News this Week

Science  06 Jan 2012:
Vol. 335, Issue 6064, pp. 18
  1. Around the World

    1 - Antarctica
    Lockheed Gets Contract For Antarctic Support
    2 - Washington, D.C.
    NIH Launches Translational Center
    3 - Washington, D.C.
    Second Paper Pulled on Viral Link to CFS
    4 - Beijing
    'Big Dipper' Goes Online
    5 - Los Angeles, California
    UCLA Professor to Be Charged In Lab Death

    Antarctica

    Lockheed Gets Contract For Antarctic Support

    Cold science.

    McMurdo Station in Antarctica.

    CREDIT: JEFF SCANNIELLO/NSF

    Lockheed Martin has won a contract worth up to $2 billion to support U.S. science in Antarctica. The National Science Foundation (NSF) selected the Maryland-based aerospace giant in a competition that lasted more than 2 years longer than expected and featured a record seven bidders, including incumbent Raytheon Polar Services. The agreement, which runs until 2025, extends NSF's history of choosing a new winner each time it rebids the contract, the biggest ever for the agency. The contractor is responsible for providing all of the non-scientific needs of researchers based at NSF's three Antarctic stations. “It's like running a small town,” says Erin Tassey, a spokeswoman for Lockheed.

    Washington, D.C.

    NIH Launches Translational Center

    As 2011 drew to a close, the National Institutes of Health (NIH) said goodbye to one center and welcomed another. The reorganization became official on 23 December when President Barack Obama signed a 2012 spending bill that includes funding for NIH. The law creates the $575 million National Center for Advancing Translational Sciences (NCATS), which will aim to push basic discoveries more quickly to the clinic. And it moves the programs of the National Center for Research Resources to NCATS and other components of NIH. NCATS's acting director is Thomas Insel, director of the National Institute of Mental Health; acting deputy director is Kathy Hudson, NIH deputy director for science, outreach, and policy. A search is underway for a permanent director.

    Washington, D.C.

    Second Paper Pulled on Viral Link to CFS

    A Proceedings of the National Academy of Sciences (PNAS) paper from 2010 supporting a link between mouse retroviruses called MLV's and chronic fatigue syndrome (CFS) was struck from the scientific record on 27 December—5 days after Science fully retracted a controversial 2009 paper suggesting that another mouse-related retrovirus, known as XMRV, is linked to CFS. The retraction took away the only paper left indicating a role for mouse retroviruses in CFS.

    The Science study, by Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada, and colleagues, came under fire because other studies couldn't replicate the data. The PNAS paper, whose lead researcher was Shyh-Ching Lo of the Food and Drug Administration, initially seemed to lend support to the findings, although scientists pointed out that it fingered a different group of viruses.

    All seven of the PNAS paper's authors signed the retraction, stating that they themselves had been unable to isolate the virus in subsequent work. http://scim.ag/XMRVpaper2

    Beijing 4

    'Big Dipper' Goes Online

    In position.

    China's global positioning network.

    CREDIT: ILLUSTRATION BY MENG LIJING AND GAO WEI, XINHUA GRAPHIC

    China's BeiDou navigation satellite system, also known as “Big Dipper,” had begun a trial run, making China the third country in the world to operate such a system, after the United States's Global Positioning System and Russia's GLONASS, the director of the China Satellite Navigation Office, Ran Chengqi, told Chinese reporters at a press conference 27 December. By 2012, with six more satellites added to the current ten, BeiDou plans to offer services to customers in the Asia-Pacific region; by 2020, Beidou plans to have global coverage in operation with 35 satellites.

    Meanwhile, two Chinese space science missions moved from the planning stage into an engineering design phase, the Chinese Academy of Sciences announced the same day. One of the new satellites will carry a payload for quantum science experiments, and the other will be looking for evidence of dark matter. Both satellites are part of CAS's effort to boost space science as part of its Innovation 2020 plan (Science, 20 May 2011, p. 904).

    Los Angeles, California

    UCLA Professor to Be Charged In Lab Death

    The district attorney's office for Los Angeles County filed felony charges on 27 December 2011 against University of California, Los Angeles (UCLA), chemistry professor Patrick Harran, as well as the university itself, for maintaining an unsafe work environment that led to the 2009 death of a 23-year-old research assistant in a lab fire.

    On 29 December 2008, Sheharbano “Sheri” Sangji was severely burned while working with highly flammable chemicals without a protective coat in Harran's lab. She died 18 days later (http://scim.ag/safelabs).

    According to court documents, the district attorney's office holds Harran and UCLA criminally responsible for three felony counts of violating California's occupational safety regulations, which require that employers ensure that workers receive proper safety training and wear adequate protective equipment. If convicted, Harran could face up to 4.5 years in prison and UCLA could be fined $1.5 million for each count. Attorneys for UCLA responded that they intend to fight the charges, which they say contradict the findings of California workplace health investigators.

  2. Newsmakers

    FBI Investigates Stem Cell Case

    A pathology professor is accused of harvesting stem cells from umbilical cords without any oversight and selling them illegally. The Federal Bureau of Investigation (FBI) last week arrested Vincent Dammai, 40, of the Medical University of South Carolina in Charleston, along with two other men, in a “fraudulent scheme” to “perform unapproved procedures” with the cells on patients suffering from cancer, autoimmune diseases, and other conditions. The FBI says in its indictment the three reaped more than $1.5 million from the scheme.

    While stem cells derived from cord blood are being studied in dozens of clinical trials, any testing on people must adhere to guidelines set by the U.S. Food and Drug Administration (FDA). That didn't happen here, the FBI alleges; Dammai, for example, was said to have received umbilical cord blood in the mail for the purpose of creating stem cells without FDA oversight. In a statement, the university said Dammai has been placed on administrative leave and “his laboratory and office have been locked and secured.”

    Cancer Researcher Sued

    Craig Thompson, the president of Memorial Sloan-Kettering Cancer Center in New York City, is facing a $1 billion lawsuit from the cancer center he used to head. The Leonard and Madlyn Abramson Family Cancer Research Institute, part of the Abramson Cancer Center of the University of Pennsylvania, filed a complaint on 13 December alleging that Thompson, who left Abramson in October 2011, hid his involvement with a biotechnology company and deprived Abramson of intellectual property it was owed. Co-defendants in the suit are the company Thompson helped form, Agios Pharmaceuticals of Cambridge, Massachusetts, and Celgene Corporation of Summit, New Jersey, which has invested in Agios. The institute says damages are “estimated to ultimately exceed $1 billion.”

    Through his attorney, Thompson said that “the allegations in this lawsuit are unfounded and without merit.” The defendants have until early February to file a response with the court.

    http://scim.ag/CraigThompson

    Three Q's

    CREDIT: NASA

    John Grunsfeld, who this week became head of NASA's $5 billion science mission directorate, could be a mascot for the space agency: an astronaut who is also an astrophysicist. Grunsfeld has flown on five shuttle flights, most recently on the 2009 mission to service the Hubble Space Telescope. He fills a vacancy left by the departure of Ed Weiler in September last year.

    Q:What challenges and opportunities do you see ahead?

    The James Webb Space Telescope and the Joint Polar Satellite System are both hard projects that are very important in their fields. We need to show that we have the engineering expertise and the management skills to bring them to fruition. The opportunities are huge. We have satellites like Kepler that are telling us the universe is much richer than we imagined. The opportunities for young researchers to make significant breakthroughs are huge.

    Q:Given the budgetary climate, should U.S. researchers scale down their expectations of NASA in the coming decade?

    I don't think so. I think the science should drive the expectations. If we allow politics and the budget to determine what science we aspire to do, we'll end up with mediocre science.

    Q:Do you suspect you'll be accused by planetary scientists of being prejudiced in favor of astrophysics?

    My personal research in recent years has been on exoplanet science. I led the drive that led to the current Mars program. I'm dying to know what's going on on Europa. You could call me a closet planetary scientist. I have also spent a lot of time thinking about heliophysics.

  3. Random Sample

    Angry Birds? No, Happy Pigs

    CREDIT: UTRECHT SCHOOL OF THE ARTS (HKU) AND WAGENINGEN UR

    Tired of Angry Birds, the game in which you blow little green pigs to bits? If it's up to Dutch designers, you might soon be able to download a more constructive game, designed in collaboration with animal welfare researchers, that lets you play with real, living pigs.

    To prevent boredom and aggression in the animals, European regulations require farmers to provide pigs with interesting objects—often a chain with a piece of plastic attached—but nothing seems to hold their interest very long. So designers at the Utrecht School of the Arts came up with the idea for a more interesting game (www.playingwithpigs.nl) that would involve people as well. Via an iPad, a human player would move a bright spot around a big touch screen set up in the barn. Pigs, which apparently love new stimuli, would follow the light with their snout; when the spot moves through a triangle goal, the animal is rewarded with a lightshow while the human racks up points.

    The team has yet to actually build a prototype, says designer Kars Alfrink, who admits there are technical challenges—for starters, only one human can play at a time. The main idea, he says, is to get people thinking about their relationship with pigs, which are largely “invisible animals” until they end up on our plates. Co-developer Marc Bracke, who studies animal welfare at Wageningen University and Research Centre, says such a game could be useful for studying cognition and motivation in pigs as well.

  4. Cancer Research

    Unraveling the Obesity-Cancer Connection

    1. Gary Taubes

    A growing body of research shows that insulin and a related hormone play a key role in fueling tumors. They also may be a link between obesity, diabetes, and cancer.

    High burn.

    A PET scan lights up the brain where cancer cells are consuming glucose at a rapid rate.

    CREDIT: SCOTT CAMAZINE/NEWSCOM

    Growing breast cancer cells in the lab has been a revelation to Vuk Stambolic. The protocol he follows is decades old and widely used, but there's a puzzle at its core. The recipe calls for a large dose of glucose, a growth factor called EGF, and insulin. Add these to tissue culture, and tumor cells will be fruitful and multiply. A curious thing happens if you try to wean the tumor cells off insulin, however: They “drop off and they die,” says Stambolic, a cancer researcher at the University of Toronto in Canada. “They're addicted to [insulin].”

    What makes this so “bizarre,” Stambolic says, is that this behavior is totally unlike that of the healthy breast cells from which these tumor cells are derived. Normal cells are not sensitive to insulin—or at least not nearly to the same degree. They don't have insulin receptors, and they lack key elements of the insulin signaling pathway necessary to make insulin outside the cell immediately relevant to what goes on inside. Indeed, normal cells thrive without insulin. By contrast, the tumor cells in culture can't live without it.

    Peculiar dependency.

    Vuk Stambolic says that breast tumor cells seem “addicted” to insulin.

    CREDIT: SASHA PURIC

    This observation, although not original, is one of the insights that drew Stambolic to investigate the tumor-promoting effects of insulin. It has led him to spend the past decade studying a signaling pathway that is activated by insulin in healthy muscle, fat, and liver cells. Named for one of its key components—the PI3 kinase pathway—it also happens to be among the most frequently mutated pathways in human cancers.

    Insulin, a hormone produced in the pancreas, is more commonly known for its role in diabetes. But its reputation may be changing. Insulin and a related hormone known as insulin-like growth factor (IGF) are now at the center of a growing wave of research around the world aimed at elucidating what many scientists consider to be their critical role in fueling a wide range of cancers. Elevated levels of insulin and IGF are also the leading candidates to explain a significant correlation in epidemiology that has gained attention over the past 30 years: Obese and diabetic individuals have a far higher risk than lean healthy people of getting cancer, and when they do get it, their risk of dying from it is greater. And now that obesity and diabetes rates are skyrocketing, the need to understand this link has become far more urgent.

    The correlation between obesity and cancer can be found in the medical literature going back for several decades. But it wasn't until 2004 that two cancer epidemiologists put it all together, says Robert Weinberg, a cancer researcher at the Massachusetts Institute of Technology (MIT) in Cambridge. An article that year in Nature Reviews Cancer by Rudolf Kaaks, then of the International Agency for Research on Cancer, and the late Eugenia Calle of the American Cancer Society “laid down a challenge to the rest of us … to determine why obesity is such an important determinant of cancer risk,” Weinberg says.

    New on the radar screen.

    Robert Weinberg says the link between obesity, insulin, and cancer is compelling but not well understood.

    CREDIT: © BROOKS KRAFT/SYGMA/CORBIS

    The message of this research is straightforward, Kaaks says: Excess body fat seems to account for between one-quarter and one-half of the occurrence of many frequent cancer types—breast, colorectal, endometrial, renal cell, and adenocarcinoma in the esophagus, in particular. Kaaks adds, “The list is growing.”

    “The magnitude of the effect is huge,” in large part because obesity and diabetes are now so common, says Michael Pollak, an oncologist at McGill University in Montreal, Canada. It seems that cancer “loves the metabolic environment of the obese person,” Pollak says. Epidemiologic studies have also found that not only is type 2 diabetes associated with increased cancer incidence and mortality but so are circulating levels of insulin and IGF.

    Recent drug studies have sharpened the picture: Type 2 diabetics who get insulin therapy or drugs to stimulate insulin secretion have a significantly higher incidence of cancer than those who get metformin, a drug that works to lower insulin levels (see sidebar on metformin, p. 29). There's a large and growing body of evidence implicating insulin and IGF in cancer, Pollak says, “and it's causing a lot of people to stay up at night thinking about it.”

    Parallel worlds

    Researchers have recently upped their interest in the idea that insulin and IGF drive cancer in part because other hypotheses of cancer causation have failed to pan out. W. Robert Bruce, for instance, a cancer researcher at the University of Toronto, embarked in the late 1970s on what he described as a lengthy and fruitless search for mutagens in the diet and environment that might be responsible for colon cancer. “About a ton of feces later,” he says, he had found nothing.

    Now many cancer researchers, including Bruce, have come to believe that, whatever the carcinogenic substances or factors are, they mostly work not by directly damaging DNA but by promoting tumor development through a change in the hormonal environment around incipient tumor cells, increasing, for instance, insulin and IGF levels in the circulation. “There is a change in the endocrine and growth factor environment of cells,” Kaaks says, “that pushes cells to proliferate further and grow more easily” and to evade built-in programs that cause normal cells to die.

    To learn about the research on insulin, IGF, and cancer, Bruce says he had to read the diabetes literature—and what he found was a parallel universe. “It was a complete edifice of research in and of itself, not linked by any papers with the edifice of research in the cancer field—two big towers.”

    A few bridges have been built between these two parallel worlds, however. One connects cancer to diet and obesity. It was not obesity's harmful effects that first drew cancer researchers' attention but the flip side: the observation that tumor growth in animals is inhibited if not prevented entirely if the animals are semistarved. Peyton Rous, who would later win the Nobel Prize for his discovery of tumor-causing viruses, was the first to make the observation. It was confirmed in 1942 by Albert Tannenbaum, a Chicago pathologist, who demonstrated that feeding rats a diet just sufficient to keep them alive markedly increased their life span, in part by inhibiting tumors.

    Bad signals.

    Lewis Cantley suspects that a dysfunctional PI3K pathway may be behind many cancers.

    CREDIT: BRUCE WAHL

    Tannenbaum suggested that a likely mechanism was a phenomenon known as the Warburg effect, in which cancers adopt an inefficient type of metabolism commonly used by bacteria, known as aerobic glycolysis (see sidebar, p. 31). It goes along with a significant increase in the use of glucose for fuel by the cancer cells. In semistarved, growth-stunted animals, Tannenbaum proposed, the tumors could not obtain the huge amounts of blood sugar they need to fuel mitosis, division of the nucleus, and continue proliferating.

    In the decades since, researchers have debated whether the amount of blood sugar available to the tumor could be a driving or limiting factor in tumor development. But positron emission tomography scans of patients given fluorodeoxyglucose, a traceable analog of glucose, show that tumors continue to burn high amounts of glucose even if the blood glucose levels in the patients themselves are relatively low. “There's always plenty of glucose around,” says Chi Dang, a cancer researcher at Johns Hopkins University (JHU) in Baltimore, Maryland, “so it's got to be something else” fueling the tumors.

    Cancer accelerant

    That insulin and IGF may be the relevant “something else” that fuels cancer is a relatively new idea. But the evidence, as Bruce points out, has been accumulating for decades. In the mid-1960s, researchers demonstrated that insulin acts as a promoter of growth and proliferation in both healthy and malignant tissues. By the late 1970s, C. Kent Osborne, then at the National Cancer Institute, and his colleagues reported that a line of particularly aggressive breast cancer cells were “exquisitely sensitive to insulin” and that breast cancer cells express insulin receptors, even though the cells from which the tumors derive do not.

    “You find the highest level of insulin receptors in liver, muscle, and fat tissue naturally,” says Lewis Cantley, director of the Beth Israel Deaconess Medical Center at Harvard Medical School in Boston. Cantley originally trained as a biophysical chemist and found himself working on the link between obesity, diabetes, and cancer when he started studying how hormones and growth factors regulate cell metabolism. Low levels of insulin receptors, he says, can be found in half a dozen other healthy tissues as well, but that's it. So the abundant presence of insulin receptors in prostate cancer, colorectal cancer, and breast cancer cells, among other cancers, is significant, Cantley says: “They must be there for a reason; they must be helping to grow the tumor. And one thing they're doing is giving cancer cells the ability to take up glucose at a higher rate.”

    The second suspect in this scenario, the hormone IGF, was discovered in the late 1950s; its designation “insulin-like” wasn't made for another 20 years after that. IGF's structure is similar to that of insulin, and its effects can mimic those of insulin. But its secretion is stimulated by growth hormone, says Derek LeRoith, a diabetologist who now runs the Metabolism Institute at the Mount Sinai Medical Center in New York City.

    In the early 1980s, researchers discovered that tumor cells typically have two to three times as many IGF receptors as healthy cells, making them much more responsive to the IGF in their immediate environment. In rodents, functioning IGF receptors appear to be a virtual necessity for cancer growth, according to Renato Baserga of Thomas Jefferson University in Philadelphia, Pennsylvania, who “stumbled” upon the discovery in the late 1980s. Shutting down the IGF receptor in mice leads to what Baserga calls “strong inhibition, if not total suppression of [tumor] growth”; it is particularly lethal to tumors that have already metastasized from a primary site elsewhere in the body.

    LeRoith has genetically engineered mice so that their livers do not secrete IGF, resulting in one-quarter of the IGF concentration in their circulation compared with normal mice. When colon or mammary tumors are transplanted into these mice, according to LeRoith, both tumor growth and metastasis are significantly slower than when identical tumors are implanted in normal mice with normal IGF levels. When IGF is injected into these genetically engineered mice, tumor growth and metastasis accelerate.

    The consensus among those researchers studying the role of insulin and IGF in cancer is that these hormones supply both the fuel necessary for tumors to divide and multiply and the signals to continue doing it.

    A third conspirator

    An additional player has been identified as a key member of this particular network that influences metabolism, growth, and cancer: the enzyme PI3 kinase, discovered by Cantley and his colleagues in the mid-1980s. PI3K lies in the insulin signaling pathway and is activated by both insulin and IGF. Through its effect on other molecules, PI3K effectively regulates a cell's sensitivity to insulin. When PI3K is activated, insulin is more effective at stimulating the transport of glucose into cells.

    PI3K also turns out to play a major role in cancer—a discovery that came in a series of steps in the late 1990s. The finding that “put PI3K on everybody's radar screen as something important in human cancer,” Cantley says, was the realization that it is linked with a tumor suppressor gene called PTEN. Identified in 1997, PTEN is “the most frequently deleted gene in a whole host of advanced human cancers,” Cantley says.

    When researchers set out to elucidate what exactly the intact PTEN was doing to suppress tumors, they learned that it counteracts the work of PI3K. It removes a phosphorus atom from the fat molecule that PI3K makes, an effect equivalent to decreasing the influence of PI3K itself. And it turns out, as Victor Velculescu, a geneticist at JHU, has demonstrated, PI3K itself is commonly mutated—in a way that bypasses normal mechanisms for turning it off—in colon cancer and a host of other cancers as well, including breast, lung, brain, and ovarian cancers.

    The point, Cantley says, is that researchers have identified two general ways that work to step up activation of the PI3K pathway: by mutations such as those that alter PTEN or by abnormally elevated levels of insulin and IGF in the circulation. Most obese individuals have elevated insulin and IGF levels, as do type 2 diabetics. When PI3K signaling is increased, cells take up more glucose and may convert to a high-glucose metabolism—the aerobic glycolysis described by Warburg. It may be an inefficient means of generating energy, Cantley says, but it doesn't matter to the cell because the insulin makes sure it has considerable glucose to burn.

    Full circle.

    By tweaking insulin signaling, Craig Thompson and others have induced high-glucose metabolism in mice.

    CREDIT: PHOTO COURTESY OF MEMORIAL SLOAN-KETTERING CANCER CENTER

    So what's in it for the cancer cells? The answer, according to Cantley, appears to be that the carbon backbones of the glucose molecules are shunted aside during aerobic glycolysis rather than burned for fuel, and these carbon backbones can then be used to make new fatty acids.

    Normal fat cells do the same thing when they burn glucose: They preserve the carbon backbone for storing fatty acids as triglycerides, Cantley says. In cancer cells, the fatty acids are used to build new membranes for daughter cells. The glucose is also used to make new DNA and protein for the cells. So the cancer cells are effectively trading off an inefficient means of producing energy for a means of obtaining the resources necessary to create new cancer cells. It's a tradeoff they can easily afford because there's so much glucose now pouring in. “Remember, cancer cells have to duplicate themselves,” JHU's Dang says. “So this way you see the interplay between energy production and at the same time providing the skeletons, the building blocks for the cancer cells.”

    These researchers now suggest that it may make sense to divide tumors into two types, like diabetes: insulin-dependent and insulin-nondependent. If there are no mutations enhancing the activity of the PI3K pathway, Pollak says, then the cancer process will be dependent on the insulin and IGF in the circulation. “But if PI3K is mutated,” he says, “that cell is going to be highly proliferative, highly aggressive, and it couldn't give a damn about the insulin environment.”

    Recent evidence of the power of this signaling pathway comes from work by David Sabatini of MIT's Whitehead Institute and Nada Kalaany, who's now at Children's Hospital Boston. In 2009, they showed that PI3K appears to determine whether a tumor responds to calorie restriction. When they induced different types of human cancers in mice and then put the mice on semistarvation diets, some of the tumors shrank in response and some didn't. Tumors grew less in the mice with low PI3K pathway activity, more in those with high activity.

    For cancers with one of the mutations that activates the PI3K pathway, Sabatini says, calorie restriction has little to no effect because the insulin signaling is turned on anyway. These cancers are resistant to changes in insulin levels. “In obesity,” Sabatini says, “there are many things going on, but one of them is hyperinsulinemia [high circulating levels of insulin], and that is going to be an important driver of tumor genesis in animals or people. It's like mimicking the hyperactivation of PI3K. Instead of doing it by mutation, you do it by having tons of insulin around.”

    The picture that's emerging now, Dang says—one that's “clearly simplified and needs to be tweaked”—is that many common cancer genes when activated may increase the uptake of glucose and convert the cell to the Warburg-type of metabolism.

    Cause or consequence?

    This still leaves open the question of what comes first: the Warburg effect or the mutations that drive a cell to adopt it. Craig Thompson, now president of Memorial Sloan-Kettering Cancer Center in New York City, has been working on this problem for a decade. He believes, as does Cantley, that the likely first step in the progression to cancer is the increase in insulin signaling, which then induces the Warburg effect. Genetic defects follow. Thompson and his colleagues have shown that they can induce the Warburg effect in the cells of healthy mice, or in cells associated with cancer, just by activating PI3K and increasing insulin signaling. “If you put in components of the insulin pathway into these cells,” Thompson says, “you get the Warburg effect.”

    Once this happens and cells have increased their glucose metabolism 10- to 20-fold, Thompson says, one result is a significant increase in the generation of reactive oxygen species—free radicals—that can induce mutations in the genome. Cantley describes it as a vicious cycle. “The faster you do glucose metabolism,” he says, “the more likely you are to get free radicals that can damage DNA. … If the mutations happen to be in PTEN or PI3K, that could make the whole system rev up even further, making more free radicals, causing more DNA damage. So you're getting this feed-forward acceleration of tumor growth.”

    This hypothesis still has plenty of critics—MIT's Weinberg being the most prominent. Insulin and IGF may be the “most attractive mechanisms” to explain the obesity-cancer link, Weinberg says. But he argues that their primary role is not to turn on the Warburg effect or promote proliferation but to suppress cell-suicide mechanisms. “One of the mechanisms,” he says, “by which the body protects itself from cancer is by inducing incipient cancer cells to kill themselves by a variety of mechanisms. One of those mechanisms is apoptosis, and insulin and IGF activate an enzyme that in turn emits a series of antiapoptotic signals. A minimal amount of IGF is required just to protect normal cells from killing themselves. They're always poised on the brink.”

    Still, as Weinberg says, the role of insulin and IGF in cancer only “recently came on the radar screen” of most cancer researchers. “The epidemiology connecting obesity with cancer is very compelling,” he says. But “our understanding of the mechanism is still pretty soft.”

  5. Cancer Research

    Cancer Prevention With a Diabetes Pill?

    1. Gary Taubes

    There is a caveat to the observational research linking use of the insulin-lowering drug metformin to a decrease in cancer incidence: Studies of this kind are incapable of establishing a causal relationship.

    Dual use.

    Widely prescribed and cheap, metformin lowers insulin and, it appears, the risk of cancer.

    CREDIT: FRANCIS DEAN/DEAN PICTURES/NEWSCOM

    In 2005, Andrew Morris and his colleagues at the University of Dundee in the United Kingdom were following up on therapy for type 2 diabetes patients when they reported results that have since set the world of cancer research abuzz. They found that use of an insulin-lowering drug known as metformin was associated with a significant decrease in cancer incidence. Since then, half a dozen studies have confirmed it: Diabetics treated with metformin have from 25% to 40% less cancer than those who receive insulin as therapy or take sulfonylurea drugs that increase insulin secretion from the pancreas.

    The idea that reducing insulin and insulin-like hormones in circulation may prevent tumors has become a bright hope for drug research. A host of insulin-suppressing drugs are in the pharmaceutical industry pipeline, says Lewis Cantley, director of the Cancer Center at Beth Israel Deaconess Medical Center, which is part of Harvard Medical School in Boston. But the companies may have been beaten to the punch: “Metformin may have already saved more people from cancer deaths than any drug in history,” he says. It is one of the oldest and most commonly prescribed antidiabetic therapies in the world; some 120 million prescriptions are written for it yearly.

    There is a caveat to the observational research linking metformin use to a decrease in cancer incidence, however: Studies of this kind are incapable of establishing a causal relationship. Maybe metformin prevents cancer in type 2 diabetics. Maybe insulin and the sulfonylurea drugs given instead of metformin promote cancer risk. Maybe something else entirely is going on.

    Metformin activates an enzyme called AMPK in the liver, which then reduces the organ's synthesis and secretion of glucose, and thereby lowers blood glucose levels. But the drug also stimulates a tumor suppressor gene known as LKB1. Two University of Dundee biochemists, Dario Alessi and Grahame Hardie, worked out the AMPK-to-LKB1 connection; Cantley and Reuben Shaw of the Salk Institute for Biological Studies in San Diego, California, did so independently. This connection was what prompted Morris to study cancer incidence in diabetics who are taking metformin.

    As often happens in science, however, the physical mechanism may well be different from the hypothesized one. Instead of inhibiting cancer by activating AMPK and then LKB1, say Cantley and other researchers, metformin seems to work directly by lowering insulin and insulin-like growth factor (IGF) levels. “Metformin decreases glucose in the blood, and, as a secondary effect, decreases insulin levels,” says Michael Pollak of McGill University in Montreal, Canada.

    Evidence for that mechanism comes from animal studies. In September 2010, Phillip Dennis and his colleagues at the U.S. National Cancer Institute reported that metformin reduced lung cancer in mice that had been injected with potent tobacco-related carcinogens. But, as Dennis and his colleagues reported in the journal Cancer Prevention Research, they found no sign that metformin was activating AMPK in the lung tissue, as would be expected if that was the mechanism of action. In the liver, though, Dennis says, AMPK activation by metformin was “profound,” and both insulin and IGF levels in the circulation were suppressed. The results, Cantley says, “support the hypothesis that anything that lowers insulin and IGF levels will inhibit tumor growth.”

    The results also “provide a strong rationale,” as Dennis and his colleagues put it, for a clinical prevention trial. They hope to give metformin to patients who have had early stage lung cancer surgically removed and are at high risk of cancer recurrence. They intend to test the drug for safety, look for effects on insulin and IGF, and see whether it can prevent cancer in humans as it did for mice.

    Connecting the dots.

    Andrew Morris and colleagues showed that patients on metformin had 25% to 40% less cancer.

    CREDIT: ACADEMY OF MEDICAL SCIENCES, LONDON

    Other trials are beginning. One of the largest is being run by oncologist Pam Goodwin of the University of Toronto in Canada, who has been studying insulin and breast cancer since the mid-1990s. Goodwin says her interest was sparked after she realized that insulin may mediate the effects of obesity on breast cancer outcome. Fasting insulin levels in nondiabetic women are “predictive of breast cancer outcomes,” she observes: Obese women have high insulin levels, and they “do badly.”

    Goodwin's group demonstrated 6 years ago that metformin lowers blood sugar and insulin levels by nearly one-quarter even in women who don't have diabetes. Now Goodwin and her colleagues are running a multinational clinical trial in which 3500 breast cancer patients will be randomized to receive either usual care plus a placebo or usual care plus metformin, to see if metformin helps improve survival and prevent recurrence of the disease. “We anticipate that it will take another 2 years to enroll everyone,” she says, “and maybe 2 to 3 years after that before we have results.”

    Until then, as Goodwin emphasizes, the best they can say is that metformin may be beneficial for cancer. “All the preclinical and epidemiological evidence is pretty consistent and compelling, but all it's done is help us form a hypothesis. We need to proceed from here very, very carefully.”

  6. Cancer Research

    Ravenous for Glucose

    1. Gary Taubes

    Tumor cells can survive without oxygen and generate energy by a relatively inefficient process known as aerobic glycolysis. But researchers still don't know which comes first: the metabolism change or the cancer.

    Warburg effect.

    Healthy tissues (left) get energy through the efficient process known as oxidative phosphorylation. Tumors (right) use aerobic glycolysis, the so-called Warburg effect, which is inefficient but seems to enable proliferation.

    CREDIT: ADAPTED FROM M. G. VANDER HEIDEN ET AL., SCIENCE 324 (22 MAY 2009)

    The focus on obesity, cancer, and hormones has kindled a wide interest in the metabolism of cancer cells and particularly in work done in the 1920s by the German biochemist and later Nobel laureate Otto Warburg. Warburg observed that tumor cells can survive without oxygen and generate energy by a relatively inefficient process known as aerobic glycolysis. This conversion of cancer cell metabolism to aerobic glycolysis has been known as the Warburg effect ever since. It is akin to how bacteria generate energy in the absence of oxygen, although cancer cells do it even when oxygen is present (hence “aerobic”). Rather than converting glucose to pyruvate and burning that with oxygen in the cells' mitochondria, the pyruvate is converted to lactate in the cells' cytoplasm outside the mitochondria, and no oxygen is used. The process yields only one-ninth the energy, four ATP molecules instead of 36, from each molecule of glucose.

    One result is that cancer cells have to burn enormous amounts of glucose to thrive and multiply. This abnormally high glucose consumption is what's detected by the imaging technology known as FDG PET when it's used to identify where tumors might have spread in the body. Warburg hypothesized that the high-glucose metabolism is what drives cancer. But there has always been, and still is, significant controversy about why cancer cells use it: What's in it for them, if it's such an inefficient means of supplying energy? And how can we tell whether it is a byproduct of the cancer or a cause? Most researchers studying the Warburg effect now believe that the signaling pathways driving it are the insulin and insulin-like growth factor pathways. The question they're still hoping to answer is which comes first: the metabolism change or the cancer?

  7. Profile: Kit Parker

    Engineering a New Line of Attack on a Signature War Injury

    1. Greg Miller

    By jolting neurons in the lab, an Army officer and bioengineer hopes to gain ground on traumatic brain injury.

    Brain games.

    Bioengineer Kit Parker (left) and graduate student Borna Dabiri study the cellular mechanisms of traumatic brain injury.

    CREDIT: JON CHASE/HARVARD STAFF PHOTOGRAPHER

    When hijacked planes slammed into the World Trade Center towers in 2001, Kevin Kit Parker knew he had to do something. He'd always had a patriotic streak, and years earlier, while a graduate student in applied physics at Vanderbilt University in Nashville, Tennessee, Parker had enrolled in the Army Reserve Officers' Training Corps (ROTC). By the time of the attacks, he was a postdoctoral fellow, working on cardiac electrophysiology at Johns Hopkins University in Baltimore, Maryland, and in the middle of hunting for his first faculty position. He felt certain the country would soon be going to war, and despite having several job interviews on his calendar, he transferred to a unit he knew would be deployed. “I wanted to get in the game,” he says.

    While waiting to deploy, Parker accepted a job at Harvard University. With considerable trepidation, he asked the dean who'd just hired him for an immediate leave of absence to go to Afghanistan. It was a very unusual request, says then-dean Venkatesh Narayanamurti. Few, if any, Harvard professors have taken combat leave since World War II. But Narayanamurti admired Parker's dedication to national service. “I knew right away I would support him,” he says.

    By fall 2002, Parker was leading a team that patrolled a 900-square-kilometer swath between Kandahar and the Pakistan border, providing aid to villagers and searching for Taliban and Al Qaeda fighters. He finally started his job at Harvard in the summer of 2003, then deployed again in 2008, putting postdocs in charge of running the lab in his absence. His deployments caused Parker to reconsider the focus of his research and to establish a project on a signature injury of the wars in Iraq and Afghanistan: traumatic brain injury (TBI). He has been back to Afghanistan twice more as part of a panel of experts convened to assess how the military handles TBI and combat stress.

    The Pentagon estimates that more than 200,000 U.S. troops have experienced TBIs in the recent conflicts, mostly from roadside bombs and other improvised explosive devices (IEDs). The long-term effects of these brain injuries won't be known for decades, but there are already worrisome hints that TBI may compound the effects of combat stress and predispose veterans to the type of early-onset dementia seen in football players with a history of head injuries (Science, 29 July 2011, pp. 514 and 517). Despite the urgency of the problem, frustratingly little is known about the mechanisms by which an explosive blast injures the brain, Parker says. “I kept seeing guys get hit, and I thought, all right, I'll take a look at this and see if I can get a better angle on the problem.”

    Mission shift

    On a recent morning, Parker's students and postdocs mill about a conference room before their weekly lab meeting. They pour coffee and set out a plate of jalapeño bagels for Parker, who likes to goad others into eating spicy food. He arrives a few minutes late, wearing torn jeans and a red Harvard baseball cap with the bill folded into a sharp crease. A commanding presence at just under 6′6″ (2 meters), Parker has a booming voice that bears more than a trace of his upbringing in west Tennessee. He launches into a list of lab business he's scribbled on a whiteboard. Some Italian researchers have asked about collaborating; so has a team from Merck, the pharmaceutical giant. And Parker has just returned from a molecular medicine conference in Korea. “Y'all make some damn fine fried chicken over there,” he says to one of his Korean-born postdocs. “Hyungsuk, do you make that stuff at home?” When he shakes his head no, Parker pretends to be heartbroken. A second later, he's back to his list.

    In the thick of it.

    Parker, here searching for IEDs in Afghanistan, has changed the course of his research after two tours of duty.

    CREDIT: KIT PARKER

    When Parker first arrived at Harvard, his main academic interest was the physical forces that determine how cells and tissues build themselves. His lab did cardiac tissue engineering, and that's still the focus for about two-thirds of his group. At the lab meeting, postdoc Anna Grosberg presents a computational tool she's developed for quantifying the alignment of sarcomeres, the protein fibers that make up muscle cells. How the fibers line up affects how a muscle contracts, and Parker thinks the tool could be useful for clinical pathologists or companies interested in engineering cardiac tissue for drug screens or therapies. In quick asides, he quizzes David Coon, who handles industry relations and intellectual property issues for the lab, about the commercialization prospects, and asks Sean Sheehy, a grad student with a computer science background, how hard it would be to incorporate Grosberg's metric into a graphical software package. When Sheehy says it's doable, Parker jokingly tells him: “This is your project now, baby!”

    Ideas and projects spring up freely in the lab. A cotton-candy machine inspired a new way for making nanofiber scaffolds on which to grow cells (and a 2010 paper in Nano Letters). Back in his office, Parker shows off a movie on his computer of a more recent project: an artificial jellyfish. Cut from a polymer sheet coated with rat heart muscle cells, its form lacks the organic curves of the real thing, but the ghostly flap of tissue pulses across the screen with surprisingly lifelike motion.

    Parker sees his fledgling TBI research project as a moral obligation. He saw IED explosions firsthand in Afghanistan, and he has buddies who've suffered the consequences. When Colonel Geoffrey Ling, the program manager who oversees TBI research at the Defense Advanced Research Projects Agency (DARPA), asked Parker in 2006 if he'd ever thought about studying TBI, he demurred at first. “I said, ‘There have to be better people than me; I'm not a brain guy,’” Parker says. But as he started reading the scientific literature, he was struck by how little was known about what happens at the cellular level in a TBI.

    Concussion on a chip

    One prevalent idea has been that a blast wave or physical blow to the head tears the membranes of neurons, allowing positive ions to rush in and overexcite neurons to the point of killing them. Based on his experience with tissue engineering, Parker suspected something else might be going on instead, or in addition. He was surprised to see nothing in the research literature about integrins, proteins in the membrane of all cells that connect a cell's internal protein skeleton to the scaffold of proteins outside the cell, the so-called extracellular matrix. Parker reasoned that the force of a blast could propagate through this network of proteins, interfering with integrins and the many cell-signaling pathways they interact with.

    The first challenge was figuring out how to go about studying TBI in the lab. Researchers have studied TBI by issuing blows to the heads of rats, pigs, and other animals, but it's not clear how well those experiments replicate what the human brain experiences in a car crash or explosive blast. Moreover, Parker says, “if I start blowing up goats at Harvard, I'm not going to last long.” As an alternative, his lab has devised an arsenal of devices that can subject cultured neurons or slices of brain tissue to carefully calibrated forces. “We need to think of ways to replicate this on the bench top so you can mainstream the science,” Parker says.

    Their early work supports the idea that integrins may play a role in TBI. In one study, graduate student Matthew Hemphill and others put cultured rat neurons on a stretchy, square sheet of silicone that could be given a short tug by a high-precision motor. These tugs subjected the neurons to forces that the researchers estimated would be similar to those generated inside the head of a soldier exposed to an IED blast. Within a few minutes, microscopic swellings appeared on the spindly axons and dendrites that send and receive messages from neighboring neurons. Axonal injury is a hallmark of TBI, and a diffusion tensor imaging study by a different group published 2 June 2011 in The New England Journal of Medicine found evidence of axon damage in U.S. soldiers who suffered TBIs in Iraq. Additional experiments with the cultured rat neurons implicated a particular integrin signaling pathway in this damage. Treating the neurons with a drug that inhibits a component of this pathway called Rhokinase reduced damage to neurons after a simulated blast, the researchers reported in PLoS ONE in July 2011.

    In another study, published 2 August 2011 in the Proceedings of the National Academy of Sciences, a team led by then-postdoc Patrick Alford used the same setup to investigate the effects of a simulated blast on blood vessels. In this case, the researchers used rat muscle cells from the lining of blood vessels. When subjected to a sudden stretch, these cells flipped a genetic switch that made them more likely to contract and promoted their proliferation. Both effects would tend to clamp down on blood vessels, which could exacerbate a brain injury by depriving injured neurons of oxygen, Parker says. Again, inhibiting Rho-kinase reduced these effects.

    The findings could help clarify something that has baffled clinicians, says Jack Tsao, a neurologist and neuroscientist with the U.S. Navy and the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Blood vessels often constrict after a ruptured aneurysm or severe head injury causes bleeding into the brain. This response, called vasospasm, can cause a stroke by cutting off the blood supply to areas away from the injury. But Tsao says some service members with TBIs exhibit strokelike symptoms and other evidence of vasospasm even when brain scans show no signs of bleeding. The integrin mechanism Parker's team identified might explain how vasospasm can occur in the absence of bleeding.

    “These are both very elegant papers,” says David Hovda, a neuroscientist and director of the Brain Injury Research Center at the University of California (UC), Los Angeles. They highlight a potential mechanism of TBI that hasn't been considered before, Hovda says, but one that makes a lot of sense and raises interesting possibilities for treating TBI or minimizing its effects with drugs.

    Blast damage.

    Neurons (red label) subjected to a simulated blast (left) exhibit swellings on their axons and dendrites, a sign of damage that's absent in healthy neurons (right).

    CREDIT: DISEASE BIOPHYSICS GROUP, HARVARD

    On a recent visit, Hemphill and lab engineer Josue Goss, an Iraq War veteran himself, demonstrated a “blast bioreactor” that compresses neurons instead of stretching them. An aluminum contraption with a piston, it delivers a quick punch to cells sandwiched between two layers of gel. As a shock wave from a blast propagates through the brain, neurons may be subjected to this kind of punishment in addition to stretching, Hemphill says.

    Parker now wants to recruit three postdocs with neuroscience backgrounds to help expand his TBI research. One ambitious plan is to construct an amygdala on a chip. The amygdala is a hub in the brain's emotional circuitry, and the region has been implicated in human brain imaging studies of posttraumatic stress disorder. Parker wants to grow amygdala neurons on a chip and subject them to simulated blasts to see whether they're more sensitive to injury than neurons in other parts of the brain.

    Parker's work on TBI led to an invitation to join the “gray team,” a panel of experts convened by Admiral Mike Mullen, then chair of the Joint Chiefs of Staff, to advise the military on issues related to TBI and combat stress. Parker traveled to Afghanistan with other team members twice in 2011. They visited a DARPA field station that is testing blast dosimeters to measure the forces troops experience in an explosion, and they also studied the logistics of bringing an MRI scanner to Afghanistan so neurologists can get images of soldiers' brains within hours of a TBI rather than days.

    Postdocs in command

    Parker's absences have thrust the young scientists in his lab into leadership roles early in their careers. His second deployment to Afghanistan in December 2008 lasted 8 months. He charged three of his most senior postdocs—Alford, Grosberg, and Adam Feinberg, who is now an assistant professor at Carnegie Mellon University in Pittsburgh, Pennsylvania—with overseeing a long list of projects and collaborations and $2.5 million in grants. Parker got in touch when he could by cell phone, about once a month. “Sometimes we could hear helicopters in the background,” says Feinberg, who was the person in overall charge. As a group, the postdocs managed to keep the lab running more or less smoothly, Feinberg says. “We would go to breakfast once a week and hammer out what was going on with different projects, keeping track of grad students' progress and things we needed to get done for grants [and] paper writing.”

    Feinberg says the biggest challenge was keeping his own research on track: “My bench work suffered.” But he says the experience served him well in getting a job and setting up his own lab. Alford started a job at the University of Minnesota, Twin Cities, last year, and Grosberg will begin a job at UC Irvine this spring. “I have a better idea what I'm facing,” she says.

    Parker says he tries to prepare his postdocs for the next stage in their career by pushing them to take on increasing responsibility for research decisions and mentoring grad students: “In the military, you're training all the time; you're developing your subordinate leaders.” His military training influences the lab in other ways, too, from the meticulously clean workspaces to the uniformity of the font in PowerPoint slides. (“We're Arial all the way,” says Megan McCain, a graduate student. “If you used Times New Roman there could be trouble.”)

    Parker acknowledges that his style is not for everyone, and not everyone who has joined the lab has stuck around as long as planned. But he talks passionately about the obligation he feels toward those who do. He's taken several veterans of the Iraq and Afghanistan wars into his lab. “If you give them something to do, these kids will not stop,” he says. “It raises the professionalism of the whole lab.”

    Now 45, Parker has a wife and young daughter, and an ever-growing list of responsibilities on and off campus. He played an active role in bringing ROTC back to Harvard after a 40-year absence dating back to the Vietnam War, for instance, and now serves as the campus coordinator. His lab is running at full speed, and he's eager to see the TBI project take off. He doesn't relish the thought of leaving his family or getting shot at again, but he says he needs a sense of closure on the war in Afghanistan, and perhaps, too, on a chapter of his life in which he craved more action and adventure than the academic lifestyle typically allows. When the mission in Afghanistan finally wraps up, he says, he wants to be there to see it.

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