# News this Week

Science  24 Dec 2010:
Vol. 330, Issue 6012, pp. 1730
1. Infectious Disease

# Polio Outbreak Breaks the Rules

1. Leslie Roberts

Polio is a horrendous disease, but it is seldom fatal—except now. An explosive outbreak in the Republic of Congo is writing another chapter in the book on how this ancient scourge behaves.

Polio usually strikes children under age 5, paralyzing one in 200 of those infected and killing at most 5%, occasionally up to 10% in developing countries. The new outbreak tearing through this West African country has so far killed an estimated 42% of its victims, who, in another unusual twist, are mostly males between the ages of 15 and 25. Since it began in early October, the outbreak has paralyzed more than 476 people and killed at least 179, according to World Health Organization (WHO) estimates from early December, making this one of the largest and deadliest polio outbreaks in recent history. And one of the most mystifying, too, says polio expert Neal Nathanson of the University of Pennsylvania: “There are too many things that don't fit or are unexpected.”

“We are scratching our heads,” says Bruce Aylward of WHO in Geneva, who runs the troubled 20-plus-year, $8 billion global program to eradicate polio (see p. 1736). When cases of acute flaccid paralysis first cropped up among adults a couple of months ago in the oil-rich city of Pointe-Noire on the Atlantic coast, no one suspected polio. The Republic of Congo—also known as Congo-Brazzaville to distinguish it from the Democratic Republic of Congo, its larger and unrulier neighbor to the east—had rid itself of polio in 2000 through countrywide campaigns to vaccinate each and every child. Since then, routine immunization has kept Congo-Brazzaville polio-free, even when outbreaks swept neighboring Angola and D.R.C. “It was not considered at high risk. That is why we were all surprised,” says Mark Pallansch, who is leading efforts to analyze the virus at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta. “Because this is not a typical outbreak that occurs in children, people initially looked for another cause,” Pallansch says. Unfortunately, that meant appropriate fecal and other samples were not collected at the outset, which has hindered subsequent efforts to reconstruct exactly what happened, he says. Even now, samples are just trickling in, and many are of very poor quality, he says. As a result, the polio labs in Kinshasa, Johannesburg, and CDC have virologically confirmed only about two dozen of the suspected cases—and some will never be confirmed, Pallansch says. Genetic analysis has determined that the culprit is a wild poliovirus type 1 that somehow jumped from northwest Angola to Congo in a single importation. That virus, in turn, came from India several years ago and has been circulating in Angola ever since—and has also recently spread from there to D.R.C., where a separate and distinct outbreak is under way. In Angola and D.R.C., it is behaving like “garden variety” polio that strikes young children, says Nathanson. “If it is the same type 1 from Angola and India, how can it be behaving so differently” in Congo? he asks. Nathanson wonders whether something in addition to polio is going on in Congo-Brazzaville—perhaps a simultaneous outbreak of another deadly virus with another route of transmission, although searches for other strange viruses have so far come up empty. Until more research is complete, “I reserve judgment as to what is going on,” he says. CDC and WHO have rushed in teams of epidemiologists to help country authorities investigate. Outbreaks among adults are not unheard of—one in Namibia in 2006 was traced back to inadequate routine vaccination some 16 years earlier. But there had been no such breakdown that anyone knew of in Congo. Looking back, says Pallansch, there was some political instability in the mid-1990s around Pointe-Noire. “So maybe there was a disruption in vaccination during that time to explain the adult cases. Maybe, but it doesn't line up nicely as it did in Namibia,” he adds. And what explains the concentration of cases in males—more than 67% of all cases? To Aylward, that's the most interesting question. As for why it is so deadly, Pallansch says there are a couple of possibilities. When polio does strike adults, it tends to be more severe, progressing more often to the bulbar form of the disease, which leads to cardiac or respiratory failure. But that may typically happen in 10% of adult cases, or perhaps even 20%, says Nathanson, but nothing to rival the figure in Congo. One theory being investigated is that there is some confounding factor among those who died versus those who didn't: “Did they have an underlying health problem? Were they all from the same location?” asks Pallansch. The other, disturbing possibility is that the Republic of Congo is in the midst of a much, much bigger polio outbreak and somehow the milder cases have been missed. “Everyone's got an opinion. But there are few data,” says Aylward. “You can pull together a story, but will you ever be able to prove it? It will be hard retrospectively to put all the pieces together.” All agree that the first priority is to snuff out the outbreak before the virus reinfects other countries. It is already spreading: Cases have been confirmed in the capital, Brazzaville, some 650 km to the east of Point-Noire, in Cabinda, a sliver of Angola that juts out into the Atlantic south of Congo, and in the adjacent province of D.R.C., Bas Congo. Massive emergency campaigns are under way to vaccinate the entire population, all ages, in Congo and in neighboring parts of Angola and D.R.C. They seem to be bringing the outbreak in check, says Pallansch: “The population is scared, so there is demand for the vaccine.” Aylward predicts that the outbreak will be under control in 3 to 4 months, if there is enough money—in November, WHO and partners issued an emergency appeal for$23 million—and vaccination campaigns continue to go well. But there are no guarantees.

Even if Aylward is right, the outbreak has raised a new, disturbing question, says Pallansch. Is the Congo-Brazzaville epidemic an anomaly, or does it suggest there are other polio-free parts of Africa with susceptible adult populations that would also be ripe for a explosive epidemic? “We don't know where the susceptibles are,” says Aylward—“where the next Congo could be.”

2. Science Education

# Court to Weigh University's Decision Not to Hire Astronomer

1. Jennifer Couzin-Frankel

Is it possible to separate religious and scientific beliefs when it comes to evolution? A federal court will take up that question early next year in the case of Martin Gaskell, an astrophysicist who claims that the University of Kentucky (UK) denied him a job because he is an evangelical Christian.

Pro-evolution advocates say the university was well within its rights. “It's an employment law case,” says Eugenie Scott, executive director of the National Center for Science Education, an organization in Oakland, California, that lobbies to preserve the teaching of evolution in public schools. “Can an employer discriminate based on the scientific knowledge of an employee?” she asks. “Well, yeah.”

But the case could be more complicated. “It's a rather intriguing case,” says Ehrich Koch, an attorney in Minneapolis, Minnesota, who represented a school district whose reassignment of a biology teacher who declined to teach evolution was upheld. “It appears as though what the court is saying is both sides have arguments, and they may be able to prove their case.”

On 23 November, Judge Karl Forester of the U.S. District Court for the Eastern District of Kentucky ruled that UK's motivation for rejecting Gaskell “remains hotly contested” and needs to be examined by a jury. Gaskell is seeking damages for lost income and emotional distress.

Gaskell, 57, had recently moved from a nontenured position at the University of Nebraska to a research fellow post at the University of Texas's McDonald Observatory when he applied to head Kentucky's new observatory in 2007. During the search process, a UK committee member discovered an article on Gaskell's personal Web site titled “Modern Astronomy, the Bible, and Creation.”

The article, based on talks Gaskell had given, “appeared to blend science and religion,” according to a brief filed by the university. The dean of the college decided that “since Gaskell's viewpoint was discussed in a scholarly paper, the committee should consider whether his statements were ‘good science,’” according to the brief.

Gaskell, who was one of three finalists, didn't get the job, and in 2009 he sued the university. In its legal filings, UK says that although there were other reasons Gaskell wasn't hired, “his apparent inability to separate his personal or religious beliefs from his scientific comments … raised concerns.”

In an e-mail to Science, Gaskell called himself an “old earth theistic evolutionist,” a label that deems evolution a tool God used to develop life. In his deposition and his e-mail, Gaskell says he is not a creationist or a subscriber to intelligent design, both of which, to varying degrees, discount natural selection. However, his lecture notes cite work by astronomer Hugh Ross, who embraces an old Earth, as geologists do, but rejects evolution as the guiding principle for life.

“I had no trouble with the natural selection process,” Gaskell said in his deposition. But “when it comes to trying to explain everything, and particularly the origin of life, … we just don't have any satisfactory theory.”

Jennifer Wiseman, an astrophysicist who has known Gaskell professionally for 20 years, says she doesn't consider Gaskell a creationist. “He doesn't discount or disbelieve evolution,” says Wiseman, who directs the Dialogue on Science, Ethics, and Religion program at AAAS (which publishes Science). A religious scientist who cites ongoing puzzles in evolution sets off more alarms than when an atheist makes the same point, she believes.

The trial is scheduled to begin on 8 February. On 1 March, Gaskell begins work as a professor at the University of Valparaiso in Chile.

3. Newsmaker Interview: Luc Montagnier

# French Nobelist Escapes "Intellectual Terror" to Pursue Radical Ideas in China

1. Martin Enserink

PARIS—Virologist and Nobel laureate Luc Montagnier announced earlier this month that, at age 78, he will take on the leadership of a new research institute at Jiaotong University in Shanghai. What has shocked many scientists, however, isn't Montagnier's departure from France but what he plans to study in China: electromagnetic waves that Montagnier says emanate from the highly diluted DNA of various pathogens.

Montagnier, who won a 2008 Nobel Prize for his discovery of HIV, claims that those signals—which he described in two little-noticed papers in 2009—can reveal the bacterial or viral origins of many conditions, including autism and Alzheimer's disease. The work could suggest novel therapies, he says.

But Montagnier's new direction evokes one of the most notorious affairs in French science: the “water memory” study by immunologist Jacques Benveniste. Benveniste, who died in 2004, claimed in a 1988 Nature paper that IgE antibodies have an effect on a certain cell type even after being diluted by a factor of 10120. His claim was interpreted by many as evidence for homeopathy, which uses extreme dilutions that most scientists say can't possibly have a biological effect. After a weeklong investigation at Benveniste's lab, Nature called the paper a “delusion.”

Science talked to Montagnier, who is founder and president of the World Foundation for AIDS Research and Prevention, last week. Questions and answers have been edited for brevity and clarity.

Q:Why are you going to Shanghai?

L.M.:I have been offered a professorship and a new institute, which will bear my name, to work on a new scientific movement at the crossroads of physics, biology, and medicine. The main topic will be this phenomenon of electromagnetic waves produced by DNA in water. We will study both the theoretical basis and the possible applications in medicine.

Q:What exactly are these waves?

L.M.:What we have found is that DNA produces structural changes in water, which persist at very high dilutions, and which lead to resonant electromagnetic signals that we can measure. Not all DNA produces signals that we can detect with our device. The high-intensity signals come from bacterial and viral DNA.

Q:What do you think are the potential medical applications?

L.M.:I have found these signals coming from bacterial DNA in the plasma of many patients with autism, and also in most, if not all, patients with Alzheimer, Parkinson's disease, and multiple sclerosis. It seems that the bacteria we are detecting are coming from the gut. So it is quite possible that products from gut bacteria end up in the plasma and cause damage to the brain.

The waves give us a biomarker to test for the presence of these bacteria, even when we can't detect them with classical techniques like PCR. So when we treat these diseases with antibiotics, our hope is to see the pathogen disappearing. One idea is to set up a clinical trial in autism here in France. We will first show that we can detect bacterial DNA in the plasma of autistic children and not in a healthy control group. Then, if we get agreement from an ethical committee, autistic children can be treated with antibiotics to see whether the DNA signal disappears and their clinical condition improves. In the future, we may use these findings not just for diagnostics but also for treatment. It's possible that electromagnetic waves at some frequency will kill the waves produced by bacterial DNA.

Q:Many of your colleagues seem to be extremely skeptical.

L.M.:Well, I was skeptical myself in the beginning. But these are facts. The findings are very reproducible and we are waiting for confirmation by other labs.

Q:You have called Benveniste a modern Galileo. Why?

L.M.:Benveniste was rejected by everybody, because he was too far ahead. He lost everything, his lab, his money. … I think he was mostly right, but the problem was that his results weren't 100% reproducible.

Q:Do you think there's something to homeopathy as well?

L.M.:I can't say that homeopathy is right in everything. What I can say now is that the high dilutions are right. High dilutions of something are not nothing. They are water structures which mimic the original molecules. We find that with DNA, we cannot work at the extremely high dilutions used in homeopathy; we cannot go further than a 10−18 dilution, or we lose the signal. But even at 10−18, you can calculate that there is not a single molecule of DNA left. And yet we detect a signal.

Q:Can't you pursue this research in France?

L.M.:I don't have much funding here. Because of French retirement laws, I'm no longer allowed to work at a public institute. I have applied for funding from other sources, but I have been turned down. There is a kind of fear around this topic in Europe. I am told that some people have reproduced Benveniste's results, but they are afraid to publish it because of the intellectual terror from people who don't understand it.

Q:Are the Chinese more open to it?

L.M.:I think so. I have visited Jiaotong University several times, and they are quite open-minded. The editor-in-chief of [Interdisciplinary Sciences: Computational Life Sciences,] the journal in which I have published two papers on this topic, is based there as well.

Q:Aren't you worried that your colleagues will think you have drifted into pseudoscience?

L.M.:No, because it's not pseudoscience. It's not quackery. These are real phenomena which deserve further study.

4. ScienceNOW.org

# From Science's Online Daily News Site

Celestial Ornament This gossamer ring in the sky may look as light and lovely as a soap bubble, but its appearance belies its unimaginably violent birth: The shell of reddish gas is actually the remnants of a supernova explosion riding a shock wave and ripping through space at more than 18 million kilometers per hour. The supernova remnant, dubbed SNR 0509, was first spotted by the Hubble Space Telescope in October 2006. This newly released picture combines data from that 4-year-old image, which was taken only at wavelengths that highlight glowing hydrogen, with a visible-light image snapped just last month.

What Makes Glaciers Shake? A new study has uncovered the cause of most “icequakes,” seismic tremblings of the earth that can be felt up to 200 kilometers away.

Glaciologist Chris Larsen of the Geophysical Institute in Fairbanks, Alaska, and colleague Shad O'Neel of the U.S. Geological Survey in Anchorage used 21 seismometer stations on the southeastern coast of Alaska to observe icequakes in the St. Elias mountains for a year and a half. As they will report in an upcoming issue of the Journal of Geophysical Research, 85% of the quakes originated at the ends of glaciers.

Some seismologists had predicted that icequakes begin in the glacier's interior, as the massive slab of ice slides across the ground. But given the location of the icequakes and the high rate of calving, or glacial ice falling into the sea, observed on the glaciers with the most seismic noise, the team suspects that the vast majority of icequakes are caused by calving events.

That means remote observations of icequakes can serve as an early warning system for changes in calving patterns, says Larsen. And that could eventually tell glaciologists just how much ice a glacier is losing—a concern with a warming climate and the threat of sea-level rise.

Fearless Woman Lacks Key Part of Brain “SM” is a bit of an emotional anomaly. The 44-year-old mother, given those initials to preserve her anonymity, is pretty much fearless—and now scientists think they've figured out why.

SM has interested researchers because a rare genetic condition called Urbach-Wiethe disease destroyed her amygdala, a pair of almond-shaped clusters of neurons in the brain that play a role in fear and anxiety. Justin Feinstein, a graduate student in clinical psychology at the University of Iowa in Iowa City, and colleagues wanted to test whether SM could experience fear. They recorded her reaction to snakes and spiders, horror films, and a trip to a notoriously scary haunted house. They also gave her an electronic diary that asked her to rate her current emotional state several times a day for 3 months.

SM didn't report feeling scared during her trials. Meanwhile, the emotion that received the highest average rating in her diary was “fearless.”

The results suggest that “the amygdala is a critical brain region for triggering a state of fear when an individual encounters threatening stimuli,” Feinstein and his co-authors write in Current Biology. It's the first human study to show that amygdala damage can wipe out fearful feeling, they say. But to prove it, say other researchers, the team needs to look at more than one subject.

A Dog's Growl Announces Its Size Dogs can tell another canine's size simply by listening to its growl, a new study reveals. Péter Pongrácz, an ethologist at Eötvös Loránd University in Hungary, and colleagues showed 24 canine test subjects images of two dogs projected onto a screen in front of them. One image showed a small dog less than 52 centimeters tall; the other image was of the same dog but projected to be 30% larger. The researchers then played recorded food-guarding growls—from either a large or a small dog—on a speaker placed between the two projected images. The scientists filmed the dogs, recording where the canines looked as they listened to the growls.

Twenty of the dogs looked first and for a longer period of time at the dog whose size matched the growl, the team reports online in PLoS ONE. Matching a sound to a photograph is a complex cognitive talent previously seen only in primates, the researchers say.

Read the full postings, comments, and more at http://news.sciencemag.org/sciencenow.

5. Newsmaker Interview: Felisa Wolfe-Simon

# Discoverer Asks for Time, Patience Over Arsenic Bacteria Controversy

1. Elizabeth Pennisi

Three weeks ago, Felisa Wolfe-Simon, 33, a former performance oboist with a doctorate in oceanography and a NASA fellowship in astrobiology, published a paper in Science about bacteria that can use arsenic instead of phosphorus in DNA and other biomolecules (http://scim.ag/arsenicpaper). Four days before the publication, NASA sent out a media advisory that it would hold a press briefing “to discuss an astrobiology finding that will impact the search for evidence of extraterrestrial life.” That led to wild speculations on the Web about extraterrestrial life, and when the paper was published, many headlines made the most of the “alien” nature of the discovery by Wolfe-Simon and her colleagues at the U.S. Geological Survey in Menlo Park, California. Then came a torrent of criticism by scientists. A highly critical blog post by Rosie Redfield, a microbiologist at the University of British Columbia, Vancouver, quickly drew hundreds of comments, many also finding fault with the study. Wolfe-Simon and her co-author Ronald Oremland then came under attack by journalists when they declined to respond to media calls for a response to these comments. On 16 December, the authors posted responses to some of the issues on http://scim.ag/arsenicresponse, and Science will publish technical comments and responses in early 2011. In the meantime, Wolfe-Simon agreed to share some of her thoughts in an interview with Science's news department last week. The following has been edited for brevity; a longer version is available online at http://scim.ag/arsenicqa.

Q:How would you characterize your life since the press conference?

F.W.-S.:Since the press conference, my life has been really busy and stressful. When the paper was accepted for publication, we told the Astrobiology Program and NASA. … And when they asked me to come in and talk about the paper, I said, “Sure.” I thought this would be great; I'll bring the information to the public.

Q:NASA approached you about doing a press conference, and you thought that was a good idea?

F.W.-S.:I wouldn't say I thought it was a good or bad idea. But we weren't clearly prepared, in terms of understanding how it might be, again, with the new types of media that are really rather amazing, what was exactly going to happen. We thought that our findings would generate some discussion, but we didn't anticipate the reaction we saw.

Q:Why do you think you got the reaction that you did?

F.W.-S.:I think maybe it has something to do with that there was some hype generated around it. I was receiving a lot of inquiries from all sorts of people—science journalists and scientists and other sorts of reporters—even before the paper went out under embargo. On Monday, NASA had sent out the media advisory, and it seemed to have people talking. And I thought, “Oh, we're all talking about science.” You know, as a science communicator and a person, what I'd like to communicate is how passionate I am about science and understanding these fundamental properties and principles of nature.

We, as scientists and other science communicators moving forward, need to understand how the Internet gives voice to things we can't necessarily anticipate, and I think that that's something I will think a lot more about.

Q:You answered questions at the press conference, but then after that, when did you stop talking to the press?

F.W.-S.:For the press conference, I was prepared to talk about our findings reported in the paper. I did not show any data, nor did I describe the study as definitive. I was not giving a scientific talk, so I was really not prepared to engage in a scientific debate on that spot.

Q:After Saturday [4 December], when [Rosie] Redfield's blog came out, at least some journalists took a look at the paper again and wanted to talk to you. If my information is correct, that's when you and NASA declined to talk to reporters anymore about this. Is that right?

F.W.-S.:There are two issues. One is that, well, we wanted to be able to have that discourse in the scientific community, as a record. That's the record, the literature record that we go back to—or has been up until now. So that was the one issue, and the other issue was the rapidness. We spent a lot of time really crafting our paper and crafting the SOM [supplemental online material] and crafting all the data, in terms of trying to show it as clearly as we thought. We wanted to give voice to that, in responses to these queries and some of the questions and issues brought up in the press, and we didn't want to respond to it in a way that we thought would not give us the opportunity to think as deeply as we might need to. I was under a lot of pressure, and I'll be honest, I was exhausted. I would really be lying if I told you that the barrage of criticism didn't hurt. It did. I know my colleagues in the community aren't thrilled or happy about this delay, but, again, I'm really doing my best.

Q:Some researchers have suggested that it would be very easy to conclusively tell whether the arsenic is in DNA using different techniques. One was the cesium chloride density gradient ultracentrifugation. Did you do those tests?

F.W.-S.:We're aware of all these other techniques you mentioned. In fact, I have done a cesium chloride gradient experiment, and it showed what my gel showed: something unusual that we couldn't quite explain.

We could have waited until we did a really exhaustive selection of all of these alternative techniques, many requiring collaborations with groups well outside of our field, but instead, I and my co-authors, we wanted to provide a strongly suggestive and convincing argument to our community to initiate these new collaborations and really inspire other people to go out and do this.

Q:Has anybody asked to collaborate or for your samples?

F.W.-S.:Yes, absolutely. People have asked for cells, which we had been already working on getting to make available. That was the goal: to stimulate the discussion and [have] somebody say, “Hey, we have this technique; could we help you?”

Q:But, do you have the capability of sending stuff out?

F.W.-S.:We're currently working to submit the bacteria to two culture collections so that they are available to all interested scientists. Our lab is not currently equipped to provide the cells at the scale needed to ensure fair access for everyone. We got requests from a lot of people.

Q:It's also been suggested that you didn't wash the DNA of any arsenic that may be stuck to the DNA. What's your comment on that?

F.W.-S.:First, we take the cells, and we collect them by centrifugation, and we wash them very well. We did a standard DNA-extraction protocol, multiple phenol chloroform steps to remove all the impurities, including things like any free arsenic, which the washing will have removed. The DNA fraction that was used for further analyses, including things like PCR, would require highly purified DNA. So any of those contaminants, if indeed they were there, would have been a problem [for PCR amplification]. So, we really don't feel it's a valid concern.

Q:Do you think the other researchers are overstating how easy it is going to be to resolve this matter?

F.W.-S.:I would immediately say, “If we're lucky, it's going to be very easy,” but I don't think so. The cells are not easy to deal with. They're kind of soft and fluffy, and they're different. And so testing with the alternative techniques will fill in more pieces to the puzzle, and, again, no doubt will open up new questions.

Q:Were you surprised by the personal tone of some of the criticism?

F.W.-S.:I'll be honest. Of course I was disturbed by the personal attacks, and I can only speak for myself right now. I've worked really hard on this project. I've solicited the advice and assistance from the top scientists across a variety of different fields—not just my co-authors, but many, many individuals. They've been incredibly generous with their time and expertise, and I'm deeply grateful to everyone who's helped.

Q:Are you going to start taking media calls again, or are you going to lay low for a while?

F.W.-S.:That's a hard question because, definitely, in talking to my co-authors, we want to get to work. We're scientists, and it's hard if all your time is taken up talking. I'm happy to explain the results, but there's one thing, I think, to explain the results, and there's another thing to be under what feels like an attack; it's hard to do that. There's only so many hours in a day.

Q:It sounds like what you want to do is not really spend much time with the media right now.

F.W.-S.:What we would want to iterate is that we're thrilled that the public is talking about science. I think the media is an important part of the process. We absolutely don't want to come off as evasive. We wanted the time to think. I think the physical volume at which questions and comments were coming in, I don't know how others would respond. I mean, it was so much and so quick. In fact, during the press conference, I had a couple hundred, at least, e-mails coming in. I'm still on stage. I didn't have my PDA with me. When I checked my e-mail later, they're demanding, “Answer all my questions right now.” It's really hard.

6. ScienceInsider

# From the Science Policy Blog

The U.S. government should keep a close eye on the new field of synthetic biology says a report by the president's bioethics commission, which doesn't think new regulations are needed.

A plan to use €1.4 billion in unused 2010 budget funds to fill a gap in 2012–13 caused by the ballooning costs of the ITER fusion reactor project in France has fallen apart. The ongoing dispute between the directly elected European Parliament and its 27 member states could raise the ultimate cost of the massive project and push it further behind schedule.

A new science law in Venezuela gives the government control over a large pool of tax money previously spent by companies on internal research projects or in collaboration with universities. Scientists fear that the changes could hinder progress across many fields.

A South Korean court has knocked 6 months off of a 2-year suspended sentence to disgraced scientist Woo Suk Hwang while upholding his conviction.

Personnel moves: Harvard Provost Steven Hyman is stepping down in June to resume teaching and research. … Former NIH Director Elias Zerhouni will become head of research and development at French pharmaceutical giant Sanofi-Aventis.

Beefed-up investments in malaria control are having a major impact, according to a new report by the World Health Organization (WHO), although some hard-hit countries are losing ground. … WHO needs a complete overhaul to remain relevant in the 21st century, says Jack Chow, a former high-ranking WHO official, in an online essay in Foreign Policy.

For more science policy news, visit http://news.sciencemag.org/scienceinsider.

7. Global Public Health

# What's Next for Disease Eradication?

1. Martin Enserink

It was time, once again, to bask in the glory and share heroic tales. Late in August, approximately 260 scientists and public health leaders met in Rio de Janeiro to commemorate the 30th anniversary of what is often considered one of the major human accomplishments of the 20th century: the eradication of smallpox. Leaders of the global effort—many now in their 70s or 80s—reanalyzed the dramatic 2-decade fight to obliterate a virus that had killed countless millions of people.

But many of those present in Rio wished that by now a younger generation of disease fighters would have similar victories under their belt and fresh tales to tell. Thirty years on, smallpox remains the only human disease to have been eradicated. Its demise inspired dreams that many pathogens might be wiped off the planet, and two eradication campaigns were launched in its wake. But neither has finished, and many are now questioning whether such global operations—which require extraordinary amounts of devotion and money—make sense.

That's why, just 2 days after the commemorations ended in Rio, 30 scientists and public health experts from around the world gathered for a weeklong meeting in the German city of Frankfurt am Main* to try to chart a new path for disease eradication in the 21st century.

Their meeting was triggered by several developments. Interest in tackling global health problems has surged the past decade—as has funding—but the two ongoing eradication campaigns have proven far more difficult than predicted. In 1986, the World Health Assembly called for the eradication of the painful and disfiguring guinea worm disease; 1995 was chosen as the target date a few years later. In 1988, polio received a similar death sentence, to be carried out by 2000. The deadlines came and went, and although numbers of cases have plummeted, both pathogens are still with us. Polio is currently on a demoralizing rampage through central Africa and has struck anew in Tajikistan, fueling more doubts about its demise.

Meanwhile, a key rationale for past eradication efforts—the promised financial windfall from stopping all control measures once a disease is gone—all but disappeared as a result of 9/11 and the 2001 anthrax letters. Wealthy countries in particular are determined never to let their guard down against diseases like smallpox, polio, or measles. Meanwhile, developing countries have their own questions: Why should they keep spending inordinate amounts of time and money on a disease such as polio—now down to fewer than 2000 cases a year—while their health systems are struggling with far more devastating diseases such as AIDS and TB?

And yet, getting rid of a disease once and for all will never lose its appeal, says Walter Dowdle, a consultant for the Task Force for Global Health in Atlanta. Eradication campaigns offer the inspiring promise of perpetual benefits and the chance to write health history. The 2007 call by Bill and Melinda Gates to eradicate malaria, for instance, has reenergized many of those working on the disease—even though the couple was criticized for using the term prematurely.

So the Frankfurt meeting sought a new way forward. The participants, many of them involved in past and current eradications, believed that eradication campaigns should continue. But “proceed with caution” could have been the motto of the 44-page draft report cobbled together on the 5th and 6th day. Future eradication campaigns “will be put under the microscope in a way that smallpox or polio never were,” says Stephen Cochi of the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, who co-organized the meeting and has been heavily involved in the polio campaign.

New eradication plans must be more evidence-based than the old ones, participants concluded. There should be an analysis of economic costs and benefits, a thorough funding plan, and new financial tricks to prevent perennial budget gaps like those hampering the polio campaign. Any new eradication program should also help poor countries build stronger health systems along the way, the report said. A smart communication plan that reaches out to marginalized populations is key.

Much of that was never done—or done on the fly—for polio, says Cochi. “We were well-meaning but totally naive,” he says. “We built the boat as we sailed,” adds T. Jacob John, a member of the India Expert Advisory Group for Polio Eradication.

## Annihilation

The concept of disease eradication has a long history of high hopes and dashed dreams. Edward Jenner, the British doctor who pioneered the smallpox vaccine, realized the huge potential of his discovery. “It now becomes too manifest to admit of controversy,” he wrote in 1801, “that the annihilation of the Small Pox, the most dreadful scourge of the human species, must be the result of this practice.” It would take 180 years—but at least it came true. In the meantime, several other eradication efforts died, and their ghosts haunt the field to this day.

The problem was often that scientists underestimated the problem. In 1955, the World Health Assembly endorsed a plan to eradicate malaria through an aggressive mosquito-control program that relied on spraying DDT inside homes. In the 1960s, it became evident that the strategy wouldn't work, in part because the insects began to develop resistance against DDT, an insecticide that came under fire from environmentalists as well. Eventually, political will and money ran out. The 1952-to-1964 attempt to eradicate yaws, an easily treatable disease caused by the spirochete Treponema pallidum pertenue that leads to disfiguring skin lesions, met a similar fate.

The smallpox campaign proved that eradication was feasible given the right tools—in this case, a very effective single-dose vaccine—and offered enthusiasts a fresh argument to forge ahead with new pathogens. The experiences since then with polio and guinea worm have provided new lessons in modesty—and new pitfalls to avoid.

With polio, like with malaria, part of the problem is that the tools aren't working as well as scientists believed. The oral polio vaccine is much less effective than the smallpox vaccine, especially in some regions of the world. And while it's easy to recognize a smallpox case—and roll out a mop-up campaign to protect everyone in the area—polio can cause silent outbreaks; hundreds of children can be infected before one develops paralysis or dies.

On top of that came what smallpox veteran William Foege calls “people problems.” War and civil unrest have sidetracked vaccination campaigns, and in 2004, suspicions about vaccine safety led to a vaccine boycott in northern Nigeria that sparked new outbreaks in 20 polio-free countries (Science, 6 February 2009, p. 702). This year, there have been 458 cases in Tajikistan—the first epidemic in the region since it was declared polio-free in 2002—and an explosive new outbreak in the Republic of Congo (see p. 1730). The battle has been so difficult that some suggested in 2006 that it was time to throw in the towel and just settle for keeping the disease in check.

The eradication of guinea worm disease, led by the Carter Center in Atlanta, has had fewer setbacks; it relies on a simple change in human behavior, a strategy that has worked everywhere. Guinea worm larvae are ingested via contaminated drinking water, and they make a very painful exit, usually from the lower leg, a year later. Teaching people to filter their water and preventing those with an exiting worm from walking in sources of drinking water can interrupt transmission.

Although the guinea worm campaign has taken longer than anyone expected, today it is getting tantalizingly close; so far in 2010, there have been fewer than 1700 cases in four countries, down from an estimated 3.5 million cases in 20 countries 2 decades ago. More than 95% of those cases occur in southern Sudan, however, a region expected to vote for independence in a January referendum. If that leads to a new civil war, as some expect, it could mean new delays, says Donald Hopkins of the Carter Center, who has led the campaign since its inception.

## Inflammatory word

One direct effect of these sobering experiences is that some prefer to avoid the word eradication in order to keep expectations low. That's the case for the global campaign to wipe out lymphatic filariasis (LF), a mosquito-borne parasitic infection that afflicts an estimated 120 million people in more than 80 countries.

LF is also known as elephantiasis for the grossly swollen limbs and scrotal sacs that it can cause. Five or six annual rounds of mass drug administration often stop transmission in affected regions, and that's the main strategy a global partnership is using against the disease. But its stated goal is “global elimination,” not eradication, which some dismiss as a semantic difference (see sidebar). “You don't want to use a word that is so inflammatory if you want your program to run smoothly,” says Eric Ottesen, who heads the Lymphatic Filariasis Support Center at the Task for Global Health in Atlanta.

At the meeting, participants offered many recommendations to deal with the tougher climate. Some are already being applied in the attempt to put measles on the path toward eradication, says CDC's Cochi, who is involved in those plans. Measles is an obvious next candidate because it kills hundreds of thousands of children, and there is a very effective vaccine that works even after a single dose. Stepped-up vaccination efforts have led to a plunge in global mortality since 2000. But reimportations occur frequently in measles-free countries, and this year has seen an upsurge in Africa.

At WHO's request, an expert panel has studied the feasibility of measles eradication; as part of the analysis, two independent teams have done an extensive economic analysis. Their reports, presented at a July meeting in Washington, D.C., concluded that eradication would cost an estimated $7 billion to$14 billion but would be cost-effective.

Such studies are controversial because they rely on mathematical models, which can be a poor proxy for the real world. Wars or political problems can add billions to the final tab. Still, they're better than nothing, says Cochi—and they force scientists to take into account the new reality in which control measures will continue. After smallpox was eradicated, vaccination programs around the world were halted, which saved billions of dollars. Today, security experts shudder at the notion of entire populations vulnerable to fast-spreading diseases like polio or measles, and the assumption is that many countries will keep vaccinating against them no matter what.

Both of the measles studies showed that eradication would pay off even if current vaccination schemes continue. Based on these and other findings, the expert group recommended in August that measles “can and should be eradicated,” and the World Health Assembly may adopt a resolution to go ahead at its next meeting, in May in Geneva.

## Eradication bonds

A cost-benefit analysis is one step, but advocates of eradication—often an alliance of international agencies, nongovernmental organizations, and national governments—should also have a solid business plan, the Frankfurt meeting concluded. This “investment case,” as some call it, would outline the rationale for a disease campaign, along with the risks and obstacles, to policymakers, funders, and drug- and vaccinemakers. The report also argued for innovative financing schemes. Because the benefits of eradication accrue over generations to come, government could issue bonds, for instance, just as they do for major capital investments such as roads or railways.

Nor can future eradication campaigns afford to bypass poor countries' broader health concerns, like diarrhea or respiratory disease, which kill far more children, the group concluded. The relentless focus on one disease has fueled resistance to the polio campaign, for instance, in Nigeria and India. Governments of developing countries are rightly wondering whether their sacrifices for a global public health goal make sense, says Stewart Tyson, a consultant at Liverpool Associates in Tropical Health in the United Kingdom—and they should give any new eradication plan a “good grilling” before signing on, he says.

Eradication programs should not hurt existing health services by siphoning away money and effort from basic health services for an increasingly rare disease, the Frankfurt report says—and to the extent that they can, they should have a broader beneficial effect. Current eradication efforts have tried to do this. Polio vaccination has sometimes been combined with dispensing vitamin A tablets or distributing bed nets against malaria. But everyone at the Frankfurt meeting agreed that it's not the job of an eradication campaign to fix a broken health care system. And ultimately, Dowdle points out, eradication campaigns need to be focused if they are to have any chance of success.

## More candidates

There are other candidates for eradication, despite the more demanding environment. One is the rubella virus, which causes severe malformations in newborn babies. The total burden is considered too low to warrant a standalone eradication campaign, but rubella could piggyback on measles eradication since the vaccines are combined easily, advocates say. Some also see chances for onchocerciasis, also known as river blindness, and perhaps schistosomiasis. Yaws, which has already been eliminated from India, could once again become a candidate.

But these ideas' fortunes depend in part on the success—or failure—of the current campaigns. WHO is reticent to embark on a measles-eradication campaign as long as polio isn't finished, says Cochi; it worries that two simultaneous campaigns would be too much.

Such ambivalence is one reason why many eradication enthusiasts say giving up on polio is not an option. “I'm very worried about polio,” says Hopkins. “It must succeed. If it didn't, it would be a big setback for the whole concept of eradication.”

• * Ernst Strüngmann Forum on Disease Eradication in the Context of Global Health in the 21st Century, Frankfurt am Main, 29 August–3 September.

8. Global Public Health

# Scientists' New Eradication Target: A Word in Their Lexicon

1. Martin Enserink

Malaria has been eradicated from Europe. True or false?

True—malaria no longer occurs in Europe, except for “imported” cases, of course. Yet most scientists would argue that the statement is wrong because eradication, by definition, means that a disease is gone from the entire planet. When talking about one or more countries, or even a whole continent, you have to use the second E-word: elimination. Smallpox has been eradicated. Malaria has been eliminated from Europe.

At least until now. The semantic distinction, adopted at a 1997 landmark meeting on disease eradication in Berlin, has often caused confusion, and participants at a recent follow-up meeting in Frankfurt—including some who were present 13 years ago—proposed doing away with it. Their proposal, already contested, would make the assertion at the top of this story perfectly fine.

The debate over what constitutes eradication has been going on for decades. In trying to draw up a clean set of definitions, the 1997 forum, one in a series of brainstorming sessions called the Dahlem Workshops, said that “elimination” was to become the word for anything less than the global scale, while “eradication” was reserved for pathogens completely gone from the planet—except any remaining stocks in lab freezers, as is the case with the smallpox virus. (Once those are destroyed as well, the third E-word applies: extinction. But this has never happened.)

The distinction created trouble from the start, recalls Walter Dowdle, a veteran of the polio-eradication effort. At a 1998 meeting in Atlanta, cosponsored by the World Health Organization (WHO), polio pioneer Frederick Robbins said elimination was a vague, useless word. “What do you mean, we ‘eliminated’ polio from the Americas? We eradicated it!” Dowdle recalls the Nobel laureate yelling. “Fred's words are still ringing in my ears.”

Although scientists have generally adopted the distinction, confusion has persisted. Journalists use the terms interchangeably. WHO often prefaces “eradication” with “global” or “worldwide,” which is clear but technically redundant. At meetings of Rotary International, whose members have donated more than $900 million for polio eradication, “I never use the word elimination,” says Robert Scott, chair of the group's PolioPlus Committee. People don't understand it, and it doesn't inspire enthusiasm, Scott says. (Even worse, many say, is the ill-defined term “elimination as a public health problem.”) That's why Dowdle and Stephen Cochi of the U.S. Centers for Disease Control and Prevention want to drop the term “elimination.” Talk about national, regional, and global eradication from now on, they suggested in a discussion paper for the Frankfurt meeting. The proposal sparked yet more debate. Some called it an inevitable correction of a historic mistake. “Let's simply eradicate the word elimination,” quipped Ciro de Quadros, the former head of the Pan American Health Organization. Others weren't so sure. “Why upset a system of definitions that has become firmly established in the medical literature?” they wondered. And how exactly do you define national or regional eradication? Those questions weren't solved, but the proposal to eliminate the word “elimination” carried the day. In the process, participants agreed to also drop the part of the 1997 definition of eradication that said that “all control efforts can be stopped,” as bioterror worries have put an end to that promise (see main text, p. 1736). Not that this is the final answer. In a paper on measles elimination published in the the 3 December issue of Weekly Epidemiological Record, for instance, WHO acknowledged the Frankfurt proposal in a footnote but firmly stuck to existing definitions of eradication and elimination. The confusion is unlikely to be eliminated—or eradicated—anytime soon. 9. Paleontology # Altering the Past: China's Faked Fossils Problem 1. Richard Stone BEIJING—Frozen in time, the 5-meter-long ichthyosaur embedded in dark limestone seems to be darting after prey in a turbid Triassic sea. But look more closely at the startlingly lifelike skeleton here in the Geological Museum of China, and you will see that something isn't quite right. The beast's lower jaw and shoulder girdle are visible, which requires a ventral view—but the lower body is a lateral-dorsal view. Such an odd juxtaposition can mean only one thing, says Li Chun, a marine reptile expert here at the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP): The centerpiece of the museum's prehistoric life exhibit is a composite of two individuals, and possibly more. Specialists and collectors around the world have long decried the flood of sham fossils pouring out of China. But Science has learned that many composites and fakes are now finding their way into Chinese museums, especially local museums. “The fake fossil problem has become very, very serious,” says Peking University paleontologist Jiang Da-yong. Li estimates that more than 80% of marine reptile specimens now on display in Chinese museums have been “altered or artificially combined to varying degrees.” Geological Museum officials are not inclined to remove the fishy ichthyosaur, from southwestern China. “Farmers prepared the specimen. They might have made some mistakes when they put it together, but it is not a fake. You can call it a kind of model,” says Lu Liwu, director of prehistoric life research at the museum. Nevertheless, Li is concerned about what he deems a misleading display. “This is a national museum,” he says. Another Geological Museum exhibit, a pair of huge dinosaur eggs embedded in siltstone, is also a sham: Large chunks of the shell are not the original material, says Li. Lu says the museum intends to add signage to clear up any misconceptions. Outside of Beijing, curators are not so conscientious. Chinese and Western paleontologists concur that many provincial museums are chock-full of composites, chimeras, and other phony fossils. But several contacted by Science said they are reluctant to speak out. “We would seriously jeopardize our own opportunities to work with our Chinese colleagues on very important material,” says one Western paleontologist, who requested anonymity. One consequence of the fakery is an erosion of trust in museums, which are supposed to enlighten—not con—the public. Scholars, too, pay a price: They waste time sifting authentic specimens from counterfeit chaff. And a genuine blockbuster fossil can be destroyed by attempts to enhance its appeal. “A fake part in a fossil ruins the value of the entire specimen,” says Ryosuke Motani, a paleontologist at the University of California, Davis. “Even though the genuine part of the same specimen may provide important information that is otherwise unknown,” he says, “skepticism emerges as to whether we can trust it or not.” “Normally we know right away if a fossil is fake, although it can take some time to be sure,” says IVPP Director Zhou Zhonghe. But fraudulent specimens can end up in the peer-reviewed literature. For example, the holotype—for which a species is named—of Typicusichthyosaurus tsaihuae, a marine reptile from southwestern China, is “a forged specimen” with carved features, says Motani. (Li and other paleontologists agree with that analysis; the team that described the species could not be reached for comment.) More controversially, an IVPP paleontologist asserts that a 2009 report in the Proceedings of the National Academy of Sciences (PNAS) describing a new species of early cheetah is based on a forged skull; he has demanded a retraction. The authors insist the skull is authentic and stand by the report, as has the journal. Stamping out sham fossils will require a crackdown on how fossils are collected and sold in China. A new law that comes into force next month aims to protect fossils of high scientific value (Science, 17 September, p. 1453). But experts doubt that the law will pose a sufficient deterrent: Forging fossils is simply too lucrative, they say. The art of faking fossils has a long history. Perhaps the most infamous fraud is Piltdown Man, a skull, unveiled in 1912, that was touted as a missing link between humans and apes. It was exposed as a hoax in 1923, when a German anatomist determined that Piltdown was a chimera: a modern human skull and an orangutan jawbone. In another notorious case in the annals of bogus fossils, noted paleontologist Friedrich von Huene described in 1966 a juvenile Leptopterygius from Germany. Von Huene, 91 at the time, had not realized that the ichthyosaur was a total fabrication: Its “bones” were carved from the substrate. China, too, has suffered a Piltdown moment. “Archaeoraptor,” purported to be a missing link between birds and dinosaurs, made its debut in the November 1999 issue of National Geographic. Rumors that the skeleton, unearthed in northeastern China's Liaoning Province, was a fake began to swirl even before publication, says Zhou. Archaeoraptor was later thoroughly discredited as a chimera consisting of the body of Yanornis martini—a primitive fish-eating bird—and the tail of Microraptor zhaoianus, a feathered dinosaur. Now, an IVPP paleontologist fears that a prestigious peer-reviewed journal has published a fake. In a 13 January 2009 report in PNAS, Per Christiansen of the Zoological Museum in Copenhagen and Ji H. Mazák of the Shanghai Science and Technology Museum presented a nearly complete skull of a primitive cheetah, which they have said was unearthed from a fossil layer in Gansu's Linxia Basin dated to around 2.2 million to 2.5 million years ago. Christiansen and Mazák describe a “unique combination of primitive and derived traits” that places the species, which they named Acinonyx kurteni, as “the most primitive cheetah known to date.” When IVPP's Deng Tao saw the PNAS paper, he says, “I knew immediately the skull was a fake.” Deng says the published photos show that several features of the skull had been concocted from bone or plaster. For example, he wrote in a 16 January 2009 letter to PNAS, “the parietal area is glued by some bone pieces to imitate the skull of a modern cheetah, but the forger did not make the parietal crests.” With that one slip-up, Deng says, the forger “gave the game away.” According to Deng, who has collected fossils in Linxia every year since 1998, it is common there to encounter dealers peddling fake skulls. “Unqualified collectors are often cheated,” he wrote to PNAS. Because the paper's “unfounded” conclusions are “based on a fossil forgery,” Deng urged the authors or the journal to retract the paper. IVPP's Qiu Zhanxiang, an academician and top specialist on mammalian fossils, says he concurs with Deng's opinion that the skull is a composite and that the paper should be retracted. Mazák, whose birth name is Huang Ji, told Science that the skull is genuine and that Deng's concerns amount to a “scientific dispute” because the PNAS paper did not cite Deng's 2004 description of a primitive cheetah from Linxia, Sivapanthera linxiaensis. Mazák declined to explain how he obtained the skull, and Christiansen, now at the Zoological Garden in Ålborg, Denmark, did not respond to requests for comment. In a 4 February 2009 letter to Deng, PNAS declined to publish Deng's letter and stated that his observations “can be explained by sloppy preparation, incomplete preservation of the skull, or as characters that differ from Deng's expectations that are based on an a priori hypothesis of relationship or ancestry.” Deng says he has not pursued the matter further because Mazák has declined to give him access to the skull. The growing problem of faked specimens stems from China's fossil economy. Most fossils, including prized specimens, are unearthed by farmers, who often gussy up specimens to make them look more complete or unusual and thus fetch a higher price. Some dealers are fooled, and some also engage in such chicanery, says Zhou. Few buyers are discerning. “For officials and businessmen, beautiful fossils can upgrade their reputation. For some researchers, strange fossils mean they may have a chance to publish in a top journal and get more funding and a higher position,” says Jiang. “In this hurried and blundering situation, anything may happen.” Exacerbating the problem is a recent boom in museum building across China that has resulted in sizable acquisition budgets and competition for prize specimens. In October, the Shanghai History Museum invited Zhao Lijun, curator of paleontology at the Zhejiang Museum of Natural History (ZMNH) in Hangzhou, to examine fossils it intended to purchase for an exhibition hall to open in 2012. Zhao identified a dozen specimens, including a 15-meter-long ichthyosaur, that were “totally fake,” she says. “When I told them the truth, they were astonished.” To its credit, Zhao says, the Shanghai museum canceled the deal. Many other museums, however, snap up fossils with inept or derisory expert advice. As a result, Li says, many “local museums are full of fakes.” One remedy is for museums to create closer ties with academics; few now have paleontologists on staff. A rare success is “Sea Monsters,” a yearlong exhibition of marine reptile fossils that wrapped up last month at ZMNH. Zhao joined IVPP's Li and others in the field for a few summers to collect fossils for the exhibit; other specimens were on loan from IVPP. “Without IVPP's cooperation, we would not have been able to do this,” says ZMNH Director Kang Xi Min. Another boost would be a training program for fossil preparators. And preventing fake fossils from contaminating the scientific literature, says IVPP's Xu Xing, “can be easily avoided by careful and experienced scientists.” But Li and others admit they don't have a strategy for combating the root of their ills: a legion of fakers assiduously despoiling China's paleontological riches. “Our fossils are some of the best in the world,” says Li. “But they are being destroyed, and there is little we can do about it.” 10. Regenerative Medicine # CIRM: The Good, the Bad, and the Ugly 1. Greg Miller December has been an eventful month for the California Institute for Regenerative Medicine (CIRM), the agency created by California voters to disburse$3 billion for stem cell research. Real estate developer Robert Klein, who spearheaded the 2004 ballot initiative that created CIRM and served as its first chair, had promised to step down when his term expired on 17 December. On 15 December, CIRM's governing board was scheduled to elect Klein's successor. Sounds pretty straightforward, right?

Not so. Klein initially backed Alan Bernstein, a Canadian scientist and executive director of the Global HIV Vaccine Enterprise, to succeed him. But Bernstein's candidacy ran aground because of concerns that state law precludes non-U.S. citizens from holding the job. (It's not clear that it actually does.) The governor nominated Klein for a second 6-year term. Klein accepted but said he would serve only up to 6 months more to help find a replacement. The state controller nominated a different candidate, who accepted the nomination and then withdrew 8 days later. Eleven prominent California scientists threw their support behind Klein, who is both widely admired for getting CIRM off the ground and criticized for micromanaging the agency. But the state controller wrote a letter that criticized the selection process as “fundamentally flawed” and urged the board to postpone the election and start over. Instead, they reelected Klein.

“It's the usual CIRM circus,” says Marie Csete, the institute's former chief scientific officer, who now oversees research and development at Organovo, a San Diego biotech company.

Controversy is nothing new for CIRM. Csete resigned abruptly last year after only 15 months on the job, for reasons she has declined to explain (Science, 17 July 2009, p. 249). In 2007, founding president Zach Hall resigned after a contentious meeting that exposed a rift between board members representing research institutions and those who are patient advocates (Science, 27 April 2007, p. 526). Watchdog groups have blasted the institute about what they see as exorbitant staff salaries and conflicts of interest on the board. And patient advocates are tired of waiting for the stem cell cures they feel they were promised during the campaign.

Despite all this, many scientists insist that the institute has been a tremendous success. It has so far awarded 385 grants totaling more than $1.1 billion, money that has been used to build new labs, train scientists, and conduct research throughout the state. “I see CIRM as a major advance for the entire world of stem cell research,” says Elaine Fuchs of Rockefeller University in New York City. “Its effect has spread way beyond the state of California.” Still, even CIRM supporters say the institute has to improve its relationships with industry if it hopes to fulfill its mandate: generating stem cell therapies that help people suffering from conditions like diabetes and Parkinson's disease. A recent report by a panel of external scientists convened by the CIRM board said translating basic science into therapies should be a major priority going forward. “We've fallen short on the clinical translation side,” says Jeff Sheehy, a CIRM board member and HIV/AIDS activist. “I think we can do better.” ## A solid foundation A major impetus for CIRM was the restrictions the Bush Administration imposed in 2001 on federal funding for research using human embryonic stem cells (hESCs) (Science, 17 August 2001, p. 1242). Proposition 71 authorized California to raise$3 billion for stem cell research through the sale of state bonds, offering an alternative source of funding for the state's scientists. “The ‘yes’ vote on Prop. 71 changed the world,” says Sean Morrison, a stem cell researcher at the University of Michigan, Ann Arbor. “Prior to that, the conversation in most states was, ‘Should we allow embryonic stem cell research?’” Morrison says. “But once California put that stake in the ground, the conversation shifted to, ‘How do we keep up with California?’”

Even with the Obama Administration's support for hESC research, some researchers see CIRM as a bulwark against political and economic turbulence. In August, a federal judge in Washington, D.C., issued a temporary injunction blocking hESC research on the grounds that it violates a law banning federal funding for research that destroys embryos (Science, 3 September, p. 1132). That injunction has been put on hold, but the legal battles continue. “If the injunction goes back into place, that would be a huge blow to the field,” says Morrison. “People in California may have a safe harbor, and that's a big deal.” (CIRM's portfolio now includes research on adult and induced pluripotent stem cells.) The agency also provides a buffer against increased competition for funds at the National Institutes of Health (NIH), says George Daley, a stem cell researcher at Harvard Medical School in Boston.

Not surprisingly, CIRM grantees are not complaining. “I just moved into a spectacular new building,” says Arnold Kriegstein, the director of the new Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California, San Francisco (UCSF). CIRM kicked in $35 million for the new facility, about a third of its cost. The Broad Center at UCSF is funded by one of the 12 major facilities grants awarded by CIRM. Seven of these were completed in 2010, and all but one are expected to be up and running by the end of 2011. The recent external review gave CIRM high marks for building research infrastructure and fostering high-quality research. The agency has so far committed$108 million to training more than 600 young scientists. CIRM says it has contributed funding to research published in more than 600 journal articles, with roughly a quarter of those in high-profile journals. “Progress during this first stage of CIRM's development has been remarkable,” the panel wrote in its report. (The fact that the panel was chaired by Bernstein, who became a candidate to chair CIRM's board, caused some to question its objectivity. “Was he really going to criticize the agency before he came in?” asks Sheehy.)

Even some of CIRM's frequent critics give the agency credit. “If you look realistically at the scientific work that's been done, there's been very important progress,” says John Simpson, stem cell project director for Consumer Watchdog in Santa Monica, California. “They did manage to get some world-class laboratories built, and they did it in a clever way where they used the public money as seed money to attract matching contributions,” Simpson says.

At the same time, Simpson criticizes what he sees as “outrageously high” salaries for CIRM staff members. The chair and president, for example, can be paid up to $529,000. (Klein has declined a salary for most of his tenure.) That's more than double the$199,700 paid to the director of NIH, Simpson notes—or the $225,000 paid to the state's governor: “That kind of largesse has often come back to embarrass the agency, and rightly.” Critics have also noted that the board includes many people in high positions at the institutions that receive the most funding from CIRM (see table). A June 2009 report from the Little Hoover Commission, an independent state oversight committee, found that 80% of funding had gone to institutions with representatives on the board. The commission recommended that a smaller board with more independent voices would have more credibility. ## Looking forward According to the recent external review, CIRM is now entering a second stage in which it should maintain its strength in basic research and extend its reach toward clinical applications. To do that, CIRM will have to improve its ties with biotechnology companies, says Daley, who served on the panel: “We felt that engagement with industry had been underemphasized and needs to be encouraged.” So far, slightly more than 7% of CIRM money has gone to companies. Several California biotech leaders say they have been frustrated by their interactions with CIRM. “In the past, there's been a lack of recognition that it takes a company to actually take a treatment forward from the bench top into the clinic,” says Chris Airriess, chief operating officer of California Stem Cell Inc. in Irvine. Airriess says his company has twice applied, unsuccessfully, for CIRM money. He and others place much of the blame on the review process, which he says is structured too much like the NIH review process for academic research grants. CIRM reviewers criticized his company's applications for the lack of new science, but Airriess says that misses the point. “Companies are trying to stabilize a technology and commercialize it rather than push the bleeding edge,” he says. Even companies that have succeeded say it hasn't been easy. Earlier this year, San Francisco–based iPierian won a$6 million early translation award and a \$1.5 million basic biology award. “We put a ton of effort into understanding what was being asked for,” says CEO Michael Venuti.

Some companies have been discouraged from applying for CIRM funds by terms that require paying CIRM back with equity in the company or with cash equivalent to several times the original loan if a project bears commercially viable fruit, says Hans Keirstead, a stem cell researcher at UC Irvine. Such arrangements are reasonable in principle, but the terms CIRM imposes can be onerous, Keirstead says: “CIRM has to pay a lot of attention now to becoming industry-friendly.”

CIRM President Alan Trounson says he is sensitive to these concerns but doesn't think the review process is problematic: “Companies that have put in well-formed proposals have done very well.” But he acknowledges that CIRM has had difficulty attracting proposals, particularly from larger companies. He'd like to set up an industry advisory board to help improve industry relations.

In the coming months, he and others will be waiting anxiously to see who succeeds Klein as chair. Patient advocates want an advocate at the helm. Scientists would prefer a scientist. Trounson, who may have to work most closely with the new boss, says he's hoping for someone with expertise in the delivery stage of therapeutic development. “The basic science, as long as we look after it, will take care of itself,” he says. The real challenge for CIRM, he says, is getting the science into the clinic. “We need more help on how to make it all happen.”