# News this Week

Science  21 Mar 2014:
Vol. 343, Issue 6177, pp. 1294
1. # Around the World

1 - Strasbourg, France
Parliament Tightens E.U. Data Privacy
2 - Bern
Switzerland to Replace Lost E.U. Funding Opportunities
3 - London
U.K. Report Condemns Europe's GM Crop Policy

## Strasbourg, France

### Parliament Tightens E.U. Data Privacy

The European Parliament has approved stricter rules for the protection of personal data across the European Union—a move that some research organizations fear will undermine public health and medical research.

On 12 March, the members voted overwhelmingly to approve the draft regulation, which updates 1995 rules and includes controversial amendments introduced last fall by Parliament's civil liberties committee. In a key change, research organizations must get specific consent to use or reuse patients' data unless the research serves a "high public interest … [and] cannot possibly be carried out otherwise." Supporters call the changes reasonable and necessary, but scientists argue that they are too strict and vague and will threaten important research.

Parliament must still negotiate the reform with the Council of Ministers, which represents the 28 E.U. member states. "We hope that we can still change things, for the good of biomedical research and for the benefit of patients," says Nathalie Kayadjanian, senior scientific officer for the medical scientific committee of Science Europe, an association of research funders. http://scim.ag/_EUdata

## Bern

### Switzerland to Replace Lost E.U. Funding Opportunities

The Swiss government announced last week that it will step in to help researchers compensate for a funding block from the European Union. After voters agreed in February to curb mass immigration, Switzerland lost its status as an associated country to Horizon 2020, the European Union's new research funding program, and to the higher education program Erasmus+, both of which run from 2014 through 2020. Individual scientists from Swiss institutions can no longer apply for basic research grants from the European Research Council (ERC) or for Marie Curie scholarships.

To pick up the slack, the Swiss National Science Foundation (SNSF) will offer ERC-like grants, with roughly the same rules, evaluation criteria, and funding calendar. The budget of the temporary fund is not settled yet, says SNSF spokesman Alan Knaus, but will "presumably" come from money Switzerland would have paid the European Union to become an associated country in Horizon 2020.

While the scientific community is "grateful," says Martine Rahier, president of swiss universities, "a full membership in the Horizon 2020 and ERC programs remains crucial." http://scim.ag/SwissERC

## London

### U.K. Report Condemns Europe's GM Crop Policy

Prominent U.K. plant biologists and biotechnologists criticized the European Union's "dysfunctional approval process" for genetically modified (GM) crops in a government-funded report released last week. The research, commissioned by the U.K. Council for Science and Technology, found that the European Union has stifled scientific progress with its regulations and allowed political considerations to influence its risk assessments.

The U.K. government already supports GM crops, and the authors make several suggestions for pushing the approval process forward, including a shift of regulatory power away from Brussels and the European Food Safety Authority. They suggest that the United Kingdom create a new authority to vet GM varieties, while the European Union maintains an advisory role on risk and safety.

The report also proposes that GM crops be assessed according to their traits—just like varieties produced via conventional plant breeding—rather than by the process used to produce them. "The regulation of the technology is not proportionate," says Jonathan Jones of the Sainsbury Laboratory in Norwich, U.K., one of the authors. "It's time to remove the red flags." http://scim.ag/UK_GM

2. # Random Sample

## Blarney Myths Go Under the Microscope

Ireland's storied Blarney Stone has received plenty of kisses this week, but it also got some new scientific attention recently, thanks to the chance find of a microscope slide in the Hunterian Museum of the University of Glasgow in Scotland. While digitizing the mostly handwritten catalog of the museum's 40,000 geological slides, intern Becky Smith noticed one entry referring to a slide of the Blarney Stone. The records show that Victorian mineralogist Matthew Forster Heddle acquired the slide sometime between 1850 and 1880, but he doesn't appear to have published anything about it.

Geologists at the museum analyzed the sample, which is cut thin enough to be transparent, to determine its composition. The stone is rumored to be made of Welsh bluestone, the same material used to make the monoliths of Stonehenge, or else of sandstone cleaved from the Stone of Scone, which forms the coronation seat used by the kings and queens of Scotland and Great Britain for hundreds of years. But the new analysis revealed that the landmark is Irish through and through: It is a 330-million-year-old carboniferous limestone typical of that corner of Ireland and contains fragments of fossilized brachiopod shells and bryozoans. Hunterian curator John Faithfull says he has kissed the slide, but the jury is still out on whether he has acquired the legendary "gift of the gab."

## They Said It

"This has been at once the best and worst job I've ever had."

—David Wright, director of the U.S. Office of Research Integrity, in a resignation letter describing how the "dysfunctional" federal bureaucracy drove him to quit after 2 years. http://scim.ag/WrightORI

3. # Newsmakers

## France Córdova Confirmed to Lead NSF

It's been nearly 20 years since France Córdova has worked for the U.S. government, but the new director of the National Science Foundation (NSF) says she's never really severed her ties to Washington.

On 12 March, the Senate confirmed the 66-year-old astrophysicist as NSF's 14th director. She replaces Subra Suresh, who left 1 year ago less than halfway through his 6-year term to become president of Carnegie Mellon University.

After spending 3 years as NASA's chief scientist under Daniel Goldin in the mid-1990s, Córdova returned to academia and quickly moved up the administrative ranks. In 2002, she became chancellor of the University of California, Riverside, and in 2007 she began a 5-year stint as president of Purdue University. In 2012, she was named chair of the Board of Regents of the Smithsonian Institution, a post she has relinquished to join NSF. Córdova is expected to take up the reins of the $7 billion agency in a few weeks. She says she has kept abreast with issues facing the agency but declined to comment on pending legislation affecting its programs (see p. 1298). 4. # A War Within a War 1. Leslie Roberts Fighting a major polio outbreak in the midst of Syria's bitter civil war is a test of commitment—and diplomacy. ZA'ATARI REFUGEE CAMP AND AMMAN—Za'atari, sometimes called Jordan's fourth largest city, was thrown together in the desert in a few months' time in 2012. This sprawling, dusty expanse of low-slung tents and prefab housing, 15 kilometers from the Syrian border, has 11 clinics, two schools, and a police station. On its bustling main thoroughfare, dubbed the Champs-Élysées, you can buy fresh fruit and vegetables, mobile phones, electric heaters, canned goods, and cigarettes; bright pink wedding dresses are on display, for sale or rent. Za'atari is now home to at least 100,000 refugees who have fled Syria's brutal civil war, more than half of them children. Some children arrive sick and severely malnourished. Many have witnessed horrors in the course of the war, which has killed an estimated 140,000 people and displaced 8 million or 9 million. Ripped from their homes and routines, some have seen close family members taken, shot, or killed either in their towns or on the long, dangerous walk to the border. Crammed into tents or prefab trailers with their extended families, with no running water and hand-dug latrines that overflow with the rain, these children are at risk for diarrhea, respiratory disease, hepatitis A, and measles. Scabies and lice are huge problems. And now they face the threat of polio, which erupted in Syria last October after a 15-year absence and has already paralyzed at least 37 kids—exact numbers are contentious—mostly in the opposition-held north. "It's an emergency within an emergency," says Australian polio expert Chris Maher—not just for Syria, where millions of kids are at risk, but for surrounding countries as well, including Jordan, Lebanon, and Iraq, as refugees pour across their borders. And it's another blow to the Global Polio Eradication Initiative (GPEI), a partnership of international agencies that after 25 years has managed to chase the virus out of all but three endemic countries—Pakistan, Afghanistan, and Nigeria—but last year was hit by new outbreaks in the Horn of Africa and now Syria. That's why Maher, who is 53 and has been fighting polio for more than 20 years, is in nearby Amman leading the biggest polio outbreak response ever attempted in the Middle East. It aims to vaccinate 23 million kids in seven countries, including wartorn Syria, repeatedly over 6 to 8 months and maybe longer. Doing so will involve tens of thousands of vaccinators delivering almost 100 million doses of vaccine. "Anything less and the virus will come and bite you on the ass," says Maher, a senior adviser on polio at the World Health Organization (WHO) in Geneva, Switzerland. The current crisis is "one of the most challenging and visible outbreaks the Global Polio Eradication Initiative has tackled since its launch 25 years ago," wrote Bruce Aylward, a Canadian epidemiologist and physician who leads GPEI from Geneva, and Ala Alwan, WHO's regional director for the Eastern Mediterranean, in a recent article in The Lancet. Tens of thousands of children are trapped in besieged areas, cut off from any humanitarian intervention, including polio drops. The millions of people on the move, both in Syria and the surrounding countries, are off the map and often out of reach of vaccinators. Fine-grained population mapping, precision vaccination campaigns, and monitoring—the backbone of the eradication initiative—are out of the question. WHO and other U.N. agencies are walking the finest of lines in Syria, bound by the rules of the Assad regime but determined to vaccinate children in areas where the regime cannot go. Critics have blasted WHO for colluding with the government, vastly underestimating the size of the outbreak, and generally failing the children in the opposition-held north. So far the response has been far from perfect. "We've made millions of mistakes," Maher says. But still, he adds, "in polio we are now reaching more people in a shorter period of time with an intervention than anyone else has succeeded in doing throughout the whole Syrian crisis"—some 3 million kids so far, each vaccinated multiple times. "And if we can create access for a polio campaign, we can create access for other humanitarian interventions." ## Collapse On an unusually warm day in January—the snow has just melted—Mohammad Mansour greets me and a translator outside his trailer and invites us in for tea. Mansour, 24, is one of the community health workers in Za'atari who goes tent to tent every month to deliver two drops of oral polio vaccine (OPV) to all children under age 5. He was a nurse in Syria before he and his family fled and landed in Za'atari more than a year ago. Sitting cross-legged on the carpet, Mansour talks about his life back home and how it, and the country, collapsed. Health care was excellent and affordable and routine immunization rates were high, he says. But with the conflict, "everything stopped." Hospitals and clinics were destroyed and health care workers targeted—Mansour says he feared for his life. Vaccines, once plentiful, were no longer available in towns in Dara, a southern governorate where many of the refugees at Za'atari are from. The only way to get vaccine was to make a dangerous trip to a bigger city. "People decided vaccination was not worth risking their lives," Mansour says. And now, 15 years after polio was eliminated in Syria, it is back. On 11 October, WHO got word of a cluster of 22 cases of acute flaccid paralysis, or AFP, in Deir al-Zour, a heavily contested governorate in northeastern Syria. Even before conclusive data were in, Aylward, the GPEI director, knew it was polio: The sudden, one-sided paralysis and the geographic clustering "ticked all the boxes," he told me at the time. WHO issued a global alert on 19 October warning of a suspected polio outbreak in Syria with a very high risk of spread across the Middle East. The first documented case had actually occurred on 14 July in Aleppo, but WHO only learned of it in October, after the cluster was reported. The Syrian government did not announce the outbreak until 29 October. The virus turned out to be closely related to two known strains, one detected in the sewers in Egypt in late 2012 and the other in Israel in early 2013. No cases have occurred in either country. Both of those strains were quickly traced back to Pakistan. The most recent genetic analyses suggest the virus may have arrived in Syria from Pakistan sometime earlier in 2012, then spread across the country and spilled across its borders, says Mark Pallansch, who heads the division of viral diseases at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta. But that remains a hypothesis, he emphasizes. (CDC, WHO, the United Nations Children's Fund [UNICEF], Rotary International, and the Bill & Melinda Gates Foundation coordinate the global eradication drive.) Five days after issuing its initial alert, and before the Syrian government confirmed the outbreak, WHO, in collaboration with UNICEF and the Syrian Ministry of Health, began vaccinating against polio as part of an already-planned immunization campaign against measles, mumps, and rubella. "It wasn't a great campaign but it probably wasn't a terrible campaign either," Maher says. At about the same time, Jordan and other countries strengthened their border vaccination, and the first polio campaign was conducted in Za'atari on 28 October. ## A beautiful plan On 26 October, Mike Ryan was in Dublin, where he teaches international public health at University College Dublin, when he got a phone call from an old friend from WHO. It looked like there was a polio outbreak in Syria, Bruce Aylward told him. WHO needed him urgently in Amman to draw up an emergency response plan for the entire region. "I couldn't say 'No,' " Ryan says. "Bruce and I grew up together as kids at WHO in the '90s," says Ryan, a gregarious, red-haired Irishman who led WHO's global outbreak alert and response network for more than a decade before leaving WHO in 2011. "Two days later I was on a plane to Muscat," in Oman, where on 29 October WHO's Alwan had convened the yearly meeting of all the ministers of health for the Eastern Mediterranean region. The Syrian minister was there, and polio was at the top of the agenda. Aylward led the polio discussion. A slim, intense man with a shock of sandy hair, Aylward, 50, speaks fast and emphatically. With routine immunization falling below 50%, down from 95% or so before the war, Syria is a polio tinderbox, and several of the surrounding countries—in particular Lebanon and Iraq—do not have strong firewalls. We are dealing with a reinfection of the Middle East, Aylward told the ministers, and whatever their differences, they would have to work together to stop the outbreak. To reach all children under age 5 in Syria and across the region, each country would need thousands of vaccinators to go door to door. They would need to quickly license a newer vaccine, bivalent OPV, which works against the two remaining strains of polio and is more effective than the trivalent version the countries relied on when they first wiped out the virus. And not only would the Syrian government have to commit to vaccinating every child in the country—and that meant children in opposition-held areas as well—it would have to do it six times over the next 6 months. There were a lot of deep breaths and some equivocation, Aylward says, "but no outright 'No's.' " On 30 October, the ministers adopted a resolution declaring polio a regional public health emergency. "The next day I flew back to Ireland and grabbed another bag and went to Amman for 5 weeks," says Ryan, where he set up WHO's one-man polio shop. The first job was to get the warring factions to cooperate. "The concept that really rang true with all sides of the conflict was that these were children under age 2 who were being paralyzed, who have no part in any conflict. … Without taking sides we were able to articulate the view that there is one thing that could be done, and this could be done quickly and this could be done effectively." By 26 November, Ryan, working closely with UNICEF, various nongovernmental organizations (NGOs), and ministries of health from different countries, had a draft emergency response plan for Syria, Iraq, Jordan, Lebanon, Turkey, the West Bank and Gaza Strip, and Egypt, giving top priority to Syria. Estimated to cost$40 million in its first phase, the plan clearly lays out what all of the countries would have to do over the next 6 months to a year.

But reality proved a lot messier. "It is one thing to have a beautiful plan on paper, but it is different when you are fighting a war," says Ryan, who returned to Dublin on 3 December. "It is not pretty."

## Political minefield

Blunt, with short gray hair and hooded blue eyes, Chris Maher has a reputation for getting things done. When he arrived in Amman in November to relieve Ryan, he walked into a political minefield.

The Syrian regime had laid down two red lines. First, the government would allow vaccine to move "cross line" or into rebel-held or contested areas. But no vaccine could come "cross border" from another country. (Turkey, which is aligned with the opposition, was a particular flash point.)

Second, the Syrian government would retain sole authority of the outbreak response. And that meant no collaboration with the opposition or with humanitarian groups that support it, such as the Assistance Coordination Unit (ACU) or the Syrian American Medical Society (SAMS).

U.N. agencies, which operate in Syria by invitation of the government, are bound by those rules. "We are not some independent agency that can waltz in and do what we like," Maher says. But there's a problem, he adds. "Cross line has not been working in many of the contested areas."

One challenge has been getting vaccine into the besieged areas, whether they are besieged by the government or the opposition. Another is ensuring that vaccine reaches all the areas of the north where the radical Islamic State of Iraq and the Levant, known as ISIS, and more moderate opposition factions are fighting each other. Even in areas where the conflict is less intense, the lines of political control are constantly shifting, so it is hard to know who is in charge and which NGOs might be able to get in, Maher says. "If there is a bloke with a gun in your face, you don't go."

It doesn't look like a $40 million operation. At WHO's polio command center in Amman in mid-January, the phones aren't working. Maps of Syria are taped to the walls, and the skeleton crew, several of whom have just arrived, are sharing desks. Chairs are in short supply, and the atmosphere is one of controlled chaos. At 9 a.m., Maher is huddled over a laptop with a colleague who flew in the night before with fresh data on the January immunization round in Syria. Maher wants just one uninterrupted hour with him to figure out how many kids were vaccinated, how many were missed, where, and what needs fixing for the February round. The interruptions are constant. "Sorry about that, mate," he says after each, grumbling, "I desperately need a technical person." Maher and his colleague finally reconnect later that night and finish reviewing the data and planning the next round over a bottle of whiskey in Maher's room. The next evening in the lobby bar in the Amman Marriott, the team's home away from home, Maher is fairly upbeat. The January rounds went better than expected, and for the first time vaccinators gained wide access across the opposition-held north. Turkey broke the logjam, supplying vaccine to the north in defiance of the Syrian regime, the humanitarian groups ACU and SAMS have just announced. Some 8500 well-trained vaccinators from local communities went door to door, delivering vaccine and marking every child's little finger to show they were vaccinated, says a SAMS staffer from the Turkey office who declines to be identified. An estimated 1.4 million kids in the north who had not been reached before were vaccinated, he says in an e-mail. "Now we have a mechanism to get to these communities, and the mechanism is working," Maher says. "With the January round we can say with some confidence that every governorate in the country had immunization activity, and while we may not have reached every community, an awful lot of kids got immunized … maybe 80% or plus kids got immunized in January, which is bloody good." ## The critics But by dancing with the Assad regime, WHO has opened itself up to criticism. Almost from the outset, NGOs complained that WHO wasn't doing enough to reach the kids in opposition-held areas. The accusations escalated in November and December, following articles in the German newspaper Der Spiegel and by the news agency Reuters. The news stories contended that WHO and the Syrian Ministry of Health excluded the rebel stronghold Deir al-Zour from a polio vaccination campaign in December 2012, thereby contributing to the outbreak that began there 10 months later, and that WHO was slow in testing stool samples and confirming suspected cases from rebel-held areas. The polio outbreak in Syria was both "predictable and preventable," wrote Adam Coutts and Fouad M. Fouad, of the London School of Hygiene & Tropical Medicine and the American University of Beirut, respectively, in a 1 January opinion piece in The New York Times. Asking "why the international community did not prepare better for this eventuality," they conclude: "A disturbing part of the answer is that the United Nations itself has aggravated the situation" by ignoring Syria's larger health crisis. Annie Sparrow, a pediatrician and assistant professor of global health at the Icahn School of Medicine at Mount Sinai in New York City, went further in a 20 February piece in The New York Review of Books titled "Syria's Polio Epidemic: The Suppressed Truth." She says that by going along with the government, WHO is significantly underestimating the size of the outbreak. In an interview, she puts the current number of cases at 100 "at a minimum," compared with WHO's 37, and says that WHO's long-established practice of defining a polio case by laboratory confirmation is "totally inappropriate" in the midst of a war. The long delay in confirming the July case from Aleppo was "absurd," she adds. If WHO had "been on the ball," she says, it would have picked up the outbreak earlier and, in its key role in GPEI, defied the regime and launched an emergency response across the entire country. In interviews and written responses, Aylward and Alwan bristle at the notion that WHO in any way contributed to the outbreak, noting that WHO had supported the Syrian Ministry of Health in conducting preventive polio vaccination campaigns since 2010. As for omitting Deir al-Zour in the December 2012 round, Aylward snaps: "WHO doesn't make decisions about who gets vaccinated where. These are national decisions by governments." In December, violence had flared in Deir al-Zour, so the round was postponed, he says. "And Deir was covered a month later in January [2013]. They always drop that point," he adds. Aylward concedes the organization has been in a bind because the Syrian government has so far refused to recognize any test results that are not confirmed by its own lab in Damascus or affiliated labs in Cairo and Tunis. Samples from opposition-held areas have gone an unapproved route to an accredited lab in Turkey and so are not counted on the country's official "line list." "Do we like it? No," says Aylward, who adds that WHO is in "frank discussions" with the government about the policy. Meanwhile, he says, WHO reports lab-confirmed cases from any source and continues to use all information in planning its response. Aylward says the child paralyzed in Aleppo in July was to the best of his knowledge the first documented case, and there was nothing nefarious in the delay in confirming it. The country had been polio-free for so long that no one expected the disease. He adds: "We are$10 billion and 25 years into this [trying to eradicate polio]. Do you think we would really not vaccinate kids? Come on."

Surveillance systems are so shattered that WHO is undoubtedly missing cases, Aylward concedes. But still, he adds, even if WHO is missing half of the cases, it looks like the Syria outbreak may not be as explosive as feared. "Maybe this time we got out ahead of the virus," Aylward says, although he admits the virus could surprise them yet.

So far four campaigns have been conducted in Syria—three got into the north—and several more are planned. Some 23 million kids across the entire region have been vaccinated multiple times. If the virus doesn't spread out of Syria, the surrounding countries may stop emergency vaccination campaigns after the March to April rounds.

Maher thinks they can quash the epidemic by June, at which point he can go back to worrying about the endemic countries such as Pakistan, which spark these outbreaks in the first place. "Provided we can keep getting into the north and the fighting doesn't screw things up, we've got a shot at controlling this in the next few months."

5. # The Vigilante

1. Yudhijit Bhattacharjee

When the ENCODE Project declared that there is no such thing as junk DNA, Dan Graur counterattacked. But does he go too far?

Last year on 11 July, 2 weeks before his 60th birthday, Dan Graur was at the Society for Molecular Biology and Evolution's conference in Chicago, preparing to deliver a scathing criticism of ENCODE, the biggest genomics project funded by the U.S. National Institutes of Health (NIH) since the sequencing of the human genome. An imposing 6 feet 3 inches who likes to wear Hawaiian shirts that flow smoothly over his bulging midriff, Graur speaks with a strong Israeli accent and a deliberate enunciation that lends a scalpel-like sharpness to the sarcasm with which he dissects the world. Besides food and coffee, both of which he consumes immoderately, Graur relishes what he considers to be the unvarnished truth. When a student remarked to Graur—in response to his lament about turning 60—that age was all in the mind, Graur offered a trademark blunt retort. "No," he responded. "It's not in my mind. It's in my knees, my prostate, and my lower back. So go away."

Graur's talk that afternoon was an encore to a paper he had just published with two colleagues assailing the claims made by ENCODE, short for the Encyclopedia of DNA Elements. Launched in 2003 as a successor to the Human Genome Project, ENCODE's goal was to identify all the functional elements of the human genome, in addition to the 21,000 genes that make up a mere 1% of its 3 billion nucleotides. The co-author of a well-regarded textbook, Fundamentals of Molecular Evolution, Graur had been dimly aware of ENCODE's existence until the fall of 2012, when the consortium behind the project announced the first comprehensive results of the 6-year-long endeavor with the simultaneous publication of 33 papers in five journals, including Nature and Science. ENCODE's signal claim, highlighted by the team in the main Nature paper, was that its data "enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well studied protein-coding regions."

ENCODE's leaders drove home that point in videos released by their institutions. "There is not a single place in the genome that doesn't have something that you might think could be controlling something else," said Ewan Birney, the lead analysis coordinator of ENCODE at the European Bioinformatics Institute near Cambridge, U.K., in one of the videos. In another video produced by the National Human Genome Research Institute in Bethesda, Maryland, Michael Pazin, the institute's program director for functional genomics, proclaimed: "Very little of our genomes are junk."

That finding challenged a widely held view, formed after decades of research in evolution and population genetics, that much of the human genome is nonfunctional junk. Other work had already found hints of function in some of the "junk." But Graur found ENCODE's blanket claim patently untrue. To a man of Graur's skeptical constitution, this made ENCODE an irresistible target, a plump duck calling out to a hound dog. Taking the podium in Chicago, he tore into the project.

The heart of his critique was that ENCODE researchers had made an unwarranted leap in the interpretation of their data. The project involved thousands of experiments. In some, researchers exposed cells to a multitude of transcription factors: molecules that bind to genomic DNA to initiate transcription into RNA, the first step in making a vast array of proteins required for metabolism. In other experiments, researchers identified and inventoried the different RNA molecules produced in various types of human cells. The results showed that more than 70% of DNA in the genome is transcribed into RNA; 8% latched on to transcription factors. Altogether more than 80% of the genome showed some kind of biochemical activity—the basis for ENCODE's claim that 80% of the genome is functional.

That inference, Graur inveighed, was utterly wrong because the mere transcription of a stretch of DNA or the binding to a transcription factor is not a function unto itself. He didn't say it simply; he said it with merciless mocking that, to some, undermined his message. "Graur wrote such a negative paper that it was hard to read," says Bradley Bernstein, an ENCODE researcher at Harvard University. Graur's criticism is so over-the-top that it's not worthy of a response, Bernstein adds. In his Chicago talk, Graur showed a photograph of chewing gum stuck to a shoe as an example of "a function that fits the ENCODE definition." "The fallacy of ENCODE's logic," he said, is this: "We know that some functional regions are transcribed. Ergo, all transcribed regions are functional." Toward the end of the presentation, he showed a photograph of dollar bills taped together in the shape of a toilet paper roll—his view of what ENCODE had achieved with the $288 million spent on the project so far. Graur isn't the only one who has taken ENCODE to task. Others have made some of the same criticisms, including prominent biochemist W. Ford Doolittle of Dalhousie University in Halifax, Canada, who published a critique in the Proceedings of the National Academy of Sciences a month after Graur and his co-authors published theirs in Genome Biology and Evolution (GBE). But if ENCODE has a bête noire, it is Graur. "The splashiest part of ENCODE was a conclusion that could not hold up, and Dan pointed it out in a way that was impossible to ignore," says Harmit Malik, an evolutionary geneticist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. "No matter what anybody might think of his style, the points he has raised are very meaningful." Doolittle, who calls Graur one of the "bad boys of molecular evolution," agrees. "As a reviewer of his manuscript, I did suggest he tone it down a little bit at certain places and he did," Doolittle says. "I think people like Dan are very useful. We simply do not do enough debunking in science these days. We have moved into a very positivist mode where everybody is expected to simply get with the program." The few ENCODE scientists who've responded to Graur's criticisms say these are off the mark or blown out of proportion. And judging by the continuing flow of funds to the project—$30 million and counting since September 2012, for characterizing the behavior of genomic elements in more types of human cells—Graur's furious attacks have left ENCODE unscathed.

## Faultfinder

I met up with Graur on a rainy day last December at the University of Houston in Texas, where he has been a professor of molecular evolutionary bioinformatics since 2003. When he saw me watching squirrels, which routinely surprise visitors on campus by coming within stomping distance of people to beg for food, he noted dryly that the animals are simply "rats with good PR." Walking through the drizzle, he made a series of sardonic remarks about himself and the world, much as a standup comic might. He said he'd taken to wearing colorful shirts to work because he had been told that his earlier habit of wearing black intimidated students.

Born in Romania, Graur moved to Israel with his family in 1964, when he was 11. He describes himself as being a "goody two-shoes" growing up—a dubious claim in light of the fact that he was thrown out of school in 10th grade for writing off-color jokes in the school newspaper. (His only regret is that the jokes weren't funny.) He went to a technical school to be a lab technician, but was thrown out of there, too, after 2 years for making a political joke. (This one, he claims, was funnier.) He went on to serve in the Israeli army, where one of his field assignments was to lug generators for radio sets during the war with Egypt in 1973.

After his army stint, Graur studied chemistry for his undergraduate degree. Later, after getting a doctorate from the University of Texas, Houston, he taught at Tel Aviv University until 2003, when he turned 50 and grew restless. "At that age, people change their car or wife or computer system," he said. "I changed universities." The move brought him back to Houston, where he has spent the past decade producing papers on genomic evolution, with a focus on the comparative study of genomes. His other passion is collecting modern art, including a number of creations made from household junk. He wears his atheism on his sleeve: One of his pastimes is needling a devout Christian in his department with questions about the veracity of various biblical stories. Another is challenging antiabortion campaigns run by religious groups on campus.

Graur is given to intemperate griping over whatever he finds silly or stupid or wrong. By his own admission, he has a streak of vigilantism: On occasion he'll produce a serious paper that debunks someone else's finding. In 2001, he and a colleague at Tel Aviv University published a genetic analysis showing that a bacterium claimed to be 250 million years old was likely just a modern strain. Another team confirmed that Graur was right. When we met in December, he was getting ready to publish a study designed to poke statistical and analytical holes in a claim that the last common male ancestor of humans walked on Earth 338,000 years ago. On his personal blog, labeled Judge Starling (Judge is "Dan" in Hebrew; Graur is "starling" in Romanian), he regularly excoriates science in his field that he deems shoddy or hyped.

Graur's atheism inflamed his anger at ENCODE. He perceives an echo of intelligent design in the consortium's "80% claim," which he takes to imply that most of the genome exists because it serves a purpose. "What ENCODE researchers did not take into account," he contends, "is that everything is shaped by evolution." And evolution is slow to weed out useless features.

Genetic mutations—the drivers of evolution—occur at random, and those that are deleterious are weeded out, sometimes over many generations. Other mutations, salubrious and inconsequential alike, get passed down to progeny. As a result, species like humans and elephants that have a small effective population size are expected to accumulate a lot of junk in their genomes.

Various lines of evidence support the idea that vast genomic tracts in many species are littered with junk, he says. One is the surprising lack of correlation between an organism's complexity and the size of its genome. (The onion's genome is five times larger than ours.) Researchers have also discovered that more than 70% of the human genome is interspersed with repetitive stretches of DNA known as transposable elements, which are mostly inactive. Similarly, researchers have identified nearly as many defunct genes and pseudogenes in the human genome as genes.

The true benchmark of functionality, Graur and many others say, is whether a DNA sequence has been conserved over time. Because mutations in functional regions of the genome are likely to impair function, and thereby threaten survival, such mutations are expunged from the population. From this, researchers infer that functional regions evolve much more slowly than the rest of the genome and are conserved; that is, such regions can be expected to show up as identical or similar in genomes across and within species. By sequencing and comparing genomes of different species, researchers have estimated that only 5% to 15% of the human genome is functionally relevant.

To ENCODE researchers like Bernstein, conservation is too narrow a criterion for pronouncing a region of the genome to be functional. But Graur says that view is tantamount to saying that "evolutionary laws governing all known functions in the genome do not apply to the 'functions' defined by ENCODE."

He alleges that ENCODE leaders made such broad claims because they wanted to create a media splash that would justify the project's cost. "They needed to have something big to say," Graur says. "Why did they want to publish all the 30-some articles on the same day? Because they wanted a public relations impact."

Graur contends that ENCODE is an example of how big science can go wrong. "When the average grant size in the biomedical sciences has been halved compared to 10 years ago, this is a scandal," he says. "If you pour \$288 million into one project, you do not fund 500 other projects. You kill the careers of young scientists. They are reduced to becoming technicians."

## No meeting of minds

Graur's strong words have struck a chord with some. On his webpage at the University of Houston's site, he has posted some 50 e-mails of endorsement he got from researchers soon after the publication of the March 2013 critique. "Thank you for publishing your paper about ENCODE in GBE," reads one. "[Y]ou proved what many of us thought, but didn't have the time or the courage to state." Since the Chicago conference, Graur says he has received several invitations to deliver his talk on ENCODE. "I seem to have tapped a very big anger," he says.

At the same time, Graur's combative approach has earned disapproval from some quarters. "Would a dispassionate and polite reply have been less visible?" Nature Methods asked in an editorial last fall that slammed Graur for engaging in what the journal saw as uncivil discourse. "Is provocation necessary to get attention from a 'big science' consortium such as ENCODE? We do not think so."

Birney and other ENCODE leaders have not engaged Graur directly. Birney did not respond to multiple requests from Science seeking comment on Graur's criticisms. On his blog, however, Birney appears to have backtracked from the use of the term "biological function" in summarizing ENCODE's results. He wrote that ENCODE had revealed 80% of the genome as having "specific biological activity," following up in a subsequent blog post that "we could have used different terminology to convey the concepts, consequence and massive extent of genomic events we observed." The consortium chose the 80% figure—he wrote—because it "brings home the impact of this work to a much wider audience."

Bernstein says ENCODE's value is evident in the hundreds of papers based on project data. As an example, he points to a paper in the American Journal of Hematology last November reporting the discovery of mutations associated with X-linked sideroblastic anemia. The mutations—identified through the genetic study of five families that suffer from the congenital disease—are located within a stretch of "junk" DNA that ENCODE had highlighted, which is now known to enhance expression of the ALAS2 gene.

Graur dismisses that example. The mutations were not discovered because of ENCODE, he points out. After their discovery, the researchers found that the mutations' location was on ENCODE's long list of sequences with some biochemical function. "So what?" he asks. "ENCODE claimed that 80% of the genome is functional. Therefore 80% of all truly functional elements that have been discovered or will be discovered will be found in ENCODE by chance alone."

Graur and other critics place undue emphasis on the 80% figure, says John Stamatoyannopoulos, an ENCODE principal investigator at the University of Washington, Seattle. The real take-home lesson, he says, is that "there is a tremendous amount of activity encoded in the genome"—much more than researchers had suspected.

Given the current state of knowledge, Stamatoyannopoulos says, scientists need to remain "fairly agnostic" about the potential function of various genomic elements. In other words, while the likes of Graur are asking, How do you know it's functional? Stamatoyannopoulos and others are asking the opposite: How do you know it's not?

That logic infuriates Graur. "If you don't know a function, assume as a null hypothesis that it doesn't have function, and if you find a function, you'll refute the null hypothesis," he says.

I asked Graur if his detractors were right in calling him rude. He didn't think so; moreover, he felt rudeness was irrelevant to the discourse. "Science is not about abiding by a code of behavior put forward by Miss Manners," he told me. "In science, a strong voice is sometimes needed to fight self-promotion and self-delusion."