News this Week

Science  25 Mar 2011:
Vol. 331, Issue 6024, pp. 1499
  1. Around the World

    1 - London
    Scientists Welcome Proposed Changes to Libel Law
    2 - Nightingale Island, Tristan da Cunha
    Oil Spill Menaces Penguins
    3 - Paris
    ESA Flies Solo After NASA Yanks Support
    4 - Vientiane, Laos
    Not Your Average Ant Farm
    5 - Washington, D.C.
    Guatemalans Demand Justice


    Scientists Welcome Proposed Changes to Libel Law

    Scientific discourse may enjoy greater legal protection in the United Kingdom if the provisions in the draft Defamation Bill become law. The proposals include conferring more protection on statements dealing with matters of “public interest” and requiring that a statement must cause “substantial harm” before it becomes defamatory. The new Defamation Bill comes after several scientists and science writers have been ensnared in libel suits for discussing or writing about controversial matters (Science, 11 June 2010, p. 1348). Compared with other countries, the United Kingdom is generally considered more permissive to such lawsuits. Science minister David Willetts called the proposed legislation “good news for science,” but some advocates of libel reform, including Tracey Brown, managing director of Sense About Science, have so far reacted cautiously. More change is needed, said Brown in a statement, before scientists and journalists can “focus on the question ‘is it true?’ rather than ‘will they sue?’”

    Nightingale Island, Tristan da Cunha

    Oil Spill Menaces Penguins

    A shipping disaster in one of the loneliest places in the world is threatening an already endangered penguin species. On 16 March, the Oliva, a Maltese cargo vessel carrying soybeans from Brazil to the Far East, ran ashore and broke in two at Nightingale Island, a speck midway between South Africa and Argentina. Nightingale is home to more than 200,000 penguins, including about 40% of the world's population of Northern Rockhoppers (Eudyptes moseleyi), a threatened species.


    The ship's crew was saved, but its 1500 tons of fuel oil have begun leaking out and have encircled the 3-square-kilometer island, which is administered by the United Kingdom. A local Web site has posted images of oil-covered penguins coming ashore (pictured); as Science went to press, the Southern African Foundation for the Conservation of Coastal Birds was considering whether to send a cleanup team.

    Another danger looms, says the U.K.'s Royal Society for the Protection of Birds (RSPB): Rats escaping from the ship could colonize Nightingale and create ecological havoc. “How a modern and fully-laden cargo vessel can sail straight into an island beggars belief,” RSPB research biologist Richard Cuthbert said in a statement on 21 March.


    ESA Flies Solo After NASA Yanks Support

    European space scientists are scrambling to rethink—and redesign—massive potential missions after it was confirmed that NASA, whose budget is in disarray, won't contribute significant funding to any of the efforts.

    The European Space Agency (ESA) was supposed to decide in June whether to spend about $1 billion on one of three so-called L-class missions: the International X-ray Observatory (IXO), the Europa-Jupiter mission known as EJSM-Laplace, or a space-based gravitational-wave detector called LISA. But each mission, which wouldn't launch until the next decade, has been developed with NASA as a would-be partner.


    The beleaguered U.S. space agency has now told ESA it has higher priorities for its limited space science budget. The decision “means in principle that none of the three missions is feasible for ESA,” notes Xavier Barcons of the Cantabria Institute of Physics in Spain, who has helped develop plans for IXO. But ESA will press ahead on its own, delaying its choice until 2012. European scientists working on the three missions are now reviewing what can be cut from their projects.

    Vientiane, Laos

    Not Your Average Ant Farm

    A model farm devoted to raising insects as food is set to open next week at the National University of Laos in Vientiane. The demonstration site is part of a larger research project sponsored by the U.N. Food and Agriculture Organization (FAO) designed to develop sustainable and profitable techniques for raising “mini-livestock” such as crickets, mealworms, palm weevils, and weaver ants. Laos has several advantages as a place to establish insect farming, says Paul Vantomme, senior forestry officer at FAO in Rome and an expert on entomophagy, the practice of eating insects. Wild-caught insects are a regular part of the local cuisine, he notes, and fish and chicken farms provide another potential market for the farm's products. Several studies have demonstrated that insects can be a highly nutritious source of protein—with a low carbon footprint.

    Washington, D.C.

    Guatemalans Demand Justice

    Seven Guatemalan plaintiffs filed a class action lawsuit against a raft of U.S. government officials last week, on behalf of hundreds of their compatriots who were part of unethical medical studies run by U.S.-funded scientists in Guatemala in the 1940s. Many of the study subjects were deliberately infected with syphilis. The class also includes thousands of others who, as children and partners of the subjects, were impacted.

    Six months ago, after a historian at Wellesley College discovered the decades-old research, the U.S. government apologized and pledged an inquiry. The plaintiffs' attorneys, who filed suit in the U.S. District Court for the District of Columbia, say the research violated the Nuremberg Code and the U.S. Constitution's Eighth Amendment, which prohibits cruel and unusual punishment. The plaintiffs will ask a jury to award damages for pain and suffering, medical expenses, and other hardships. The named plaintiffs include former Guatemalan soldiers inoculated with syphilis and their children.

    Attorneys argue that the successors to the U.S. officials who oversaw the experiments are legally accountable, including the heads of the Department of Health and Human Services and the Centers for Disease Control and Prevention.

  2. Newsmakers

    Three Q's


    Evan O'Dorney checked out his first math book from the library when he was just 2 years old. Last week, the now 17-year-old homeschooler from Danville, California, won first place and $100,000 in the Intel Science Talent Search with an elegant formula that solves a mathematical stumper: When do two different methods for approximating square roots of integers, one based on infinite fractions and the other on iterating functions, reach the same answer? Another nine precocious winners, whose discoveries included novel liver cancer treatments and insights into star formation, shared $530,000. O'Dorney, an avid pianist and composer, will study math at Harvard University this fall.

    Q:Why don't other teenagers like math as much as you do?

    It seems like sometimes the teachers in the public schools make it dry and boring. When I went to the library, I found books that really exposed the fun and beauty of mathematics, but teachers often just want to teach the rote memorization and skills that [students] need for the test.

    Q:What's your working style?

    For 2 weeks, when I was really getting the main ideas, I worked all day. … It's just the excitement of the math. I never need [caffeine]. … I almost have the opposite problem. If I get into math, I have to remind myself that I'm hungry and I need to eat.

    Q:Did you ever have trouble explaining your project?

    There was one news reporter who … wanted to know what my project was about, so I first stated the title [“Continued Fraction Convergents and Linear Fractional Transformations”]. … He was awestruck by it. … I tried to summarize, and after I had gotten half a sentence into it, he said, “I have no idea what that means.” He just ran off before I could finish.

    Strong Medicine

    Three scientists whose work on stem cells ignited the field of medicine will share this year's Albany Medical Center Prize in Medicine and Biomedical Research and its accompanying $500,000. The award recognizes James Thomson, who holds appointments at the University of Wisconsin, Madison, the Morgridge Institute for Research in Madison, and the University of California, Santa Barbara, for pioneering the isolation of human embryonic stem cells and for his work on induced pluripotent stem cells, which are genetically reprogrammed from adult cells. Induced pluripotency, which researchers see as a powerful tool for understanding diseases and developing therapeutic treatments, was discovered by fellow prize winner Shinya Yamanaka of Kyoto University in Japan and the Gladstone Institute of Cardiovascular Disease in San Francisco, California. Elaine Fuchs of the Rockefeller University in New York City was also honored, for her investigations of skin stem cells and how they develop into skin and hair. That work has led to a better understanding of skin diseases and cancers.

    Northern Lights

    Seven medical researchers have won Canada's Gairdner Foundation Awards, valued at CAD $100,000 each. Jules Hoffmann of France's National Center for Scientific Research (CNRS) in Strasbourg and Shizuo Akira, director of the Immunology Frontier Research Center in Osaka, Japan, were recognized for identifying proteins involved in pathogen recognition. Developmental biologists Howard Cedar and Aharon Razin of the Hebrew University of Jerusalem and geneticist Adrian Bird of the University of Edinburgh were honored for their discoveries in the field of DNA methylation and related gene expression. Robert Black of Johns Hopkins University in Baltimore, Maryland, won a special Global Health award for his research on reducing childhood deaths from diarrheal diseases, while geneticist Michael Hayden of the University of British Columbia, Vancouver, was lauded for leadership in “medical genetics, entrepreneurship and humanitarianism.”

    Since the awards were created in 1959, 76 Gairdner winners have also garnered Nobel prizes.

  3. Random Sample

    MESSENGER Arrives Safely at Mercury


    After 6½ years in space, almost 8 billion kilometers traveled, six orbit-altering flybys of planets, and 15 minutes of blasting its main engine, the MESSENGER spacecraft finally slipped into orbit around Mercury last week. The smallest, innermost planet is the last of the classical, naked-eye planets to get an orbiter. Tagged with the most contorted of acronyms (standing for MErcury Surface, Space ENvironment, GEochemistry, and Ranging), MESSENGER will probe everything from the mineral elements the sun continually blasts off the planet's surface to its relatively huge metallic core, which occupies nearly half of its volume. Also of interest are the subsurface ice deposits thought to linger near the poles of the sun's nearest neighbor. MESSENGER's seven scientific instruments, battened down for the rocket burn (after taking images during three earlier Mercury flybys), will be turned on and checked out for the start of science observations on 4 April.

    By the Numbers

    $753 million — Cost to ferry U.S. astronauts to the International Space Station aboard Soyuz spacecraft under a new contract with Russia for 2014 to June 2016. That's $63 million per astronaut.

    17% — Percentage of the Massachusetts Institute of Technology's science and engineering faculty who are women. That's up from 7% in 1995.

    5000 — Number of homes that could run on an underwater turbine array just authorized by the Scottish government. Planned for a narrow strait between the islands of Islay and Jura, the turbines will also power several distilleries.

    Proof Positive


    Space scientists at the University of Leicester are working to protect the people of Britain from a terrifying scourge: counterfeit whisky.

    Detecting fake whisky actually isn't that hard. “The trick with high-value whiskies is to measure there's something wrong without opening the bottle” and ruining its value, says George Fraser, whose day job is working on instruments that go on space probes.

    So he and colleagues are working on a device, based on another one that they developed to detect counterfeit pharmaceuticals, that measures whisky the same way an astronomer measures the spectrum of a star. “It's basically holding the object up to the light in a technological fashion,” Fraser says. A spectrometer records which wavelengths of light pass through the bottle of whisky, and researchers can then compare them with the spectrum transmitted by, say, a 15-year-old Glenlivet. (The technique can also flag watered-down spirits.) And, because it's tough for counterfeiters to print a label exactly the same color as the real thing, the scientists are also measuring the wavelengths reflected off the label.

    The group hopes to have the instrument on the market in 18 months. In the meantime, Fraser doesn't mind leaving the bottles closed. He's a native of Scotland's Spey Valley, the home of some of the world's finest whisky, but says, “I don't much like it, actually.”

  4. Energy Supplies

    Peak Oil Production May Already Be Here

    1. Richard A. Kerr

    Outside of OPEC's vast resources, oil production has leveled off, and it's looking like it may never rise again.

    The hard way.

    Depletion of conventional oil fields outside of OPEC is driving the mining of oil sands in Alberta, Canada.


    Five years ago, many oil experts saw trouble looming. In 10 years or so, they said, oil producers outside the Organization of the Petroleum Exporting Countries (OPEC) would likely be unable to pump oil any faster (Science, 18 November 2005, p. 1106). Non-OPEC oil production would peak, no matter the effort applied. All the high-technology exploration and drilling, all the frontier-pushing bravado of the oil industry would no longer stave off the inevitable as OPEC gains an even stronger hand among the world's oil producers.

    Five years on, it appears those experts may have been unduly optimistic—non-OPEC oil production may have been peaking as they spoke. Despite a near tripling of world oil prices, non-OPEC production, which accounts for 60% of world output, hasn't increased significantly since 2004. And many of those same experts, as well as some major oil companies, don't see it increasing again—ever. In their view, it's stuck on a flat-topped peak or plateau at present levels of production for another decade or so before starting to decline. “Stable [non-OPEC] production is the best we can hope for,” says energy economist Robert Kaufmann of Boston University. “I have trouble seeing it increase more. It's a wake-up call.”

    Optimists remain. Some experts still see production from new frontiers, such as Kazakhstan, the deep waters off Brazil, and the oil sands of Canada, pushing production above the current plateau in the next few years. But time's running out to prove that newly discovered fields and new technology can more than compensate for flagging production from the rapidly aging fields beyond OPEC.

    Running to stay in place

    There's no debate about the reality of the 6-year-and-counting plateau of non-OPEC production. Output stagnated at about 40 million barrels a day beginning in 2004 after rising from an earlier plateau in the early 1990s, one induced by a low price for oil. But prices have been anything but low lately. They have gone from about $35 a barrel early in the past decade to double and nearly triple that. Normally, higher prices would encourage more production, but not this time. Since 2004, “there's been a tremendous increase in price, yet this is all we get for it, stable production,” Kaufmann says. “It's quite stark.”

    The problem up to this point, all agree, has been increasing difficulties extracting conventional oil. That's the easiest oil to get at, oil that freely flows out of a well of its own accord or with a minimum of encouragement, such as pumping it out or pushing it out with water. Production of conventional oil from any one well or field typically increases, peaks, and then goes into decline. Larger producing regions behave the same way. Production from the United States, once the world's largest oil producer, peaked in 1970 as rising output from newly discovered fields failed to compensate for declines in old fields. Mexico's production peaked in 2004 as its huge, aging Cantarell field went into steep decline. North Sea production peaked in 1999, just 28 years after starting up.

    The same pattern now seems to be emerging across much of the world. “We believe—and pretty much everybody else believes—that non-OPEC [conventional] production has plateaued,” says oil analyst Michael Rodgers, a partner with PFC Energy in Kuala Lumpur. “Arguing that you're going to get continued and sustained growth of conventional oil is a very hard case to make.” PFC Energy has just done a complete reassessment of the prospects for non-OPEC conventional production, he says. As in most oil outlooks, a country-by-country or even field-by-field survey of what producers are planning for the next 5 to 10 years was combined with an educated guess of how much oil remains to be discovered in each region.

    That forecast of added production is balanced against how fast production from existing fields is declining. In the past decade, analysts have realized that rather than the 2% to 3% per year decline once assumed, production from existing fields is declining 4% to 5% per year. Some believe the depletion is even faster. The balance between added and declining production, in the PFC Energy assessment, is a plateau, though the plateau may undulate from year to year. “You bring on a [new] 100,000-barrel-a-day field,” Rodgers says, “and somewhere else you've lost a 100,000-barrel-a-day field.”

    Tough oil to the rescue?

    But what about unconventional oil, the hard-to-get-at oil that's only extractable using the latest in high technology? There's the oil beneath kilometers of seawater far offshore of the U.S. Gulf Coast, Brazil, and West Africa. It wasn't reachable until development of the necessary deep-water drilling and production technology. There is also the oil—more like tar—that is so viscous that steam must be piped underground to thin it before pumping it out. In Alberta, Canada, huge shovels just dig up the “oil sands” so it can be trucked to oil-extraction plants. And American drillers have lately taken to drilling into rock formations that would normally only dribble oil and fracturing the rock with high-pressure fluids in order to wrest worthwhile amounts from the rock. That's how drillers have been “fracking” stingy natural gas formations (Science, 25 June 2010, p. 1624).

    Such unconventional oil is out there in abundance, everyone agrees, and more will be produced than in the past. However, some major oil companies as well as other analysts don't see unconventional oil boosting non-OPEC production much in the next 20 years. In their most recent annual energy outlooks to 2030, both ExxonMobil and BP—two of the world's largest independent oil companies—forecast that non-OPEC production will more or less hold its own, no better. “It's quite an accomplishment to keep non-OPEC supply flat level,” says analyst Kyle Countryman, who as a member of ExxonMobil's energy and economics group in Dallas, Texas, helped put the outlook together. Adds his colleague, group manager Robert Gardner: “We're not optimistic we'll see a significant increase in unconventional liquids.”

    The problem with unconventional oil is that, by definition, it is hard to extract. “It's a matter of timing,” Gardner says. “It depends on the pace of technology development.” And even after the essential technology is developed, unconventional oil will still be difficult—as well as expensive—to extract, limiting the rate at which it can be produced. All in all, “technology matters, economics matters, but geology really does matter,” says oil analyst David Greene of the U.S. Department of Energy's Oak Ridge National Laboratory in Tennessee. “Progress in technology is not fast enough to keep up with depletion” of oil reservoirs. Oil analyst Richard Nehring of Nehring Associates in Colorado Springs, Colorado, is more optimistic about prospects on oil's frontiers and how fast some kinds of unconventional oil can be brought online, but he still finds that “non-OPEC will be stable or at the very best slowly increasing” over the next couple of decades.

    Running flat out.

    An ExxonMobil outlook has non-OPEC oil (orange plus blue) plateauing. Natural gas–derived liquids (green) and biofuels (yellow) will help, but OPEC (purple) must pitch in.


    Optimism not dead

    “We're a little more bullish about non-OPEC than some others,” says Peter Jackson of Cambridge Energy Research Associates (CERA) in London. Along with the U.S. Energy Information Agency (EIA), CERA sees real promise in underdeveloped oil provinces such as offshore Brazil and Kazakhstan. Likewise, if prices stay high, unconventional oil will contribute substantially, both find, especially the Canadian oil sands. Beyond the next few years, “we're seeing a gradual increase in non-OPEC supply,” Jackson says.

    Such optimism has not always served forecasters well. In 2005, Jackson and his CERA colleague Robert Esser of the New York office predicted that “global oil production capacity is actually set to increase dramatically” up to 2010. It didn't; both OPEC and non-OPEC oil production remained steady. Likewise, in its 2005 outlook, EIA projected a jump in non-OPEC production by 2010 if prices were high, which they mostly were. But 2010 production was about 40 million barrels per day, right where it was in 2005.

    So what if the pessimists turn out to be realists and non-OPEC producers can't answer the call for more oil? Demand will increase in this decade, mainly from developing countries like China and India as populations grow and incomes rise. That rising demand might be met by several sources. In decreasing order of reliability, production of another sort of petroleum liquid, natural gas liquids (NGLs), is expected to increase. NGLs are the lighter-weight hydrocarbons that condense from natural gas when it cools. The expected increase in global natural gas production—at least half of which would come from OPEC—would lead to increased production of NGLs.

    A remaining hope.

    Some analysts see untapped oil fields in frontier areas, such as offshore Brazil (above), pushing up non-OPEC production.


    OPEC would, it is fervently hoped outside of the cartel, be willing and able to boost its output of conventional oil. ExxonMobil has OPEC production rising from about 29 million barrels per day today to about 36 million barrels per day in 2030. That would increase OPEC's share of oil production even further, but Kaufmann, among others, expects that OPEC will see an opportunity to make more money from its oil by curbing production and driving prices up. That would tend to encourage production of liquid biofuels, but whether output could be ramped up quickly enough to bring relief remains unclear. The clearest outcome, according to Greene, is likely to be continued or even greater volatility in the price of oil with all the economic downsides that would entail.

    Perhaps the most sobering outcome of a non-OPEC plateau might be reminding everyone that even planet-scale resources have their limits. And that when you are consuming them at close to 1000 gallons a second, the limits can catch you unaware. The next 5 years, assuming oil prices remain on the high side, should show who the realists are.

  5. Archaeology

    Texas Site Confirms Pre-Clovis Settlement of the Americas

    1. Heather Pringle*

    Very ancient stone tools help confirm what many have long suspected: Clovis hunters, with their distinctive spear points, were not the first to people the Americas.

    Near the headwaters of a small creek, a group of hunter-gatherers made their camp and began to craft stone tools. The riverbanks rang with their blows, as they struck flakes off chert nodules to create tools for cutting hard materials such as bone; they also knapped small blades for processing hides. They left thousands of sharp stone flakes and chips discarded on the ground.

    At one time or another, similar scenes have played out almost the whole world over. But the remarkable thing about this one, as detailed on page 1599 of this issue, is that it happened near Buttermilk Creek, Texas—about 15,500 years ago. That's long before the Clovis hunters, once thought to be the very first people in America, had appeared. Lead author Michael Waters of Texas A&M University in College Station says this site “tells us for once and for all that we can abandon this Clovis-first model.” The ancient tools also offer a first glimpse into how the distinctive fluted Clovis points may have developed over millennia.

    Although some previous claims of pre-Clovis artifacts have been controversial, other archaeologists say the new research is highly convincing. “The many distinct and superbly documented lines of evidence … offer pretty unequivocal confirmation that people were in interior North America south of the ice sheets before the Clovis radiation,” says David Anderson of the University of Tennessee, Knoxville, founder of the online Paleoindian Database of the Americas.

    Archaeologists have been locked in an acrimonious debate over the early peopling of the Americas for nearly 30 years. Advocates of the Clovis-first theory argued that the big-game–hunting Clovis people were the first to arrive from Asia, about 13,200 years ago. Other archaeologists reported nearly two dozen pre-Clovis sites in North America. In each case, however, the evidence was incomplete or flawed. Even so, says archaeologist Dan Sandweiss of the University of Maine, Orono, the pre-Clovis theory “has been getting more and more traction.” But advocates have had trouble pointing to a particular North American site that offered strong proof in one place.

    The new paper claims to change all that. In 2006, Waters and his team began excavating at the Debra L. Friedkin site in central Texas, not far from a known Clovis site. The site lies near a year-round water supply and close to an abundant source of high-quality chert for toolmaking. Repeated incremental deposits of clay from flooding over the millennia offered good preservation.

    As the team dug down into the clay, they found a sequence of cultural horizons, each with diagnostic stone tools in correct stratigraphic order, ranging from Late Prehistoric artifacts in the uppermost horizon to Folsom, Clovis, and finally pre-Clovis in the three lowest levels. But they found no charcoal or other organic material, which is often poorly preserved in this region, and so had no way to radiocarbon-date the layers.

    Time team.

    Excavators unearthed pre-Clovis stone tools, including (inset, top to bottom) a biface, flake tool, and flake core.


    The team opted to use optically stimulated luminescence (OSL), a technique that measures the amount of light energy trapped in quartz and feldspar grains in the clay and dates the last time they were exposed to sunlight. The lowest tool-laden horizon dated to 15,500 years ago—more than 2 millennia before the first Clovis sites. And the dates of the overlying horizons correlated with those of their diagnostic tools. “The OSL dates are almost perfect top to bottom,” says archaeologist Dennis Jenkins of the Museum of Natural and Cultural History in Eugene, Oregon, who was not involved in the study.

    The team did four other analyses, such as examining whether artifacts were sorted by size, to be sure that artifacts from upper levels had not fallen down into the pre-Clovis layer. “All [the analyses] pointed to an intact sequence,” says Sandweiss, another outsider familiar with the findings.

    Use-wear studies on tools from the lowest layer reveal that the pre-Clovis people used the tools to work bone, wood, or ivory and to cut or process hides. And their blades, bladelets, and bifaces bear some important resemblances to the later Clovis toolkit, pointing to continuity between the two groups. “The thing I find really neat,” Waters says, “is that we found 12 [pre-Clovis] bifaces, and they were making them by bifacial reduction, similar to the technique used by Clovis people.”

    Longtime Clovis-first advocate Gary Haynes of the University of Nevada, Reno, is impressed by the paper, saying that it includes key stratigraphic analyses missing from studies of other possible pre-Clovis sites in North America. And “there's no question that the artifacts are really stone tools,” he says, a problem raised at other pre-Clovis sites. “These are really things that could be technologically and logically ancestral to Clovis.” But Haynes isn't sure the tools date to pre-Clovis times and would like radiocarbon dates to be certain.

    Despite such doubts, Anderson expects that the new findings will move studies of the first Americans into a new phase. “As more attention focuses on pre-Clovis lifeways, we can begin to get a better handle on many major questions: how did the colonization proceed, [and] how widely did these folks range over the landscape,” he concludes.

    • * Heather Pringle is a contributing editor at Archaeology magazine.

  6. Microbiology

    Going Viral: Exploring the Role Of Viruses in Our Bodies

    1. Elizabeth Pennisi

    'Virome' surveys reveal our vast number and variety of viruses.

    VANCOUVER, CANADA—In the past decade, scientists have come to appreciate the vast bacterial world inside the human body. They have learned that it plays a role in regulating the energy we take in from food, primes the immune system, and performs a variety of other functions that help maintain our health. Now, researchers are gaining similar respect for the viruses we carry around.

    For a start, the variety and sheer number of viruses that inhabit us put our bacterial companions to shame. Many of the viruses prey on the bacteria in our bodies, altering their numbers and diversity and shuffling genes—including genes for antibiotic resistance—from one bacterium to another. “Ultimately, those viruses are incredibly important in driving what's going on” in the human microbiota, says Curtis Suttle, a virologist at the University of British Columbia (UBC), Vancouver, in Canada. “To understand the bacteria associated with humans, you can't do that without looking at the viruses as well,” he says. Studies presented here at the International Human Microbiome Congress earlier this month have begun to do just that. One provocative, albeit preliminary, finding has already emerged: Infants with unexplained fevers harbor many more viruses than healthy infants.

    For years, virologists have documented specific viral infections, including HIV and SARS, by detecting identifiable viral DNA within blood or other tissues. But to do a comprehensive survey of the viruses in the body—the so-called virome—“is a true frontier,” says B. Brett Finlay, a microbiologist at UBC Vancouver. Last July, Jeffrey Gordon, a microbiologist at Washington University (WU) School of Medicine in St. Louis, and his colleagues described one such effort in a group of seemingly healthy people. They isolated and characterized the viromes of adult identical twins and their mothers, sampling stools for viral genetic material three times over the course of a year. The overall conclusion: Healthy people “are full of viruses,” says WU's George Weinstock.

    By one measure, the number of distinct viruses in the stool samples ranged from 52 to 2773. The viromes varied significantly from one individual to the next; they were even more diverse than the bacterial communities within the same individuals. But each person's viral community remained stable over the course of the year.

    WU microbiologist Kristine Wylie and her colleagues have begun to look at how the virome may influence health, in particular what role it might play in unexplained fevers in infants. For children under 3, fevers are the most common cause of emergency room visits, but almost 90% of the time there's no clear cause for the high temperatures.

    Expanding universe.

    The tally of known viruses is exploding, and this graph doesn't even include the incredible number that prey on bacteria.


    Wylie, Weinstock, WU's Gregory Storch, and their colleagues sequenced the DNA obtained from nasal swabs or blood plasma of 151 individuals, about half of whom had unexplained fevers. The team estimated there were 10,000 viral sequences in the plasma samples of the children with fever and only about 1000 in healthy children. Some of the viruses found were common human pathogens, such as herpes and cold viruses. But there also seem to be unusual viruses, including an astrovirus, in the mix, Wylie reported. “There were new isolates that you might not have thought would be associated with febrile illness,” says Frederic Bushman, a virologist at the University of Pennsylvania.

    Much more work is needed to establish that any of these viruses explain the fevers, but proving that could mean fewer antibiotics for infants, Wylie points out. To be on the safe side, physicians tend to prescribe antibiotics for unexplained fevers, but such drugs are ineffective against viruses.

    While Wylie has focused on the viruses that infect human cells, Bushman has homed in on the bacteriophages, viruses that attack bacteria. For every bacterium in our body, there's probably 100 phages, with an estimated 10 billion of these viruses packed into each gram of human stool. As part of a study of the interplay of diet, human gut microbes, and Crohn's disease, an inflammation of the digestive system, Bushman and his colleagues have looked at the viromes of six healthy adults. These volunteers were sequestered for 10 days and fed either a high-fat or a low-fat diet, and the researchers analyzed their stool samples for bacteria and viruses.

    Overall, the median number of different kinds of phages was 44 per sample, Bushman reported at the meeting. But within 24 hours of a person starting the new eating regimen, the community of phages and bacteria began changing. Because the phages live in the bacteria, one would expect the number and kinds of bacteria and phages to change in parallel, but that was not always the case, Bushman noted. There was also a lot of variation between individuals, with the number of viral types differing by as much as 40-fold in the samples. But in those people eating the same foods, the repertoire of viruses tended to converge.

    These studies drive home that the human virome needs to be studied more closely, Suttle says. But there are many challenges. For one, most of the viral sequences that have turned up so far don't have matches in any known databases, so the viruses can't be characterized. And all the virome survey techniques have their drawbacks. Bushman filtered out all the human and bacteria cells and cleared out all nonviral DNA before sequencing any remaining DNA in his samples. “What [that approach] probably does is throw out most of the virus that was there,” Suttle says. Wylie and her colleagues, on the other hand, sequenced all of the DNA in the stool samples and used computer programs to sort sequences into human, bacterial, and viral bins. But with that strategy, “you usually wind up with a big bin of unknown [sequences],” Suttle adds. Bottom line, says WU's Herbert “Skip” Virgin, “Bacteria are easier to count.”

  7. News

    Cancer Research and the $90 Billion Metaphor

    1. Eliot Marshall

    In the 40 years since President Richard Nixon first declared "War on Cancer," the cancer campaign has changed therapy and saved lives, as demonstrated in this infographic Science has created of indicators for the seven deadliest cancers.

    There never was an official “War on Cancer.” That phrase from news reports and debates attached itself to the U.S. program that began when President Richard Nixon signed the National Cancer Act in December 1971. The law made big promises and gave the U.S. National Cancer Institute (NCI) a token measure of independence. It also encouraged the idea that cancer could be targeted, like a trip to the moon, and cured. The law was important for research, RAND medical historian and policy analyst Richard Rettig has written: It stopped a decline in NCI's budget.

    This reversal began in Congress. Urged on by health activists such as Mary Lasker, leading Democrats in 1970 adopted curing cancer as their cause. Aware that it might become a national issue, Nixon embraced it, too. The resulting legislation raised NCI's budget almost overnight by 23% to $233 million; NCI's funding has continued to climb since then to more than $5 billion per year—although in recent years inflation has grown faster. Since the 1971 act, NCI has spent about $90 billion on science, treatment, and prevention of cancer.


    U.S. Cancer Trends


    [View the Infographic]


    The war metaphor remains part of this legacy—and a target for skeptics. In 1986, former NCI biostatistician John Bailar stirred controversy with a bleak analysis in The New England Journal of Medicine, noting that cancer incidence and mortality rates hadn't changed fundamentally in 15 years. He suggested that the nation was “losing the war against cancer.” Sweeping declarations continued. In 2003, then–NCI Director Andrew von Eschenbach set a goal of ending suffering and death from cancer “by 2015.” Such broad claims invite balloon-pricking.

    But if one sets aside the rhetoric, says Allen Lichter, executive director of the American Society of Clinical Oncology, it's evident that the cancer campaign has changed therapy and saved lives (see indicators for the seven deadliest cancers, right). It is true that for certain cancers—of the pancreas, brain, and liver, for example—the picture has not improved. But the overall U.S. cancer mortality rate began to decline in the 1990s. And clinical care “looks nothing like it did 40 years ago,” says Lichter, who began training as an oncologist in the 1970s. He speaks of a revolution that took lessons from the 1960s advances against childhood leukemia to develop “adjuvant therapy”: the “crazy idea” that chemotherapy should be given to patients in remission to treat “presumed microscopic disease” that has spread. His list of benefits continues with breast-conserving and microscopic surgery, imaging for diagnosis and disease management, molecular analysis of tumors and targeted drug therapy, longer survival times, and much better palliative care. Looking for progress in cancer can feel “like watching the hands of a clock,” Lichter admits. “But things are definitely moving in the right direction.”

  8. News

    40 Years of the War on Cancer

    Science presents a timeline chronicling notable events in the war on cancer, launched 40 years ago when U.S. President Richard Nixon signed the National Cancer Act.




    President Richard Nixon signs the National Cancer Act promoting the National Cancer Institute.


    NCI launches Surveillance Epidemiology and End Results program to collect U.S. cancer data.



    Clinical testing begins of interferon-α, the first biological cancer therapy. FDA approves tamoxifen to prevent breast cancer recurrence.


    Researchers discover p53, the mutated gene most often seen in tumors.



    Robert Gallo and others isolate human T-cell lymphotropic virus-1, a cause of cancer.


    First cancer-prevention vaccine introduced— against human hepatitis B virus.


    Researchers create severe combined immunodeficient mice, a model for cancer research.



    Randomized trial shows that lumpectomy plus radiation are as effective as mastectomy for breast cancer.


    Biostatistician John Bailar writes in The New England Journal of Medicine, “We are losing the war against cancer.”



    Nobel Prize for discovering the first proto-oncogene (Src) awarded to Harold Varmus and Michael Bishop.


    National Breast Cancer Coalition launched, in the AIDS activist style.



    FDA approves synthetic yew bark derivative, Taxol (paclitaxel), for breast cancer.



    Congress orders study of environmental causes of breast cancer on Long Island; the 10-year study will yield no significant findings. Science names p53 “Molecule of the Year.”


    BRCA1 gene, identified as a risk for breast and ovarian cancer, is cloned; BRCA2 cloned the next year.


    American Cancer Society and others report the “first sustained decline” in overall U.S. cancer deaths, a drop of 2.6% from 1991 to 1995.


    FDA approves Herceptin (trastuzumab), a monoclonal antibody, for metastatic breast tumors that overproduce HER2.



    Nobelist James Watson tells The New York Times that blocking the growth of tumor blood vessels (antiangiogenesis) can “cure cancer in 2 years.”


    FDA approves Gleevec (imatinib), a targeted drug, for chronic myelogenous leukemia; Time calls it a “magic bullet.”



    NCI Director Andrew von Eschenbach vows to “eliminate suffering and death from cancer by 2015.”


    FDA approves Avastin, an antiangiogenesis drug, for colon cancer, with chemotherapy. Childhood cancer landmark: nearly 80% of those treated for acute lymphoblastic leukemia are free of cancer “events” for 5 years or more.



    NIH launches The Cancer Genome Atlas to catalog genomic changes in tumors.


    FDA approves Gardasil vaccine to prevent HPV infection, which can lead to cervical cancer.


    Breast cancer incidence declines, attributed to better screening and reduced use of hormone replacement therapy.


    James Watson writes that it's time to turn from cancer genetics to “understanding the chemical reactions within cancer cells,” or cell metabolism.



    National Lung Cancer Screening Trial finds that helical CT screening can reduce cancer deaths among smokers. FDA approves Provenge, an immune treatment for metastatic prostate cancer. It extends life about 4 months and costs $93,000.


    PLX4032, a targeted cancer drug, extends life in patients with advanced melanoma.

  9. News

    Combining Targeted Drugs to Stop Resistant Tumors

    1. Jocelyn Kaiser

    Even the most successful targeted therapies lose potency with time. Researchers hope to figure out how tumors escape; they aim to turn months of survival into years.

    One of the best hopes for anticancer drugs in the past decade comes from a simple idea: Find a weak point in a tumor's molecular machinery and throw a well-aimed wrench into it. The strategy has led to some dramatic successes, stopping the growth of certain cancers in their tracks while doing little or no harm to healthy tissue. But the pursuit of what's known as “targeted therapy” has taken many of those involved on a roller-coaster ride. The new treatments, after a brilliant debut, tend to lose potency as tumors develop resistance. After a pause lasting weeks or months, the cancer may begin to grow again.

    Understanding why this occurs and devising therapies that will overcome resistance are the main focus of a growing community of cancer researchers. A recent example of their quest involves a drug designed to stop metastatic melanoma, a highly aggressive disease for which there is no effective treatment today.

    In late 2007, Roche and a biotech company called Plexxikon began testing a new targeted drug called PLX4032 for patients with advanced melanoma. When researchers presented the f irst scans from treated patients, audiences were stunned: In some cases, the tumors had almost disappeared. Eighty percent of patients got better, a remarkable response that seemed to validate the concept of targeted therapy. There was “jubilation about how well it works,” says Charles Sawyers, a cancer researcher at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. Sawyers is a pioneer of the targeted approach and co-developer of the drug Gleevec that has been spectacularly effective against chronic myelogenous leukemia (CML).


    But then came the letdown: After about 7 months, most melanoma patients on the PLX4032 pill saw their tumors begin to grow again; many died. Last fall, trying to learn what enabled that puzzling regrowth, several research teams showed that resistant tumor cells had found ways to switch back on the cell pathway that the PLX4032 drug had jammed. They gave some of the relapsed patients another new drug that blocks the pathway at another point, hoping their tumors would shrink under the dual assault. The results are still coming in.

    In the past few years, researchers have reported dramatic responses to a handful of new drugs that are given to patients with a specific mutation in their tumors. But the emerging pattern is that although these drugs can shrink solid tumors and extend patients' lives, they never completely eliminate the cancer. For reasons still not well understood, the initial success is only “a foot in the door,” says cancer geneticist Michael Stratton of the Wellcome Trust Sanger Institute in Cambridge, U.K., whose team has found several genetic weak spots in tumors.

    Researchers are still working out exactly what to do next. On the surface, the answer is straightforward: Identify the ways that tumors resist the drug, then find or develop second-generation drugs that block these escape routes. With the right drugs on hand, researchers envision designing a cocktail—perhaps two, three, or more drugs—that, if given when a patient is first diagnosed, could stop tumors from ever evading the blockade. This approach has worked for patients infected with HIV, who usually take three antiviral drugs. Sawyers and many other researchers say there's no reason it shouldn't work for cancer.

    But getting a therapy to work and getting it to endure are two different things. Even if a combination therapy stops tumor growth, it may not buy patients more than a temporary reprieve, researchers admit. To stretch the benefit over years, it might be necessary to devise one complex cocktail after another, each tailored to a patient's evolving tumors.

    Tossing in the wrench

    Molecular targeting builds on what researchers have learned from 30 years of work on the genetic changes behind cancer. Uncontrolled cell growth is often driven by an aberrant protein in the cell membrane that transmits a spurious signal to the nucleus, instructing it to divide. Antibodies or small molecules can be used to block these overactive cell receptors, or a mutated protein farther down the signaling chain, causing tumors to shrink dramatically. (By contrast, standard chemotherapy targets all dividing cells in the body, which makes it much more toxic.)

    But because tumors are genetically diverse, resistance seems inevitable. Once a targeted drug wipes out the bulk of a tumor, cells harboring “resistance genes,” or alternative growth instructions, have a chance to grow. Even a tiny population of resistant cells can expand and take over. “Every single targeted therapy will select for resistance” in this way, says Carlo Maley, who studies the evolution of cancer at the University of California, San Francisco.

    Gleevec is the classic example. In 95% of patients with CML, the cancer is driven by a gene called BCR-ABL that is formed when two chromosomes swap pieces, making a fused segment known as the Philadelphia chromosome. Gleevec, made by Novartis, is a small molecule that blocks the BCR-ABL fusion protein. The drug was approved for CML by regulators 10 years ago this May, and many patients on it live for at least a decade. But about 17% of patients develop resistance within 5 years.

    Gleevec's developers anticipated this, they say. Sawyers and others have shown that in most cases resistance results from mutated versions of the BCR-ABL protein that are not affected by the drug and continue to tell cells to grow. Companies developed other specific drugs, dasatinib and nilotinib, that block most forms of the mutated enzyme and are given to patients who relapse. Trials published last year show that the drugs work so well as an alternative to Gleevec as initial therapy for CML patients that they may delay resistance for years, Sawyers says.

    Two ways out.

    (A) The lung cancer drug Tarceva (blue spheres) blocks the EGFR receptor from transmitting a signal. (B) The T790M mutation prevents the drug from binding. (C) Tumor cells can also overexpress the MET receptor, which takes over when EGFR is blocked.


    However, no cocktail for CML has yet been tested as an initial therapy in a clinical trial. One reason, Sawyers says, is that the cocktail mix is not quite complete. There is one important mutant version of the BCR-ABL protein, T315I, that no existing drugs target. (A promising candidate is in clinical trials, though.) Furthermore, patients aren't that interested in enrolling in a combination trial because Gleevec alone works very well for most patients, says Gleevec co-developer Brian Druker of Oregon Health and Science University (OHSU) in Portland. And as a researcher, Druker says he finds it hard to ask people to take an experimental drug as well as Gleevec when only a small fraction will likely do any better than they would on Gleevec alone. “Would I treat 90 people for the benefit of 10?” Druker asks. “People are so comfortable with one drug,” Sawyers says.

    Gleevec has been used with good effect to treat another cancer, gastrointestinal stromal tumor (GIST), a rare disease usually caused by mutations in genes called PDFGRA or KIT, says Michael Heinrich of OHSU. But resistance mutations can appear in the KIT protein. Although a drug called sunitinib targets some of them, there's no current drug that can “patch up all the holes,” Heinrich says. And because GIST patients live a relatively long time on Gleevec—5 years versus 15 months on chemotherapy—it's hard to interest companies in testing a cocktail for GIST, he says.

    Resistance is a more urgent problem for lung cancer patients treated with Iressa and Tarceva (gefitinib and erlotinib), the first big success for targeted therapy after Gleevec. These nearly identical drugs block a cell receptor called EGFR that transmits growth signals. The drugs didn't help most patients in trials for non-small cell lung cancer, but researchers realized that they work extremely well on the roughly 10% of patients who have an EGFR mutation in their tumors (they tend to be women, never-smokers, or Asian). Some of these patients' tumors almost vanish when they receive an EGFR inhibitor. However, the average patient develops resistance after about a year.

    As with Gleevec for leukemia and GIST, the trouble is often that tumor cells appear in which the EGFR receptor has a specific new mutation (T790M) that prevents the drugs from binding well. Companies are still moving toward clinical trials of drugs that block EGFR proteins with this mutation, which about half of all patients develop, says Jeffrey Engelman of Massachusetts General Hospital (MGH) in Boston. Lung cancer cells have another way of evading the drug, moreover: They can make more of a different cell receptor, called MET, that can take over for EGFR and maintain the growth signaling pathway. These escape routes and a couple of others are problematic but “a manageable list,” says Jeffrey Settleman, who left MGH last year for Genentech in South San Francisco, California.

    Hoping to close off two escape routes at once, a few companies are running trials combining an EGFR inhibitor and a MET inhibitor. Early results are mixed, Engelman says. One problem is that the cocktails didn't target the T790M mutation, says William Pao of Vanderbilt-Ingram Cancer Center in Nashville. Pao is optimistic about another early clinical trial, however, that is treating patients who became resistant to Tarceva or Iressa with a new, more potent EGFR inhibitor and an approved EGFR-blocking antibody called cetuximab; the combination shrank T790M-carrying tumors in mice. Initial results are expected this summer.


    Gleevec co-developer Charles Sawyers, lung cancer researcher Jeffrey Engelman, and melanoma trial co-leader Keith Flaherty are working on ways to overcome acquired resistance to targeted drugs.


    New escape routes

    How melanoma tumors become resistant to the initially powerful PLX4032 drug is more complex. Plexxikon began developing the drug after Stratton's team reported 9 years ago that tumors in half of advanced melanoma patients have the same mutation in a protein called BRAF. This protein is part of a key growth signaling pathway. Because PLX4032 blocks mutated BRAF and inhibits this pathway only in tumor cells, it can be given at high doses (Science, 18 December 2009, p. 1619). But nobody was surprised, says trial co-leader Keith Flaherty of MGH, when patients on PLX4032 whose tumors melted away eventually relapsed.

    But researchers were surprised to find that biopsied tumors from patients who developed resistance didn't have mutations in the BRAF protein. Instead, several teams reported recently that tumor cells appear to use three different escape routes. This was disappointing, but some also saw good news: Two of these forms of resistance function in the same way—restoring the growth pathway by activating a downstream protein called MEK. This suggests, says David Solit of MSKCC, that combining a BRAF inhibitor and a drug that blocks MEK could block both escape routes.

    These studies “still don't account for the lion's share” of resistance cases, Flaherty says; there is more work to be done. But they have inspired GlaxoSmith-Kline, which makes a BRAF inhibitor similar to PLX4032, to launch a trial combining its drug with a MEK inhibitor. This “will provide proof of concept” of the cocktail idea, Sawyers says, within a couple of years. Another cocktail combining PLX4032 with an immunotherapy drug developed at MSKCC is also under study (Science, 22 October 2010, p. 440).

    Cocktails with caveats

    Testing combinations of drugs is not new in cancer research. But these cocktails would be different because they would be “rationally designed” to block tumor escape routes, researchers say. Although researchers are eager to begin, they will need to overcome some barriers.

    One is commercial competition. Many drugs that target the newly found resistance pathways are still in development. Companies are loath to test two unapproved drugs simultaneously, especially if one comes from a business rival. They worry that side effects from one product will “bloody” a drug that is safe on its own, Flaherty says. “People in my line of work are all about trying to make this happen because the biology is so obvious,” he says, but drug development is another matter.

    Flaherty and others are encouraged, however, by recent examples of companies teaming up: In 2009, Merck and Astra-Zeneca agreed in a groundbreaking decision to test a Merck MEK inhibitor and a drug blocking another key pathway, PI3K/Akt. Since then, a couple more companies have signed such agreements. The motivation is not just to overcome resistance but also to explore an exciting possibility: It has become “increasingly clear” from cell studies that pairing two drugs aimed at different pathways can result in synergistic effects, says D. Gary Gilliland, senior vice president and franchise head for oncology at Merck in North Wales, Pennsylvania. He also praises new draft U.S. Food and Drug Administration guidelines that allow for flexibility for testing combinations.

    Researchers testing combinations must also face the fact that tumors are constantly evolving, Engelman notes. His group published a study on non-small cell lung cancer this week in Science Translational Medicine (STM) that illustrates this complexity. His team analyzed 37 biopsy samples from patients with the EGFR mutation who were given Iressa or Tarceva and later became resistant. Although some resistance mutations were known, others were new, and for 30% of the samples, his team could not identify the mechanism. Some tumors even morphed into a different type of lung cancer that requires an entirely different treatment. In addition, biopsies from three patients collected during the course of treatment showed that tumors changed: Some that developed resistance mutations later lost them. “It's very, very complex. It's not fitting into the simple boxes that we've made until now,” Engelman says.

    Cocktail therapy will face another issue that has not been well explored so far: the risk that combining two drugs—particularly ones that target different pathways used by normal cells—can lead to unacceptable side effects. Engelman thinks that for this reason, patients will be able to tolerate a cocktail for only a short time. He envisions putting them on a single drug, then intermittently giving them a “pulse” of a cocktail for several days. As his STM study suggests, clinicians would need to constantly biopsy patients and tailor the cocktail to the mutations in their tumor. This could stretch responses out to years, Engelman says.

    “A lot of this is going to have to be done by trial and error,” Pao agrees. Sawyers and others point out, however, that such combination therapies developed in the 1960s and '70s eventually vanquished most cases of childhood leukemia, Hodgkin lymphoma, and testicular cancer.

    Major cancer centers are already routinely genotyping biopsies from patients throughout their treatment using procedures that are less invasive than surgery, such as collecting a few tumor cells with a thick needle. Engelman says this is essential: “We can't be afraid to rebiopsy to see what's going on.”

    Cancer researchers acknowledge that coming up with cocktails to corner cancer will be much more difficult than it was with HIV. Cancer geneticist Bert Vogelstein of Johns Hopkins University in Baltimore, Maryland, points out that cancer is different from AIDS: Among other things, tumors vary more from patient to patient than HIV does; the genetic heterogeneity of cancer cells within a single patient is “orders of magnitude greater” than HIV genotypes in patients, so tumors have a “much larger reservoir of resistance mechanisms” that go beyond those already uncovered. “Unfortunately, we've got billions of cancer cells ready to become resistant, and it takes 15 years to develop each new drug,” Vogelstein says. Moreover, to wipe out a tumor completely, he and others say, a cocktail might also have to include a drug that targets stem cell–like cells in a tumor that continuously give rise to tumor cells.

    Turning cancer into a manageable disease, however, “would be wonderful,” Vogelstein says, if it can be done. Advocates of targeted therapy think they will get there. “Melanoma was completely untreatable 18 months ago,” says Neal Rosen of MSKCC. “Give us a chance.”

  10. News

    Can Treatment Costs Be Tamed?

    1. David Malakoff*

    More patients and the rising costs of new cancer treatments spark debate over how much is too much—and who should decide.

    The afternoon Jeff Gustafson lost his life to stomach cancer, a rainbow appeared above his Arlington, Virginia, hospice. Even if the shimmering arc had led to a pot of gold, however, it's not clear whether the treasure would have covered the cost of treating the 48-year-old builder, who was known for his wit and compassion. The bills for just 4 months of dogged, full-tilt treatment totaled more than $350,000—including one drug that cost more than $12,000 per dose.

    Four scenarios.

    Experts predict total U.S. spending on cancer care could rise by as much as 66% by 2020, depending on shifts in disease incidence and survival, and treatment costs.


    Gustafson's story isn't that unusual to experts who track the costs of treating cancer in the United States—and are increasingly worried about where they are headed. Over the past 3 decades, total U.S. spending on cancer care has more than quadrupled, reaching $125 billion last year, or 5% of the nation's medical bill, according to a recent estimate. By 2020, it could grow by as much as 66%, to $207 billion. Multiple forces are driving the spiral: a growing and aging population, more people living longer with cancer, and new “personalized,” or “targeted,” therapies that can come with sticker-shock prices of $50,000 or more per patient.

    New and more costly, however, haven't necessarily meant better. Although targeted treatments, which attack a molecular weak spot in the tumor's support system, have helped improve survival rates for many cancers, some extend life for just a few weeks or months (see p. 1542). And the prices can be sobering: more than $1.2 million to extend a lung cancer patient's life for 1 year in one scenario involving a costly but common drug. That example is unusual, but such numbers have sparked a growing—and sometimes feisty—debate over how best to calculate the benefits of new cancer treatments, whether their use will lower or raise per-patient expenses, and who should decide whether using them is worth the cost. “The question is, ‘Are we spending too much for too little?’” says oncologist Antonio Tito Fojo of the U.S. National Cancer Institute (NCI) in Bethesda, Maryland.

    Demographic drivers

    Tallying the current and future costs of treating cancer isn't easy. “Cancer” now includes more than 100 different diseases that affect more than 13 million people in the United States each year, and there is no single source of uniform statistics. To come up with their recent forecasts, a team led by NCI's Angela Mariotto turned to a massive trove of data kept by the federal government's Medicare health insurance program, which now covers some 40 million Americans over age 65. Sieving the data, they were able to extract a rough snapshot of the costs associated with treating nearly 1.8 million Medicare patients diagnosed with cancer between 1975 and 2005. Overall, they examined incidence, survival, and cost trends for 13 cancers in men and 16 cancers in women, and estimated costs for patients younger than 65.

    The result, published last January in the Journal of the National Cancer Institute (JNCI), reveals some of the complex demographic and technological forces that are pushing costs down, even as the overall total rises. Earlier studies, for instance, have suggested that average per-patient costs for many cancers have declined slightly in recent years, largely because outpatient treatment has often replaced more expensive in-hospital stays. The JNCI study, however, shows that those savings are being swamped, in part, by the growing number of older people, who are more likely to get cancer. Medicare predicts its rolls will nearly double, to 70 million people, by 2020. And the JNCI study forecasts that some 16% of these older Americans—about 11.4 million people—will have cancer, up from 8 million today. Another 6.6 million younger people will also be living with cancer. Even if all other trends—such as the cost of individual treatment—don't change, they estimate that those demographic changes alone will push national cancer care costs up 27% by 2020.

    Ironically, another factor driving up costs is that people are now surviving cancers that might have killed them quickly decades ago. Some of the largest projected cost increases, for instance, are linked to providing “continuing care” for people living with breast and prostate cancer, a group expected to grow by as much as 41%, to nearly 8 million in 2020. It will cost some $18 billion to provide continuing care for these patients, the team estimates, some 30% to 40% more than current costs.

    The study notes, however, that spending tends to follow a u-shaped curve over the period of cancer treatment, with the highest costs coming just after diagnosis and in the last year of life, but with relatively less spent in between. For instance, men under 65 with stomach cancer—such as Gustafson—spent an average of $94,000 per year on “initial” care in 2010 and $161,000 in the last year of life, but just $4200 per year for continuing care. In part, that's because stomach cancer can kill quickly, and for those who don't die early, end-stage costs can be very high. But the numbers also reflect the fact that younger patients typically get more aggressive—and more costly—care than older ones, perhaps because society perceives a greater potential benefit to extending the life of a younger person. Patients under 65 now make up about 40% of all cancer cases, the JNCI team estimated, and typically receive care that costs about 35% more than that of older patients.

    One life.

    After standard treatments failed to stop Jeff Gustafson's stomach cancer, his insurer approved the experimental use of one expensive drug, but it failed to extend his life.


    One of the major drivers of increased costs is that more people are living longer with cancer.


    Worth the cost?

    The impending demographically driven increases are “inevitable,” the authors note. Harder to pin down, however, is the future impact of technological changes that, overall, have been rapidly pushing up costs. In particular, chemotherapy prices have been escalating faster than other medical costs, largely because of the introduction of targeted drugs that come with price tags higher than those of many older compounds. Although studies suggest that cancer drugs typically account for less than 15% of a patient's total treatment costs, experts say that is changing. For instance, an increasingly used drug called bevacizumab—sold under the name Avastin—can cost from $30,000 to $62,000 per patient per course of treatment, depending on the targeted cancer, according to estimates compiled by NCI's Fojo and colleagues. In contrast, some drugs used at the beginning of the war on cancer in 1971 cost just a few hundred dollars per patient.

    Part of the problem, Fojo and his colleagues have argued in a pair of provocative papers, is that the new, costlier drugs often fail to improve survival appreciably. They don't work for all patients, and when they do work, the effect is often limited. To highlight such problems, in both a 2009 JNCI paper and a 2010 paper published in Clinical Cancer Research, Fojo's team focused on a “breakthrough” treatment that was touted at a major annual cancer research meeting in 2008. A study had shown that non-small cell lung cancer patients treated with cetuximab (sold as Erbitux) lived, on average, 1.2 months longer than those receiving standard treatments. One scenario, which called for using cetuximab for 18 weeks at a cost of $40,000, translated to a cost of $496,000 for one extra “quality-adjusted life year” (QALY). In contrast, they noted, kidney dialysis, a lifesaving technology Medicare made universally available in 1972, costs $129,090 per QALY.

    Another scenario, using bevacizumab at a cost of $30,000, translated to a QALY cost of $1.2 million. And such drugs are “not alone among treatments offering marginal benefit at very high cost,” they wrote: More than 90% of the cancer drugs approved by the U.S. Food and Drug Administration (FDA) in the previous 4 years had cost more than $20,000 for 12-week treatments. “We must stop deluding ourselves into thinking that prescribing … expensive chemotherapies and tests are an aberration, a temporary deviation from an otherwise reasonable cost trajectory,” they concluded.

    Along with their critique, Fojo and his colleagues offer solutions. They argue that Medicare and other U.S. insurers, for instance, shouldn't pay for drugs that would cost more than $129,090 per QALY. That would still make the United States somewhat more generous than other nations, including the United Kingdom, Australia, and Canada, whose government-run health services routinely reject the use of new cancer drugs because they can't meet certain QALY costs. Fojo's group also says that drug companies shouldn't fund trials designed to detect survival improvements of fewer than 2 months unless the drug will cost less than $20,000 and should even consider reducing charges if a drug doesn't work in a particular patient. Doctors should use costly drugs only in the subset of patients proven to gain benefit, they say, and avoid using new drugs “off-label,” i.e., to treat cancers other than those for which the drug was approved by FDA. Such steps, Fojo says, “would focus our attention on using drugs that deliver proven benefits” until researchers can find better ways to efficiently develop and use targeted therapies.

    Varying costs.

    The average annual cost of treatment can vary, depending on the patient's age and cancer type. In general, costs are higher just after initial diagnosis and in the last year of life.


    Some disagree sharply. Such ideas are based on “flawed premises,” Joshua Cohen and William Looney of Tufts University School of Medicine in Boston argue in a November 2010 response published in Nature Biotechnology. Using QALY calculations to rule out therapy, for instance, is a biased, “blunt instrument” that ends up denying drugs to patients who need them, the authors say. They view this as a “radically egalitarian” approach that forces insurers to choose between drugs they “can afford for all, as opposed to those they will fund for no one.” They also argue that preventing doctors from using drugs off-label would hobble the proven practice of freeing doctors to find promising new uses for existing drugs. And it would stand “in stark contrast with clinical practice.” Studies, for instance, suggest that up to 75% of anticancer drugs are already used off-label. And price controls would, they argue, ultimately cause investors to reduce funding for research into new drugs because they couldn't be sure of recouping their costs. There is one thing the two sides do agree on: Better, more organized studies could help steer the right drugs to the right patients. Better genetic tests, for instance, could identify patients unlikely to benefit from a particular drug. They could also help researchers design smaller, less costly trials that better identify smaller groups of patients likely to respond; current trials often “wash out” these drugs because the benefits seem statistically negligible.

    Another idea gaining ground is “coverage with evidence development” (CED), in which insurers link payments for certain drugs to efforts to collect data on comparative effectiveness, with the aim of discontinuing coverage for drugs that don't work. Cohen and Looney even suggest that CED could be combined with “risk-sharing arrangements,” in which insurers and manufacturers agree to link a drug's price to its performance. U.S. Medicare managers have already launched a number of CED experiments, and the new health care reform law authorizes extensive new efforts to compare the effectiveness of different medical treatments, including cancer drugs. In 2014, it also requires private insurers to cover the routine costs of enrolling cancer patients in clinical trials, removing a major barrier to their participation.

    Agonizing decisions

    Although such studies didn't help Gustafson, his treatment did reflect both the challenge and opportunity inherent in efforts to tamp down the costs of cancer care. His oncologists, for instance, talked with him and his wife, Molly Sim, about the costs they were likely to encounter. That's something that a recent statement from the American Society of Clinical Oncologists says needs to happen more often, given how many families exhaust their savings fighting cancer. “We were fortunate, we had really good insurance,” says Sim, who ended up paying less than $6000 out of pocket.

    Gustafson's doctors also gave him genetic tests to determine whether he should be given one expensive but promising drug; unfortunately, the tests indicated that he wouldn't benefit. But when he failed to respond to standard treatments, they proposed a last-ditch strategy: Sim successfully appealed to her insurer to pay for off-label use of Avastin at a cost of nearly $40,000. Gustafson died in November 2009, before he could complete the treatment.

    It's a story that Fojo—who urges caution in using expensive drugs—says he knows all too well. “In the abstract, you say using these marginal drugs is crazy,” he said recently, shortly after coming off his rounds treating cancer patients. “But when you have the patient in front of you, and nothing else is working, well, I might try the crazy thing, too. We used to do it with cheap drugs, but now we are doing it with really expensive drugs. The problem is they really don't work any better.”

    • * David Malakoff is a writer in Alexandria, Virginia.

  11. News

    A Push to Fight Cancer in the Developing World

    1. Martin Enserink

    Cancer and other chronic diseases have received little attention from global health advocates. That's beginning to change.


    Women wait to be screened for cervical cancer at a Partners In Health clinic in Rwanda.


    BOSTON—In one of his PowerPoint presentations, Lawrence Shulman has a series of photographs that are hard to forget. One shows Tushime, an 11-year-old girl in Rwanda suffering from rhabdomyosarcoma, a rare cancer of the muscles. A tumor resembling a cauliflower is growing out of her right cheek.

    The good news comes in Shulman's next three slides. Over a 10-week treatment course with drugs donated by a U.S. program, the mass started to shrink until eventually it could be removed surgically. The last picture shows Tushime, standing with her happy family and—despite a somewhat lopsided face—looking healthy.

    Shulman is chief medical officer at the Dana-Farber Cancer Institute here, which is affiliated with Harvard Medical School (HMS), and to him the pictures carry a powerful message: Given that treatments are readily available, how can you not treat a child suffering from a very curable cancer?

    It's a message that is beginning to be heard. Global health has gained in prominence on political agendas in recent years, but attention has been overwhelmingly focused on infectious diseases. Now, some argue, it's time to start closing an equally unconscionable gap between rich and poor nations in cancer prevention, diagnosis, and treatment.

    Life and death.

    For many cancers, the case fatality rate (of which the ratio of mortality to incidence is a proxy) is much higher in poor countries than in rich countries.


    The numbers speak volumes. A child suffering from leukemia in Western Europe has an 85% chance of survival; in the 25 poorest countries in the world, it's just over 10%. For a man with testicular cancer, the numbers are about 95% and just over 40%. Estimates suggest that less than 5% of the world's cancer resources are spent in the developing world. In many countries, even painkillers are hard or impossible to come by—“a violation of human rights,” Shulman says.

    In a bid to change that, oncologists at topflight centers in the United States and Europe are now taking time out to help improve cancer care in low- and middle-income countries. In an article last month, World Health Organization Director-General Margaret Chan said that cancer needs to be “acknowledged as a vital part of the global health agenda.” Cancer will also feature on the agenda at the United Nations High-level Meeting on Non-Communicable Diseases in September in New York City.

    Shulman and Harvard School of Public Health Dean Julio Frenk co-chair the new Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries (GTF.CCC), which aims to move cancer up on the global priorities list. The group—which combines expertise in cancer, global health, economics, finance, and policy—published a 10-page call to action last year in The Lancet and is now working on a collection of papers for the same journal that details what needs to be done.

    The obstacles are major, and some people question whether battling cancer is the wisest use of scarce global-health money. Similar doubts were once raised about infectious diseases, says HMS physician and GTF.CCC member Paul Farmer: 15 years ago people questioned the logistical and financial feasibility of treating HIV and multidrug-resistant tuberculosis (TB) in poor countries. Yet as Farmer points out, both are now being addressed on a large scale. Great strides have been made recently in a range of other tropical diseases, too. So why can't it be done for cancer?

    A more difficult job

    Cancer takes a markedly different toll depending on the country. Lung cancer, a major killer in the West, is rarer in Africa, where fewer people smoke and life expectancy is shorter. Several virus-related cancers, on the other hand, are much more prevalent in poor countries. Cervical cancer, caused by the human papillomavirus (HPV), has become quite rare in rich countries thanks to screening with Pap smears. But it is common in the developing world, where 93% of the estimated 273,000 annual deaths from this disease occur.

    Taken together, however, the burden of cancer is still lower in the poorer countries, which is one reason why it has failed to get global health policymakers' full attention. Unfortunately, the developing world is catching up. In many middle-income countries, life expectancy is increasing, and obesity and smoking are on the rise, all of which lead to more cases of cancer. Women are having their children later in life and breastfeeding for a shorter time, which increases their risk of breast cancer.

    And treating cancer is “much more difficult” than treating malaria or TB, Shulman says. Diagnosis is complex, requiring competently staffed and well-equipped pathology labs. Physicians in many countries are in short supply; oncologists are extremely scarce. There aren't enough surgeons or operating rooms; 30 countries—half of them in Africa—don't have a single radiation therapy machine.


    Still, in The Lancet paper, Shulman and colleagues at the task force identified a list of cancers for which a lot can be done even in places with poor infrastructure (see table). These measures include battling tobacco use—which increases the risk of various cancers as well as cardiovascular disease—vaccinating against HPV and hepatitis B, improving early detection, treating eminently curable tumors such as Tushime's sarcoma and childhood leukemia, and improving life-extending treatment for cancers like Kaposi sarcoma, an HIV-related cancer of the skin.

    The price of drugs is not insurmountable, says HMS health economist and breast cancer advocate Felicia Knaul, who runs the task force's secretariat (see sidebar, p. 1549). Of a list of 27 essential cancer drugs compiled by the task force, 24 are off-patent, and prices could be brought down further through negotiations with the pharmaceutical industry, Knaul says. A recent study showed that drugs needed to treat a case of Burkitt's lymphoma—a cancer that primarily affects African children and is associated with the Epstein-Barr virus—cost less than $50, a bargain in terms of life years saved per dollar.

    The biggest challenges in combating cancer—as for other diseases—are to build up expertise and infrastructure and extend care to the poorest people. Some private groups are intervening directly. For the past 18 years, pediatric oncologists at St. Jude Children's Research Hospital in Memphis, Tennessee, which sets aside about 1% of its annual budget for global health, have pioneered so-called twinning programs that provide assistance to hospitals in 20 countries to improve cancer care for children. Several other pediatric hospitals have followed suit. The impact is real: In El Salvador, where the twinning started, the 5-year survival rate for children with acute lymphoblastic leukemia went from 10% to 60%, and is still climbing.

    Partners In Health (PIH), best known for its pioneering work fighting AIDS and TB in Haiti, has long treated cancer patients as well, says co-founder and director Farmer: “They often go from one clinic to the next, seeking care.” But PIH is also working with governments to strengthen their health systems—and expanding cancer care is a key goal. The Rwandan government is very keen on it, Farmer says.

    Currently, the PIH network still relies on Boston's medical infrastructure for backup. Brigham and Women's Hospital's pathology department examines specimens to identify tumors, for instance, an indispensable part of diagnosis. (Shulman himself has returned from Malawi with a suitcase full of specimens. “Fortunately, nobody at customs checked,” he says.) But the plan is to develop pathology expertise and infrastructure locally. Brigham and Women's has donated equipment for Haiti and Rwanda, and its chief technologist is training staff members. “We're totally committed to doing this,” Shulman says.

    Going horizontal

    Expanding cancer care will cost money. Take the new HPV vaccines. So far they have been introduced in wealthy countries, but cancer experts say they would prevent far more cases of cervical cancer in poor countries, where Pap smears are seldom done. Their cost, more than $300 per vaccinated teenage girl in the West, has been a barrier to their introduction in the developing world.

    But with the economy in a global dip, it's hard to see where the money will come from. Cancer is competing for attention with the infectious diseases, which have seen a major increase in program support over the past decade but are still underfunded. Meanwhile, other diseases such as diabetes and mental illness are vying for attention as well. Mental health advocates are already disappointed that they won't have a seat at the September U.N. meeting on noncommunicable diseases, where the task force is trying to make cancer well-represented. But it's not one or the other, Farmer argues: “We have to get away from the whole notion of choosing between diseases.”

    Gene Bukhman, head of Harvard's Program in Global Non-communicable Disease and Social Change, advocates building up health systems broadly so that they can deal with not just cancer but also diabetes, heart disease, and a variety of other chronic ailments that each make up a small percentage of the disease burden. But this approach—sometimes dubbed “horizontal” as opposed to “vertical” disease-specific programs—isn't particularly popular. The Bill and Melinda Gates Foundation is spending its billions mostly vertically, focusing on specific diseases. Likewise, many advocacy groups want to extend their work—say, on breast or prostate cancer—to the world's poor, but they're less interested in helping fledgling health systems.

    Farmer, too, wants to channel the enthusiasm generated by single diseases into help for a better health system: “The breast cancer advocate needs to see that without a proper health system we're never going to get early detection or good treatment.” Emotional appeals can help, Bukhman says, and that is where Tushime's pictures come in. “I don't think we've said this enough. When you see someone dying needlessly of cancer, it is an obscene inequality”—no different from seeing someone die from TB or HIV.

  12. Making Her Life an Open Book to Promote Expanded Care

    1. Martin Enserink

    Felicia Knaul, a health economist at Harvard Medical School in Boston, is one half of a Mexican-Canadian power couple that aims to end the neglect of cancer as a disease of the poor—and will succeed, if anyone can, say colleagues.

    SUDBURY, MASSACHUSETTS—“You can ask me absolutely anything,” says Felicia Knaul—and she's serious. Knaul, a health economist at Harvard Medical School in Boston, doesn't mind telling in detail how breast cancer changed her marriage, her family, and her career. In her mission to shatter taboos around the disease and improve the lives of patients in developing countries, her professional and private lives have become one.

    Knaul is one half of a Mexican-Canadian power couple that aims to end the neglect of cancer as a disease of the poor—and will succeed, if anyone can, say colleagues. The other half is Julio Frenk, the former health minister of Mexico and a much admired reformer, who is now dean of the Harvard School of Public Health (HSPH).

    Knaul, born and raised in Toronto, says she has always had a keen interest in poverty and health. She lived in Bogotà for 2 years in the early '90s, working on a project for street children and helping the Colombian government reform its health system. After meeting Frenk, who comes from a family of doctors, she moved to Mexico; she now considers it home. She joined the Mexican Health Foundation in Mexico City, where she still leads a research group. When Frenk became minister in Vicente Fox's Cabinet in 2000, she worked pro bono to help him push through a major reform that extended basic health coverage to the country's poorest and took effect in 2003.

    That didn't prepare her for her own terrifying brush with illness. In October 2007, a technician in Cuernavaca discovered a lump in Knaul's left breast. It was malignant. After weeks of anguish, she underwent a mastectomy and started on chemotherapy. Knaul says she was lucky. She had access to the best doctors in Mexico, and—because her husband took a job at the Bill and Melinda Gates Foundation after he left the government in 2006—she even had insurance coverage in the United States. Knaul used it to seek additional treatment at the Seattle Cancer Care Alliance. She now rates her 5-year survival chance at between 85% and 90%.

    That's much more than most Mexican women with breast cancer can expect. Coverage for breast cancer treatment was added to Frenk's insurance plan for the poorest in 2007; in reality, some women still don't get treatment, for instance, if they live far from a hospital. Early diagnosis is rare. Many women forgo mammograms even where they are available, Knaul says, and a culture of machismo often leads men to abandon their wives or girlfriends if they lose a breast. Knaul recalls a woman recently diagnosed with breast cancer at one public event saying: “A woman without breasts is ugly. I don't want to be ugly.”

    Knaul decided to start a program—it is now a not-for-profit group—called Càncer de Mama: Tómatelo a Pecho (Breast Cancer: Take It to Heart) that aims to raise awareness of and improve access to prevention, early detection, and treatment. Sharing her own story might help other women, she thought, so she wrote a frank book about her experience. The resulting TV interviews with her and Frenk made waves.

    In sickness and in health.

    Felicia Knaul—with husband, Julio Frenk—wrote about her disease.


    She and Frenk took the campaign to the next level after he was appointed dean of HSPH in 2008 and she became director of the Harvard Global Equity Initiative, a research program founded by Nobel laureate Amartya Sen. She had the idea to start a global task force to expand cancer care in poor countries. Frenk now co-chairs it with Lawrence Shulman, chief medical officer of the Dana-Farber Cancer Institute in Boston. Many of their well-placed friends signed on: former UNAIDS chief Peter Piot, director of the London School of Hygiene and Tropical Medicine; Columbia University economist and poverty warrior Jeffrey Sachs; and CNN chief medical correspondent Sanjay Gupta. “They have really brought this to the doorstep of many people at high levels,” says Carlos Rodriguez, a pediatric oncologist at Dana-Farber.

    The task force is now collecting evidence on how cancer care in developing countries can be improved, she says. To do so, she has helped recruit a series of papers for publication in The Lancet (see main text, p. 1548). Her own story, she realizes, is atypical for a woman in Mexico. Still, it reinforces her message, she says: “When you say at a meeting, ‘I have cancer,’ people listen in a way that happens with very few other diseases.”

    Her frankness is part of her strategy. Mexican couples thanking her for her book will sometimes mention “chapter 18,” she says, in which she discusses how the chemotherapy-induced menopause shut down her sex life. At her art-filled house 30 kilometers west of Boston, Knaul also discussed, matter-of-factly, why, in her case, reconstructive surgery was not successful. (“The implant dropped a couple of inches,” she says, because of a lack of tissue to hold it up.)

    Her own marriage didn't suffer, she adds—on the contrary, the disease brought the two closer, and for the book, Frenk contributed fragments of four love letters written when she was ill. As Knaul wrote, “I had my boyfriend back.”

  13. News

    Brothers in Arms Against Cancer

    1. Mitch Leslie

    Cancer researchers are trying to harness siblings of p53, the famous tumor-blocking protein.

    You've heard of Charles Darwin, but do you know of his elder brother, Erasmus? He was a physician, inventor, and philosopher of some repute. Familiar with Cassandra Austen, the amateur painter and Jane's sister? Probably not. Famous brothers and sisters often overshadow their siblings.

    The same thing happens in molecular families. Take p53, the tumor-suppressor protein that was named Science's Molecule of the Year in 1993 and has been dubbed “guardian of the genome.” Few nonspecialists know that the celebrated p53 is closely related to two other proteins, p63 and p73. Yet these unheralded siblings are grabbing the attention of cancer biologists. New research suggests that p63 and p73 are fierce cancer killers that deserve equal billing with p53. Instead of a single genome protector, “there's a family of guardians,” says cancer biologist Elsa Flores of M. D. Anderson Cancer Center in Houston, Texas.

    Because efforts to exploit p53 in cancer therapies haven't yet paid off, some researchers are now looking to p73 and p63 as alternative tumor treatments. Researchers have shrunk or prevented tumors in animals by targeting p73, and the first clinical trials—attempting to use p73 to combat a hard-to-treat type of breast cancer—have already started. “It would be very attractive to find a way to activate these proteins” in people with tumors, says cancer biologist Alexander Zaika of Vanderbilt University Medical Center (VUMC) in Nashville. Strategies that capitalize on the tumor-fighting capability of the p53 family “belong in the armamentarium against cancer,” adds molecular oncologist Wafik El-Deiry of the Penn State Hershey Cancer Institute in Pennsylvania.

    p53, the hard target

    When a cell suffers DNA damage that can lead to uncontrolled growth, p53 comes to the rescue. The p53 protein can trigger DNA repair, stop the dodgy cell from dividing, or, when the damage is grievous, prompt it to commit suicide. Because p53 is so potent, cells normally keep levels of the protein low. Spurring cancer cells to produce more protein, the argument goes, could prompt tumors to self-destruct. “p53 is a great therapeutic target,” says cancer biologist Kevin Ryan of the Beatson Institute for Cancer Research in Glasgow, U.K. “Its involvement in tumor suppression is without question.”


    Scientists are pursuing a number of strategies to enlist p53 in the cancer fight (Science, 2 March 2007, p. 1211). They have completed or are running several clinical trials for gene therapy approaches, which involve introducing extra copies of the p53 gene into cancer cells. Researchers at six institutions in the United States and the United Kingdom have also begun safety trials on a compound, developed by the pharmaceutical company Roche, that hikes p53 levels in cells by impeding the protein's natural recycling.

    So far, however, no p53-based treatments have been approved for clinical use in the United States. The practical difficulties are formidable. For one thing, thanks to a variety of mutations in p53's gene, more than half of all tumors don't carry a working version of the protein. Some harbor misshapen mutants that are inert or that turn traitor and subvert antitumor defenses. Even when cancer cells have a functional form of p53, they often neutralize it, for example, by overproducing enzymes that prompt the protein's destruction.


    Attacking many kinds of tumors through p53 will require pharmacological feats—restoring the gene or reshaping the malformed protein—that are tougher than the standard tactic of blocking a molecule's unwanted function. “Many of us appreciated it [p53] would be difficult to target,” says cancer biologist Leif Ellisen of Harvard Medical School (HMS) in Boston. “Throwing a wrench into the system is much easier than fixing the system.” Yet many researchers remain confident that they will eventually overcome these obstacles. “My personal bet is still on p53,” says cancer biologist Anna Mandinova, also of HMS. But in the meantime, researchers are looking at other options, namely, p63 and p73.

    Band of molecular brothers

    Scientists discovered the p53 protein in 1979 but didn't recognize its importance for cancer until 10 years later. In 1997, biologists identified p73 as a molecular relative, after discovering a DNA sequence closely resembling the gene for p53. “That came as a bit of a surprise,” says cancer biologist Gerry Melino of the University of Rome “Tor Vergata” in Italy. “Nobody expected a protein so close to p53.” Yet researchers reported another relative, p63, the next year.

    Although p53 was the first family member discovered, p63 and p73 are the older siblings, evolutionarily speaking. Comparisons of their genes suggest that p53 evolved from the ancestral version of p63 and p73 more than 450 million years ago. These elders have a range of responsibilities. Unlike p53, p63 and p73 are essential during embryonic development. Shaping limbs and giving the skin its layered structure are among p63's tasks in an embryo. Formation of brain regions such as the hippocampus and cortex depends on p73, as does maturation of the immune system. Both proteins are also necessary for female fertility.

    For cancer researchers, p63 and p73 have a big advantage over their sibling: Their genes are almost never mutated in or lost from cancer cells. So p63 and p73 could in theory take over for p53 in almost all cancers, and researchers wouldn't have to fret about restoring a lost gene or reshaping a distorted protein.

    That strategy will work, of course, only if p73 and p63 are tumor suppressors like their brother. But that turned out to be surprisingly tough to confirm. A standard experiment for gauging a molecule's relevance to cancer—deleting its gene from mice—didn't clarify the issue. Whereas mice missing p53 live to adulthood and are beset by tumors, mice lacking p63 or p73 die young from other causes, revealing little about their cancer susceptibility. Complicating the matter, although some studies found that levels of p73 or p63 fell in cancer cells, suggesting that the proteins are antitumor, other work indicated that their levels soared, implying that they foster abnormal growth.

    The solution to that apparent contradiction may lie in the discovery more than 10 years ago that cells don't manufacture just one kind of each protein. They can fashion at least 12 variants, or isoforms, of the p73 protein, and at least eight isoforms of the p63 protein. Scientists divide these varieties into the longer, or TA, isoforms and the shorter, or ΔN, isoforms. In 2008, Melino, molecular geneticist Tak Mak of the University of Toronto in Canada, and colleagues engineered mice that lack all of the TA isoforms of p73 but retain the ΔN versions. The mice were prone to cancer, though they weren't as vulnerable as rodents lacking p53. The TA isoform-deficient mice “really convinced people that these genes are acting as tumor suppressors,” says Flores.

    Researchers now hypothesize that in cancer, TA isoforms are generally good guys, suppressing unchecked cell growth. The ΔN isoforms, for the most part, are bad guys. They can latch on to and disable p53 and the good TA isoforms, thus aiding cancer. For example, cancer biologist Alea Mills of Cold Spring Harbor Laboratory in New York and colleagues reported in February in Cell Stem Cell that a common ΔN isoform of p63 spurs the growth of skin tumors.

    Taking on tumors

    p63 and p73 battle cancer in several ways. Like their famous brother, the proteins cull cells that carry potentially cancer-causing DNA damage, activating their apoptotic, or cell suicide, pathways. Fortuitously, some chemotherapy already takes advantage of this ability, causing DNA damage that spurs p63 or p73 to kill tumor cells.

    On the attack.

    Researchers are testing antitumor compounds that rely on p73.


    Recent studies suggest that p63 also reins in metastasis, the migration of tumor cells to a new location in the body; that's what usually kills cancer patients. In 2009 in Cell, a team led by Stefano Piccolo of the University of Padua School of Medicine in Italy revealed that some mutant forms of p53 found in cancer cells prevent p63 from activating two genes that curtail metastasis. And last fall, in a study in Nature, Flores and colleagues showed that the TA isoforms of p63 curb metastasis through another mechanism: boosting levels of microRNAs, RNA snippets that turn down gene activity. The team discovered that p63's TA isoforms increase production of Dicer, an enzyme that snips and activates inert microRNAs. The isoforms also raise levels of a specific microRNA, miR-130b, that prevents cells from moving on. p63 may be the master regulator of metastasis, says Flores, and activating it might increase levels of several metastasis-halting microRNAs by flipping on Dicer.

    The big question is whether drug designers can capture p63's and p73's cancer-quelling talents. The research directed at this goal isn't as intense or advanced as the work on p53, but scientists can claim some encouraging findings.

    One therapeutic strategy attempts to reduce sibling rivalry in the p53 family. The mutant p53s found in cancer cells often latch onto and neutralize p63 and p73. Three years ago, a research group from the Cleveland Clinic in Ohio screened more than 46,000 compounds and pinpointed one, named RETRA, that in test tubes breaks mutant p53's embrace of p73. To test whether freeing p73 destroys tumors, the researchers then transplanted human cancer cells into mice and administered RETRA. The treatment cut the number of tumors that sprouted in the animals, the scientists revealed in the Proceedings of the National Academy of Sciences.

    To liberate p73 from a different inhibitor that is abundant in cancer cells, one known as iASPP, Ryan and colleagues ironically turned to p53 for inspiration. They developed a snippet of p53, just 37 of its nearly 400 amino acids, that in the test tube separates p73 from iASPP. Dosing cancer-ridden mice with the snippet, known as 37AA, shrank the rodent's tumors, the team reported in The Journal of Clinical Investigation in 2007.

    RETRA's effects were fairly weak, and 37AA was fragile, so neither is likely to become a drug. But the importance of studies like these, says El-Deiry, is that they show it's possible to uncover compounds that rouse p53's siblings to attack cancer cells. Scientists are hunting for other molecules that might spur p73 and p63 into action and that could make effective drugs. El-Deiry's group, for example, is in the middle of a project to screen thousands of small molecules—they've assessed more than 70,000 so far—in hopes of finding ones that switch on genes in the p53 pathway. Some of the candidates, he says, appear to work by activating p73.

    At least one group has started clinical trials. Medical oncologist Ingrid Mayer and cancer biologist Jennifer Pietenpol of VUMC are targeting a form of breast cancer—known as triple-negative because the tumor cells lack three key receptor proteins—that defies standard treatments such as tamoxifen and Herceptin. The tumor cells harbor large quantities of the ΔN isoforms of p63, which the researchers suspect prevent p73 from killing the cells. Along with standard chemotherapy, patients will receive an existing drug, everolimus, that boosts p73 levels by inhibiting a p73 blocker called mTOR. The goal is to overcome p63's interference and enable p73 to kill the tumor cells.

    It's too late for Erasmus Darwin to match his brother's fame. But these clinical trials and the surge of research on p63 and p73 suggest that the proteins are finally stepping out of the shadow of their famous sibling.

Log in to view full text