News this Week

Science  25 Oct 2013:
Vol. 342, Issue 6157, pp. 406

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  1. Around the World

    1 - New York City
    Papers Condemn '50s Cancer Research
    2 - Deir Al Zour, Syria
    Suspected Polio Outbreak in Syria
    3 - Tehran
    Rouhani Promises Academic Freedom
    4 - Palo Alto, California
    Replication Project Scores $1.3 Million
    5 - Brussels
    Manifesto Calls for Borderless European Science
    6 - Madrid
    €70 Million Will Keep Spanish Science Afloat
    7 - Geneva, Switzerland
    WHO Sounds Alarm on Drug-Resistant TB

    New York City

    Papers Condemn '50s Cancer Research

    Health exchange.

    A Bowery resident sees doctors at New York's Francis Delafield Hospital in 1957.


    A medical historian chronicled a shameful chapter in U.S. medical history last week, detailing in two publications how 1200 homeless alcoholics in a Manhattan neighborhood were offered a few days of food in exchange for a biopsy of their prostate. The papers by Robert Aronowitz of the University of Pennsylvania, published in the American Journal of Public Health and the Bulletin of the History of Medicine, describe the "Bowery series," studies named after the neighborhood where the men lived that began in 1951 and ran more than a decade. Researchers from Columbia University recruited the men "and subjected them to many invasive tests and procedures," Aronowitz writes. Many of the men also suffered complications, including rectal lacerations and incontinence. He notes that despite its ethical flaws, the series presaged the "early detection and radical treatment paradigm" adopted for prostate cancer decades later.

    Deir Al Zour, Syria

    Suspected Polio Outbreak in Syria

    After a 14-year hiatus, polio is back in Syria, health officials fear. As of 21 October, 22 cases of acute flaccid paralysis had been reported in Deir Al Zour, one of the contested areas near the Iraq border. Although lab confirmation was still pending, the World Health Organization (WHO) and the government were treating the cases as "hot" because they meet the clinical and epidemiologic criteria for polio, including asymmetrical paralysis and clustering within a geographical area. "This one ticks all the boxes," says Bruce Aylward, who leads the Global Polio Eradication Initiative from WHO. An emergency vaccination campaign is planned for as early as 27 October, to be followed by a coordinated campaign across seven countries in November or December. Wild polio was last seen in Syria in 1999. The country "had a fantastic vaccination program, very strong public health," Aylward says. This apparent relapse reflects "the deterioration in health services in the face of the crisis."


    Rouhani Promises Academic Freedom

    New era?

    Iranian President Hassan Rouhani at the University of Tehran last week.


    After a long, dark night, a new dawn may have arrived for Iranian academia. In a speech last week at the University of Tehran, Iranian President Hassan Rouhani called for greater academic freedom on university campuses and looser regulations on overseas travel.

    His predecessor, former Iranian President Mahmoud Ahmadinejad, saw academia as a hotbed for discontent and sought to expunge liberal elements during his administration's 8 years in power. Last autumn, for instance, Iranian news agencies reported that former science minister Kamran Daneshjoo had ordered universities to purge open-minded faculty to "prevent secular lecturers from trying to disseminate anti-religion beliefs."

    What a difference a year makes. "The security atmosphere [on campuses] must be relaxed," caretaker science minister Jaafar Towfiqi told Asharq Al-Awsat newspaper last month. Rouhani expanded on that theme last week. "I will ask the intelligence ministry to trust academia," Asharq Al-Awsat quoted him as saying. "The security environment will lead to hypocrisy and we do not want that."

    Palo Alto, California

    Replication Project Scores $1.3 Million

    The Reproducibility Initiative, which aims to repeat the results of published research, has received $1.3 million from the Laura and John Arnold Foundation, which it said last week will fund an effort to reproduce 50 landmark cancer studies published between 2010 and 2012. The initiative was launched last year by breast cancer biologist Elizabeth Iorns to address a widely acknowledged problem in biomedical research: Many published studies can't be repeated, and many researchers aren't enthusiastic about replicating existing work. So far, the initiative has relied in part on authors to pay to have their work reproduced, but with the new money infusion, it can target the most influential studies for scrutiny. The online marketplace Science Exchange, which Iorns co-founded in 2011, will farm out the experiments to various companies, and PLOS ONE has pledged to make the results freely available.


    Manifesto Calls for Borderless European Science

    Two members of the European Parliament have proposed legally binding measures to create the European Research Area (ERA), making it easier for scientists to work with colleagues across borders and relocate within the European Union. In a manifesto presented last week, former Italian science minister Luigi Berlinguer and Amalia Sartori, chairwoman of the European Parliament's research committee, said the time has come to "speed up" the advent of the ERA through E.U. directives or even a "constitutional commitment." The ERA idea has been discussed for more than a decade, but progress has been slow. Berlinguer and Sartori argue legal measures are needed to coordinate national research programs, improve cross-border arrangements for pension and social security rights, and make research grants portable from one country to another. Six other Parliament members have endorsed the manifesto, but many universities and research funders favor a nonbinding, voluntary approach. Concrete action is unlikely until after the European Parliament elections in May.


    €70 Million Will Keep Spanish Science Afloat

    Spain's government last week agreed to a €70 million ($96 million) cash injection to save the Spanish National Research Council (CSIC) from imminent bankruptcy. The fresh money ends months of uncertainty about the immediate future of Spain's largest research organization, which has faced financial woes since 2009, largely due to across-the-board funding cuts. The infusion allows CSIC "to face the immediate future with a greater optimism," CSIC President Emilio Lora-Tamayo wrote in a letter to CSIC staff.

    A 2014 draft budget bill calls for increased spending on civilian research, and the government also plans to increase CSIC's annual lump-sum operating funding by about €50 million ($69 million). But Carlos Andradas Heranz, a mathematician at the Complutense University of Madrid and president of the Confederation of Spanish Scientific Societies, predicts that Spanish research will continue to face funding pressures.

    The cash injection came one day after scientists at many public research organizations and universities held "a mourning day for science," asking the government to further boost research spending.

    Geneva, Switzerland

    WHO Sounds Alarm on Drug-Resistant TB

    The World Health Organization (WHO) has added an alarm bell to its assessment of multidrug-resistant tuberculosis (MDR TB), calling it "a public health crisis" in an annual update on the disease, released on 23 October.

    WHO has declared for nearly 2 decades that tuberculosis, which sickened 8.6 million in 2012, is "a global public health emergency." Mortality rates have declined in drug-susceptible cases, which are curable with a 6-month course of three well-tolerated drugs. But in the new assessment, WHO scolds countries for being "far off track" in the diagnosis and treatment of MDR TB, which requires giving patients more toxic drugs for up to 2 years. WHO estimates that 450,000 people developed MDR TB last year, but only 94,000 of the cases were detected, and 82% of these received treatment.

  2. Random Sample

    They Said It

    "Non-sarcastic hugs to those at NASA who will be returning to their jobs as awesome science wizards of the stars."

    —Tweet on 16 October from @SarcasticRover, the Mars Curiosity rover's unofficial alter ego, after news that the government shutdown had ended.


    Join us on Thursday, 31 October, at 3 p.m. EDT for a live chat exploring the science of fear.

    Big Break


    Scientists have recovered the largest fragment to date of the 10,000-metric-ton meteor that exploded over the Russian city of Chelyabinsk in February. While the meteorite hunters were hauling their find out of Lake Chebarkul, however, the alien boulder broke into three pieces. Photographers and onlookers encircled the chunks of damaged space rock as they were clipped onto a steelyard balance, which displayed "570 kg" … and then broke as well. The fragment is an exciting find, says Mark Boslough, a physicist at Sandia National Laboratories in Albuquerque, New Mexico, who predicts that "this will be the lion's share of the total mass recovered." Although it might not change estimates of the parent body's orbit and trajectory, "it will give us more confidence that what we have is correct," he says.

    Baby Dinosaur Had a Baby Voice


    It was the field trip of a lifetime. Not only did high schooler Kevin Terris get to visit a dinosaur dig site at Grand Staircase-Escalante National Monument, but the bone he spotted—after experienced paleontologists walked right past it—revealed the most complete skeleton ever found of Parasaurolophus, a duck-billed, plant-eating dinosaur from the Late Cretaceous. It's also the smallest: The dino, nicknamed "Joe," is a baby.

    Just a tyke.

    Size comparison of humans with baby (green) and adult Parasaurolophus.


    Parasaurolophus adults bore impressive headgear. Scientists believe they blew into their enormous crests like trumpets to vocalize. "One of the standing questions has been, how did it grow this big crest?" says Andrew Farke, a paleontologist at the Raymond M. Alf Museum of Paleontology in Claremont, California, who is the lead author on a study of the new skeleton, published in the journal PeerJ this week.

    Some dinosaur species didn't start growing their ornamentation until puberty, but baby Joe, less than a year old when he died, already had a small, hollow bump on his head. Farke's team calculates that he would have called with a high-pitched baby voice, which may have helped other dinosaurs identify him. "If you're a baby and you hear a big, booming call, you know the adults are nearby. If you're an adult and you hear little squeakers, you know the young are nearby."

    Paleontologist David Evans of the Royal Ontario Museum in Toronto, Canada, who was not involved with the research, agrees with that interpretation and says Joe is "a truly remarkable specimen of a rare and iconic dinosaur."

  3. Newsmakers

    CIRM Director Steps Down



    Alan Trounson, the Australian scientist who has headed California's $3 billion stem cell institute for nearly 6 years, is stepping down to be closer to his family.

    Trounson, 67, a leading in vitro fertilization researcher, left Monash University in Melbourne, Australia, to become president of the California Institute for Regenerative Medicine (CIRM) in late 2007. He oversaw the agency's shift from basic research and new buildings to projects aimed at moving discoveries to the clinic. Overall, CIRM has disbursed $1.9 billion in grants. During his tenure, CIRM also went through various controversies, including the abrupt departure of two of its leaders.

    "I have loved working at CIRM … but ultimately it came down to a choice between CIRM and a life including my family," Trounson stated in a press release. He has four children in Australia.

    Trounson leaves at a challenging time for the agency, which will run out of its funding from state bonds in 2017. He has agreed to stay on while the CIRM board searches for his successor.

  4. Varmus's Second Act

    1. Jocelyn Kaiser

    Years after steering the National Institutes of Health into a 5-year budget doubling, the Nobel Prize–winning virologist is now helping the cancer institute deal with the aftermath.


    With the threat of a government shutdown days away, the mood here in the office of the scientist who leads the nation's efforts to beat cancer is tinged with gloom. National Cancer Institute (NCI) Director Harold Varmus reflects on the current state of biomedical research in the United States, which hasn't seen meaningful budget growth in a decade. "What bothers me most is this sense of hypercompetition," Varmus says. "There's an imbalance between the money available, the work that needs to be done, and the number of people who would need to be supported to make the world feel like a more comfortable place. … The atmosphere is not as healthy as it ought to be."

    No one is in a better position than Varmus to know what ails the U.S. biomedical research community and the agency that sustains it, NCI's parent, the National Institutes of Health (NIH). His research career began here 45 years ago when the English graduate student-turned-physician joined an NIH lab as a research trainee. In November 1993, not long after he shared the 1989 Nobel Prize in physiology or medicine for using retroviruses to discover cancer genes, he returned to lead NIH.

    Political scientist.

    Varmus's testimony in Congress during the 1990s helped win support for doubling NIH's budget over 5 years.


    When Varmus left in 1999, biomedical research was on a roll: Aided by a federal budget surplus, Congress had begun to double NIH's budget, which stood at $13.7 billion in 1998, over 5 years. Although biomedical research lobbyists came up with the doubling plan, Varmus is credited with winning lawmakers' support with his effective political skills. Now, a decade after the doubling ended in 2003, Varmus is coping with its legacy: what many call the "undoubling."


    By July 2010, when Varmus returned to NIH to direct NCI, the funding climate had decisively chilled. For a decade, NIH has received flat or declining budgets. And last year, thanks to the budget cuts known as the sequester, its $30.6 billion budget dropped another 5.5%. "There was no soft landing," he says. Yet Varmus says his "mantra" is that NCI's $4.8 billion a year—the largest single slice of NIH's spending—is still a lot of money, and NCI should focus on using it to fund the very best science. He has looked for bloated programs to trim and launched new efforts, such as one that explores the biggest mysteries in cancer and another to find drugs to target a family of mutated proteins that could be an Achilles' heel of many tumors (see sidebar, p. 418).

    "You might think that in these times, you would go into a sort of bunker mentality and just hope for a better day. That's not what's happening. He's trying very hard to keep the ship sailing forward in an important new direction," says cancer biologist Tyler Jacks of the Massachusetts Institute of Technology in Cambridge, a former graduate student in Varmus's lab who now chairs NCI's main advisory board. "Harold's chief characteristic is that he's always focused on the science (in the broadest sense) and his judgments reflect that perspective," writes Thomas Kelly, chief of basic research at the Memorial Sloan-Kettering Cancer Center in New York City, in an e-mail. That hasn't stopped grumbling in the community, however, that Varmus isn't doing enough to rescue foundering research labs.

    Although his brown hair has thinned more since his last tour at NIH, Varmus looks much the same: tall and slim, with a thick mustache and large, round wire-rimmed glasses. He still favors khaki pants and shirts without a tie. He often bikes his old route 12 miles to work from his apartment in Washington, D.C. But he now considers home to be Manhattan, where he lives with his wife in an apartment on the Upper West Side, not far from his two grown sons. The New York City area is also where he grew up, later went to medical school, and spent 10 years directing Sloan-Kettering between his two tours at NIH. He spends four long workdays in Bethesda—a "compressed week"—then often takes the train to New York City on Friday morning, or flies to his country home near Albany, to work remotely.

    In a 1-hour interview in his office, where his staff members are scurrying around planning for the 1 October government shutdown that ended last week, Varmus is candid yet careful, and sometimes prickly. He notes that his middle name is misspelled in the Wikipedia entry someone wrote about him. (It is Eliot, not Elliot.) He alludes, as he often does in public meetings and speeches, to frustration with the government bureaucracy. He says he doesn't particularly want his age mentioned (he's 73) because he's now one of the oldest directors at NIH. But he notes that his "vitality," as he puts it, outstrips his age.

    Lure of science

    The son of a Long Island doctor and a social worker, Varmus was pulled between following his father's path and pursuing the humanities. He earned a master's degree in English literature, then went to medical school, which whetted his interest in research. He landed at NIH as a so-called "yellow beret," a participant in a program that allowed physicians to work for the Public Health Service instead of going to Vietnam. There he joined the lab of endocrinologist Ira Pastan, studying bacterial genetics and witnessing the power of early molecular biology. He soon developed a fascination with understanding how some viruses can cause cancer, an interest also driven by the death of his mother from breast cancer.

    At the University of California, San Francisco, he formed a 20-year collaboration with Michael Bishop that centered on a retrovirus that causes cancer in chickens. In work that won them the Nobel Prize, they found that such viruses don't cause cancer on their own, but instead carry mutated versions of genes picked up from animals. Those genes control cells' normal growth and development but can go awry—revealing what are now known as proto-oncogenes.

    When he accepted President Bill Clinton's offer to direct NIH, Varmus had virtually no administrative or political experience. He quickly learned the ropes of Washington, however, moderating demands from patient groups, fending off conservatives' efforts to ban stem cell research, and winning support from Congress to double NIH's budget. As NIH director, he also proposed a then-radical idea—that biomedical papers should be freely available online—which led NIH to establish a free archive for full-text papers, PubMed Central, and seeded the open-access journals movement. Making papers and data free would speed the pace of scientific research, Varmus argued.

    Years later, when he was preparing to step down after his 10-year stint as Sloan-Kettering president and was helping the Obama transition team look for an NCI director, he accepted a suggestion that he take the job himself, taking a sharp salary cut from $2.6 million a year to a sum in the mid-$300,000s. Despite flat budgets, there was "no better time" to head NCI, he later said, because genomics studies were revealing a detailed portrait of cancer cells that could transform treatment and diagnostics. Compared with heading the entire NIH, "this is much more fun. I don't want to go down to the department [of Health and Human Services] for meetings, I don't want to spend all my time on the Hill" testifying before Congress, he says. He's also said he came back because he has a "profound affection for the NIH."

    Varmus now works for NIH Director Francis Collins, who as genome institute director in the 1990s reported to Varmus. The two longtime friends have differed over at least one issue: Collins's swift decision in 2010 to create a new center at NIH aimed at speeding the translation of basic discoveries into treatments. Varmus and National Institute of Allergy and Infectious Diseases Director Anthony Fauci cautioned that a new body devoted to translational research could overlap with other institutes' existing large translational programs. Years earlier, as NIH director, Varmus had warned that the proliferating number of institutes made NIH less effective; he wanted fewer. Varmus now says that Collins worked "collegially" with him and other directors "to make sure that the definition got right," adding that the National Center for Advancing Translational Sciences is "catalytic" and "works as partners" with other institutes.

    Dealing with the pain of tight budgets has been unavoidable. Partly because rising salaries consume so much of NCI's intramural research budget, the program has closed about 130 of its 300 labs over the past 10 years and reopened only half with new recruits, a "dramatic" change, says intramural Center for Cancer Research Director Robert Wiltrout. Coupled with recent federal government-wide restrictions on travel and conferences—NIH cannot even pay for coffee at meetings—morale is very low on the Bethesda NCI campus, researchers say. Wiltrout credits Varmus with being "a strong advocate" for allowing staff to continue to travel to conferences.

    Looking across NCI, Varmus has found a few places to trim sharply: communications and public relations, such as educational websites and newsletters, and a $350 million effort to build data-sharing software that was widely recognized as a failure, for example. But in general, he has applied cuts fairly evenly across cancer centers and ongoing grants that have already been funded. His goal is to preserve money for new investigator-initiated grants, the mainstay of cancer research labs. He has also tried to dispel the notion held by some researchers that NCI now favors translational research, not basic science. "I try to emphasize the fact that there is no one thing that's going to help you get a grant except by doing really interesting science."

    To make the grant-review process fairer for proposals that are very similar in quality, Varmus added new steps. Proposals that reviewers rank in roughly the top 9% are now funded without further review. But applications that score between 9% and about 25% get a second look from top NCI leaders, who consider program priorities, novelty, and how much funding a researcher already has. This means some grants far below the 9% cutoff receive funding.


    Improving how NCI works won't solve a bigger problem: too many biomedical researchers chasing a dwindling pot of research money. "Our whole system of operating is basically one that is probably not sustainable. That is, the idea that we're going to continue to fund more and more people, train a lot of people, and expand to meet all the opportunities that are there scientifically just does not accord with the current economic situation," Varmus says.

    The roots of the problem go back to the NIH doubling, he says. He has no regrets about his support of the doubling itself: "It certainly wasn't a mistake," he says. "But we said at the time, and many people agreed, that this was only going to work well if the … rapid increase was followed by what we called the soft landing"—budget increases that kept pace with rising costs of doing biomedical research.

    Congress did not give NIH those increases, and meanwhile, research institutions built new buildings and labs and hired faculty in the expectation that biomedical research funding would keep growing. This "was understandable," Varmus says, but it has created cutthroat competition for grants, with only about one in six proposals now receiving funding, compared with one in three a decade ago. The result, Varmus says, is an "insidious and pervasive problem of people and labs competing for jobs, grants, etc."

    There are no easy solutions, he says, and one inevitable result—academic labs downsizing or closing altogether—is already under way. "We all know that, in a fashion nobody can be comfortable with, there's a certain amount of attrition going on," he says.

    Meanwhile, a flood of young trainees are seeking scarce academic posts. Varmus says he sees "eye to eye" with Princeton University molecular biologist Shirley Tilghman, who led an NIH-commissioned report last year that urged the agency to shorten the number of training years and channel more young scientists into alternative careers. Like Tilghman, he also wants to encourage labs to rely more on permanent staff scientists rather than exploiting the labor of cheap trainees.

    Varmus also wants to address what he calls the "flawed values system" that the competitive atmosphere has spawned. He laments that researchers feel they will win funding only if they publish in top journals such as Science, Nature, and Cell. At NCI, he is pilot-testing a way to change this part of the scientific culture: by revising the "biosketch," the summary of a researcher's record that accompanies a grant proposal. Varmus wants to replace a section that now lists major publications with a narrative describing the investigator's five major accomplishments.

    This approach, already used by the Howard Hughes Medical Institute (HHMI), should not only discourage reviewers from assessing their colleagues based only on where they're published; it will also help researchers on large teams whose names are buried in a list of authors receive the credit they deserve, Varmus says. And he thinks that easing the rush to publish in high-impact journals might help address a much-discussed problem: that many NIH-funded studies have proved difficult to reproduce.

    Encouraging openness among scientists could also help, Varmus says. He remains a staunch supporter of free access to research results, and he notes with satisfaction that PubMed, NIH's abstracts database, will soon add new tools so researchers can comment on published papers. This will "promote a higher level of engagement and to-and-fro on work that's been published," he says. He's pleased that the White House science office is now asking all research agencies to follow NIH's lead and require that grantees make their papers freely available within a year, although he thinks the directive "could have been stronger," with a shorter embargo period.

    Varmus Career Highlights

    • 1962 M.A. in English literature from Harvard University

    • 1966 M.D. from Columbia University

    • 1968–1970 Research trainee in Pastan lab, NIH

    • 1970 Postdoctoral fellowship in the lab of Michael Bishop at UCSF leads to collaboration

    • 1976 Bishop/Varmus Nature paper reporting that cancer-causing gene in Rous sarcoma virus resembles noncancerous gene in normal bird cells

    • 1989 Awarded Nobel Prize in physiology or medicine with Bishop (pictured)

    • 1993–1999 Director of the National Institutes of Health

    • 2000–2010 President of the Memorial Sloan-Kettering Cancer Center

    • July 2010–present Director of the National Cancer Institute

    To relieve the constant pressure on investigators to write grant proposals to keep their labs afloat, Varmus is creating a new award at NCI for "outstanding investigators." It will give highly productive labs support for 7 years, with the possibility of renewal. Although NIH already has a long-term award for established investigators, the winners are chosen largely according to their peer-review scores for a specific project. The new award will go to researchers nominated by their institutions and will be based on their overall track record. Like HHMI awards, it will go to "people," not "projects." Varmus wants NCI to fund hundreds of these awards.

    Varmus ticks off other items on his to-do list: controlling cancer in the developing world, for example, by expanding use of the vaccine against human papillomavirus, which causes cervical cancer; getting oncologists to incorporate tumor genetics into treatments; finding better ways to predict whether tumors detected early on will grow or remain small and harmless.

    How many of these tasks he will accomplish will depend, he admits, on the next election. "I'm a presidential appointee. Some make it across that boundary, some don't," he says. But for now, he says, "I have no plans to leave."

  5. A Cancer To-Do List

    The current climate of austerity has not stopped NCI Director Harold Varmus from launching new initiatives.

    Even as National Cancer Institute (NCI) Director Harold Varmus contends with tight budgets (see main story, p. 416) he has an unusually long list of priorities.

    Provocative Questions


    Pancreatic cancer cells are usually driven to grow by mutations in RAS genes.


    Why does obesity increase cancer risk? Why are some cancers easily cured with conventional chemotherapy? Those are among about two dozen little-explored or neglected cancer puzzles that Varmus wants researchers to explore in NCI's Provocative Questions initiative, which has awarded $35 million in new grants since 2012 and is now taking proposals for a third round of funding.

    Global Cancer

    NCI's new Center for Global Health aims to help developing countries create cancer registries and national cancer plans. Another priority is to study the high rates of certain cancers in some countries—gallbladder cancer in Chile, for example.

    Oncogene Initiative

    Varmus is directing $10 million at NCI's large contract lab in Frederick, Maryland, to finding drugs that target the cell signaling pathway controlled by RAS, a family of oncogenes. Mutations in RAS drive uncontrolled cell growth in one-third of all cancers, so drugs blocking this pathway could help many patients. The initiative is part of an effort to revamp Frederick to focus on large goal-oriented projects, following the model of the Department of Energy's major research labs.

    The Cancer Genome Atlas

    The Cancer Genome Atlas (TCGA), a $375 million sequencing project launched with the National Human Genome Research Institute 7 years ago, is winding up its analysis of major mutations in 10,000 tumor samples covering about 20 cancer types. One of TCGA's original proponents, Varmus says NCI will soon launch a cloud computing pilot project to support further data mining.

    Unconventional Trial

    NCI plans to genotype the tumors of about 1000 patients who are no longer helped by conventional treatments and match them with an experimental drug aimed at a mutation in the patient's tumor. NCI has assembled a medicine chest of about 30 drugs contributed by a dozen companies. This "unconventional" clinical trial is "one way to dramatically extend our efforts to explore new therapies with genetic tools," Varmus says.

    Exceptional Responders

    Varmus has asked the research community to comb through their records for rare cases in which a patient's cancer shrank or disappeared in response to a drug that failed to help most patients. The goal is to learn whether specific genetic defects in the patient's tumor can explain such exceptional responses.