News this Week

Science  28 Jun 2013:
Vol. 340, Issue 6140, pp. 1506
  1. Around the World

    1 - Washington, D.C.
    DOE Labs Need Shakeup
    2 - Tokyo
    Japanese Minister Defends Emphasis on Targeted Research
    3 - Washington, D.C.
    House Panel Seeks Changes in NASA Programs
    4 - Phnom Penh
    New Treasures at Angkor Wat

    Washington, D.C.

    DOE Labs Need Shakeup

    Energized.

    NREL is part of DOE network.

    CREDIT: DENNIS SCHROEDER/NREL

    A new report says that the U.S. Department of Energy needs to remove the red tape preventing its 17 national research laboratories from building stronger ties to industry. The report, from think tanks holding the left, right, and central ground politically, says that the labs are stuck in a Cold War–era management structure that is particularly chafing in an era of tightening budgets. The report recommends a single bureaucratic overseer, greater flexibility for contractors, and market-based prices for industry to use the lab's extensive facilities. "The labs have been largely running on autopilot for too long," the report's authors conclude. "A jolt to the system is needed now more than ever." http://scim.ag/DOElabs

    Tokyo

    Japanese Minister Defends Emphasis on Targeted Research

    Japanese scientists want more details about a government proposal for a new funding entity to support applied biomedical research. The heads of 50 academic organizations want the government to maintain funding for investigator-initiated, innovative approaches as well as continuing its support for younger scientists.

    "We have no intention to tie down the people who are involved in very fundamental research," says Akira Amari, minister for economic revitalization, about the government's plans for a Japanese version of the U.S. National Institutes of Health that would "strongly support the commercialization of innovative medical technologies." At the same time, Amari told scientists that "it is very important to have someone in [a research] group who can look at the industrialization or commercialization aspects and provide some direction to the research." http://scim.ag/JapanResearch

    Washington, D.C.

    House Panel Seeks Changes in NASA Programs

    Moonstruck.

    Bill backs lunar base.

    CREDIT: NASA/RENDERING COURTESY OF BEHNAZ FARAHI AND CONNOR WINGFIELD

    NASA would be forced to shelve an initiative to capture an asteroid and re-embark on a plan to establish a base on the moon under legislation authored by Republican lawmakers in the U.S. House of Representatives who have long butted heads with the Obama administration's vision for the space agency. The draft bill, vetted last week at a hearing of the House science committee, would also downsize NASA's Earth Science portfolio—a program that the Obama administration would like to see grow—and redirect some of those funds to planetary science.

    The bill's proponents are particularly opposed to NASA's proposal to capture an asteroid and drag it into a lunar orbit, calling it a "costly and complex distraction [that] lacks in details, a justification or support from NASA's advisory bodies." http://scim.ag/NASAchanges

    Phnom Penh

    New Treasures at Angkor Wat

    Airborne laser imaging, or LiDAR, has revealed the imprint of a vast medieval cityscape surrounding Angkor Wat, Earth's largest religious monument. The findings were unveiled last week at a U.N. World Heritage meeting in Phnom Penh.

    The Angkor kingdom was the heart of the Khmer Empire of the 9th to 15th centuries C.E., and Angkor was the most extensive city of its kind in the preindustrial world. The helicopter-borne survey, in April 2012, laid bare the imprints of a 9th century city, known from inscriptions as Mahendraparvata. The findings, in press at the Proceedings of the National Academy of Sciences, also lend weight to a hypothesis that the complexity of Angkor's vast waterworks was its ultimate undoing. http://scim.ag/AngkorLiDAR

  2. Random Samples

    Noted

    Speaking this week at Georgetown University about climate change, President Barack Obama reiterated how his administration plans to limit carbon emissions from power plants and other sources, improve the energy efficiency of appliances and buildings, create more green energy on federal lands, and promote mitigation and adaptation strategies without requiring action by Congress.

    They Said It

    "The stem of the flower is STEM education, and the humanities are the blossom. Without the blossom, the STEM is completely useless."

    —A new report from the American Academy of Arts and Sciences, The Heart of the Matter, makes the case for increased support for the humanities and social sciences.

    Cracking Open Science

    CREDIT: ANJELIKA DEOGIRIKAR

    Championing the sharing of data can sometimes be a lonely pursuit, says art historian William Noel, one of 13 people honored by the White House last week for promoting so-called open science. "I feel like I've been handed the first telephone and have nobody to talk to," says Noel, who has helped digitize centuries-old scientific and medical tomes (digitalgalen.net).

    The 20 June event, part of an Obama administration initiative called "Champions of Change," highlighted projects ranging from astrophysics to genomics. Some researchers have been slow to embrace the new technologies, says Noel, director of special collections at the University of Pennsylvania: "People have to relearn how to release their data." And pediatrician and bioinformaticist Atul Butte of Stanford University in California chided his fellow researchers for "having to come to the White House to talk about something we were taught to do in kindergarten." The 2-hour discussion is posted on the White House website, but the poster sessions and reception were by invitation only.

  3. Newsmakers

    Into the Breach at Fermilab

    Lockyer

    CREDIT: 2013 ANNE-MARIE COMTE AND FERMILAB

    The new director of the sole U.S. particle physics lab inherits an institution in transition. Nigel Lockyer, now director of the Canadian lab TRIUMF, takes the reins at the Fermi National Accelerator Laboratory (Fermilab) in Batavia, Illinois, on 3 September.

    Lockyer, 60, a U.S. citizen who was raised in Canada, has long worked on experiments at Fermilab. Its Tevatron was shuttered in 2011, and the lab is struggling to launch its next megaproject, the Long-Baseline Neutrino Experiment (LBNE), which has been chopped down from its original $1.9 billion design. Since 2010, Fermilab's budget has fallen by 8% to $366 million.

    Particle physicist H. H. "Brig" Williams of the University of Pennsylvania thinks that Lockyer is up to the challenges. "He sleeps 4 or 5 hours and has tremendous energy," Williams says. "He can do things I wouldn't even try." In particular, Williams hopes that Lockyer will try to restore the original scope of LBNE. http://scim.ag/NLockyer

    World Food Prize

    Van Montagu

    CREDIT: COURTESY OF THE WORLD FOOD PRIZE 2013

    Fraley

    CREDIT: COURTESY OF THE WORLD FOOD PRIZE 2013

    Chilton

    CREDIT: COURTESY OF THE WORLD FOOD PRIZE 2013

    Three scientists who made key contributions to the development of genetically modified crops will share this year's World Food Prize. Working at the Ghent University Medical School in Belgium, Marc Van Montagu and colleagues discovered in the 1970s that a ring of DNA, called a plasmid, in the microbe Agrobacterium tumefaciens caused a plant disease called crown gall. Then, in 1983, Robert Fraley of Monsanto and Mary-Dell Chilton at Washington University in St. Louis independently figured out how to use Agrobacterium to swap foreign genes into plants. The prize, founded by plant breeder Norman Borlaug in 1986 to recognize improvements to the amount and quality of food worldwide, is $250,000. http://scim.ag/FoodPrize

  4. The Dizzying Journey to a New Cancer Arsenal

    1. Jennifer Couzin-Frankel

    Carl June and others are on a quest to make T cell therapy a cancer treatment success. Getting there is filled with highs and lows and lots of uncertainty.

    Experimenting.

    A life of twists and turns has Carl June pressing forward with a radical cancer therapy.

    CREDIT: ERIC MENCHER/PENN MEDICINE

    One January Afternoon in 2011, oncologists Carl June and David Porter settled themselves at a table at Gia Pronto, the coffee shop in the atrium of the Perelman Center for Advanced Medicine. The glass and steel building sits at the nerve center of the University of Pennsylvania's (Penn's) massive medical complex in West Philadelphia, a few blocks from the Schuylkill River that cuts the city in two. Outside, construction cranes rise up, a sign of Penn's ongoing expansion.

    June and Porter had a problem. In an exhilarating 6 weeks in the summer of 2010, they had treated three men with leukemia who were out of options. In a cell therapy experiment, the patients' own T cells were genetically engineered in a lab to proliferate inside their bodies and seek and destroy cancer. The strategy had worked beyond the doctors' wildest expectations, melting away pounds of tumor in each patient. In one case, the modified cells didn't grow well in the lab, and the patient, a 64-year-old scientist at a biotechnology company named Douglas Olson, received a mouse-sized dose. Now, he'd taken up running as a hobby and was teaching his grandchildren how to sail.

    But generating the cells for all three patients had cost $350,000. The scientists were out of money and out of "vector," the disabled HIV viruses that they were using to insert new genes into T cells. They had applied to the National Cancer Institute (NCI) and elsewhere for funding to continue their clinical trial, sharing unpublished data on patients 1, 2, and 3. Cancer had vanished in Olson and one other patient. The third man responded partly but later died of his disease. Funders deemed the therapy too experimental and too impractical. Everywhere, Porter and June were turned down.

    "It was one of these best of all times, worst of all times," says June, who had assembled his small team, including Porter, more than a decade ago. They weren't the first to test this radical new approach in people, but their results were the most striking. "We knew something worked," even if the remissions ended tomorrow, June says. "We knew it wasn't an accident."

    Sipping coffee, Porter and June weighed their next step. They were itching to test the cell therapy in more people with leukemia, and to do that they needed money that they didn't have. "We basically decided that we would just publish with three patients," June says. Getting the word out, he hoped, could shift the dynamic in their favor. Porter was game to try, but skeptical that any reputable journal would accept a paper with an n of 3.

    He turned out to be wrong. The New England Journal of Medicine welcomed a report about Olson and his mouse dose of T cells. Science Translational Medicine, Science's sister journal, snapped up a manuscript detailing all three patients. The papers were published simultaneously on 10 August 2011. The university put out a news release that day. Its title: "Genetically Modified 'Serial Killer' T Cells Obliterate Tumors in Patients with Chronic Lymphocytic Leukemia, Penn Researchers Report."

    Porter was en route to vacation in western Maryland with his family when the embargo lifted. His phone started ringing. "I was in the car for 8 hours that day," he says. "I spent 8 hours straight on my phone, answering e-mail, answering phone calls. It was a story that took us all by surprise. It kind of went viral." June fielded 5000 requests from patients and their families for the therapy. Eight hundred media outlets worldwide covered the story.

    NCI reversed course and awarded June's team nearly $500,000 a year for 4 years, in part to create engineered T cells for patients. Pharmaceutical companies began courting June and his colleagues. Almost exactly a year after publication, Novartis signed a multimillion dollar agreement with Penn, licensing rights to the therapy with the goal of getting it approved by drug regulators. Three patients, two of them still in remission today, proved to be the tipping point that June had imagined.

    Two years later, nearly all of the thousands of cancer patients desperate for engineered T cells are a long way from getting them. For one, the therapy can tackle only a subset of blood cancers, and it remains highly experimental. About three dozen people at Penn have received it, along with more than 50 elsewhere. Not everyone is helped, and many of those who are suffer serious side effects. In those whose disease has disappeared, no one knows yet how long the calm will last. "The medical literature is just littered with examples of drugs that look great on your first 10 patients, and they don't pan out for one reason or another," Porter says.

    History may urge caution, but it's hard not to be swept up in the moment. Despite the small numbers, many oncologists believe that what June's team and others now replicating it have seen is unprecedented. No cell therapy has proliferated in the body, endured, and slain cancer quite like this one.

    A looming question now is how to move engineered T cell therapy forward—how to test it in more patients, at more centers, in different forms of cancer. Drug companies "don't care if it costs $500 million to develop the first vial, as long as you can make the second vial for $1," says Steven Rosenberg, an NCI surgical oncologist in Bethesda, Maryland, who's spent decades developing cell therapies. As Rosenberg knows well, that's not how T cell treatment works. Every batch is a distinctive drug, and right now, every step toward making it holds the chance of human error.

    As academic cancer researchers and companies work to expand the therapy's reach, June and his colleagues are in the public eye. Along with the accolades are critics charging that they've claimed more than their share of scientific credit and lawsuits alleging violations in agreements with collaborators. They are deeply driven to save lives; cancer looms large in June's own autobiography. But at stake, too, for the researchers and their institution, is money and scientific glory, and the chance to combat cancer with immunology on a grand scale.

    T cells remodeled

    The backbone of June's work was forged in the mid-1980s by an Israeli immunologist. Zelig Eshhar was on sabbatical in Palo Alto, California, when he began toying with an unorthodox question: whether T cells, the sentries of the immune system, could be coaxed to destroy different targets. To accomplish this, Eshhar knew that he needed T cells to recognize and latch onto molecules that they normally ignore. And the only way to make that happen was by inserting foreign DNA into T cells, to alter the receptors they produced.

    Eshhar returned home to the Weizmann Institute of Science in Rehovot, Israel, and got to work. Failure after failure followed. The technology to insert DNA was rudimentary. Then, in the late 1980s, Eshhar triumphed, adding a combination of gene sequences into a type of immortalized T cell that more readily accepts foreign DNA and endowing the cells with new targets they could kill. "The moment we realized it was working … we became, I don't want to say obsessed, but really invested," he recalls.

    Eshhar's feat was only the first step. To treat a disease like cancer, researchers needed to identify protein targets unique to certain tumor cells—otherwise, the modified T cells would destroy healthy tissue, too. They also had to ensure that the cells multiplied inside the body and persisted, wiping out every trace of cancer and preventing it from coming back.

    Slowly, a handful of researchers picked up on Eshhar's accomplishment and carried it forward. At Memorial Sloan-Kettering Cancer Center in New York City, cell therapist and oncologist Michel Sadelain set to work introducing genes into human T cells. "It took me 3, 4 years to better transfer genes into more than 0.5% of the culture," Sadelain says. "Today, we can take a high school kid [and] in an afternoon, they know how to take T cells and blast genes in all of them." Sadelain pushed for a name, and "chimeric antigen receptor" cells, or simply CAR cells, stuck.

    Cautious optimist.

    Oncologist David Porter hopes that early results will hold up as more patients are treated.

    CREDIT: PEGGY PETERSON PHOTOGRAPHY/PENN MEDICINE

    While Sadelain focused on cancer from the start, June got there circuitously. His career trajectory tracked Cold War history, and the reason for that was Vietnam. In 1971, when he was 18, a lottery gave June a near-certain chance of being drafted. He abandoned plans to enroll at Stanford University and applied to the U.S. Naval Academy in Annapolis, Maryland. The war ended 2 years later, but June remained with the military, which financed his medical education. With fears of nuclear attacks running high, he trained as an oncologist and a bone marrow transplanter to treat those exposed to high doses of radiation. In 1989, the Berlin Wall collapsed. The Cold War ended soon after. The military "didn't care about bone marrow transplants after that," June says. He needed a new passion.

    The Navy didn't fund cancer research, so June, then at the Naval Medical Research Institute in Bethesda, turned to HIV. The decision proved prescient, as he learned the ins and outs of T cells and the immune system, knowledge that would later serve him well. He spent a decade training T cells to flourish in HIV patients, whose own T cells are destroyed by the virus. An immunologist in the lab, Bruce Levine, explored how to grow T cells and what signals could best "activate" them, turning them on outside the body to help them destroy their targets.

    Then in 1995, June's personal and professional lives abruptly converged. His wife Cynthia was diagnosed with ovarian cancer. The couple had a 3-year-old daughter and two teenage sons. "I saw for the first time what it was like to be on the other side of the bed," he says. June was a believer in manipulating the immune system to treat cancer, but suitable immunotherapies weren't ripe at the time.

    Cynthia June was 46 when she died in 2001, shortly after her husband left the Navy and the family relocated to Philadelphia. Their daughter was 9 years old. "It took a long time to recover," he says, speaking slowly as he thinks back on those years. "A lot of people helped me out."

    The ripples hit those around June, too. "We knew Cindy, we had socialized with her," Levine says. "We saw what happened and what it did to Carl. Those are hugely significant events for people, and also for the program."

    Advances and acrimony

    At Penn, June continued his HIV work but also threw himself into cancer, motivated by his wife's death and by a belief that the pieces were falling into place to successfully treat patients with CAR cells at last. He was enthusiastically welcomed by two oncologists: Porter, who cares for adults with blood cancer at Penn's Abramson Cancer Center, and Stephan Grupp with the Children's Hospital of Philadelphia (CHOP), who showed up at June's office door one day and asked to collaborate.

    A handful of researchers elsewhere were also in the race to bring CAR therapy to people. In addition to June, they included Sadelain at Sloan-Kettering, Rosenberg at NCI, and Malcolm Brenner at Baylor College of Medicine in Houston, Texas. All were converging on the same cancer target, a marker called CD19. The only cells sporting CD19 are B cells, which proliferate dangerously in B cell leukemias. This was valuable for two reasons. The marker was a promising bull's-eye, because it was all but universal on these cancer cells. And although B cells are an important component of the immune system, they are not needed for survival—which was reassuring, because attacking CD19 would surely destroy healthy B cells, too.

    How to design the very best CAR against CD19 was the big question. CARs "come in multiple flavors," Sadelain says. There are different ways to engineer a new receptor that will latch on to CD19. One important ingredient is the "co-stimulatory signal," which is embedded in the CAR cells to activate them and keep them alive in a patient. Sadelain's group, like the others, studied a slew of possibilities in mice and settled on one, called CD28, which looked the most promising. Rosenberg and groups at two other centers picked CD28 as well. All four had clinical trials up and running when June's trial opened.

    June chose a different co-stimulatory signal, called 4-1BB, in part to distinguish his efforts and also because lab studies suggested that it helped T cells proliferate. It was a strong candidate in mice but not quite as impressive as CD28. A group at St. Jude Children's Research Hospital in Memphis, Tennessee, led by an oncologist named Dario Campana, had designed the first CAR construct with 4-1BB. Unlike the other groups, June's also used a disabled HIV virus to genetically engineer the T cells and a different recipe for growing them in the lab.

    As it turned out, combatting cancer was in the details. The first to publish an anti-CD19 CAR therapy success was Rosenberg's team in 2010. They used the CD28 strategy, and one patient with a form of lymphoma achieved a long-lasting partial remission. But it was Penn's results in the three men with leukemia, with a 4-1BB CAR, that transfixed the cancer community and the wider world.

    "It made a believer out of a lot of people who were pretty skeptical," says Ravi Bhatia, who treats blood cancers at City of Hope in Duarte, California, and counts himself among past doubters. His own hospital had been studying CAR cell therapy for several years, but there and elsewhere the transplanted T cells had quickly disappeared from the bloodstream. "That," Bhatia says, "was a big concern."

    June, Porter, Levine, and Grupp—who was gearing up to treat the first children—sought to stay anchored amid the hype. "You try and keep your feet on the ground and say, 'We still have work to do,'" Levine says. The competition was fierce and not always friendly. In the pages of The New England Journal of Medicine, Rosenberg's group and June's sparred over whether Rosenberg's CAR therapy success, published 12 months before June's, was due to engineered T cells or attributable to chemotherapy that the patient received first, to make room for new cells. "There's acrimony out there," Sadelain says.

    The most bitter came in July 2012. St. Jude sued the trustees of the University of Pennsylvania for breaching materials transfer agreements signed with St. Jude in 2003 and 2007, when Campana had shared his CAR materials with June.

    Penn shot back with a lawsuit of its own, arguing that June's CAR cell construct was different than Campana's. Less than 3 weeks after that suit, in August 2012, Novartis and Penn unveiled an alliance to commercialize the T cell treatment. The company said that it would devote $20 million to build a cell therapy research center at the university.

    In the months that followed, the legal dueling continued. Then in March of this year came a turning point: St. Jude's application for a patent on Campana's T cell construct, with its 4-1BB signaling domain, was approved.

    Three days later, Penn sued St. Jude again, claiming that the Campana patent was invalid. That lawsuit exposed an undercurrent of concern over who owned what. Penn's lawyers are seeking "a judicial determination" that they are not infringing on the St. Jude patent.

    Neither June nor Campana, who is now at the National University of Singapore, would comment on the lawsuits. Novartis spokesman Scott Young wouldn't say much either—the company is not a party to any of the three suits—but he stressed in an e-mail message that "we have complete confidence in the viability of our collaboration with UPenn."

    Jumping the hurdles

    That collaboration is now moving swiftly ahead. At Novartis, dozens of people are strategizing over how to manufacture personalized T cells for patients. Novartis needs to determine how long the cells can hold up outside the body, because that determines how many costly cell-processing facilities the company must open worldwide. It has to automate its method of growing and manipulating the cells as much as possible to reduce costs and the chance of human error. It has to consider whether the time from "vein to vein," when the cells are removed until they're put back in, can be shortened. It now stands at about 3 weeks.

    "All of this has to be thought through very carefully, not only for the U.S. but also on a global scale," says Manuel Litchman, who is overseeing the therapy's development program for Novartis Oncology. In the cramped lab at Penn, Levine is busy training Novartis employees. Company officials meet several times a week with June's team. In December, Novartis paid $43 million for an immunotherapy manufacturing facility in Morris Plains, New Jersey, which had been owned by a company, Dendreon, making a prostate cancer vaccine. "It's not going to look that different in Morris Plains than it looks in Bruce's lab," Litchman says. "It's just going to be replicated many, many times over, to fill up the suites there."

    One top priority is consistency. Every batch of T cells will be different because each originates with a different patient. But other scientific and manufacturing variables—the vector that inserts the foreign DNA, techniques to grow the cells, how they're transported—can make the outcome unpredictable.

    June's group learned this the hard way: After the fanfare around their first three patients, they treated three more in January 2012 with a new vector lot. None responded. "I was just stumped out to the max," June says. He had no idea what had happened and still can't say whether something went awry with the vector material or whether the outcome was due to random fluctuations in the therapy's success. "All we knew was, it worked three times, and then it didn't work three times." All three of those patients later died of their disease.

    Next in line was patient 7, who turned out to be another roller coaster. She was Emily Whitehead, a 6-year-old with end-stage leukemia whose parents turned to June's cell therapy as a last-ditch hope. The experimental treatment sent her body into a deadly immune overdrive. She spent 2 weeks on a ventilator in the CHOP intensive care unit while doctors tried everything they could think of to save her.

    "We thought it was over," June says. He drafted an e-mail message to Penn's provost: "It is with regret that I inform you that our first pediatric patient on the CART19 trial will likely die," he wrote. "There is nothing to do at this point other than hope for a miracle." June pledged to "conduct a full investigation." It turned out that he didn't need to, and the e-mail was left unsent.

    As doctors parsed Emily's lab results, they found that her revved up T cells were causing overproduction of a molecule called interleukin-6. She was saved, in a tale that became hospital lore, by an arthritis drug that disables it. June knew about the drug only because his daughter Sarah had been diagnosed with rheumatoid arthritis shortly after her mother's death. Grupp happened upon it independently, when a colleague found it by Googling on his iPhone.

    Survivor.

    Eight-year-old Emily Whitehead was the first child on the experimental Penn protocol, and she's now cancer-free 1 year later.

    CREDIT: KARI WHITEHEAD

    Emily remains in remission more than 1 year later, her hair long enough now for pigtails and her 8th birthday behind her. In her DNA, Grupp discovered a gene mutation that predisposes to a hyperactive immune response, which could help explain why the therapy sickened her as it did. Grupp has since switched to giving other children a tenth of the T cell dose that Emily received, although "in my heart of hearts I'm not sure the dose matters that much," because the cells multiply with abandon inside the body. All those on the Penn trial became deeply attached to Emily after her harrowing experience. Levine displays pictures of her in his office. June, who remarried and now has a 10-year-old daughter of his own, chokes up when he speaks of Emily and her family.

    For the Penn team, Emily and the other patients are teaching laboratories, showing what the engineered T cells can do. "I've never been involved in anything like this in my life," Grupp says. In addition to the crush of media attention and hundreds of inquiries from patients and families, Grupp was taken aback by parents reporting their child's progress on Facebook before he'd shared the news with the wider scientific world. "I am in a position of having my results publicly disclosed without having them subject to peer review," he says. "That's the aspect of this I was least prepared for," and it's one that makes him "extremely uncomfortable."

    Grupp has treated 14 children with acute lymphoblastic leukemia so far. Of the five reported at scientific meetings or published, four went into remission but one of those later relapsed. Porter's most recent data on adults, presented at a meeting in May, includes 10 responders out of 17 treated, with five of those in complete remission for at least 3 months.

    For every T cell infused, between 1000 and 93,000 leukemia cells die, showing just how dramatically the engineered T cells are multiplying inside the body. The group is still studying why their T cells proliferate like this, although they suspect that it's partly due to the 4-1BB construct that Campana pioneered. As expected, healthy B cells are destroyed, and the long-term effects of that remain uncertain. The expense of CAR treatment has plunged, but it still costs $20,000 to $40,000 to generate the cells. That doesn't include supportive care in the hospital after patients receive them.

    In March, Sadelain reported on five patients with acute leukemia in Science Translational Medicine. That disease is more aggressive than chronic leukemia in adults, and oncologists were heartened by what they read: Four of the patients went into remission, a necessary precursor to getting a bone marrow transplant, which they then received. Three are still alive at least 5 months after treatment. "That it was verified at another center, at Memorial, was very important," says Bhatia at the City of Hope. It was "not just something strange that happened" in the people treated at Penn.

    Still, physicians like Porter and Grupp are mindful that this isn't life-changing for everyone. "When I'm doing informed consent with these families, the first thing I say is, 'Forget everything you've read about this,'" Grupp says. "Nothing could possibly be as promising as the various articles about this make it seem." Only four people, including Emily, have been followed for more than a year. A looming question is whether CAR therapy can work in solid tumors, and June and others are opening clinical trials to try and find out.

    Nearly 3 years after the summer that changed everything, the Penn group is still working flat out to keep up: enrolling as many patients on the trials as they can, working with drug regulators to discuss how best to study the cells with an eye toward approval, collaborating with Novartis to train their employees and streamline the cell-generating process. "I'm tired," says Porter, and he sounds it. June, a serious bike racer and runner, has scaled back his hobby, though he did manage to fit in a 34-mile ultramarathon last weekend. "I didn't used to work as many hours as I do" now, he says. "I mean, I used to work, but I'd take more time off." He's eagerly waiting for the handoff, the day when Novartis starts processing T cells and making CARs. Neither June nor Novartis can say when that will be, but for June, it will mark a return to normalcy. "Until then," he says, "it's overdrive."

  5. Canada

    Scientists Bristle at Canadian Leader's Applied Research Push

    1. Wayne Kondro
    1. Wayne Kondro is a freelance writer in Ottawa.

    Prime Minister Stephen Harper has drawn criticism for an autocratic style and cuts to environmental research, but supporters applaud his focus on commercialization.

    OTTAWA—In the aftermath of the Boston Marathon bombings in April, newly minted Liberal Party leader Justin Trudeau proposed that Canada's researchers explore the root causes of terrorism. Prime Minister Stephen Harper mocked Trudeau's suggestion, declaring that "this is not a time to commit sociology."

    That response was the latest—and quintessential—example of what Harper's critics have described variously as his "anti-intellectual," "antievidence," or "antiscience" attitude. An economist turned politician, Harper became Canada's 22nd prime minister in February 2006. According to his opponents, Harper soon began waging a subtle "war on science" that has only intensified since his Conservative party captured a majority of Parliament in 2011.

    Arctic priority.

    Prime Minister Stephen Harper (center) in a tour last year of the High Arctic Research Station in Cambridge Bay, which boasts a fishing trawler refitted as a research vessel.

    CREDIT: PMO/JASON RANSOM

    That war has operated on many fronts, his detractors say. Stagnant budgets for the country's three granting councils have sent a message that academic research is not a priority for the Conservative government, they say. Climate and atmospheric research have been hit especially hard as part of what critics regard as an assault on environmental stewardship.

    Many scientists believe that these and other policies threaten to marginalize the federal government's entire $11-billion-a-year research portfolio. And last month, Harper's handpicked 18-member Science, Technology and Innovation Council (STIC) provided them with additional ammunition by reporting that Canada, since Harper's election, had fallen from 16th to 23rd among industrialized nations in overall research expenditures relative to gross domestic product.

    But despite the widespread belief that Harper's government has been bad for science, the reality may be far more nuanced. Harper has generally maintained funding for the raft of multibillion dollar programs begun by the predecessor Liberal government. They include efforts to rebuild the nation's scientific infrastructure (Canada Foundation for Innovation), reverse a perceived brain drain (Canada Research Chairs), and cover the indirect costs of research.

    Harper's government has even built on the underlying premises of those original investments by giving $10 million apiece over 7 years to 20 superstar researchers in four designated priority areas: the environment; natural resources and energy; health; and information and communication technologies. And in 2011, the government announced its plans for a second competition to set up 10 more superstars.

    The Harper government has also been eager to toss large pools of money at specific disciplines and groups, often without peer review. In 2007, Harper gave seven existing research institutes a total of $105 million to establish Centres of Excellence for Commercialization and Research (CECRs) and then held a $195 million competition that resulted in the creation of 14 more. In 2009, it launched a $100 million brain research initiative led by a private foundation whose honorary chair was a former Conservative finance minister.

    Taken together, these policies show that Harper is "a great supporter of science," says Gary Goodyear, Harper's minister of state for science and technology. A chiropractor who assumed his current post in 2008, Goodyear says that his instructions were to ensure the health of the "entire ecosystem" of Canadian science, from fundamental to applied research. "And if you can create any jobs by Saturday, do it," he quips.

    Scientific mercenaries?

    For its part, the Harper government doesn't apologize for its focus on wealth creation. Study after study has shown that Canada's industrial sector is heavily based on natural resources and reluctant to invest in research. The only multinational juggernaut remaining in the country is besieged communications innovator BlackBerry (formerly Research In Motion).

    Dealt a weak hand, the Harper government is simply trying to overcome chronic problems in Canada's innovation system, says Alan Bernstein, president of the Canadian Institute for Advanced Research in Toronto. Those deeply rooted flaws, he says, include the fact that Canadians are "risk-adverse" by nature, live in the shadow of a scientific superpower, and have a branch-plant economy with a weak venture capital community. Even the world's most generous R&D tax credits have done little to promote industrial research.

    However, Harper's top-down initiatives and his demand that the academic community become more directly involved in the commercialization of research have infuriated scientists. Some argue that the government's propensity for large, elitist programs is an assault on the fundamental tenets of investigator-initiated research that is eroding the health of the scientific base. Others are simply queasy about being nudged into becoming what some call "mercenaries for industry."

    It's difficult to determine, however, if the changes pursued by Harper have affected the nature of research that Canadian scientists are conducting, says Timothy Caulfield, Canada Research Chair in Health Law and Policy at the University of Alberta. Some shifts may just be cosmetic, he says, involving minor modifications in the way that grants are written. "Researchers are nimble. They know how to get money."

    Still, Caulfield is skeptical that the government will achieve the desired economic transformation. "Part of the package of justification is that it will lead to economic growth," he says. "But the evidence is thin that a commercialization directive from the government leads to economic growth."

    Playing favorites.

    Programs with the potential for economic payoff have received the most attention in the research garden of Canadian Prime Minister Stephen Harper. At the same time, core research activities and many environmental initiatives have stagnated or withered away under his government.

    CREDIT: G. GRULLÓN/SCIENCE

    Still, the Harper government has been nothing if not steadfast in using science as a tool to restructure the economy. It has heavily promoted academic collaborations with industry, including roughly $255 million sunk into the 21 CECRs structured around subjects such as vaccine development, imaging technology, surgical innovation, and energy efficiency. The latest manifestation of that philosophy was last month's announcement that Canada's National Research Council (NRC), the government's primary in-house research arm, is being converted into a toolbox for industry.

    Goodyear says that the government, having solidified support for fundamental research, is now turning its attention to the other end of the innovation chain. Transformation of NRC, efforts to spur industry-academic collaborations, and the creation of new pools of venture capital, like the $400 million that the government set aside last year, are all designed to make industry more innovative and productive. More of the same will soon follow, Goodyear hints, possibly in the form of expanded procurement programs. "This isn't a picture or an x-ray," he says. "Our strategy is a video. You haven't seen the next chapter yet."

    Scientists say that the book is quite clear when it comes to Harper's attitude toward environmental research and regulation. While Harper's supporters argue that the government's policies are simply a way to remove an impediment to economic development, most scientists regard them as an egregious example of a wrong-headed ideology and the prime minister's tight control over all government activities.

    For example, when Harper announced in 2011 that Canada was bailing from the Kyoto Protocol, the global treaty to limit greenhouse gas emissions, (which Harper once called a "socialist conspiracy"), his rationale was that meeting the treaty's targets would cripple the country's economy. A similar rationale was offered in 2012, when government ministers gained the authority to override environmental assessments in approving industrial projects, and again this spring, when the government announced that it would withdraw from the U.N. Convention to Combat Desertification.

    A slew of environmental programs have been axed since Harper earned a majority government, including the Canadian Foundation for Climate and Atmospheric Sciences (a nonprofit organization that distributed funds to research facilities such as the Polar Environment Atmospheric Research Laboratory), the National Round Table on the Environment and the Economy (which advocated the introduction of carbon taxes, which Harper finds anathema), the Ocean Contaminants and Marine Toxicology Program, the World Ozone and Ultraviolet Radiation Data Centre, and the Experimental Lakes Area program. Such moves are a far cry from Harper's decision in 2007, as head of a minority government, to spend $2 billion on a pair of clean environmental technology programs that sought to develop "green energy generation and transmission infrastructure, carbon transmission and storage infrastructure."

    Researchers say it's no coincidence that a policy requiring government scientists to obtain permission from Harper's office before speaking to the media seems so often to impinge on environmental researchers. Last year, 2000 researchers in lab coats descended on Parliament Hill for a mock funeral for the "death of evidence." The policy has spurred an ongoing investigation by the federal information commissioner into whether Harper has placed undue limits on the ability of federal scientists to disseminate findings.

    Goodyear dismisses the proposition that the government has trained its guns on the environmental sciences. "The perception is wrong," he says, quickly pointing to the $135 million that the Natural Sciences and Engineering Research Council of Canada (NSERC) set aside for climate change research.

    One environmental area that has benefited from Harper's policies is Arctic science. Harper's support for consolidating Canadian control of its Arctic territory has long been tagged as his personal "legacy" project. That has translated into commitments such as building a Canadian High Arctic Research Station and launching three next-generation Constellation radar satellites, a project with an estimated price tag topping $1 billion.

    Those initiatives haven't placated critics. Andrew Weaver, Canada Research Chair in Atmospheric Sciences at the University of Victoria and a member of the British Columbia legislature from the Green Party, accuses Harper of trying to "control the message" on climate and related issues by either ignoring or suppressing evidence that is antithetical to his objectives, such as developing Alberta's oil sands.

    To Scott Findlay, associate professor of biology at the University of Ottawa, Harper's Arctic policy demonstrates his willingness to run roughshod over evidence if it challenges government priorities or orthodoxy. He and other scientists argue that the same ethic led to Harper's decision in 2008 to eliminate the position of national science adviser, his scuttling of Statistics Canada's mandatory long form census in 2010, and his axing this year of the Health Council of Canada.

    Abolishing the national science adviser's position was particularly egregious, says Kennedy Stewart, science critic for the opposition New Democratic Party. The result, he says, is that the Harper government is now crafting science policy "without getting advice from scientists."

    The shift to a voluntary census, meanwhile, prompted the resignation of then–Chief Statistician Munir Sheikh. It was ostensibly made because libertarian back-benchers within Harper's caucus were fretting that a Canadian might be charged with failing to fill out a census form. And many fear that the elimination of the national health council, part of a broader policy to leave the provinces entirely in charge of health care, puts Canada on the fast track to becoming 14 splintered systems.

    These and other policy moves have left many scientists feeling that they're the victims of "bad science policy," argues Canadian Association of University Teachers Executive Director Jim Turk. Another poster child for those "bad" decisions, he and others say, is the loss of purchasing power by Canada's granting councils, which fund academic science.

    Years of flat budgets for NSERC, the Canadian Institutes of Health Research (CIHR) and the Social Sciences and Humanities Research Council (SSHRC), at about $1 billion, $1 billion, and $700 million, respectively, mask an enormous transformation in their operations, Turk says. What modest increases they've received have often been tied to industrial programming or targeted at community colleges (which, prior to Harper, were precluded from tapping council budgets). In addition, as a general rule, the increases have merely offset the effects of multiyear cuts imposed during various deficit reduction exercises.

    The councils have coped with no-growth budgets in different ways. CIHR, for example, has opted to help grantees keep up with rising costs by offering larger grants to fewer researchers, whereas NSERC has decided to increase the share of its budget going to promote industrial collaborations. Its so-called "fettered" research has grown in the past 5 years from $208 million to $360 million, while expenditures on basic research grants have dropped from $389 million to $322 million over the same period.

    As a result, the core budgets of each council have plummeted since 2007: The drop is 6.4% for NSERC, 7.5% for CIHR, and 10.1% for SSHRC. Not surprisingly, the success rate for discovery grants has also sunk, from 21% to 9% at CIHR, from 73% to 62% at NSERC, and from 40% to 27% at SSHRC, Turk says.

    Divided opinions

    University of Toronto professor of mathematics James Colliander says that the largest impact of Harper's policies on academic scientists has been a shift in the incentive system to reward those whose work has industrial application. "What the government is in some sense saying is: These eclectic people, with their ideas at the edge of knowledge of all human beings, are not important in Canada. Instead, we want those people in the academy that are closer to the business questions to be rewarded with funding. That's the message that is illuminating the exit signs for scientists and engineers to depart from Canada because their special skills aren't valued."

    Gregory Marchildon, Canada Research Chair in Public Policy and Economic History at the University of Regina, says that the "federal government is dismantling key aspects of the scientific infrastructure" and that it will take "a generation or two to rebuild" the damage. The opposition's Stewart says that the Harper government is coasting on investments past and that its strategy of "barking an order at someone" and telling them "to go from being a scientist to somebody who does industrial applications" is doomed to fail.

    But Harper's supporters say that the criticism of his policies is little more than overheated rhetoric from a disgruntled community that now finds itself forced to survive on less-than Cadillac budgets in an era of fiscal constraints. Canadian science is actually quite robust, argues Eliot Phillipson, Sir John and Lady Eaton Professor of Medicine Emeritus at the University of Toronto. Phillipson chaired a Council of Canadian Academies' panel that found only two fields—natural resources and environmental S&T—had lost ground between 2005 and 2010.

    The expressions of anxiety are a function of a culture that is forever fretting about future funding, he adds. "It's part of the scientific DNA."

    Harper's critics see the 2015 election—and a new prime minister—as the only way to get the country's scientific enterprise back on track. But Bernstein, who once led CIHR and the Global HIV Vaccine Enterprise, argues that the growing polarization and unease could be erased if Canada simply abandons its "out-of-date" debate over basic versus applied research and sets ambitious national science targets.

    "I think we need to raise our sights," he says. "I don't think we should strive to be in the middle of the pack. It's no different than the 'Own the Podium' approach that Canada used in the Olympics," he explains, a strategy in which lavish funding for training produced an abundance of medal winners at the 2010 Vancouver Winter Games. "There's no reason that Canada shouldn't be at the very top, and we're not."

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