# News this Week

Science  30 Aug 2013:
Vol. 341, Issue 6149, pp. 944
1. # Around the World

1 - Los Angeles, California
Genomics XPRIZE Cancelled
2 - Brussels
Pesticidemakers Challenge E.U. Ban in Court
3 - Tohoku, Japan
Panel Picks Possible Collider Site

## Los Angeles, California

### Genomics XPRIZE Cancelled

The XPRIZE Foundation has scrapped its $10 million genomics challenge, set for next month, after attracting only two competitors to the sequencing contest. First announced 7 years ago, the Archon Genomics XPRIZE was revamped in 2011 to offer$10 million to the first team to sequence the entire genomes of 100 centenarians with high accuracy within 30 days—and for $1000 or less apiece. But only two of the eight contenders in the original contest registered by the 31 May deadline—the company Ion Torrent, and George Church's lab at Harvard University. On 22 August, XPRIZE CEO Peter Diamandis announced that the foundation was calling off the contest because it "was not incentivizing the technological changes" laid out by the XPRIZE board and the genomics prize's chair, Craig Venter. Companies are already sequencing human genomes in a few days for$5000 and "are moving quickly towards the goals we set for the prize," Diamandis wrote.

Church, who says he's spent "embarrassing" amounts of money to prepare, calls the decision "a totally avoidable slap at innovators." http://scim.ag/Xprizegen

## Brussels

### Pesticidemakers Challenge E.U. Ban in Court

Two agrochemical companies have taken legal action against an E.U.-wide ban on three widely used neonicotinoid pesticides. In April, the European Commission introduced a 2-year moratorium on the compounds—clothianidin, imidacloprid, and thiamethoxam—following reports by the European Food Safety Authority that the substances pose an "acute risk" to honey bees essential to farming and natural ecosystems.

But this week, Bayer CropScience and Syngenta Crop Protection, two firms that manufacture and sell the pesticides in Europe, announced that they have brought two separate legal cases before the Court of Justice of the European Union earlier this month. "In suspending the product, [the European Commission] breached EU pesticide legislation and incorrectly applied the precautionary principle," Syngenta's Chief Operating Officer John Atkin said in a statement.

It may take the court years to reach a decision. The legal cases have no suspensory effect, so the restrictions on the three chemicals will apply as planned from 1 December in all 28 E.U. member states.

A site near the northern end of Japan's main island is the best spot for the International Linear Collider (ILC), a Japanese panel announced on 23 August—if the proposed $10 billion facility ever gets built. The ILC would be the follow-on to Europe's Large Hadron Collider. Physicists in North America, Europe, and Japan are collaborating on a design, and Japan had proposed two possible sites: on the southern island of Kyushu; and in the northern Tohoku region, where engineers propose boring a 31-kilometer-long tunnel through the Kitakami Mountains. The Tohoku site is preferable because of its geology and infrastructure, the panel said. Backers also hope that the spot might make the ILC eligible for recovery funding from the 2011 tsunami, because most of the tunnel would be in Iwate Prefecture, which was battered by the disaster. But politicians will have to make that decision, warns Satoru Yamashita, a University of Tokyo physicist who chairs Japan's ILC Strategy Council. And Japan isn't likely to start the project, he adds, without international partners. http://scim.ag/ILCsite 2. # Random Sample ## The Incredible Shrinking Springtail Many organisms, from fish to earthworms, grow throughout their lives. But, when it gets hot, the already tiny springtail (Folsomia candida) dwindles in size. Graduate students Alexandre Peluffo and François Mallard from Ecole Normale Supérieure in Paris looked into the shrinking ability of the 2-millimeter-long, six-legged creature after noticing the relatively small average size of a group of springtails raised at high temperatures. The researchers raised eight populations of springtails at 16°C then put half of the adults into chambers warmed to 26°C. Each time the animals molted over the 70-day test period, the researchers measured them. Different lines responded differently, indicating that shrinking was genetically controlled: None grew bigger, a few stayed the same size, and many got smaller by as much as 30%, the team reported last week at the annual XIV Congress of the European Society for Evolutionary Biology in Lisbon. So what's the advantage of shrinking? "When temperature is high, metabolic rates increase and energy requirements increase," says Glauco Machado, an evolutionary biologist at the University of São Paulo in Brazil. "Small individuals survive better under these conditions." Because springtails live about 6 months, long enough to experience consistently warm or cool temperatures depending on the seasons, computer simulations showed that it was advantageous for them to shrink to match the temperature. ## They Said It "One thing that I certainly read from viable sources is that a lot of the research that's being done—when you put your application in to get a grant, if you don't submit to the, you know, orthodoxy of climate change by the radical environmentalists, you're not going to get a grant." —Representative Mike Coffman (R–CO), responding to a League of Conservation Voters ad that portrays him as an "ostrich" on climate change issues. ## Reeling Them In Among a squid's most defining characteristics is its long pair of tentacles, or "tentacle clubs." Most squid extend and retract these tentacles—armed with suckers or hooks—to snatch their prey. But the tentacles of the deep-sea squid Grimalditeuthis bonplandi are unique: thin and unarmed, and easily broken—prompting scientists to wonder just how the animal captures its food. Now, video captured by ROVs in the Atlantic and North Pacific oceans, deployed by scientists led by Hendrik Hoving at California's Monterey Bay Aquarium Research Institute, reveal G. bonplandi's unusual tentacle technique. Rather than rapidly extending and retracting its fragile tentacle stalks, it undulates them, which may serve to stimulate bioluminescence, produce a wake, or create low-frequency vibrations—any of which may attract small marine organisms and lure them to their fate, the team reports this week in the Proceedings of the Royal Society B. 3. # A Teacher's Quest 1. Jeffrey Mervis Biologist Steve Robinson is leaving a high-level White House post for a high school in New York City in a career-long quest to understand the secret behind great teaching. Some scientists come to Washington and contract Potomac fever—a disease triggered by the proximity to power that produces a hunger for national attention. And then there's Steve Robinson. What motivates the former university biology professor turned secondary school science teacher turned education policymaker isn't power. It is figuring out what it takes to be a good teacher. He has looked for answers at every stage of his unusual career arc, both to improve his own skills and to contribute to the ongoing debate about how to boost the quality of the nation's teacher corps. And this week, at the age of 62, Robinson begins his latest quest. Last month, Robinson walked away from an influential education policy position at the White House to teach science to disadvantaged students attending Democracy Prep Charter High School in New York City's Harlem neighborhood. (Charter schools are run by private organizations but receive government money to teach students who would otherwise attend public schools.) He hopes to make use of what he's learned in Washington and as a teacher at both the secondary and college level to hit an educational trifecta: Prepare his students for college and career success, make himself into a better teacher, and foster Democracy Prep's role as a test-bed for improving U.S. K–12 education. "There are lots of things I could have done," Robinson says about his decision. "But I wanted to teach. I want to see whether I'm a good teacher." Those who know him are not surprised by his latest career twist. "Steve is a person who would follow his star," says Edward Klekowski, a retired plant biologist at the University of Massachusetts (UMass), Amherst, who 25 years ago was Robinson's departmental colleague and running partner. "He was always an idealist. And it sounds like he still is." Robinson's biggest challenge will be applying his policy experience to the day-to-day problems of teaching in an urban school, says another friend, George Sugai, an education professor now at the University of Connecticut, Storrs, who taught Robinson while he was earning a master's degree in 2002 at the University of Oregon. "It's the handshake—how to transfer his knowledge of what works to these kids," Sugai says. "But I don't think it'll take him long." ## Be like Benton Growing up in a wealthy suburb of Chicago, Illinois, Robinson says that he never envisioned working at the White House. But he did think a lot about becoming a science teacher. In fact, last year Robinson recorded a public tribute to his former high school biology teacher (StoryCorps.net). "Mr. Benton, I always wanted to grow up and be you," Robinson told James Benton, now 81, who taught for 37 years at Lake Forest High School before retiring in 1994. In addition to thanking Benton "for making science fun," Robinson praises his Socratic approach to teaching. "You would often answer my question by saying, 'Well, think about it.' Perhaps it was your way of saying that science is not a group of facts, but rather a different way of thinking about things." Benton's influence helped steer Robinson toward an undergraduate degree from Princeton University and a Ph.D. in cell and molecular biology at the University of Michigan. "People said I was pretty good at research, so I stuck with it," says Robinson in a matter-of-fact tone that reflects his no-frills personality. In 1984, he landed a tenure-track position in the botany department at UMass. But once there, he realized that being a successful academic required more than a love of bench science. "I didn't like running a small lab and scrounging for research funding." Robinson says that he chose not to go up for tenure because he couldn't imagine spending his entire career as an academic. Former colleagues say that his modest research productivity would have made it extremely difficult for Robinson to meet the university's benchmark. At the same time, however, his classroom skills generated rave reviews. "He was one of those gifted teachers who could explain something complex really clearly," says Klekowski, who taught a seminar with Robinson and sat in on one of his courses. "He was on the cutting edge of plant molecular biology, and there should have been a place for him at the university as a distinguished teaching professor. But there wasn't." Once Robinson decided to leave academia, he headed west and eventually settled in Eugene, Oregon. (His wife, Jan Cuny, was a member of the computer science department at UMass, and in 1993 she joined the University of Oregon faculty.) Robinson worked in a university lab and helped raise the couple's three children. But soon the itch to teach returned. He tried to scratch it by spending 5 years as the only science teacher at a small private school. But it wasn't quite what he wanted. "I'd always been a public school person," he says. "It's one of the great American innovations." Public school teachers need to be certified by the state, however, and for Robinson that meant going back to graduate school for the additional course work he needed to become eligible. But the classes and student teaching brought him no closer to his goal of "becoming a more effective teacher, whatever that means." Nor did the next 3 years he spent at North Eugene High School. Robinson believes that many teachers fail to convey the essence of how science is actually done. "Everybody teaches the scientific method—developing a hypothesis and then doing the experiments to test it," he says. "But scientists don't actually follow the scientific method." Instead, Robinson's academic training has taught him the importance of the right hypothesis in making progress. "Most of the time when you do an experiment, it says to you, 'Hey buddy, that wasn't the right experiment.' You didn't ask the question well enough, or there's something that you just didn't think about." Of course, knowing the subject matter is also important, and he says teachers who lack that knowledge can do serious harm. "I would even go so far as to say that many of my students would be better off if they never had a science teacher before me because they have to unlearn so many bad things" from elementary school teachers who were afraid of science. Robinson is confident that he understands what he is trying to teach: "It's pretty hard to stump me on content," he says. But he was disappointed in the lack of pedagogical guidance that he received during his high school teaching career. "Three times a year I'd be asked when I wanted to be evaluated, and I'd say, 'Why don't you come next Wednesday?' You'd have to be a total idiot not to have three good days of lessons in your back pocket. And the other 177 days I could do anything I wanted." The follow-up was no more rigorous, he adds. "There'd be a checklist, with a scale of 1 to 5. I'd get mostly 5s, and a few 4s. When I asked about the 4s, they'd say, 'Well, there's always room for improvement, right?'" ## Obamaworld In 2004, Cuny, his wife, decided to come work at the National Science Foundation to start a program on broadening participation in computer science. Looking for a way to join her in Washington, Robinson applied for and won a federally funded fellowship allowing classroom teachers to work for Congress or a federal agency. In the fall of 2005, he lucked into a job with the newly elected Democratic senator from Illinois, Barack Obama. "They were looking for someone who knew something about education, and I was free," Robinson says. Within 2 weeks, Robinson was helping to write a speech in which Obama previewed many of the policies that have marked his administration's approach to education. They include incentives for school districts to raise standards, linking teacher evaluations to student performance, and creating better tools to assess learning. He also emphasized the importance of a well-trained teacher workforce, including the use of alternative certification, a popular tool for charter schools to attract people who might not otherwise consider teaching. Those ideas resonated with Robinson, who quickly fell in love with the job. "I thought I would be here a year," he says. "But [Obama's] office was a great place to work. There was an amazing group of talented people. If I had been in another office I probably would have returned [after the fellowship ended] to Oregon." Robinson rose swiftly in the Washington policy world. After the 2008 election, he became special adviser on STEM (science, technology, engineering, and mathematics) education to Education Secretary Arne Duncan. In September 2009, he became special assistant on the White House Domestic Policy Council, where STEM education was part of his portfolio. That position—"I had the best policy job in Washington"—gave him a front-row seat in the political tug-of-war with Congress over revising the Bush administration's unpopular No Child Left Behind Act, the 2002 law that spells out the federal government's role in elementary and secondary education. He also worked closely with officials from a dozen federal agencies to develop a strategic plan to improve the government's$3 billion investment in STEM education.

Despite his loyalty to Obama and his policies, Robinson was upset earlier this year when the administration proposed to reshuffle the federal STEM portfolio by designating three lead agencies and drastically cutting back the involvement of other agencies (Science, 26 July, p. 338). "I'll be honest," he says. "It's hard for me to defend [that proposal] because I argued against it pretty strongly." But he emphasizes that the budget proposal "is not the reason I'm leaving. I want to make that really clear."

Robinson says that he definitely wasn't looking for a new job last September when he heard Seth Andrew, a former teacher and the founder of Democracy Prep, talk about improving K–12 education at an event that included Duncan and other education luminaries. But what he heard that day at the Brookings Institution rekindled his passion for the classroom.

Charter schools are a rapidly growing part of the U.S. education landscape. Their flexibility pleases many conservatives, who want to reduce the federal role in education. But their autonomy worries some liberals, who fear that the charter movement threatens a 200-year tradition of public education.

Democracy Prep, which began in 2006 and now operates eight schools in Harlem and one in Camden, New Jersey, is part of a wave of so-called no excuse charters that has attracted national attention by sharply raising test scores among traditionally low-achieving populations. "One of their schools is the highest performing charter in New York City," Robinson notes. The organization is also growing rapidly: Last year, it received a 5-year, \$9.1 million federal grant to train the additional staff members needed to open or expand another 15 schools in New York City and elsewhere.

School officials say that their success is based on a five-part formula—more time in the classroom, targeted interventions for students who need them, an extensive use of student performance data to improve practices, a culture of high expectations, and high-quality teaching. Their approach to teacher development has a special allure for Robinson. "People think it's just about setting high standards and firing bad teachers," he says. "But it's really about how to cultivate good teaching."

Invited to deliver a 40-minute practice lesson to students as part of the school's hiring process, Robinson was impressed by the extensive feedback that he received from staff and school administrators. "They gave me a very thorough debriefing of what I had done well and poorly," he says. "They asked me how I would have taught the class differently if I had to do it again tomorrow and next week. Nobody had ever asked me that question. One of the things that schools like Democracy Prep do well is to create a culture in which teachers support each other and offer constructive criticism."

Katie Duffy, who succeeded Andrew this year as the organization's CEO, says that culture is critical to what the school hopes to achieve. "It isn't enough to come in as a good teacher," says Duffy, who has been with the school since its early days. "We want to be sure they continue to get better." The absence of tenure for teachers may also play a role.

Robinson says the school's emphasis on civic engagement was another attraction. "That civic mission appealed to me because of all the time I've spent in Obamaworld," he says. "I also think that teaching in Harlem is very much of a public act."

In fact, Robinson hopes that working at Democracy Prep will also promote one of the original goals of the charter school movement. "The promise of charter schools was that they would be laboratories for innovation that would help us improve public schools," he says. "But we've failed to do that. Instead, we've allowed an amazing variability in the system—many schools are terrific, and some are horrible.

The solution, according to Robinson and many educators, lies in improving the quality of the professional workforce. And despite his admiration for his former high school teacher, Robinson takes issue with Benton's assertion during last year's recorded conversation that "a good teacher is born, not made, and that most teaching is intuitive." Likewise, Robinson says, studies that show a teacher with a master's degree is no more effective in the classroom than someone with an undergraduate degree are flawed.

"First of all, a master's degree is a very large variable," Robinson says. "You can get one off a matchbook cover, or you can get one in math education from Deborah Ball [dean of education at the University of Michigan]. And you can't convince me that studying with Deborah Ball for a year doesn't make you a better teacher.

"As educators, we have to believe that making people smarter can help. So if the studies don't show an effect, all it means is that we're not doing a good job of teaching those people what they need to know."

The poor quality of most teacher professional development—improving the skills of those already in the classroom—aggravates the problem, he believes. "As a teacher, if I said I was going to teach all my students the same way, it would be considered professional malpractice," Robinson says. "But that's what we do with most professional development.

"We assume they all need the same thing. And that's why almost no professional development works. It needs to be differentiated, but to do that, you need a good evaluation system. And that's been a hard political battle."

Robinson acknowledges that he is taking a big risk by returning to the classroom after 8 years in the political arena. But he says that it feels like the right thing to do. In the meantime, he scoffs at former colleagues who teased him about deciding to take it easy. "Sure, working at the White House means long hours," he says. "But teaching is just plain exhausting." And while he may be under less scrutiny in Harlem than in the White House, Robinson hopes that his work will have just as big an impact on U.S. education.

4. Medical Research

# The Promise of Poop

1. Jop de Vrieze*

Fecal transplants offer hope for treating many diseases. But they need to be studied more scientifically, says one of the treatment's pioneers.

AMSTERDAM—Soon after Max Nieuwdorp started his residency at the internal medicine department of the Academic Medical Center (AMC) here in 2006, he was confronted with a sad case: an 81-year-old woman hospitalized for a complication after a urinary tract infection who seemed unlikely to survive. She had bed sores and high fevers and was unable to eat. After antibiotics had wiped out her colon's microbial population, an opportunistic bacterium called Clostridium difficile had taken over, causing terrible diarrhea and bowel inflammation.

C. difficile is a notorious pathogen that kills at least 14,000 patients a year in the United States alone; many patients suffer repeated bouts with the microbe. To treat it, the woman was given several courses of vancomycin, the standard antibiotic in such cases. But, as often happens, the bacteria had become resistant.

Nieuwdorp refused to accept the patient's fate—"I was young and naive," he says—and started searching PubMed for anything that could save her. When he found a 1958 paper by Ben Eiseman, a physician who was then at the University of Colorado, Denver, he knew what to do. "I want to try a fecal transplant," he told his supervisor, Joep Bartelsman.

Once he realized that Nieuwdorp wasn't joking, Bartelsman agreed. The plan was simple: The duo would flush the contents from the woman's colon, including, hopefully, the C. difficile population, and replace it with the healthy bacterial flora from a donor, in this case her son. To do so, they would mix the son's feces with saline in a blender and squirt it straight into the patient's duodenum, the upper part of her intestine, via a thin plastic tube inserted through her nose.

Three days after her treatment, the woman left the hospital—walking. Nieuwdorp and Bartelsman decided to treat another six C. difficile patients in the following months. Embarrassed about the unusual experiment, they waited for colleagues to break for lunch before infusing the stools. Four patients recovered immediately, the other two after another transplant from a second donor. The transplanted bacteria were apparently restoring the intestinal flora to health.

But when Nieuwdorp presented the results at a hospital meeting, an internist approached him with a condescending smile. "If you seriously want us to treat our C. diff patients with poop, why don't you infuse our cardiovascular patients as well?" the man asked, and left the room.

That skepticism is gone. Many doctors now agree that intestinal C. difficile infections can be cured by transplanting stools from healthy people. Backed by a growing body of work linking the gut's microbial ecosystem to overall health, researchers also think that a wholesale replacement of the gut's microbial flora might help treat many other diseases, such as inflammatory bowel disease, diabetes, and the elusive chronic fatigue syndrome. More and more doctors perform fecal transplants, and online manuals for patients desperate enough to overcome the yuck factor show how to do it yourself.

What's still missing is a truly scientific approach to fecal transplants, says Nieuwdorp, who has become a leading advocate of more research. A paper that the AMC group published in The New England Journal of Medicine (NEJM) in January described a randomized controlled clinical trial of the transplants—the first such study ever reported. Nieuwdorp has also set up collaborations with lab scientists to better understand the underlying mechanisms. He hopes that these studies will eventually allow doctors to move from stool transplants to a more subtle approach: administering selected bacterial strains.

## Becoming mainstream

The pioneering Eiseman paper, published in Surgery, described how the anal infusion of liquidized stool cured four patients from a disease called pseudomembranous enterocolitis, which had symptoms very similar to a severe C. difficile infection, although it was likely caused by a different microbe. It wasn't the first medical use of poop; fecal suspensions to treat food poisoning and severe diarrhea were first reported in the 4th century by a Chinese doctor and writer named Ge Hong, and as early as the 17th century, they were used to treat cows with intestinal problems.

Eiseman's paper was followed by occasional case reports, but for decades, the medical community paid little attention. Antibiotics had rendered the primitive, distasteful technique obsolete, it seemed.

Nieuwdorp didn't initially put his money on it either. After his first seven patients, he went to the University of California, San Diego, as a postdoc to study sugar molecules on the linings of blood vessels and intestines. After his return to Amsterdam in 2008, he resumed his work on the relation between gut microbiota and metabolism. He chose a Dutch medical journal to publish his fecal transplant results in that same year.

But recurrent C. difficile infections were still on the rise, as was antibiotic resist ance in the bacteria. Interest in fecal transplants grew in the United States after a 2010 article in The New York Times about the successful treatment of a very serious C. difficile case by Alexander Khoruts, a gastroenterologist at the University of Minnesota Medical Center in Minneapolis. "I realized that to let this therapy become accepted by the community of physicians, we would have to do a randomized clinical trial," Nieuwdorp says.

That study compared fecal transplants with vancomycin, the standard treatment for C. difficile, or vancomycin combined with bowel flushing. The researchers aimed to enroll 120 patients, but the study's data and safety monitoring board halted the study after just 43 patients, because continuing would be unethical: Ninety-four percent of the transplant patients were cured, versus 31% and 23%, respectively, in the control groups. The resulting NEJM paper "did bring the procedure closer to mainstream medicine," Khoruts says.

## More evidence needed

Some doctors needed no convincing. One was gastroenterologist Thomas Borody of the Australian Centre for Digestive Diseases in Five Dock, who since 1988 has performed fecal transplants in more than 3000 patients, suffering not just from C. difficile but also from irritable bowel syndrome; inflammatory bowel syndrome; constipation; arthritis; and sacroiliitis, an inflammation of the sacroiliac joint. Borody has published some of his results; last year, for instance, he reported some improvement in 92% of 62 ulcerative colitis patients treated with fecal transplants and full recovery in 68%.

But although Borody is widely recognized as a pioneer, he has never carried out a randomized trial. Other researchers have reported encouraging results for nongastrointestinal disorders that appear to be associated with changes in the microbial flora, such as Parkinson's, autism, and multiple sclerosis. In most cases, however, the claims are based on a few cases, or a series of cases without a control group. (See table).

More rigorous trials are now under way, including one in ulcerative colitis at McMaster University in Hamilton, Canada, and another in Crohn's disease at Nanjing Medical University in China. Nieuwdorp himself has just embarked on his second trial in patients with metabolic syndrome, the dysregulation of the body's metabolism as a result of overweight that is often a precursor to diabetes. Last year, his group reported that transferring the intestinal microbiota from lean donors increases insulin sensitivity in these patients—an encouraging sign.

Meanwhile, Lawrence Brandt of the Montefiore Medical Center in New York City, another fecal transplant pioneer, is doing a second trial with recurrent C. difficile. The study started before Nieuwdorp's NEJM paper, and unlike Nieuwdorp's, it is blinded and includes a placebo group. Both the patient and a donor donate their stool; the patient is infused with either the donor stool or his own. That design is now standard, says Nieuwdorp, who uses it in the metabolic syndrome trial as well. "Some people claimed to smell that they had not received their own poop," he says. "They weren't always right, actually."

Borody says he is "very much for blinded trials"—he is involved in one with ulcerative colitis himself that is about to start at his university. But in the case of C. difficile, Nieuwdorp's study wasn't needed, he says—let alone Brandt's—because the evidence from case series was already overwhelming. "This trial should not have been approved by the ethics committee in the first place," Borody says, comparing Nieuwdorp's study to a randomized controlled trial to test whether parachutes can save lives.

## Begging for a transplant

As word of mouth about fecal transplants has spread, many other doctors have gotten in on the game, and many private clinics see handsome profits from a relatively simple procedure. "The first generation of physicians involved in this technique were of the most idealistic type I can imagine," Khoruts says. "This changed, unfortunately." Patients are often desperate for the treatment; Nieuwdorp says he receives frequent phone calls, e-mails, and visits from people begging him for a transplant. He says that he rejects all such requests but refers some people to Borody.

Meanwhile, do-it-yourself transplants appear to be on the rise as well. Instructions on how to flush out your colon, prepare donor stool—at "chocolate milkshake thickness," as one website helpfully explains—and infuse it by enema or nasal tube have proliferated on the Internet. In one YouTube video, a patient describes how putting Vicks VapoRub under one's nose can help suppress the odor. There have even been reports about people drinking liquidized feces.

Such experiments are worrisome, scientists say, because fecal transplants aren't without risks. Earlier this month, for instance, two patients were reported to have developed norovirus gastroenteritis and diarrhea around the time of their fecal transplant. (The donors had tested negative for norovirus, and the doctors believe the patients may have picked up the virus somewhere else.) Also this month came a report of a 78-year-old man whose ulcerative colitis flared up instead of disappearing after a fecal transplant—although that may have been because his doctors stopped administering prednisone, a drug that reduces inflammation, prior to treatment.

To reduce the risks, most doctors screen donors for a battery of harmful viruses, bacteria, and parasites that might be transmitted through stool—including HIV, hepatitis B and C viruses, cytomegalovirus, Epstein-Barr virus, Campylobacter jejuni, and Blastocystis. But they can't be sure they're catching everything, and noninfectious diseases are a concern as well. Diabetes, atherosclerosis, autism, and colorectal cancer have all been shown to be associated with certain gut microbiota compositions. Scientists are only beginning to tease out cause and effect, but Khoruts says that it's best to err on the side of caution and not use donors whose gut flora might cause trouble.

Khoruts is investigating the optimal donor characteristics and has set up a donor bank with frozen stool from healthy people who meet a long list of criteria. So far, most of his patients have brought in family members as donors, and few of them are in perfect health. "If the patient is 70 years old, you won't need a Greek god to cure her," Khoruts says. "But for a younger patient, you give bugs for the rest of his life—you want something better."

## Underlying mechanisms

Knowing how fecal transplants work is key to making them safer. Do the donor populations take up residence in the gut after the transplant? Which strains make the difference, and how do the transplanted microbes interact with the resident ones? Nieuwdorp collaborates with Willem de Vos, a microbial ecologist at Wageningen University in the Netherlands, whose expertise is anaerobic bacteria, the group that dominates in the human gut. "We have shown that in C. difficile patients, some important species are absent, while others that you don't want are dominant," De Vos says. His research has also shown that the low microbial diversity in C. difficile patients is comparable to that of a 1-year-old child. But after a transplant, anaerobic bacteria from the donor settle in the recipient's gut and the diversity is restored.

Nieuwdorp also works with Fredrik Bäckhed of the University of Gothenburg in Sweden, who runs a facility housing mice that grow up without a single bacterium in their bodies. This allows the scientists to investigate the effects of specific microbial strains. "We are playing with different donors to find the superbacteria that make the difference between health and disease," Nieuwdorp says.

The hope is that in the end, doctors can abandon the poop and infuse just these bacteria. Such cultured cocktails might have downsides, however. They could be less powerful than the complete ecosystems found in stool, Borody says, and the bacteria might mutate in the lab, losing their healing power, as they are grown generation after generation.

Still, many others believe the cocktails are the way to go. A group led by Kenya Honda at the University of Tokyo recently reported curing mice of colitis and allergic diarrhea by treating them with 17 harmless Clostridium strains that had previously been shown to induce regulatory T cells of the immune system, quenching an overactive immune response.

In a project called RePOOPulate, a Canadian team led by Elaine Petrof of Queen's University in Kingston and Emma Allen-Vercoe from the University of Guelph has developed a stool-derived set of 33 microbial strains for the treatment of C. difficile and inflammatory bowel disease. They hope the strains will offer the benefits of a full fecal transplant but with less risk. Allen-Vercoe initially cultured 70 strains, from which Petrof made a selection based on each strain's pathogenicity and resistance to antibiotics. For the final selection, she says she used her judgment: "Would I put this bug into my mom? No? Then I would take it out."

A U.S. company called Rebiotix is going the same route; the Food and Drug Administration recently greenlighted a phase II clinical trial of its mix of several hundred stool-derived strains to target C. difficile infection. "We don't consider our product a fecal transplant," Rebiotix founder and CEO Lee Jones writes in an e-mail. "Instead, we are developing a microbiota restoration therapy in the form of a biologic drug."

Nieuwdorp sees enormous possibilities for such therapies—but he says it will take time. "I'm 36 now. I'll be happy if by the time I'm 60, microbiota analysis will be standard procedure in hospital labs," he says. For now, he's happy that the taboo on fecal transplants is gone. At his own center, "specialists are lining up to test the impact of transplant on 'their' diseases," Nieuwdorp says. And yes, the list now includes cardiovascular diseases.

• * Jop de Vrieze is a science writer in Amsterdam.

5. # Regulators Grapple With an Unorthodox Therapy

1. Jop de Vrieze*

As fecal transplants are becoming popular, governments wonder how to respond.

Taking one person's stool and putting it into the gut of another may be simple enough—but regulating it is not. The rapid rise of fecal transplantation, coupled with pressure from enthusiastic patients and doctors, has regulators wondering how to respond. The procedure occupies an odd place somewhere between tissue transplants and "probiotic" therapies—infusions of beneficial bacteria—and its risks are unknown. Coming up with sensible regulation is even harder because unlike, say, a blood transfusion, anyone can perform a stool transplant at home.

So far, the European Medicines Agency has not stepped in to regulate fecal transplants; the only thing that doctors need to do is get the patient's informed consent and comply with a donor screening protocol. Australia, where gastroenterologist Thomas Borody has carried out thousands of fecal transplants (see main story, p. 954), has similarly relaxed regulations.

In the United States, by contrast, the Food and Drug Administration (FDA) recently asserted its authority over the procedure. At a workshop on 2 and 3 May in Bethesda, Maryland, FDA's Jay Slater said that transplants are considered "an unapproved new drug." That meant any transplant can be done only as part of an official clinical trial, and doctors need to file an Investigational New Drug (IND) application—which can take months. (The agency said it might make exceptions for life-threatening conditions on a case-by-case basis.)

An FDA spokesperson says that Slater's comments didn't represent a policy change. But many researchers interpreted them as a clampdown. Lawrence Brandt of the Montefiore Medical Center in New York City says that he rejected 25 patients suffering from recurrent Clostridium difficile infection—where the evidence that fecal transplants work is strongest—after hospital lawyers told him to stop.

Patients and doctors have long urged the agency not to interfere with the treatment. At the Bethesda workshop, FDA officials heard testimony from Catherine Duff, a 57-year-old former medical case manager from Carmel, Indiana, who related how a fecal transplant had cured her recurrent C. difficile infection—and saved her life. "Please, do something not only for me, but for all those around the country and everywhere," she implored the FDA. "Please do something quickly."

Duff's appearance "definitely left an impression on the FDA officials," says Alexander Khoruts, a gastroenterologist at the University of Minnesota Medical Center in Minneapolis who attended the meeting. In new guidelines issued on 18 July, the agency announced it would "exercise enforcement discretion" in the case of C. difficile—meaning that, if they meet certain conditions, doctors can perform fecal transplants without prior approval. An IND is still needed for all other diseases and for C. difficile therapy in infants. The new guidance is widely regarded as a stopgap measure that gives the agency time to develop more comprehensive regulations.

FDA's task might get easier if scientists can replace fecal transplants with standardized mixes of microbial strains grown in the lab, which are simpler and presumably less risky. On 29 July, FDA approved a phase II trial with such a cocktail, developed by a company called Rebiotix. But Canada's federal regulatory agency clamped down on a similar product. After an academic collaboration named RePOOPulate treated two C. difficile patients with a mixture of 33 stool-derived microbial strains, Health Canada ordered a halt to the procedure in 2011; it said the mix is a "synthetic" product for which drug approval is needed and gave the scientists a long list of criteria to meet.

"Actually, they are not unreasonable," says RePOOPulate project leader Elaine Petrof. "Health Canada realizes this technique is not going away, and they want to sort this out with us."

• * Jop de Vrieze is a science writer in Amsterdam.