# News this Week

Science  20 Jan 2012:
Vol. 335, Issue 6066, pp. 268
1. # Around the World

1 - India
Country Marks Year Without Polio
2 - Germany, the Netherlands, and Belgium
New Virus Spreads to Dozens of Farms in Three Countries
3 - Milan, Italy
Health Mogul Nabs Bid For Research Center
4 - Beijing
Ministry Moves Against Unauthorized Stem Cell Treatments
5 - Quito
Rainforest Conservation Effort Passes Hurdle
Government Takes Aim at Science Funding
7 - Washington, D.C.
Reshuffle Would Shift NOAA to Interior

## India

### Country Marks Year Without Polio

The country celebrates a hard-won victory in its fight against polio: As of 13 January, India appears to have gone 1 year without a single case of the disease.

Since the Global Polio Eradication Initiative (GPEI) began in 1988, polio cases worldwide have dropped by more than 99%. The disease has remained in a few strongholds, including India, Afghanistan, Pakistan, and Nigeria, where wild poliovirus transmission has never been interrupted. And for years, India reported more cases than any other country. But cases there dropped from 741 in 2009 to zero in 2011, thanks to the redoubled efforts of India, the GPEI partners, and a recent infusion of support from the Bill and Melinda Gates Foundation.

India's achievement is a major boost to the beleaguered GPEI, which has spent more than $8 billion over the past 23 years trying to rid the world of the disease. Still, success is not assured. More than 600 cases of polio were recorded worldwide last year, with an alarming rise in neighboring Pakistan, which poses a huge threat to India's fragile success. http://scim.ag/IndiaPolio ## Germany, the Netherlands, and Belgium ### New Virus Spreads to Dozens of Farms in Three Countries The Schmallenberg virus, a newly discovered pathogen infecting cattle, sheep, and goats, has now been found at 86 farms across Germany, the Netherlands, and Belgium, animal health officials have reported—and the number is rapidly climbing. The virus, named after the German town from which the first positive tissue samples came last November (Science, 2 December 2011, p. 1186), causes drastically reduced milk production as well as fetal malformations and stillbirths. Infections likely began during the summer and autumn of last year, but fetuses exposed to the virus in the womb are only now being born, meaning that cases seen so far could just be the first wave. “This is a serious threat to animal health in Europe,” says Wim van der Poel of the Dutch Central Veterinary Institute in Lelystad. A team at the Friedrich Loeffler Institute, a German federal animal health lab, has isolated the virus and has sequenced its genome. Experts say that it's unlikely that Schmallenberg can cause human disease, but urge monitoring of those who come into contact with infected animals. http://scim.ag/Schmallenberg ## Milan, Italy ### Health Mogul Nabs Bid For Research Center A long-running Italian drama takes another twist: The imperiled hospital and research center run by the San Raffaele del Monte Tabor Foundation may have found a buyer. But it's not the Vatican Bank as many expected. On 10 January, health industry entrepreneur Giuseppe Rotelli won the bidding for the Milan center, which specializes in gene therapy and molecular medicine. Last year, San Raffaele had announced that it was facing a €1.5 billion debt, a shortfall that media reports suggested led to the July suicide of center vice president Mario Cal. In October 2011, a bankruptcy court ruling paved the way for the Vatican Bank to assume leadership. But in a surprising turn, Rotelli outbid the Vatican City–based private institute, promising to take on more than €500 million of debt and to invest a further €405 million. Although the agreement isn't final, some San Raffaele scientists have expressed doubts about Rotelli's support of basic research. In a statement, the entrepreneur addressed those worries, saying that his first priority “is the protection and further development of the professional skills of all those involved.” http://scim.ag/GRotelli ## Beijing ### Ministry Moves Against Unauthorized Stem Cell Treatments China's Ministry of Health has announced that it will crack down on unproven stem cell treatments. Representatives from the ministry and the State Food and Drug Administration will inspect approved stem cell clinics and hospitals while rooting out unauthorized ones—desperate mainlanders and medical tourists have fueled to a boom in such clinics. A hold will also be put on new approvals of stem cell clinics until 1 July, ministry spokesman Deng Haihua said at a press conference in Beijing on 10 January. The government introduced a regulation in 2009 requiring health ministry approval of stem cell clinics. But it has been widely flouted, says Douglas Sipp, an expert on stem cell ethics and policy at the RIKEN Center for Developmental Biology in Japan. While Sipp is skeptical that the latest announcement will be thoroughly enforced, Deng Hongkui of Peking University's Laboratory of Stem Cell and Generative Biology in Beijing says the plan is a “good sign.” “In the long run, this action will push stem cell trials in China to follow international standards,” he says. ## Quito ### Rainforest Conservation Effort Passes Hurdle After receiving pledges totaling more than its goal of$100 million by a year-end deadline, the Ecuadorian government has announced that it will move forward with its Yasuni-ITT Initiative. This innovative plan aims to leave untapped more than 900 million barrels of crude oil beneath a pristine Amazonian nature reserve in exchange for annual international donations (Science, 26 November 2010, p. 1170). Last summer, many in the conservation community feared that Germany would back away from a nearly $50 million pledge to the effort. But now$116 million in contributions have been collected from that nation, other foreign governments, foundations, and individual donors, according to Ivonne Baki, the head of the initiative. “We've created amazing momentum,” says Baki. That momentum will be needed as the Ecuadorian government has set a new goal of securing $291 million in contributions in both 2012 and 2013 to keep the initiative going. http://scim.ag/YasuniITT ## Madrid ### Government Takes Aim at Science Funding Warning of unemployment and a “brain drain,” Spanish scientists are anxiously waiting to hear exactly which programs will be affected by another round of belt-tightening. A package of austerity measures announced late last month by Spain's new, conservative-leaning government seeks to cut about €600 million from the nation's science budget. That amounts to nearly a 7% decrease from 2011 spending levels. Many scientists have raised concerns that Spain's national research centers, which have absorbed a significant part of past funding cuts, will be hit again. The National Research Council (CSIC), for example, has already seen delays and cancellations in some programs. Adding to researcher's apprehensions, the Spanish government also abolished the Ministry of Science and Innovation. The country's new top scientist, biochemist Carmen Vela, has taken on a leadership role under the new Ministry of Economy and Competitiveness. Vela, who has gained the ire of some Spanish conservatives for her support of socialist political candidates, moved to reassure the scientific community. “The panorama is difficult,” she told the Spanish press. But “we are going to do the impossible.” http://scim.ag/VelaSpain ## Washington, D.C. ### Reshuffle Would Shift NOAA to Interior The National Oceanic and Atmospheric Administration (NOAA) would move to the Interior Department under a White House plan announced last week that would eliminate the Department of Commerce. President Barack Obama said the proposed changes, which include a new agency focused on trade and business development, would save$3 billion over 10 years and make government more efficient.

Commerce now includes NOAA, the National Institute of Standards and Technology, the U.S. Patent and Trademark Office, and the Census Bureau. The latter three agencies would be part of a new department with a technology and innovation office and a statistical branch that would also include the Bureau of Labor Statistics.

The president is taking the first step by making the Small Business Administration a Cabinet-level agency. But demolition of the Commerce Department, creation of a new agency, and any additional reshuffling will require approval from Congress. Such bipartisanship is rare these days on Capitol Hill.

2. # Random Sample

## Noted

>The German chemical company BASF will move the headquarters of its plant science division from Limburgerhof, Germany, to Raleigh, North Carolina, officials announced 16 January. BASF will also shut down two more research facilities in Europe. European consumers and farmers are leery of genetically modified crops, officials said, so the company will no longer develop crops for that market.

## Meet the World's Smallest Vertebrate

Drop a dime in the middle of an eastern New Guinea rainforest, and you might squash a newly discovered frog species. Paedophryne amauensis has taken the top spot as the world's smallest vertebrate. Adults attain an average size of 7.7 millimeters in length, less than half the diameter of a U.S. dime. That beats out the former record holder, an Indonesian fish from the carp family whose females grow to about 7.9 millimeters. The new frog species lives in rainforest leaf litter, likely dining on springtails, mites, and ticks, the researchers report online in PLoS ONE. Miniaturization is nothing new for frogs. The 29 smallest species all come in under 13 millimeters. The researchers propose that the repeated evolution of extreme small size in frogs, coupled with their exclusivity to moist habitats, has allowed them to exploit the nooks and crannies in the vegetation of the rainforest floor. http://scim.ag/DimeFrog

## Kepler Spies Smallest Alien Worlds Yet

NASA's Kepler space telescope has found the three smallest extrasolar planets know to science, researchers reported 11 January at the 219th meeting of the American Astronomical Society in Austin, Texas. The planets, the tiniest of which has a radius barely larger than Mars, orbit a star called KOI-961. This red dwarf isn't too big itself—only 70% larger than Jupiter. The entire planetary system stretches less than 5 million kilometers across, which makes the trio plus star more akin to Jupiter and its moons that to our solar system.

Using data from two other telescopes, John Johnson of the California Institute of Technology in Pasadena and colleagues confirmed that periodic dips in KO1-961's brightness were due to passing planets. While the star is a relatively cool dwarf, the three rocky planets are likely too hot to sustain life because of their closeness to the star, Johnson says.

According to a very rough statistical analysis from his team, the new discovery suggests that up to one-third of all red dwarf stars in the Milky Way galaxy could be accompanied by similar small, rocky planets. http://scim.ag/TinyPlanets

## Funky Fresh Science

“Tevatron, OG atom smasher/say hello to CERN's party crasher/the new ‘Lord of the Rings’ LHC, hear me/this be competitive collaboration baby.” That's the opening verse of rapper funky49's song “Particle Business” off his latest album Dirty Apes Discover Science. funky49, whose real name is Steve Rush, is a self-described “IT worker/nerd/science enthusiast.” He raps about what he loves: particle accelerators, Benjamin Franklin, and, uh, swapping genes.

Rush, who works for a company that manages radiology labs, says that growing up he was inspired equally by Philadelphia's Franklin Institute and the Beastie Boys. As funky49, he fused his passions together and began rapping about science over beats and samples he produced himself on his computer.

In 2008, he recorded the album Rapbassador to promote the Tampa Museum of Science and Industry. Its success has kept him busy performing on the nerd circuit, including gigs at an arcade and pinball convention in Atlanta and an upcoming performance at the USA Science & Engineering Festival this April in Washington, D.C.

But just because Rush writes songs rather than journal articles doesn't make his rhymes immune to criticism. “I've been peer-reviewed by scientists,” he says. “With ‘Gene Swap,’ some scientists e-mailed me to tell me that genes don't really get swapped, they get exchanged.” That they were paying enough attention catch that, though, was “kind of an honor.”

Hear Rush's rhymes at www.funky49.com.

$10 million — Winnings offered in the Qualcomm Tricorder X Prize to the researcher that can design a hand-held device capable of diagnosing certain diseases (think Star Trek tricorders). 13% — Percentage of about 2700 academic and medical researchers that had witnessed scientific misconduct in the past, according to an informal survey by the British Medical Journal released at a research integrity meeting in London 11 January. http://scim.ag/BMJsurvey 3. # Newsmakers ## SFI Gets New Chief Ireland's largest public source of funding for science this week appointed Professor Mark Ferguson to its top leadership position. Science Foundation Ireland (SFI) named the Northern Ireland native, of the University of Manchester in the United Kingdom, to succeed interim Director General Graham Love on 16 January. Expectations for Ferguson are high, as many in the Irish science community will be looking to him to protect government funding for science. He's also stepping into a spot vacated by Frank Gannon, who was hugely influential and had the ear of government ministers. Gannon resigned from SFI at the end of 2010 following a major slash to SFI's research budget from €171 million in 2009 to €150 million in 2010. Ferguson, for his part, has been adamant that the huge advances made in Irish science since SFI was launched in 2000 could be put at risk by more cuts to its research budget. “We cannot afford slippage to occur,” he says. “If due consideration is given by key decision makers to our scientific achievements thus far, I am confident that every effort will be made to accommodate Ireland's continued development as an emergent force in science.” ## They Said It “This is simply not censorship; it is scientific responsibility. We must all remember that science research is a privilege, not a right. If our work can potentially harm the world, we must consider that along-side any benefit.” —Michael Osterholm, influenza expert and National Science Advisory Board for Biosecurity member “Without all the details of these experiments, follow-up studies will be difficult to perform and [those studies] may also be subjected to some form of redaction. This short-circuits the entire scientific process.” —Virologist Andrew Pekosz of Johns Hopkins University Both comments from “Should Science Be Censored?” the 12 January ScienceLive chat on how to safely publish recent avian influenza studies. http://scim.ag/flu-chat ## Red Wine Researcher Accused of Fraud A 3-year fraud investigation at the University of Connecticut Health Center in Farmington has come to a close. The school alleged on 11 January that Dipak Das, who heads the cardiovascular research center, “is guilty of 145 counts of fabrication and falsification of Data.” The university dispatched a 60,000-page report to the federal Office of Research Integrity, which is now conducting its own inquiry. The University of Connecticut also says it has “declined to accept$890,000” awarded to Das in federal funding.

Das worked in the hot field of resveratrol, a molecule found in red wine. Dozens of papers co-authored by Das assert that resveratrol protects the heart.

The university says it has begun dismissal proceedings against the scientist. Meanwhile Das, who is of Indian descent, has charged that racism is behind the allegations. The goal, he wrote in a 2010 document released by the university, was to “remove the Indians in a well planned CONSPIRACY.” He also wrote that he has “not performed bench work for at least 20 years” and thus did not construct the images the university has accused him of manipulating.

4. # Archaeologist of Sound

1. Ron Cowen*

With near-obsessive determination, audio historian Patrick Feaster has been tracking down remnants of long-vanished voices and noises—and in some cases resurrecting them against the odds.

WASHINGTON, D.C.—In a quiet storage room three floors above the din of the exhibit halls at the Smithsonian Institution's National Museum of American History, sound historian Patrick Feaster is in nirvana. Donning latex gloves, he shows a visitor some of the ancient audio treasures he had discovered among a stack of more than 200 carefully wrapped glass plates, hollow wax cylinders, and flat metal records.

The collection dates from the 1880s, just after Thomas Edison invented the phonograph, when the idea of capturing and playing back a human voice or the toot of a trumpet seemed nothing short of magical.

Inventors during that early era experimented with glass, cardboard, cardboard covered with wax, tin foil, and mixtures of paraffin and wax as their recording mediums. They shouted into a mouthpiece, causing a vibrating needle to cut grooves into a record; some used photoengraving and variable beams of light to imprint a pattern.

And now Feaster, a friendly but intense 40-year-old with a slender build and a photographic memory for anything phonographic, had first crack at helping bring back to life the lost sounds of 130 years ago. His 2-month stint in the “nation's attic” had turned up undreamed-of finds, including long-lost cylinders recorded at the 1889 World's Fair in Paris and what may be the first-ever sound recording on a disk. Archives and artifacts, however, are only part of Feaster's chosen work. Just as important, he says, is his mission of using modern technology to resurrect long-vanished voices and sounds—some of them never intended to be revived.

## Listening backward

Feaster has been obsessed with sound recordings for as long as he can remember. Growing up an only child in Valparaiso, Indiana, in the 1970s, Feaster became fascinated with his parents' vinyl 33-rpm records and started making paper cutouts of his own LPs at age 4. (His mother still has a few.) When his father started frequenting outdoor auctions and swap meets in search of parts for restoring a 1930 Model A Ford pickup, Patrick tagged along, marveling at the old phonographs and records that were on display.

In 1993, Feaster joined the master's degree program in history at Indiana University, Bloomington, but switched to the folklore and ethnomusicology department, where he found an outlet for his love of 19th and early 20th century recorded sound. The research for his 2007 thesis on how the phonograph affected the performances of Victorian musicians, vaudevillians, and orators could have filled several books, recalls his adviser and collaborator, Richard Bauman.

By then, Feaster and colleagues David Giovannoni, Richard Martin, and Meagan Hennessey had formed FirstSounds.org, a group devoted to finding and disseminating the earliest sound recordings. The team had been nominated for a Grammy for its CD Actionable Offenses, a compilation of bawdy wax-cylinder recordings from the 1890s. Another CD, Debate '08, reissued 22 recordings by presidential candidates William Howard Taft and William Jennings Bryan during the 1908 campaign—the first time sound bites were used in a presidential election, Feaster says.

In 2007, FirstSounds embarked on a much more daring quest: unearthing and playing back transcribed sounds that predate by 17 years Edison's phonograph and his needle-cut tin foil records. It began over beers at an Italian restaurant near Union, Illinois—the site of a large antique phonograph show—when Feaster and his colleagues began brainstorming about what might be the world's oldest sound recordings. Feaster mentioned the Parisian typesetter and amateur inventor Édouard-Léon Scott de Martinville, who in the 1850s designed and built a machine that used a horn and stylus modeled on the human ear to pick up vibrations from the air and trace them onto paper coated with soot (see figure, above). The inventor had no interest in playing the sounds back; rather, he hoped that people could learn to read the “phonautograms” and mentally reproduce words, songs, and theatrical recitations exactly as originally performed.

Feaster had come across Scott's work while reading over Edison's papers. He also remembered a rare, self-published book in which Scott, who claimed credit for the idea of recording sound, mentioned having deposited several phonautograms at institutes in Paris. Might those ghostly 150-year-old tracings—undulating scratchings resembling a cardiogram—still be legible, or even playable?

Listen (MP3)

1878 phonautogram recording of the New York elevated railway made by Thomas Edison's lab. [Credit: FirstSounds.org and Thomas Edison National Historical Park.]

To test that possibility, the FirstSounds team took high-resolution, digitized scans of similar phonautograms that Edison's laboratory had made in 1878 to help New York City officials reduce the din of the newly built elevated railway on Manhattan's Sixth Avenue. After processing the scanned images, FirstSounds sent them to two physicists at Lawrence Berkeley National Laboratory in California who had developed software that reproduces sound from high-resolution scans of the grooves of wax cylinders and disk records too fragile or misshapen to be played with a stylus. Adapting the software, the Berkeley Lab scientists, Carl Haber and Earl Cornell, succeeded in playing the Edison phonautogram. After 133 years, the ghostly rumblings of a New York City train track rang out once more.

## Sound from soot

In late 2007, Giovannoni of FirstSounds flew to Paris and took digital scans of some of Scott's phonautograms the team had tracked down in the French patent office. At first, the wiggly lines seemed unplayable. The traces seemed a mess, and there was no way to tell how fast Scott had turned his hand-cranked machine or how the speed had varied. On some of the other phonautograms Giovannoni examined in early 2008, however, Scott had included what turned out to be a Rosetta stone: a second trace due to the vibration of a tuning fork, its frequency noted on the sheet. By getting the vibration of the tuning fork right and holding it steady, Feaster and his colleagues realized, they could decipher the primary sound print as well.

Haber and Cornell at the Berkeley Lab had produced a raw audio file from some of the tracings, but variations in the speed of Scott's cranking caused the sound to waver unintelligibly, Feaster recalls: “I stayed up into the wee hours of the morning adjusting the [sound of the] tuning fork to a consistent frequency, and bit by bit the recording gradually resolved itself.” About 5:30 a.m., listening through headphones plugged into his computer, Feaster heard the muffled strains of what sounded like a young girl in 1860 singing the French lullaby Au Clair de la Lune. Later that morning, he e-mailed his parents: “After a few hours of audio restoration work last night, I was (I believe) the first person now living to hear a vocal music performance from before the American Civil War.”

Listen (MP3)

Recording from a phonautogram of "Au Claire de la Lune," made in 1860.

Listen (MP3)

Corrected version of a recording from a phonautogram of "Au Claire de la Lune," made in 1860.

Listen (MP3)

Recording from a phonautogram of a passage from Aminta, a pastoral drama.

[Credit: FirstSounds.org and the Académie des Sciences de l'Institut de France.]

Some of Feaster's FirstSound collaborators were less restrained. “EUREKA!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!” sound archivist Réné Rondeau e-mailed him after hearing the sound file. “Congratulations, my friends, you have made THE breakthrough!! I am beyond stunned.” When the group unveiled the file a month later at the annual meeting of the Association for Recorded Sound Collections, The New York Times ran a front-page story on the discovery, and TV crews mobbed the French patent office. Scott, who died believing he might never get the credit he deserved, posthumously got his due.

Follow-up work revealed further surprises. In early 2009, Giovannoni scanned a trove of Scott's phonautograms that Feaster's research had turned up at the French Academy of Sciences in Paris. Feaster had adapted a different type of software, designed to convert optical film soundtracks into digital audio files, to play them.

One of the newfound phonautograms—a passage from Aminta, a pastoral drama by the 16th century Italian poet Torquato Tasso—also included a trace from a tuning fork. But when Feaster played back the recording, it was too fast. “It sounded like the Chipmunks—unquestionably wrong,” he recalls. “I wondered if I'd miscalculated somewhere.” Scott's notes on the sheet suggested that he had dictated the recording himself. Feaster concluded that Scott's marking of “500” for the tuning fork's frequency must refer to the number of half-cycles, not the full oscillations researchers measure today. In that case, the recording would be an octave lower than he had been assuming. Returning to Au Clair de la Lune, he slowed the playback down to the proper speed. The “girl's” voice became that of a man—almost certainly Scott himself.

In 2009, Feaster traveled to Paris to examine some of the phonautograms Scott had deposited at a French scholarly society in 1857. There he met Laurent Scott, a descendent of the inventor. Through headphones attached to Feaster's laptop, Laurent heard his great-grandfather's voice for the first time.

Listen (MP3)

Sound file transcribed and played from notation in a 10th-century manuscript of the Enchiriadis treatise. [Credit: Courtesy of Patrick Feaster.]

Inspired by the success with Scott's phonautograms, Feaster began exploring other visual recordings that he could attempt to convert into sound. “Today, we can listen—with a little work—to virtually any waveform we can see on paper,” he says. Two years ago, in some of his most far-ranging efforts to date, he applied his software to the musical notation found in a 10th century manuscript of the Enchiriadis treatise, a medieval work on music theory. The result was a 7-minute sound file that Feaster calls “the closest thing you're likely to hear to a 1000-year-old phonautogram.” Feaster has also applied software to “play” other historic musical notations—“as though a sound synthesizer were being programmed directly by medieval monks,” he says.

## Scouring the attic

In comparison, Feaster's sleuthing at the Smithsonian Institution seems almost contemporary. The little-publicized Smithsonian collection of 1880s recordings is the largest repository of its kind in the world. When Feaster first visited it in December 2010, an old catalog card with the obscure inscription “WJH—damaged record” caught his eye.

He leapt to the conclusion that “WJH” might be William J. Hammer, Thomas Edison's agent at the Paris Exhibition of 1889. That was the world's fair for which the Eiffel Tower was built and the first time that most Europeans heard Edison's talking machine. If Feaster's hunch was correct, the records could contain the only sounds known to exist from the 1889 fair.

But when Feaster returned to the Smithsonian in October 2011 on a 2-month fellowship, he found that a renovation several years earlier had forced the collection to be moved to several temporary storage units. He and Smithsonian curators Carlene Stephens and Shari Stout combed the shelves for anything resembling a box of wax-cylinder records.

In the next-to-last cabinet, Feaster found a closed wooden box stamped “WJH—Newark, N.J.” Inside were 28 hollow wax cylinders, some broken, many discolored, each on its own wooden peg. A torn piece of paper describes 16 of the recordings. Among the inscriptions: “Violin recorded on Eiffel Tower, Nov. 6, 1889.” The 12 untitled cylinders may include recordings Hammer is reported to have made of native American Indians visiting the fair as part of the Buffalo Bill show, officials from Africa speaking in their native tongues, and prominent French politicians of the day.

Because the records are so fragile—some literally held together by a core of string—it will take time and patience to remove them from the pegs and find out whether any sound can be coaxed out of the 122-year-old grooves, he notes. But the condition of the cylinders looks promising, Giovannoni says.

Listen (WAV)

Sample from experimental recordings that the Volta Laboratory made in the 1880s. [Credit: Lawrence Berkeley National Laboratory.]

One of Feaster's latest discoveries sprang from a painstaking perusal of the laboratory notebooks of 1880s sound pioneers in the Washington, D.C.–based Volta Laboratory, which included Alexander Graham Bell, his cousin Chichester Bell, and Charles Sumner Tainter. In 1881, Tainter described his attempts to record sound on a flat metal record incised with a spiral pattern of grooves and then play it back with a magnet after filling the grooves with a mixture of iron filings and wax. As part of the ultimately unsuccessful work, he cut two ridges along the narrow circular edge of the same record. On one ridge he recorded the word “potato”; on the other, a trilled “r.”

Then Feaster had a eureka moment. One of the records he examined in the Smithsonian collection bore an odd, two-ridge pattern on its edge. He had a match. “There's no doubt in my mind that this is the record that Tainter had referred to,” he says, cradling a metal record in gloved hands. If so, it is the earliest known recording on disk.

When Feaster isn't contemplating sounds from past generations, he's thinking about those from the newest—in particular his son Perrin. Before Perrin was born last February, Feaster and his wife, Ronda Sewald—a sound archivist whom he met in graduate school—recorded him in the womb and sang to him, putting their own lyrics to a catchy but unknown tune the couple had heard on a century-old wax cylinder. (Their wedding, in June 2006, featured a wax-cylinder processional, vows recorded and played back on a 1906 Edison wind-up phonograph, a century-old recording of Felix Mendelssohn's “Wedding March” as the recessional, and a Victrola-shaped cake.) In the delivery room, the couple banned cameras during the birth but kept the sound recorders rolling. “Perrin is likely to have strong feelings, one way or the other, about old records,” Feaster says.

• * Ron Cowen is based in Silver Spring, Maryland, and writes about physics, astronomy, and the history of technology.

5. Autophagy

# Explaining Exercise

1. Ken Garber*

Cellular "self-eating," which helps cells meet their energy demands, may account for some of the benefits of exercise.

Few would contest that exercise is a healthy habit. It strengthens muscles, keeps weight down, and, population studies suggest, protects against diabetes, cancer, and Alzheimer's disease. Still, the mechanisms behind exercise's many benefits remain murky.

Beth Levine of the University of Texas Southwestern Medical Center in Dallas had a hunch that her research interest might help solve the mystery of exercise. Since 1998, Levine has studied autophagy, the “self-eating” process by which cells recycle used or flawed organelles, membranes, and other internal structures. She has largely focused on its role in cancer and infectious diseases, but elevated autophagy can, at least in animal models, produce widespread health benefits, including protection from diabetes, cancer, and neuro-degenerative disease.

Because autophagy's recycling helps cells meet energy demands, Levine began to wonder whether exercise triggers autophagy and if that could somehow account for exercise's benefits. The exercise-autophagy parallel, Levine says, is “one of those things that's so obvious that it got overlooked.”

No longer. In the December issue of Autophagy, an Italian research team reported the first evidence that exercise induces autophagy in the skeletal muscles of mice. This week in Nature, Levine, her Dallas colleague Congcong He, and others confirm that observation and extend it much further, documenting that autophagy is required for exercise's beneficial metabolic effects. “This paper shows that autophagy really plays a critical role in response to exercise,” says Reuben Shaw, a cancer and diabetes researcher at the Salk Institute for Biological Studies in San Diego, California. “It's a stronger effect than I would have personally imagined.”

In autophagy, a double membrane encircles target material inside a cell, forming a sphere that then spills its contents into another compartment, the lysosome, where enzymes chop them up so the cell can use it all again (Science, 25 November 2011, p. 1048). Organisms from yeast to humans maintain a background level of autophagy, then boost it under stress.

Exercise is one such stress, Levine found. Running mice for short periods on a treadmill sharply elevated autophagy in many organs, her group reports. The Italian group documented a similar effect in skeletal muscle of healthy mice as part of a study of mice with a form of muscular dystrophy.

To isolate downstream effects of this exercise-induced autophagy, Levine compared normal mice with mutant mice that have typical background autophagy but don't induce more when stressed or stimulated. “A very elegant approach,” says exercise physiologist Zhen Yan of the University of Virginia in Charlottesville, who has unpublished mouse data showing that exercise training leads to more autophagy.

In subsequent work, Levine focused on skeletal muscle. Muscle soaks up about 85% of the glucose derived from food. Strenuous exercise normally lowers glucose and insulin in the bloodstream, but autophagy-impaired mice couldn't do this nearly as well. On the cellular level, following exercise, the autophagy-impaired mice didn't relocate a glucose transporter to the cell membrane as do normal mice. Levine's conclusion: Autophagy is necessary for the short-term metabolic benefits of exercise.

To examine exercise's long-term effects, Levine fattened normal mice and the autophagy mutants, which gave both groups a form of diabetes, then put them through 2 months of daily treadmill workouts. Only the normal were able to reverse their diabetes through physical training. Such exercise also brought down elevated cholesterol and triglyceride levels in these mice, but not in the autophagy-impaired mice. Autophagy may also be required to produce the lasting beneficial effects of exercise in diabetes, Levine concludes.

How do exercise and autophagy cooperate? Levine found that, after short-term exercise, normal mice activate in muscle the enzyme AMP-activated protein kinase (AMPK) but the autophagy-defective rodents don't. AMPK reprograms cells to boost energy production, and its induction by autophagy, Levine says, could explain how exercise training reverses diabetes.

Exercise training also causes lasting adaptations in muscle, including the replacement of old mitochondria, organelles where cellular energy is generated, with new, fuel-efficient ones—what Yan calls a “cash for clunkers” response. Yan believes autophagy following exercise training contributes to the mitochondrial upgrade, and Levine doesn't rule that out. “We're not trying to claim that AMPK activation is the only beneficial effect of exercise-induced autophagy on muscle metabolism, or on other organs, and other aspects of health,” she says. “This is probably the tip of the iceberg.” Indeed, Levine is now investigating whether exercise-induced autophagy can slow or prevent cancer and neurodegenerative disease.

Marco Sandri, a researcher at the University of Padova in Italy and an author of the December Autophagy paper, suggests that autophagy activators could treat forms of muscular dystrophy. Might such drugs even act as “exercise pills” for otherwise healthy people? Scientists may have trouble demonstrating safety of such drugs, Levine says, because autophagy is a tightly regulated process, and too much can lead to cell death. But exercise itself seems to safely boosts autophagy, and for the first time since college, Levine has started to work out. “I've always known exercise is good for you,” she says, “but when we found that it increases autophagy, I finally got a treadmill.”

• * Ken Garber is a science writer in Ann Arbor, Michigan.

6. Clinical Trials

# Experimental Cancer Therapies Move to the Front Line

1. Jennifer Couzin-Frankel

It's standard to test drugs in advanced cancer; now, some doctors are using experimental drugs earlier in disease and juggling the challenges that come with doing so.

On a Wednesday in mid-March nearly 2 years ago, an unusual cancer trial opened its doors. The study, called I-SPY2, was looking for at least 800 women recently diagnosed with a high-risk form of breast cancer willing to try something new. Before surgery to excise their tumors, they would receive experimental drugs along with the usual chemotherapy. In these women, cancer hadn't spread beyond the lymph nodes, but the tumors they harbored were aggressive and their chance of eventually dying from the cancer was 40%.

A remarkable feature of I-SPY2, one that engendered much behind-the-scenes debate before it launched, was that these women were at an early stage of the disease and standard treatments were at least modestly successful. Patients like these aren't normally recipients of untried therapies. Trials typically follow a well-worn path: Test the drugs in those who have exhausted their options and whose bodies are riddled by disease. The most remarkable successes might add an extra 6 months of life; many drugs are approved for accomplishing much less. Virtually no one expects these volunteers to be cured.

There are good reasons for this paradigm. Novel drugs carry risks and could kill patients faster than the disease itself. It's also easier, researchers say, to measure the effectiveness of new therapies in people at death's door. Tumors can shrink rapidly, and a modest improvement in survival—even in patients with weeks or months to live—means the treatment is working. But this approach also means that patients with, say, early-stage breast cancer, melanoma, or lung cancer don't have access to new treatments for years after testing begins.

A rush of new treatments that attack molecular vulnerabilities in tumors and may be less toxic than traditional chemotherapies has prompted some oncologists, pharmaceutical companies, and drug regulators to reconsider how cancer drugs are tested. While new drugs are often tried in patients whose disease is curable, this tends to happen later in development, frequently after the treatment has been under study for 10 years or been approved based on data in those with terminal cancer. Meanwhile, some doctors are wearying of therapies whose ability to extend life is measured in weeks.

“There's now a fork in the road,” says Razelle Kurzrock, an oncologist who heads the department of investigational cancer therapeutics at M. D. Anderson Cancer Center in Houston, Texas. “We can break our heads over advanced disease, or we can learn from newly diagnosed disease. … When the patient comes in with a 1-centimeter tumor, that's the time to figure out the molecular profile and eradicate the cancer.”

## Wake-up call

For oncologist José Baselga, this shift in strategic thinking started with the drug Herceptin, which nails breast tumors that overexpress the HER2 protein. Baselga was a young doctor at Memorial Sloan-Kettering Cancer Center in the early 1990s when he began working with Herceptin's maker, the California company Genentech, leading the first study to test Herceptin's effectiveness in patients with advanced disease. “The response rate was 12%,” with tumors shrinking in roughly one in 10 women, he says. It was a disappointing outcome and didn't bode well for the drug's future, says Baselga, now chief of oncology at Massachusetts General Hospital (MGH) in Boston. “Genentech had a big discussion, I was involved in that, and they almost, almost dropped the whole program.”

But instead of relegating Herceptin to the dustbin of history, Baselga says, Genentech gave it another chance. It launched a larger trial in advanced disease and later had Baselga lead a study in which Herceptin was the first treatment patients received instead of one of the last; here, the response rate was dramatically higher, about 40%. Women received it before surgery, and when physicians went in to operate, often there was nothing to take out. Those results, Baselga says, were a “wake-up call for me.” He's now working with the drug company Novartis on trials of other experimental therapies in early-stage breast cancer.

But testing new drugs in disease that hasn't spread far is easier said than done. The weightiest questions are ethical: What if giving a new therapy causes side effects that delay surgery or radiation in patients who might be saved by the standard approaches? “You cannot in any way jeopardize the chance of cure in these patients,” Baselga says.

Melanoma poses an interesting challenge. About three-quarters of newly diagnosed patients have disease that appears localized to the skin, and surgery is the treatment of choice. But doctors know that a subgroup already harbor tiny metastases, invisible to imaging machines, elsewhere in the body. Those people will likely die, while the rest will be cured. “We're not smart enough to figure out” who falls into which group, says Keith Flaherty, a melanoma specialist at MGH.

Deciding whether to test a new drug in patients like these means considering risk from two angles: “It's a spectrum of risk from the disease side”—how likely disease is to kill, Flaherty says—“and it's a spectrum of risk from the therapy side,” meaning the severity of a drug's side effects. In advanced disease, patients are virtually 100% certain to die, making that calculus relatively easy: Gamble on a drug and see what happens. If “you swing to the 15% risk scenario, you better have a safe therapy,” Flaherty says.

But what qualifies as a reasonable risk is matter of debate. A case in point is a drug Flaherty was intimately involved in testing, called vemurafenib. Approved by the U.S. Food and Drug Administration (FDA) in August for metastatic or inoperable melanoma, it targets the roughly 50% of melanoma tumors that carry BRAF mutations.

While testing of vemurafenib continues, no trials so far have included patients with early-stage disease that can be surgically removed. One reason is that BRAF inhibitor drugs have a dark side: While they shrink BRAF-positive tumors, they can also fuel the growth of BRAF-negative tumors. Patients getting vemurafenib sometimes develop BRAF-negative squamous cell skin cancers that are easily treated. But doctors worry about something more insidious: whether the drug might nourish virulent BRAF-negative cancers elsewhere in the body, such as an undetected tumor in the pancreas unrelated to a patient's melanoma. “You really want to be cautious,” says David Solit, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City, who has studied vemurafenib. “The drug can in fact be dangerous.”

For Flaherty, it's all about the numbers. Some subsets of melanoma patients with localized disease, treated only by surgery because there is nothing else, have a 50% chance of being cured. “That risk is solid, you know it's there,” Flaherty says. Yes, a handful will have a dormant pancreatic tumor, too, but the chance that the drug will make it grow is unknown. “If we were to say, ‘We are not willing to take any risk in this population of patients, these people who have a 50-50 chance of dying,’ … then we'll just never make any progress.”

## When to treat

Reworking the cancer trial paradigm also means rethinking at what point in therapy a new drug is offered. At Johns Hopkins University in Baltimore, Maryland, Charles Rudin, a lung cancer specialist, recently launched a trial in patients with early (stage I) lung cancer, for whom the standard of care is surgery and then no other treatment. Forty percent of this group will see a resurgence of their cancer and likely will die of it.

Last year, Rudin reported on a small trial of two experimental drugs that modify gene expression in tumors; that trial in advanced lung cancer showed hints of efficacy, so Rudin and doctors at five other centers are recruiting 258 patients with early-stage disease in hopes the drug combination will be more effective. They will offer drugs to half the patients after surgery. The trial is funded by a nonprofit organization, Stand Up To Cancer, with drugs supplied by a program at the U.S. National Cancer Institute that collaborates with drug companies to test experimental and approved drugs. Right now, “the patients get surgery and then are told, ‘We're going to watch your CAT scans and hope for the best,’” Rudin says. Joining a trial when there's no evidence of disease is “somewhat easier,” he says, when it involves a “decision to get something versus just watching.”

Because patients often relapse within a year, Rudin will use the time to relapse as a measure of how well the drugs work. In a disease like breast cancer, women might go 5 years before relapsing. For that reason, breast cancer trials can be “very large and very expensive because you have to [include] so many patients and follow them for such a long time,” says Barbara Weber, senior vice president for Oncology Translational Medicine at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts. “The path to registering a drug”—gaining regulatory approval—“in metastatic disease is much faster” than in less advanced cancer because you get data sooner, Weber says. “Virtually any company will pick the fastest path to registration.”

In part because of this, I-SPY2, which is currently testing four different experimental drugs made by several companies, is taking a different tack: giving drugs presurgery. This has the added benefit of providing critical information about a therapy's effect on a tumor, which doctors can glean once the tissue is surgically removed. What researchers are hoping, though, is that there won't be much tumor to find: I-SPY2's success will be measured based on something called “pathologic complete response,” essentially a tumor's disappearance before surgery. This is what Baselga saw in his early-stage Herceptin trial.

A burning question is whether these endpoints—a tumor's disappearance presurgery, or, in Rudin's study, a longer time to relapse—really mean a better shot at a cure. “It's obviously something we and everybody else talk about and struggle with all the time,” Weber says.

FDA is considering this issue as well, because companies are unlikely to commit to early-stage cancer trials unless they can use them for drug approval. Last month, Janet Woodcock, who heads FDA's Center for Drug Evaluation and Research, co-authored a paper in The Journal of the American Medical Association with Laura Esserman, a breast cancer surgeon at the University of California, San Francisco, and a leader of I-SPY2. They wrote that in certain breast cancers, pathologic complete response does predict the risk of relapse and that FDA considers this a reasonable basis for approving a drug. The agency plans to issue guidance to companies and scientists spelling out how to use endpoints in early-stage cancer trials.

“Just because we've always done it [one] way doesn't mean we have to do it that way,” Esserman says. More than anything, she says she's motivated by a concern for her patients. Efforts to permanently erase metastatic disease haven't worked. More women, she believes, could be saved if trials chased after earlier disease. “The results may turn out to be curative,” Esserman says. And that would be something to celebrate.