

## Are you concerned about falling grant success rates?

We look at two things. We look at success rate per application and success rate per investigator. And the success rate per investigator is higher than the success rate per application. [But the trend] is not good. Whenever you go at a flat [budget] level, you're not going to keep that. The optimal support for principal investigators is really what's of great interest to me. And that's why I want to make a special effort for young investigators, to preserve their potential.

This topic has been talked about for the last 20 years. … If you look at the past 10 years, we've spent almost $6 billion on translational training, if you combine GCRCs [General Clinical Research Centers], the K12 [training grants], and all of the awards, and they haven't transformed anything. … We want to challenge the community to put together real academic homes for translational science and for clinical science. Where, A, you can have a joint appointment, [and] B, you can really train in what you need to train in translational science. … And it needs degree-granting programs, it needs graduate programs, it needs postdocs. … If the institution is interested and they want to get a fusion reaction, we will supplement that. … Let's stimulate institutions to come forward with innovative ways of truly supporting what I think is just as much of a discipline that requires rigor, that requires a faculty that's dedicated to it, and is not just a service to companies. Because it is the hardest field of science to go into. It's much easier to go into basic science or clinical science. It's so hard because you don't really publish 10 papers a year, what you do is often a failure, as you can see from pharmaceutical research. But this is not something you can do in 1 year. This is going to take 10 years, 15 years. If you look at transformations like this in academic life, if you look at molecular biology departments, the first started [around] 1955, and it took about 25 years for the transformation to occur. ## The National Cancer Institute has set a goal of eliminating suffering and death from cancer by 2015. Is that realistic? All goals are goals: something you strive for. And I think [NCI] firmly believes that this is a way to energize their field, to really go toward a—not eliminating cancer, but making cancer a chronic disease. That's what [NCI Director] Dr. von Eschenbach will tell you. That's really what the idea of doing that is, to sort of project the need for a measurable endpoint. ## NIH hasn't been very visible in the debate over intelligent design. Why would it? Why do you think NIH should be visible in that debate? … Nobody has asked NIH what our position is, [although] I think we've made it very clear. ## Are you concerned that if the intelligent design movement really takes off in schools and colleges across the country, it will be harder to get the biologists the country needs? I am very concerned about it. And I don't think it's a good direction. I think we should continue to teach science based on facts and experiments and provable hypotheses. ## Have you encouraged the president to speak about the issue? I think he has enough problems of his own. I don't think that it's come up. I'm not the creationism adviser. ## What do you want your legacy at NIH to be? I tell you, the last thing I expected was to clean up an ethics mess. I don't want to be associated with that for posterity. … I had the guts to challenge the organization, to challenge institutes, to change the governance. It is an internal revolution, to truly lower the barriers to adaptation and make the agency more nimble. I've been able to recruit top-notch directors. I have two vacancies right now. I've been able to preserve NIH in a rocky time. Remember, we were challenged by Congress on the sex grants. I responded very forcefully to them. I think defending science is going to be important as we go into these cultural, political times. 13. THE BIOLOGY OF GENOMES MEETING # Reading Ancient DNA the Community Way 1. Elizabeth Pennisi COLD SPRING HARBOR, NEW YORK—At the Biology of Genomes meeting here, 11 to 15 May, genomicists reported on past as well as future genomes. There's a reason Jurassic Park is in the fiction aisle. Extracting and sequencing ancient DNA has proved difficult and controversial, in a large part because it is likely to be contaminated with DNA from a host of organisms that have come in contact with the fossilized source over the millennia—not to mention DNA from the humans trying to extract it. But at the Cold Spring Harbor meeting, James Noonan and Edward Rubin of Lawrence Berkeley National Laboratory in Berkeley, California, presented a new way to distinguish ancient DNA from that of more recent hangers-on. And they reported that they successfully used the method to sequence nuclear genes of cave bears from the Pleistocene epoch. (Their work is also published online by Science this week; see www.sciencemag.org/cgi/content/abstract/1113485). Next, they hope to use this so-called paleometagenomics technique to decipher Neandertal DNA. As DNA in fossils ages, it falls apart; water and other chemicals degrade the molecules. That makes it an extreme challenge to interpret any changes seen in a fossil's DNA. “One of the key issues is disentangling the evolutionary changes from DNA degradation,” says Stephen Brown, a mouse geneticist at the Medical Research Council in Harwell, U.K. Microbes colonizing bone and the surrounding soil also leave behind their genes, which greatly complicates isolating the DNA belonging to a skeleton. “It's really been a hurdle” to get clean, decipherable samples, says Rubin. His and Noonan's brute-force solution: Take whatever DNA the fossil contains, sequence it all, and then use comparative genomics to pull out the DNA of interest. “In some ways, we are looking for a needle in a haystack,” Rubin explains. “But in this case, we have a magnet.” That magnet is already-sequenced DNA from related, living organisms. For their first foray into paleometagenomics, he and Noonan, a postdoctoral fellow, worked with Svante Pääbo and Michael Hofreiter of the Max Planck Institute for Evolutionary Anthropology in Jena, Germany. They studied bones from two extinct 40,000-year-old cave bears. Weighing a ton, these ancient bears (Ursus spelaeus) made grizzlies seem puny. But they were gentle giants, and before the last ice age, they lumbered throughout Europe, feasting primarily on berries, honey, and grass and passing time in caves, where their fossilized bones remain today. The researchers chose U. spelaeus because its fossils are plentiful and because the bear bones are about as old as Neandertal material, thus providing DNA as degraded as one would see when looking at bones of the hominid. Bears offered another advantage, compared to fossil humans: Any DNA contamination from the researchers themselves would be quite apparent. Once Noonan sequenced all the DNA samples from the bear fossils, he looked for any sequences that resembled canine DNA; dog genomes are about 93% the same as a bear's. Noonan found that about 6% of the total fossil DNA resembled the dog's. That small fraction was expected, says Rubin, given that microorganisms had thousands of years to settle in and around the bear bones. Indeed, “we found a lot of [DNA] matches to dirt [microbes],” Rubin reported. Even though they had only fragments of U. spelaeus DNA sequences, he and Noonan matched many of them up with a modern bear's genetic sequence and came up with 27,000 bases of real bear material. The DNA of the fossil and extant animals was 98% the same. Rubin and Noonan were also able to match the fossil DNA up against dog genes. And when they used the fossil DNA to build a bear family tree, the cave bear fit in right with black bears, grizzly bears, and polar bears. “The study serves as a proof of principle for the Neandertal Metagenome Project,” says Rubin. Piecing together Neandertal DNA could shed light on how closely related they were to humans or whether breeding between them and modern humans occurred, says Peter Little, a geneticist at the University of New South Wales in Sydney, Australia. Still, he has reservations about the new approach, noting that Neandertals are likely to be only as different genetically from modern humans as individuals are from each other. Making sure identified base differences are real, and not the result of degradation, will be key, Wales notes: “But if they can do it, it's going to be great.” 14. THE BIOLOGY OF GENOMES MEETING # Extinct Genome Under Construction 1. Elizabeth Pennisi COLD SPRING HARBOR, NEW YORK—At the Biology of Genomes meeting here, 11 to 15 May, genomicists reported on past as well as future genomes. The chromosomes of animals from the distant past may be long gone, but that hasn't stopped bioinformaticists from trying to reconstruct what that old DNA looked like. At the meeting, collaborators from two laboratories—those of David Haussler of the University of California, Santa Cruz, and Webb Miller, a computer scientist at Pennsylvania State University, University Park—described how they analyzed DNA sequence data from living placental mammals, including humans, dogs, mice, and rats, to trace the ancient evolution of individual bases in those animals. Miller's lab already has a rough idea of what one chromosome looked liked in the animals' common ancestor, which lived an estimated 100 million years ago, and the two groups hope to know the sequence of its entire genome by the end of the year. Once they have determined the sequence of the “mother” of all placental mammal genomes, researchers should be able to make evolutionary sense of the genetic differences between species, especially as the data stream in from the more than a dozen vertebrate genomes now slated for partial sequencing. “Reconstructing mammalian sequence to the base [level]—this is amazing,” says Francis Collins, director of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. Haussler and Miller focused on placental mammals because the various subgroups alive today arose at basically the same time, from a shrewlike ancestor. The rapid subsequent evolution of these groups makes it easier to verify base changes through time. In contrast, determining the ancestral genome of all mammals would be much more difficult, if not impossible, because marsupials and monotremes branched off at very different times, making DNA comparisons less reliable. The approach Haussler, Miller, and their colleagues took resembles that of molecular evolutionists, who for decades have used DNA differences to build evolutionary trees. Typically, those researchers focus on one gene, such as that for a ribosomal RNA. They count the number and type of base changes in that gene: The more changes between two species, the more distant the kinship. Those DNA bases shared by all the species under consideration likely represent ancestral ones. With new computer programs and sophisticated simulations of genome evolution, Haussler's and Miller's groups have taken this approach considerably further by looking across the whole genome and not just at one gene. The computers search among the DNA of many species for common sequences in large stretches of chromosomes and then check individual bases for changes in each species. The group validated the accuracy of the reconstructed genome by crosschecking the simulations with phylogenetic trees derived from modern DNA. Last year, Haussler's postdoctoral fellow Mathieu Blanchette, now at McGill University in Montreal, Canada, did a test run analyzing a 1-million-base piece of chromosome 7, the region that contains the cystic fibrosis gene, from 19 placental mammals. The simulations indicated the ancestral sequence of that region is about 98% right. Miller's graduate student Jian Ma has now taken on the task of reconstructing a much bigger chunk of DNA, the ancestral chromosome 15. Although it remains fairly intact in some living mammals, in others it has become quite chopped up and redistributed. In both mice and rats, this ancient DNA is now scattered among five chromosomes, she reported. In humans, however, most of the sequence of the reconstructed ancestral chromosome 15 now appears to make up one arm of human chromosome 13. In dogs, it's divided up between chromosomes 22 and 25. These whole-chromosome studies include just nine placental species, leading Blanchette to estimate that the ancestral chromosome 15 is only about 90% accurate. But that percentage will improve, says Ma: “The more species we have, the more accuracy we can get.” Robert Waterston, a geneticist at the University of Washington, Seattle, believes the goal of rebuilding the entire genome within a year is achievable. “[They] will be able to reconstruct most of it,” he predicts. Researchers will then be able to work from these reconstructed chromosomes to determine how long a particular base has been part of the human genome and how it has changed, says Haussler. Geneticists will also learn more about how chromosomes evolve, says Waterston: “It provides a chance to think about genome evolution systematically and to look at all that's happened.” 15. ORNITHOLOGY # Citizen Scientists Supplement Work of Cornell Researchers 1. Yudhijit Bhattacharjee A half-century of interaction with bird watchers has evolved into a robust and growing collaboration between volunteers and a leading ornithology lab BOYCE, VIRGINIA—On a sunny April morning, Kaycee Lichter has driven 32 kilometers to the Virginia State Arboretum here in the Shenandoah Valley to meet her friend Greg Baruffi. Walking to the edge of a meadow, the two open a box containing a bluebird nest and place an electronic device no larger than a coat button under the five eggs inside. The button will record the fluctuating temperature inside the nest as the female bluebird departs and returns periodically in search of food. In 3 days, Lichter and Baruffi will download the data to a computer and reset the button. Lichter, 46, is a medical transcriptionist at a nearby mental health clinic and Baruffi, 50, is a carpenter. They are not scientists, but their work is crucial to a study by researchers at the Cornell Lab of Ornithology in Ithaca, New York, of whether birds lay fewer eggs in cooler climates because of the energy costs of incubation. The results could provide insights into how environmental factors affect the number of hatchlings in a brood. Over the past decade, Cornell has harnessed the enthusiasm of such volunteers—or citizen scientists, as they are known—to explore questions such as the dynamics of infectious disease in bird populations and the impact of acid rain on their reproductive success. Those efforts have resulted in a long list of peer-reviewed publications, demonstrating the value of citizen science as a research tool. “Having an army of assistants on the ground allows you to ask questions that require simultaneous observation across large spatial and temporal scales,” says Andre Dhondt, an ecologist at Cornell. “It opens up a world of scientific possibilities.” Nobody has pursued those possibilities as seriously and successfully as Dhondt and his colleagues at Cornell. “There are 15 million citizens in the U.S. alone who spend untold amounts of time and money on bird watching. The Lab of Ornithology has capitalized on this public interest to produce some very good science,” says Peter Marra, an ecologist at the Smithsonian Environmental Research Center in Edgewater, Maryland. Cornell has even created an endowed professorship dedicated to citizen science—the first position of its kind in the country—that it hopes to fill this year. ## Helping hands Cornell's tradition of engaging citizens in bird studies dates to the 1950s, when lab founder Arthur Allen conducted informal Monday evening seminars to raise public awareness about ornithology. At those sessions, Allen would read out a list of birds and ask for a show of hands indicating how many people in the audience had sighted each species. He logged the results of the weekly poll in a register, providing a rough picture of the relative abundance of different birds over time. Decades later, lab researchers thumbing through those registers wondered if they could get volunteers to be more scientific. That idea led to Project Tanager, a large-scale experiment begun in 1994 to study the impact of forest fragmentation on tanager populations and their nesting success. Over 3 years, nearly 1500 volunteers around the country took a census of four tanager species—often by playing taped calls supplied by the lab—and recorded signs of predation in their nests. Researchers found that tanagers in fragmented habitats were more likely to thrive in regions that had a high percentage of forest cover. Volunteers also played a key role in helping scientists understand an epidemic of conjunctivitis among house finches in the mid-1990s. Following up on sightings in Maryland of finches with red, crusty eyes, Dhondt printed and distributed 60,000 computer-scannable forms to 9000 volunteers to record daily sightings of both healthy and sick birds. Within months, researchers had documented the spread of the disease across the Northeast and Midwest. “The speed at which we were able to track the epidemic was simply amazing; we couldn't have dreamed of doing it without a volunteer network,” says Dhondt. Over the next 5 years, more data revealed patterns showing seasonal and geographical variations in the spread of the disease. In 2000, Dhondt and his colleagues used those data to win a$2.4 million grant from the National Institutes of Health and the National Science Foundation (NSF) under a joint program on the ecology of infectious diseases. The team developed predictive models of the spread of aerially transmitted bacterial diseases.

The grant marked a coming of age for Cornell's citizen science efforts, which had previously been supported through NSF's informal science education program. Dhondt says NSF reviewers had rejected earlier proposals because of doubts that volunteer-generated data could be trusted. But the publications from the house finch survey “countered that skepticism effectively,” says NSF program director Samuel Scheiner.

Cornell researchers have also studied the reliability of citizen scientists. During the pilot phase of Project Tanager, for example, ornithologist Ken Rosenberg and his colleagues compared observations made by volunteers to data collected by researchers themselves. At 17 of the 19 sites where this comparison was made, the data were identical. “Volunteers are extra-careful because they aren't professionally trained,” says Rosenberg. “They doubt themselves.”

By using statistical tools to look at broad patterns, the Cornell researchers are able to detect and discard individual data points that appear suspect. And although there are differences between volunteers in their ability to see and hear birds, “the variation tends to be random,” says ecologist Wesley Hochachka. “The larger the data set, the greater the chances of detecting a signal.”

Even so, Cornell researchers face constant reminders that volunteers are not trained scientists. Dhondt remembers a lament from one despondent volunteer in Quebec, who wrote him that “I've been reporting for 48 months, and I've yet to see a sick house finch.” Dhondt used his reply as an instructional tool. “Your data are so valuable,” Dhondt wrote back. “As soon as you have seen your feeder and recorded your observation, you've made your contribution. Not seeing birds is biologically important information.”

The lab thinks citizen scientists are capable of even more sophisticated observations. For example, Stefan Hames is using volunteers to investigate the mechanism by which acid rain affects wood thrush populations. The protocol asks them to soak a square piece of cardboard in unchlorinated water and place it on a patch of earth covered with twigs and fallen leaves. The next day they record the number of snails and other invertebrates found under the cardboard. Eating these calcium-rich animals helps the birds lay eggs with secure shells. Knowing that acid rain takes a toll on these invertebrates, Hames and his colleagues hope to find out whether the scarcity of calcium-rich prey explains the decline of wood thrushes at sites with high levels of acid rain.

The lab also hopes to expand its network of volunteers. “Right now, the northeastern seaboard is well covered,” says lab director John Fitzpatrick. “We'd like more observers on the ground in states like Arizona and Nevada. Eventually, we'd like to test hypotheses and conduct experiments on a continental scale.”

16. PONCE DE LEÓN AND ZOLLIKOFER PROFILE

# Building Virtual Hominids: Musical Duo Reconstructs Ancient Fossils

1. Michael Balter

Researchers team up professionally and personally to perfect the art of putting distorted fossils back together in the computer

ZURICH, SWITZERLAND—By the time anthropologist Marcia Ponce de León and neurobiologist Christoph Zollikofer received permission to analyze the famous Le Moustier Neandertal skull, it was in bad shape. Uncovered in France's Dordogne region in 1908 by an amateur archaeologist, the specimen is still the most complete adolescent Neandertal skeleton known. But during the first 2 decades after the find, researchers made numerous crude attempts to reconstruct the fragmented skull, using glue and varnish to put it together and take it apart again at least five times and damaging and losing some pieces in the process. During World War II, the cranium, housed in a Berlin museum, was thought to have been destroyed in a bombing raid, but it eventually turned up again. In recent decades, curators at Berlin's Museum for Pre- and Early History have wisely refused requests by scientists to have yet another go at it.

In 1995, however, the museum allowed Ponce de León and Zollikofer to take the skull to their shared office at the University of Zurich and dismantle and reassemble it once again. But they didn't use glue or varnish. Instead the pair scanned the fragile cranium, now a patchwork of several dozen fragments, using high-resolution computed tomography (CT). Then they used a specialized computer graphics program they had developed, along with their own formidable knowledge of human anatomy, to electronically isolate each fragment and recreate missing ones. They were able to put the entire long-abused cranium back together inside the computer, unveiling a complete skull that could be analyzed and compared to other specimens.

This study was one of the first in a series of high-profile projects carried out by Zollikofer and Ponce de León, the acknowledged leaders in computer-aided fossil reconstructions. The pair, who share personal and professional lives, are in ever-increasing demand by researchers the world over who seek to extract the maximum information from rare and often fragmentary and distorted hominid fossils. “They have raised the art of reconstructing fossil material to the level of a science,” says Harvard University anthropologist Daniel Lieberman.

Most recently, they reconstructed the skull of Sahelanthropus tchadensis, claimed to be the oldest member of the human lineage, in collaboration with discoverer Michel Brunet of the University of Poitiers, France, Lieberman, and others. The team uncovered new evidence that Sahelanthropus was not a gorilla ancestor, as some had argued, and that it was bipedal, a basic requirement for hominid status (Science, 8 April, p. 179). “For virtual reconstruction, they are the best in the world,” says Brunet, who packed up his priceless skull and took it to Zurich for scanning because Ponce de León and Zollikofer do not work on casts.

“Their work shows up with increasing frequency and has had a growing impact,” says Harvard paleoanthropologist David Pilbeam. “More and more researchers want them to ‘dedistort’ their finds.” The pair has become a regular fixture at top anthropology meetings, where the tall, soft-spoken Zollikofer and the petite, intense Ponce de León are invariably seated together.

## Making music

The paths that led Ponce de León and Zollikofer to the small office and laboratory they now share in the University of Zurich's Anthropological Institute followed very different trajectories. Ponce de León, 48, was born in La Paz, Bolivia, where she studied civil engineering and was also a serious piano student. In the mid-1980s she moved to Zurich, entered the university there, and switched to biology. In 2000, she received a Ph.D. in anthropology, focusing on Neandertal development.

Zollikofer, 47, was born and raised in Zurich. Although he showed an early interest in the sciences, his greatest passion was music, and he long planned a career playing cello. He took up biology at the University of Zurich but then studied cello at a Zurich musical conservatory for 3 years before returning to the university for his Ph.D. studies on the locomotion of desert ants. The ants “run incredibly fast, about 1 meter per second,” says Zollikofer. “And when they really get going, they raise up on their hind legs. That's how I got interested in bipedality,” he says with a smile.

Even after receiving his doctorate in neurobiology in 1988, Zollikofer continued to vacillate between science and music, teaching at the university while playing professionally in a local orchestra. “That's when Marcia came on the scene,” he says. The two met when Ponce de León took an undergraduate neurobiology course he was teaching. Yet both agree that at first it was a shared love of music, not science, that brought them together. “We would play together and go to concerts,” Ponce de León says. Adds Zollikofer admiringly: “She knew all of the cello suites of [Johann Sebastian] Bach.”

The turning point in both their careers came in 1990 when Ponce de León urged Zollikofer to attend a university seminar she was taking from computer graphics pioneer Peter Stucki. The pair realized that computer graphics could help solve the problems that plague interpretation of hominid fossils. “The fossils are usually incomplete and deformed and often encrusted with sediments,” explains Zollikofer. Ponce de León, who spent countless frustrating hours trying to measure casts of Homo erectus for her master's degree, adds that conventional methods of analyzing skulls and other fossils rely on taking measurements of the distances between two fixed points. “You can't get information about the three-dimensional shape of a fossil this way,” she says.

The pair landed two grants from the Swiss National Science Foundation to develop a prototype of the computer program they use today, which they named FoRM-IT (Fossil Reconstruction and Morphometry Interactive Toolkit). But the grants paid them both only part-time salaries. To raise funds, they began building three-dimensional plastic models for local doctors preparing to do surgery on patients with facial deformities. The models, based on CT scans, use a computer-guided laser beam to polymerize liquid resin into an exact model of a skull. “We raised more than \$100,000 making those models,” says Ponce de León. The model-building, which they call “real virtuality,” later came in handy as a way of doing reality checks on their computerized reconstructions and is now an integral part of their reconstruction process.

Paleoanthropologist Robert Martin, director of the Anthropological Institute at the time and now provost of the Field Museum in Chicago, Illinois, says it is no surprise that Ponce de León and Zollikofer were able to turn their nascent ideas into virtual reality. “I was struck by Marcia's originality and her striking ease with quantitative concepts,” says Martin. “And Christoph was outstandingly brilliant.”

## No more calipers

The pair made their first big splash with FoRM-IT in 1995, when they published a short paper in Nature detailing their reconstruction of the skull of a 3- or 4-year-old Neandertal child found in Gibraltar. From five existing fragments, Ponce de León and Zollikofer recreated the entire skull and also solved a long-standing debate about whether the fragments represented one child or two. Earlier researchers had noted that the apparent state of eruption of the teeth suggested an older child, whereas the development of the skull's inner ear region seemed younger. But the reconstruction showed that the pieces of the skull made a precise fit, meaning that it belonged to only one individual—and that the teeth of Neandertal children erupted earlier than those of modern humans.

This conclusion led the two onto a whole new research track: the study of Neandertal growth and development. They analyzed the Le Moustier skull and then compared virtual reconstructions of Neandertal skulls ranging from babies to adults to those of modern humans of similar ages. In each reconstruction, they used anatomical points of reference called landmarks to measure the shapes of three-dimensional objects rather than two-dimensional measurements. Human origins experts say that although a number of researchers now use landmark analysis, the combination of landmark analysis with virtual reconstruction has put Ponce de León and Zollikofer on the cutting edge of physical anthropology. “Just 8 or 10 years ago we were still using calipers” to measure the distances between points on skulls, says paleoanthropologist Chris Stringer of the Natural History Museum in London. “We were getting only a very poor measure of the three-dimensional shapes.” Stringer adds that unlike virtual reconstructions, which can be scaled up or down and compared directly on a computer screen, these older techniques made it very difficult to compare “a very big skull with a very small skull”—comparisons essential to tracking development as well as to understanding the relationships among different-sized species.

Ponce de León and Zollikofer developed new mathematical techniques to make it easier to use landmark analysis to follow the growth of different parts of the skull at the same time. Recently, after studying specimens of all ages, they concluded that the notable differences in skull and jaw shape between Neandertals and modern humans arise very early during development, possibly even before birth—thus making it more likely that they represent different species. “Their work demonstrates more clearly than anyone else's that the ontogeny of Neandertals and modern humans is different from as early an age as we can document,” says Lieberman. Stringer agrees: “They have made a wonderful contribution; … we now have a much clearer view of the developmental and evolutionary processes that produce both Neandertals and modern humans.”

In addition to the Neandertal work, Zollikofer and Ponce de León have also been called in to reconstruct a series of 1.8-million-year-old hominid skulls found at Dmanisi, Georgia, which represent the first known hominid migration out of Africa. In the case of the most recently discovered skull, a nearly toothless individual who might have been cared for by other hominids, the pair began their reconstruction while the cranium was still embedded in a hardened block of sediments, working from CT scans of the entire block. These scans also helped the Dmanisi team to excavate the skull without damaging it. “Both of them are unassuming, collegial, and unfailingly helpful,” says Dmanisi team leader and Georgian National Museum general director David Lordkipanidze. “You rarely meet people so dedicated to our profession.”

Although they are often called in to solve such technical problems, Ponce de León says that gaining new insights into ancient hominids is what matters most to them. “A lot of researchers think that we are technical or methods people,” she says. “But this is not true. We only developed these methods so that we could carry out the research we want to do.”