News this Week

Science  04 Feb 2011:
Vol. 331, Issue 6017, pp. 516
  1. Around the World

    1 - Cairo, Egypt
    Antiquities in Peril Amid Political Turmoil
    2 - Palo Alto, California
    Intel Commits $100 Million To University Innovators
    3 - Washington, D.C.
    U.S. Pushes Blue Sky Research
    4 - Bentong, Malaysia
    GM Mosquito Release Surprises Opponents and Scientists
    5 - Mali and Burkina Faso
    Malaria Treatments Triumph
    6 - Geneva, Switzerland
    CERN Gives Higgs Hunters An Extra Year
    7 - Berlin, Germany 7
    Picking Up the Pieces

    Cairo, Egypt

    Antiquities in Peril Amid Political Turmoil

    CREDIT: TARA TODRAS-WHITEHILL/AP PHOTO

    Egypt's famed antiquities, from its museums to archaeological sites, are under siege from the political upheavals that began last week. “My heart is broken and my blood is boiling,” wrote Zahi Hawass, the director of the Supreme Council of Antiquities, in a fax to an Italian colleague.

    Hawass was lamenting the actions of a small band of looters who on 29 January entered Cairo's Museum of Egyptian Antiquities, sliced the heads off of two mummies, smashed display cases, and damaged other artifacts. Thirteen cases were destroyed. A human chain soon formed outside the museum to protect the institution, which holds some 120,000 artifacts from prehistoric to Roman times, including King Tutankhamen's gold death mask.

    As Science went to press, attempts to enter the Coptic Museum, the Royal Jewelry Museum in Alexandria, and the Alexandria National Museum were so far unsuccessful, according to Egyptologist Sarah Parcak of the University of Alabama, Birmingham. But more exposed sites in the south, such as the cemetery of Saqqara and Abusir, were reported to have suffered extensively from looting before being secured. http://scim.ag/egypt-news

    Palo Alto, California

    Intel Commits $100 Million To University Innovators

    The computer chip giant Intel announced it will invest $100 million in U.S. universities to support cutting-edge research in computing and communications. Beginning with a multi-institutional collaboration devoted to computer visualization based at Stanford University, the funds will create a network of Intel Science and Technology Centers, each focusing on a particular area of research. Intel will initially fund each center for 3 years, with the option of two more years of support. Up to four Intel researchers will work at each center to promote the transfer of successful research results to the company.

    Intel officials say each center will adopt its own arrangements on intellectual property rights. But they say the preferred approach is to publish all research in the open literature and to make available with an open-source license any software that is developed.

    Washington, D.C.

    U.S. Pushes Blue Sky Research

    Following U.S. President Barack Obama's declaration of a “Sputnik moment” for competitiveness and energy innovation in his State of the Union address, the Department of Energy announced it will request big increases in two signature Administration energy-research initiatives: the blue-sky Advanced Research Projects Agency-Energy (ARPA-E) and the interdisciplinary Energy Innovation Hubs.

    In the president's 2012 budget request, the Administration will ask for more than $415 million for ARPA-E, more than doubling its total funding to date. The 4-year-old agency has received $415 million so far, but a $300 million request in 2011 may end up going unfulfilled because the previous Congress failed to pass a new budget, leaving most programs' funding flat.

    Congress has funded three of eight intended hubs, for nuclear power, energy efficiency, and solar fuels. Energy Secretary Steven Chu now says he wants three more, for a total of six in 2012. Current hubs are supported by $25 million a year.

    Bentong, Malaysia

    GM Mosquito Release Surprises Opponents and Scientists

    CREDIT: JAMES GATHANY/CDC

    Some 6000 transgenic mosquitoes developed to help fight dengue were released in Malaysia on 21 December, the country's Institute for Medical Research (IMR) announced last week. Developed by the U.K. biotech firm Oxitec, the bugs are male Aedes aegypti mosquitoes that have been genetically modified so that they can't father viable offspring—a strategy that could eventually decimate populations.

    Just like the first releases ever of the mosquitoes, on the Caribbean island of Grand Cayman in 2009 and 2010, the news came as a surprise both to groups that oppose the release of genetically modified insects and to scientists who support the strategy. Scientists worry that surprise releases may erode public trust and provide anti-GM groups with ammunition.

    Carried out in a remote area of Bentong, a district in the central state of Pahang, the study was designed to test transgenic males' survival and mobility. The study ended on 5 January, after which insecticides were sprayed to kill any remaining mosquitoes, says IMR. In last summer's Grand Cayman study, some 3 million mosquitoes were released to test whether they could actually help bring down the local population. http://scim.ag/gm-mosquito

    Mali and Burkina Faso

    Malaria Treatments Triumph

    Two studies involving more than 6000 children in Mali and Burkina Faso showed that treating them for malaria once a month during the rainy season—without testing to see if they are infected—can add to the benefit of sleeping under insecticide-treated bed nets. The World Health Organization recommends intermittent preventive treatment (IPT) with malaria for pregnant women and infants in regions with high transmission rates. The drugs are given to expectant mothers as part of routine prenatal care and to babies when they receive their vaccinations. However, it had been unclear how beneficial IPT would be in older children—up to age 5—in regions where bed nets are in wide use. The two new studies, published this week in PLoS Medicine, found that IPT can make a big difference to such children, reducing severe malaria by 70% or more.

    Geneva, Switzerland

    CERN Gives Higgs Hunters An Extra Year

    CREDIT: MAXIMILIEN BRICE/CERN

    Particle physicists at the European particle physics lab, CERN, have announced that they will chase the elusive Higgs boson for an extra year before a scheduled shutdown of their accelerator, the Large Hadron Collider (LHC). The announcement came just days after their U.S. counterparts at the Fermi National Accelerator Laboratory in Batavia, Illinois, were told to shutter their Tevatron machine in September.

    The feverishly sought Higgs boson is a key part of the mechanism that explains why particles have mass. The newer and more powerful LHC has a much greater chance of finding the particle than the Tevatron had, but CERN had planned to shut the machine down at the end of the year to fix teething troubles with superconducting magnets that forced them to run at half power. Now LHC operators say the accelerator has been running so well over the past year that they feel confident enough to put off the modifications until 2012 and continue colliding particles with a combined energy of 7 teraelectron volts. Guido Tonelli, spokesperson for the CMS detector, says the extra time might allow physicists to “exclude [the existence of] the Higgs from large mass regions and possibly even discover it, if nature is kind to us.” http://scim.ag/CERN-2012

    Berlin, Germany

    Picking Up the Pieces

    CREDIT: © STEPHANIE PILICK/EPA/CORBIS

    A collection of 3000-year-old artifacts that were destroyed in a World War II bombing raid have been pieced back together and went on display on 28 January in Berlin's Pergamon Museum. German adventurer and diplomat Max von Oppenheim led several excavations between 1911 and 1929 at the site known as Tell Halaf in what is now northern Syria, bringing back hundreds of artifacts, including a dozen giant basalt sphinxes, griffins, lions, and human figures. In 1943, a bomb set fire to his private museum in Berlin; when water from fire hoses hit the overheated statues, they splintered into thousands of pieces. After the war, the debris was collected and brought to the Pergamon, where it languished in the basement for half a century. In 2001, a team of archaeologists began piecing the 27,000 fragments back together. “Everyone had assumed the collection was a total loss,” says project director Nadja Cholidis. “It disappeared from the archaeological canon.” Restoring it, she says, “was a moral responsibility.”

  2. Random Sample

    Gene Ed

    CREDIT: HATNIM LEE

    This week, 200 Cornell undergraduates took a different kind of test: a genetic one. As part of the Cornell University Genetic Ancestry Project, these volunteers swabbed their cheeks and submitted DNA samples to the Genographic Project (Science, 15 April 2005, p. 340), which for 5 years has tracked the history of human migration through DNA studies. Sponsored by National Geographic and IBM, the project has analyzed genetic markers from 72,000 indigenous people and 400,000 people who bought $99.95 mail-in test kits in return for “deep ancestry” information.

    Cornell population geneticist Charles Aquadro organized the event to get students thinking about the legal, social, and ethical implications of genetic testing. He teamed up with the Genographic Project's Spencer Wells to map ancient wanderings of the students' ancestors from variations in mitochondrial DNA or the Y chromosome. “It's but one small snippet of ancestry,” says Aquadro. “But there's no marker relevant to medical [history].” (Results from a genetic testing project at the University of California, Berkeley, were never released to students after the California Department of Public Health said the genes being tested had health implications.)

    Aquadro is curious to see if the Cornell group is as diverse as volunteers Wells tested at a 2009 street fair in Queens, a famously multicultural borough in New York City; they turned out to represent all the major migration routes from Africa. Before the results come back in April, Aquadro's lesson plans will cover the pros and cons of genetic testing. “We're trying to address building a knowledge base before these things really hit them,” he adds.

    Noted

    >Members of Alzheimer's disease scientist Hui Zheng's lab at Baylor College of Medicine in Houston, Texas, have obviously struck a nerve with “Bad Project,” their YouTube parody of Lady Gaga's hit single “Bad Romance” (http://scim.ag/gaga-science). The video, which tells the story of a new Ph.D. student who inherits a research project that just won't work, has been viewed more than 1.5 million times since it was posted on 20 January.

    They Said It

    “Researchers of Canada: pay attention. Get on this. It's a fully funded grant opportunity in a very interesting area of research.”

    —Lorna Tessier, director of public relations for Canadian Blood Services, quoted in the Montreal Gazette, on a $500,000 grant available for research investigating whether it could be safe for gay men to donate blood. In Canada, as in the United States, all men who have had sex with another man since 1977 are barred for life from giving blood, due to concerns about spreading HIV. No one has yet applied for the grant, which was created 2 years ago.

    By the Numbers

    $100 million — The amount pledged by the Bill and Melinda Gates Foundation and United Arab Emirates leader Sheikh Mohammed bin Zayed Al Nahyan to vaccinate Afghan and Pakistani children against common childhood diseases, including polio.

    10.5 — Tons of carbon dioxide produced by an average New Yorker in 1 year. Residents of Denver, who rely much more on cars, generate about twice as much, according to a study in the journal Environment and Urbanization.

    11.9% — The average growth of U.S. university endowments in the 2010 fiscal year, according to the National Association of College and University Business Officers. Due to big losses in 2009, however, the median is still down $15.1 million from 2008.

  3. Human Genome 10th Anniversary

    Waiting for the Revolution

    1. Eliot Marshall

    Having the complete human DNA sequence hasn't yet produced big advances in primary medicine, prompting some to ask what's delaying the genomic revolution in health care.

    In 2009, the school of medicine at Johns Hopkins University turned itself inside out for the human genome. Although ranking consistently among the top medical schools in the United States, it scrapped the existing curriculum and installed a shiny new “Genes to Society” agenda over the summer. A committee slotted genetics into every nook and cranny of the school's 4-year program. Edward Miller, dean and CEO of Johns Hopkins Medicine, who backed the change, said at the time, “It's the biggest thing to happen in 100 years.”

    CREDIT: MARK M. MILLER/WWW.MILLERMEDART.COM

    Among the faculty members, geneticist David Valle took the lead in championing the overhaul. Valle says the impetus came from his late colleague Barton Childs, a geneticist who argued in his writings that doctors have been trained in an overly rigid concept of disease. Students are “taught everything … in terms of the average patient and the classic case,” Valle explains. But there are no such patients. Every case is unique because each person's genome is unique, Valle says. With its new education strategy, Johns Hopkins set out to show students that they should treat each patient as an individual.

    To do this, the school redid its course plan. Breaking with tradition, it added clinical encounters to the first 2 years—normally a time for book-learning—and inserted basic science into the third and fourth years, when doctors in training generally leave such lectures behind for clinical rounds. Johns Hopkins further added a series of short seminars over the 4 years to meld genetics and medicine in focused studies. With $20 million in gifts so far, Johns Hopkins has created a $2 million simulation center and a $52 million new curriculum building—complete with an anatomy lab where every dissecting table has an Internet connection.

    This departure is a gamble, but Johns Hopkins isn't taking it alone. Other medical schools and research centers are investing tens of millions of dollars each to join the genomic medicine bandwagon. Yet despite the excitement, some say this is a huge leap into uncharted clinical territory.

    This News article and another on gene patents (p. 530) launch a series of features this month commemorating the 10th anniversary of Science's and Nature's publications of the human genome (see Editorial, p. 511 and Essay, p. 546) and looking forward to the next decade of genomic research. All the stories and related material, including a podcast by the author of this story, will be gathered at http://scim.ag/genome10.

    Most doctors have not embraced the genomic revolution, according to leaders of medical professional groups, because they have trouble seeing how it will benefit their patients. A survey of American Medical Association members last year found that only 10% of respondents thought they had enough knowledge to use gene tests in prescribing medicines, although nearly all thought such tests were useful. DNA testing is growing rapidly in oncology to guide the treatment of some cancers, and in screening couples before conception and newborns to find dangerous mutations. Based on recent studies of cancer cell genetics, many labs are developing therapies to narrowly target tumor DNA. But aside from these situations, applications are scant; most public health reviews of DNA-based approaches have not found a health benefit.

    As doctors and scientists look back over the decade since the human genome was published, some are asking tough questions. Is the translation of DNA research into medical practice taking longer than expected? Has the genomic medicine revolution faltered?

    Such questions can elicit a sharp response from leaders in clinical genomics. Eric Topol, a pioneering researcher on DNA-related treatments in cardiovascular disease and cancer at the Scripps Translational Science Institute in San Diego, California, says the medical establishment is slow to change because it's “sclerotic.” In his view, studies that find insufficient evidence of benefit are often used as an “excuse” for not learning about new science.

    Still, Topol and many others in the field agree that proof of clinical usefulness is in short supply. “We need to … demand evidence and not get caught up in a naïve view that just because something sounds good, it's going to be good,” says James Evans, a medical geneticist at the University of North Carolina, Chapel Hill.

    Can you prove it?

    No one is more aware of the gap between today's health care and the promised future of genomic medicine than Greg Feero, an M.D.-Ph.D. who lives in both worlds. Feero studied neuromuscular diseases but now practices as a family doctor in Fairfield, Maine. From 2007 to 2009, he worked at the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. The agency employed him (and now retains him from afar) as an adviser. More than ever, he says, he is aware of the “stresses” piling up on primary care. In fact, you could say he is adding to them.

    Feero's job at NHGRI is to integrate genomics into medicine. Specifically, he aims to nudge primary care doctors, along with nurses and physician's assistants, to join the revolution, building up networks of like-minded medical leaders. They push credential-granting bodies to test for and certify “competencies,” or practical knowledge, of genetics. The approach has bite, because candidates learn whatever is required for board certification.

    Organizations that represent nurses and physician's assistants are quickly embracing genetic competency testing, Feero says. Specialist groups in cancer and cardiovascular disease have been “ramping up” training, too. But primary care physicians “have been very difficult to engage.” One reason, Feero says, is that doctors already have too many obligations. They are tying to adopt digital recordkeeping methods, follow more stringent rules in training, and adhere to new working-hour rules for residents. Their “plate is more full than when I left [Maine]” half a decade ago, he says. That often leaves physicians with little time for taking detailed family histories or learning about other genetic tools (see sidebar, p. 528).

    “We need to quit trying to push genetics into medicine.”

    —JAMES EVANS, UNIVERSITY OF NORTH CAROLINA, CHAPEL HILL

    CREDIT: KAREN TAM

    Competition for time is an important issue. But the bigger one, many doctors say, is the scarcity of data showing that gene-based methods actually protect or improve patients' health. “Practitioners are looking for evidence of impact before they make [genomic medicine] a priority,” says Gary Rosenthal, president of the Society of General Internal Medicine and a professor at the University of Iowa Carver College of Medicine in Iowa City. Like many, he argues that doctors will move fast if they see clear benefits—but they don't see them now and don't want to jump the gun.

    Evans, who is also editor of Genetics in Medicine, agrees. “We need to quit trying to push genetics into medicine,” he says. “We hear these grandiose statements that genomic technology is going to revolutionize medicine.” That may be true, but the revolution is going to take “decades,” he thinks. Like Rosenthal, he believes doctors will embrace technologies as they prove valid.

    But relatively few genomic approaches have been reviewed for clinical utility. For example, in 2 decades, the government-funded U.S. Preventive Services Task Force (USPSTF) has looked at just two topics in genetics. It approved one: In 2005, it recommended that women whose families have a high risk for BRCA cancer gene mutations be evaluated for genetic testing. Genetics “was not very much on [USPSTF's] radar screen,” says Muin Khoury, director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC) in Atlanta.

    That's why Khoury, a geneticist, pushed CDC to help evaluate DNA-based technologies for public health. In 2005, CDC created an independent working group called Evaluation of Genomic Applications in Practice and Prevention (EGAPP). Khoury says he hoped its seal of approval would speed new ideas into clinical use.

    EGAPP has done six comprehensive reviews in 6 years. Four more are planned this year, says Khoury, adding that the group is trying to become “faster and nimbler” to take on a growing caseload. “In the last 6 to 9 months, we have identified more than 200 new applications, mostly new genomic tests, and mostly in cancer,” says Khoury. But rumors are circulating in the genomics community that CDC may cut funding for this office. Khoury has no comment.

    All but one of EGAPP's reviews have been unfavorable or neutral, generally because the panel didn't see evidence of a health benefit. For example, in January an EGAPP group recommended against routine testing for factor V Leiden and prothrombin gene variants in people with a history of deep-vein blood clots. Both genes influence such clotting. People who have had such clots should be treated with anticoagulants anyway, regardless of genetic status, the panel concluded. And in a second group—relatives of people who have had clots but who themselves have not—the panel judged that it would be too risky to treat preemptively with anticoagulants (which can cause hemorrhaging) based on genetic status alone.

    The exception to EGAPP's general pattern was a decision in 2009 in favor of a test for mutations linked to an inherited type of colorectal cancer, called Lynch syndrome. The evidence, EGAPP concluded, justifies testing colon tumors of newly diagnosed patients—not to help the patient but to alert relatives of those who test positive that they have a 50% risk of being affected. Although it won EGAPP's blessing, the Lynch syndrome test has complexities that may put off some clinicians. It looks “simple and straightforward,” says Douglas Campos-Outcalt, a leader in family medicine and associate head of the University of Arizona Cancer Center in Phoenix. But it isn't. “What if the patient doesn't want their test results spread around?” Campos-Outcalt asks. And what do you tell the relatives about their own risk? “Basically,” he says, the message is, “refer them to a genetic counselor.”

    There's another practical question: Who should pay? There's no evidence so far that this test can be used to guide the treatment of the person with the tumor. So doctors must be creative about billing. At Intermountain Healthcare in Salt Lake City, clinical geneticist Marc Williams has persuaded hospitals in the system that they should pay because the test “returns money to the health plan” in the long run. It “appropriately” enables the system to recruit other individuals who would subsequently pay for their own testing. And it identifies a certain number of people who may be able to avoid cancer, and the accompanying health care costs, by having a polyp removed.

    Some genetic tests make sense primarily in a public health context, Khoury says. This is one of them. He speaks of using the Lynch syndrome assay for “cascade testing” of affected families. By screening 150,000 people, one can find 4000 to 5000 high-risk individuals.

    Making medicine precise

    In contrast to those who focus on missing evidence, Topol sees genomic medicine's glass as half-full—and filling fast. He rattles off a series of recent DNA-based technologies that appear to have important uses in medicine already. Tumor analysis heads his list: Topol points out that major clinical centers—including the Massachusetts General Hospital in Boston, MD Anderson Cancer Center in Houston, and the U.K. National Health Service—are now sequencing DNA from patients' tumors with an aim to improving therapy. The data are used in research, but Topol expects DNA-guided clinical approaches to emerge soon.

    Limited resource.

    The number of U.S. medical geneticists certified each year has declined while the number of genetic counselors, who hold master's degrees, has risen.

    For a decade, oncologists have been using the drug Gleevec to target tumor cells in patients with chronic myeloid leukemia. The same concept now drives the search for a host of other therapies. With a complete list of normal proteins (and mutations in tumors) from the human genome, they aim to narrowly target colon cancer, lung cancer, glioblastoma, and melanoma.

    Topol's institute has recently been studying another hot topic: DNA mutations that affect how patients respond to medicines in cardiovascular therapy. Specifically, his group has been sequencing the exomes—all the protein-coding DNA—of hundreds of patients being treated with clopidogrel (Plavix), a drug given to prevent the formation of clots after a stent has been placed in a coronary artery. Some versions of the gene for the enzyme CYP2C19 have been identified as a “major” risk factor in patients who metabolize clopidogrel poorly, increasing the danger of blood clots and death. The stakes are high, says Topol, because the mutation is common and clopidogrel is widely prescribed. In March 2010, the U.S. Food and Drug Administration (FDA) added a black-box warning, the highest level of alert, on the drug's label. It describes the genetic risk and notes that it can be tested for.

    This is one of hundreds of pharmacogenomic risks under study. Some have been well nailed down, such as those involving the patient's response to warfarin (an anticlotting medicine), mercaptopurine (for immune suppression), abacavir (for HIV/AIDS), and interferon (for hepatitis C). “There are many others in the on-deck circle,” says Topol.

    One indication that genetic testing has value is that business clients are willing to pay for it, says epidemiologist Robert Epstein, president of the Medco Research Institute of Franklin Lakes, New Jersey. Several years ago, his company began to look for customers who would pay for expert advice on the utility of gene tests, particularly those used in prescribing drugs. Since 2008, he says, the company has signed up 300 health plans, insurers, and unions, representing 65 million individuals. In that time, Medco has reviewed “hundreds” of genetic tests and approved 12 as valid and worth paying for—a judgment that is both about clinical efficacy and economics.

    Epstein is “bullish” on pharmacogenomic tests. “They give more precision to medicine,” he says, and who could not want that? In his view, EGAPP has been unduly conservative in its approach to vetting new technologies, and he thinks its high rejection rate in the past may not be a good indicator of the quality of products now in the pipeline. His company is now running half a dozen major pharmacogenomic trials.

    Speaking last October in Washington, D.C., FDA Commissioner Margaret Hamburg noted that despite $2.7 billion spent to decode the human genome and a decade of analysis, “fewer than 50 therapies actually have genetic tests as part of their labeling” to guide users. Still, FDA expects to see a surge of new gene tests and gene-targeted therapies this decade, and Hamburg is concerned that the agency may not have the data or the scientists it will need to do the necessary evaluations. She made a pitch in her October talk for funds to do more “regulatory science.” And to help keep up with the pace of discovery, FDA and the National Institutes of Health last year agreed to work together to identify, monitor, and evaluate new therapies as they emerge from research labs.

    If Johns Hopkins's gamble is right, it's not only FDA that will need to adapt. Medical geneticist Bruce Korf of the University of Alabama, Birmingham, has been involved in national efforts to reshape medical school curricula, and he argues that although there's little published evidence of health benefits from genomics, clinical institutions across the board will need to keep up or risk finding themselves “behind the eight ball.” Changes are coming, perhaps slowly at first, but the effect over time will be “pervasive” and “transformational,” he maintains.

    The genomic revolution is sometimes described as a tidal wave that's racing toward the shore, says Feero. He thinks that's the wrong metaphor. New ideas are flooding in, he says, but they are filtering through the health care system in spurts, as they always have. Most people will perceive the change not as tsunami but as a “slowly rising tide.”

  4. Human Genome 10th Anniversary

    Human Genetics in the Clinic, One Click Away

    1. Eliot Marshall

    At Intermountain Healthcare network in Salt Lake City, geneticists are using digital tools to slip up-to-date education into the daily run of medicine in ways that doctors may find helpful.

    The number of genes identified as factors in human disease has exploded in the past decade. Although the exact influence of many remains elusive, the potential impact on medicine is huge, as suggested by a global tally on a public Web site called GeneTests (www.genetests.org). It now lists 2267 available genetic tests.

    Do it yourself.

    Marc Williams helped create a Web site at Intermountain Healthcare that invites patients to create their own family medical histories.

    CREDIT: COURTESY OF INTERMOUNTAIN HEALTHCARE.

    The volume and the tentative nature of the information are a problem for medicine, however. “The fact is, it is not possible for most primary care doctors to be highly knowledgeable about all aspects of medical conditions,” wrote Gary Rosenthal, president of the Society of General Internal Medicine and a University of Iowa professor of medicine, in comments last year to a U.S. Health and Human Services panel on genetic education. He told the group that it seemed “unjustified” to ask doctors to keep up with everything in genetics. They don't have time.

    Finding a way to give medical practitioners the right genetic information, but not too much, at the point of care is one of the biggest challenges in the field, says Bruce Korf, chair of human genetics at the University of Alabama, Birmingham. Indeed, Korf ranks this issue as second only to the main one: developing evidence that genomic medicine can make patients healthier (see main text, p. 526).

    Computer technology may come to the rescue. At Intermountain Healthcare network in Salt Lake City, geneticist Marc Williams (right) is using digital tools to slip up-to-date education into the daily run of medicine in ways that doctors may find helpful. One trick is to insert “info buttons” into Intermountain's data files. This health care network uses electronic records throughout the system to track patients' progress. As doctors fill in the forms, they see an “i” surrounded by a small blue circle pop up at certain points, explains Williams, director of the Intermountain Healthcare Clinical Genetics Institute in Salt Lake City. These clickable spots offer help when doctors are describing a patient's complaint, ordering a lab test, or prescribing drugs.

    This News story and the one it accompanies, plus another on gene patents (p. 530), launch a series of features this month commemorating the 10th anniversary of Science's and Nature's publications of the human genome (see Editorial, p. 511 and Essay, p. 546) and looking forward to the next decade of genomic research. All the stories and related material, including a podcast by the author of this story, will be gathered at http://scim.ag/genome10.

    If one entered “Marfan syndrome” as a patient problem, for example, a blue info button would appear with a list of links offering a genetic reference service, gene reviews, or perhaps more readable articles from Internet resources. “You get the content much, much more quickly than going to Google,” he says.

    Info buttons of the future may gently direct the course of treatment. For example, cardiac patients can get into serious trouble if, because of the genes they've inherited, they metabolize the anticlotting agent Plavix (clopidogrel) too slowly. An info button might therefore note a genetic test to evaluate how fast a person metabolizes the drug. But Williams says that Intermountain's cardiology department has decided that the genetic test isn't as useful as a platelet reactivity test, which gives a more direct indication of clotting risk. So the info button could say, “Maybe you shouldn't order the genetic test,” or “Maybe you should consider a different test.”

    Intermountain aims to use digital methods to crack another knotty problem in primary care: the failure to gather useful family medical histories. Asking patients about their relatives is a quick way to get into genetic risks. But doctors typically don't do this thoroughly, many studies have concluded, mainly because they don't have time. Intermountain is trying a new tack. A few months ago, it added a program to its Web site, Williams says, in which patients are invited to build their own family medical history. It's too early to say whether the strategy is working, but the idea is that the patient gathers the raw information, the computer analyzes it, and the doctor and patient together discuss the results. It should help identify high-risk cases of genetic diseases.

    CREDIT: COURTESY OF INTERMOUNTAIN HEALTHCARE.

    Intermountain is one of several networks in the United States that are beginning to integrate genetic data into primary health care. A wave of innovation in point-of-service education is likely to spread over the wider health community in time, but this may be limited by the sluggish rate of change in electronic health recordkeeping. At the moment, Williams says, not one of the commercial programs he's seen is capable of converting results from genetic tests into data files. This means that automated tools like those at Intermountain designed to scour medical records and give summary reports to physicians can't incorporate genetic data. Williams is waiting for two revolutions: one in medicine and another in records management.

  5. Human Genome 10th Anniversary

    The Human Genome (Patent) Project

    1. Sam Kean

    A decade of research has scientists asking if patent priorities are misaligned.

    Legal limit.

    Patents can limit a company's ability to test for multiple genes with gene chips.

    CREDIT: AFFYMETRIX

    The start-up company Foundation Medicine in Cambridge, Massachusetts, has an impressive pedigree. Its founders and advisers include veterans of the Human Genome Project (HGP) as well as scientists from various elite institutions around Boston. But when Foundation Medicine hired its first official employee last April, it ignored the scientific community and tapped Gary Cohen—a lawyer. That turned out to be a good thing.

    Foundation Medicine plans to offer a type of diagnostic cancer test: Oncologists would send the company tissue, and it would search for aberrations in 100 or so genes to determine how to treat the cancer. Many important cancer genes are covered by patents, however, so not everyone can legally analyze them for commercial purposes. And when Cohen surveyed the patent landscape, it appeared grim: Investigating all the relevant patent claims (issued and pending) for possible infringement would cost at least $35 million, he estimated. On top of that, the company would have to negotiate licenses and possibly pay to use many genes. The company has $25 million, total, in venture capital.

    Once upon a time, before the HGP, patenting criteria aligned very nicely with genetics. “The patents granted early in the game—that period of intense gene discovery from the mid-1990s to early 2000s—read like the science of the day: all Mendelian traits, focusing on one gene associated with one disease,” says Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy in Durham, North Carolina. He pauses. “We now know that's wrong.”

    This News story and another on genomic medicine (p. 526) launch a series of features this month commemorating the 10th anniversary of Science's and Nature's publications of the human genome (see Editorial, p. 511 and Essay, p. 546) and looking forward to the next decade of genomic research. All the stories and related material, including a podcast by the author of this story, will be gathered at http://scim.ag/genome10.

    Scientists now realize that any one gene accounts for only a small risk for most diseases. What's more, many “common” diseases like diabetes are in fact idiosyncratic on a molecular level, the result of many distinct DNA variations. Many diagnostic companies have therefore shifted focus and offer so-called multiplex tests, which can scan dozens of genes and study the molecular products of each. Cheap sequencing technology already has some scientists talking about whole-genome scans for diseases. “Many diseases are caused by multiple factors, so we want our products to be as unbiased as possible,” says Sandra Wells, chief intellectual property counsel at Affymetrix, a diagnostics company in Santa Clara, California.

    Patents last up to 2 decades, however, so they cannot evolve as quickly as genetics has. Many companies have already set up businesses around one or a few genes, most notably Myriad Genetics, which tests for hereditary breast cancer genes. In fact, one-fifth of human genes—especially potential moneymakers associated with diseases—are covered by patents. So a commercial outfit developing a diagnostic test faces quite a “patent thicket.” One survey by Mildred Cho of Stanford University in 2003 found that one-quarter of diagnostic labs had already stopped providing a test because of patent worries, and half had scrapped plans to develop one.

    Diagnostics is the most obvious area in which critics say gene patents and gene science have become misaligned. But disputes over the proper way to patent genes—especially how many patents to grant and how broad to make them—have affected most areas of biotechnology. “Because the patent system has collided with something inherently huge and inherently balkanized like the genome,” says Cohen, “the ability to analyze each relevant gene and do one-at-a-time licensing has become untenable.”

    Workarounds?

    There are two basic kinds of gene patents. The first covers gene sequences and related products. Some patents of this kind cover stretches as short as 15 nucleotides and also cover any attempt to synthesize that DNA. Other patents claim all genetic variation within a stretch of DNA and variation in the protein it produces—even products not identified by the patent filer.

    Most DNA sequencing machines still rely on synthesizing DNA, says James Evans, a geneticist at the University of North Carolina, Chapel Hill. As a result, he says, even with research sequencing, “it's extraordinarily hard to argue that when we sequence an individual's genome we aren't violating patents right and left.” Testing for the presence of certain DNA variations also strays into gray legal territory, says Cook-Deegan. For instance, the hip sequencing companies 23andMe and Navigenics test for, respectively, Myriad's breast cancer genes and variants of APOE, a gene linked to Alzheimer's disease.

    The second gene patents are method patents, which are often extremely broad—many cover any attempt by any means to associate a stretch of DNA with a given disease, like heart disease or hereditary colon cancer. A 2009 study in Nature Biotechnology examined two dozen commonly tested-for genetic diseases and concluded that three-fourths of method claims are “difficult” or “impossible” to circumvent.

    The danger for companies hoping to use patented genes in their products isn't necessarily getting sued by hundreds of opportunistic patent trolls. Universities and nonprofits—groups less likely to enforce patents aggressively—own most patents on genes used in diagnostic tests, and when Cohen fully analyzed the patents on a handful of genes that Foundation Medicine might use, he was encouraged, finding plenty of room to operate. But that doesn't lower the cost of investigating hundreds of patents, because biotech patent holders swap rights constantly and because most licensing agreements are confidential.

    To avoid potential lawsuits, a Foundation Medicine or an Affymetrix has to negotiate individual royalties with each patent holder, which presents its own problems. One is “royalty stacking”: If 50 companies each want 2% of net profits, that's not a good business model. Even flat fees can make diagnostics untenable, a situation Cohen describes as a “$1000 genome with a $100,000 royalty burden.”

    Biotechnology isn't the only field to face dense patent thickets, of course. Electronics companies do, yet they still manage to inundate consumers with goods—often by “inventing around” certain patents. Scientists such as Steve Rosenberg, chief scientific officer at CardioDx in Palo Alto, California, which diagnoses cardiovascular diseases via genes, see a lesson here. Many genes are always expressed together, he explains, so tests can circumvent a patented gene by searching for the products of an unpatented one. “You can substitute genes,” he says. “That can give you a workaround.”

    However, some scientists argue that genetic workarounds can fall short of clinical standards. In April, the National Institutes of Health's Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) published a report on gene patents. (Both Evans and Cook-Deegan sat on the committee.) The report noted that, if a test uses only freely accessible genes, “individuals with the disease who have a mutation in the patented gene would go undetected and undiagnosed. … Moreover, given the number of existing patents, … an unpatented substitute may not be available.”

    Hopes that new sequencing technologies—say, graphene-based DNA sequencers, which read bases electronically—can circumvent patent restrictions on gene synthesis might be overblown, too, says Evans. “It's not clear what platform will be the technology of choice. … In fact, it's almost assured that a variety of platforms will be used for the foreseeable future.”

    For these reasons, many lawyers and scientists argue that the sheer number of patents poses unnecessary barriers for biotech companies and can even squelch investment. Says Wells: “The absence of clear guidance on the patentability of genetic information almost certainly results in delays of new product launches.” As for basic research, Evans says it moves ahead nowadays because scientists blatantly ignore patent claims. “But as the financial stakes get higher,” he says, “it's less likely that people will continue to ignore them.”

    Solutions?

    While some despair, a few people think they've found a machete to hack through the human genome thicket. But before they start cutting, most are waiting for the outcome of an important and likely precedent-setting court case involving Myriad. A state court in New York recently invalidated its sequence and method patents, but Cook-Deegan notes that the “heavy betting among intellectual-property types” is that the patents will be upheld in federal court. If that happens, he says, “in a plain-English reading,” most sequencing and diagnostic technologies would violate many patents.

    This confusion is unlikely to evaporate no matter how the Myriad case turns out, so policymakers have considered other solutions. The SACGHS report recommended exemptions from infringement liability when using genes in diagnostic tests, for instance. But it's hard to imagine this solution appealing to patent holders who did the hard work of discovering genes and want remuneration. And most biotech companies don't want the government involved anyway; they prefer their own, voluntary solutions.

    One solution could involve an independent clearinghouse to manage intellectual property, which could reduce the cost of compliance by providing a single place to find patents and licenses. Along these lines, MPEG LA, a company headquartered in Washington, D.C., that specializes in creating patent pools (it brought 900 patents together to create the MPEG digital video standard), announced plans in April to set up a “supermarket” for diagnostic gene patents in the latter half of 2011. “In the ‘supermarket,’ people will have choices. They can literally shop for what they need,” said Lawrence Horn, president of MPEG LA. He can't ensure a company will find every patent it needs, but given that nonprofits own many patents, he feels confident that many will stock the supermarket with diagnostics licenses, even if they reserve other rights (like the right to develop DNA therapeutics).

    Meanwhile, in the absence of a central group, some companies have developed their own machetes. Navigenics posted a formula on its Web site that outlines how much it is willing to pay (not much) for any one gene among the thousands it sequences with every customer. Cook-Deegan, among others, praised the idea, saying it's “really smart. It says, ‘We respect intellectual property but don't want to let it get in our way.’”

    It will take a similarly Solomon-like solution to appease both patent holders and companies clamoring to pursue promising genetic research in DNA diagnostics and sequencing and other fields. The HGP has yet to fulfill the implicit promises it made to revolutionize medicine, and multiplex and whole-genome analysis could be the start. But “when it comes to intellectual property,” says Cohen, “lawyers, businesspeople, and policymakers need to be as diligent and creative as the scientists working to bring this transformation to the clinic.”

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