Tapping the crowds for research funding

Scientists are exploring crowdfunding as a potential new source of cash for their research.One day early in 2011, Jarrett Byrnes and Jai Ranganathan, both ecologists at the National Center for Ecological Analysis and Synthesis, Santa Barbara, CA, USA, had a great idea about an alternative way to fund research projects. Byrnes was sitting in his office when Ranganathan came in to tell him about a proposal he had seen on the crowdfunding website Kickstarter (www.kickstarter.com) to erect in Detroit a statue of RoboCop, the robot-human hero of a US science fiction action film. “The RoboCop project seemed a little esoteric, but the proposers had done a fabulous job at communicating why it was both interesting and important,” Byrnes said. It took the internet by storm and raised more than US$65,000 from almost 3,000 backers.If this could be done for RoboCop, Byrnes and Ranganathan wondered whether it could be done for science as well. They asked friends and fellow scientists whether they would be interested in crowdfunding a research project and, after receiving substantial positive feedback, launched #SciFund Challenge in November 2011 with 59 research proposals. #SciFund Challenge helps researchers put together a crowdfunding proposal, supports their outreach activities and launches coordinated campaigns on the crowdfunding website of their partner RocketHub (www.rockethub.com). “We thought we would do it all at the same time so we could help each other out,” explained Byrnes, who is now chief networking officer for #SciFund Challenge.Crowdfunding is the practice of funding a project by raising many small contributions from a large number of individuals, typically via the internet. An artist, film-maker or musician would put together an online profile of their project and choose a platform such as Kickstarter, RocketHub or Indiegogo for its presentation. If people like the project, they can pledge money to it. Backers are usually charged only if the project succeeds in reaching its funding goal before the deadline. Kickstarter is one of the largest crowdfunding portals and focuses on creative projects; in 2012, more than 2 million backers pledged more than US$320 million to Kickstarter projects (http://www.kickstarter.com/year/2012?ref=what_is_kickstarter#overall_stats).Creative projects always work towards a concrete product—an exhibition, a DVD or a computer game—which is not necessarily the case for science, particularly basic researchThe challenge for Byrnes and others is whether crowdfunding works for science. Creative projects always work towards a concrete product—an exhibition, a DVD or a computer game—which is not necessarily the case for science, particularly basic research. Would people donate money for the pursuit of knowledge? In a time of economic crisis and budget cuts, many scientists are eager to give it a try. Crowdfunding of science has exploded in recent years, with funding goals becoming increasingly ambitious; some projects have attracted US$10,000–20,000 or even more. New platforms, such as Petridish, FundaGeek or Microryza, specifically cater to research projects [1]. The academic system is starting to adapt too: the University of California, San Francisco, CA, USA, has made a deal with the crowdfunding site Indiegogo that allows backers to make money donated via the site tax deductible [2].Kristina Killgrove, now assistant professor in the department of anthropology, University of West Florida, USA, became interested in crowdfunding when traditional ways of funding research were not available to her. “At the time, I did not have a permanent faculty job. I was an adjunct instructor, with a contract for only one semester, so there was no good way for me to apply for a grant through regular channels, like our National Science Foundation,” she explained. Her proposal to study the DNA of ancient Roman skeletons to learn more about the geographical origins and heritage of the lower classes and slaves in the Roman Empire was part of the first round of #SciFund Challenge projects and attracted donors interested in ancient Rome and in DNA analysis. She exceeded her financial target of $6,000 in less than 2 weeks and eventually raised more than $10,000 from 170 funders.Ethan Perlstein had also reached an academic deadlock when he first turned to crowdfunding. His independent postdoctoral fellowship at Princeton University, USA, came to an end in late 2012 and his future was unclear. Grants for basic research came in his experience from the government or foundations, and he had never questioned that premise. “But as I felt my own existential crisis emerging—I might not get an academic job—I started to think about crowdfunding more seriously. I searched for other scientists who had tried it,” Perlstein said.“It is time to experiment with the way we experiment,” Perlstein''s crowdfunding video proclaims. Indeed, he approached crowdfunding in a scientific way. He analysed various successful projects in search for some general principles. “I wanted a protocol,” he said. “I wanted to do as much as I could beforehand to increase the likelihood of success.” Together with his colleagues, David Sulzer, professor in the departments of neurology and psychiatry at Columbia Medical School, New York, NY, USA, and lead experimentalist Daniel Korostyshevsky, he asked for $25,000 to study the distribution of amphetamines within mouse brain cells to elucidate the mechanism by which these drugs increase dopamine levels at synapses. The crowdfunding experiment worked and their project was fully funded.Creation of a good website with a convincing video is a crucial step towards success. “When crafting your project, it is important to try to put yourselves in the shoes of the audience,” recommended Cindy Wu, who founded San-Francisco-based science crowdfunding company, Microryza, with Denny Luan when they were in graduate school. “You as a scientist find your work absolutely fascinating. Communicating this passion to a broader audience is absolutely key,” said Byrnes. However, recruitment of people to the website is at least as important as the site itself. Many successful crowdfunders build their campaign on existing social networks to channel potential funders to their own website [3]. “Building an audience for your work, having people aware of you and what you are doing, is of paramount importance,” Byrnes explained, and added that crowdfunding can be as time consuming as grant applications. “But it''s a different kind of time. I find it actually quite satisfying,” he said.“Be scientific about it,” Perlstein advised. How many donors are needed to reach a funding goal? How many page views would be required accordingly, assuming a certain conversion rate? “If you approach a crowdfunding campaign methodically, it doesn''t guarantee success, but at least you implement best practices.” Perlstein is now an independent scientist renting laboratory space from the Molecular Sciences Institute, a non-profit research facility in Berkeley, CA, USA. “Academia and I were in a long-term relationship for over a decade but we broke up,” he explained. With federal and state funding flat or on a downwards trend, he sees his future in fundraising from patrons, venture philanthropists or disease foundations in addition to crowdfunding. Yet Perlstein remains an exception. Most scientists do not use crowdfunding as an alternative to normal funding opportunities, but rather as a supplement. A typical crowdfunding project nowadays would raise a few thousand dollars, which is enough to fund a student''s work for a summer or to buy some equipment [3].A typical crowdfunding project nowadays would raise a few thousand dollars, which is enough to fund a student''s work for a summer or to buy some equipmentCrowdfunding is also ideal to get new ideas off the ground, which was a key incentive to found Microryza. Cindy Wu''s experience with the academic funding system in graduate school taught her how difficult it was to get small grants for seed ideas. Together with her colleague Denny Luan she interviewed 100 scientists on the topic. “Every single person said there is always a seed idea they want to work on but it is difficult to get funding for early stage research,” she said. The two students concluded that crowdfunding would be able to fill that gap and a few months later set up Microryza. “Crowdfunding is a fantastic way to begin a project and collect preliminary data on something that might be a little risky but very exciting,” Byrnes said. “When you then write up a proposal for a larger governmentally funded grant you have evidence that you are doing outreach work and that you are bringing the results of your work to a broader audience.”Crowdfunded projects cover a wide range of research from ecology, medicine, physics and chemistry to engineering and economics. Some projects are pure basic science, such as investigating polo kinase in yeast (http://www.rockethub.com/projects/3753-cancer-yeast-has-answers), whereas others are applied, for instance developing a new method to clean up ocean oil spills (http://www.kickstarter.com/projects/cesarminoru/protei-open-hardware-oil-spill-cleaning-sailing-ro). Project creators may be students, professors or independent scientists, and research is carried out in universities, companies or hired laboratory space or outsourced to core facilities. Some projects aim to touch people''s heartstrings, such as saving butterflies (http://www.rockethub.com/projects/11903did-you-know-butterflies-have-std) and others address politically relevant topics, such as gun policy and safety (https://www.microryza.com/projects/gun-control-research-project).Some proposals have immediate relevance, such as the excavation of a triceratops skeleton to display it in the Seattle museum (https://www.microryza.com/projects/bring-a-triceratops-to-seattle). Backers can follow the project and see that the promise has been kept. For many projects in basic research, however, progress is much more abstract even if there are long-term goals, such as a cure for cancer, conservation strategies to save butterflies or so on. But will a non-scientist be able to evaluate the relevance of a particular project for such long-term goals? Will interested donors be able to judge whether these goals are within reach? Indeed, science crowdfunding has drawn criticism for its lack of peer review and has been accused of pushing scientists into overselling their research [1,4,5]. “There is a risk that it provides opportunities for scientists who are less than scrupulous to deceive the general public,” commented Stephen Curry, professor of structural biology at Imperial College, London, UK.…science crowdfunding has drawn criticism for its lack of peer review and has been accused of pushing scientists into overselling their researchMany scientific crowdfunding sites have systems in place to check the credibility of research proposals. “At #SciFund Challenge we have what we like to call a gentle peer review. If an undergraduate is promising to overthrow they theory of gravity we will have some questions about that,” explained Byrnes. Microryza would also not let any project pass. The team checks the proposal creator''s identity and evaluates whether the proposal addresses a scientific question and the project goals are within the capabilities of the researcher. “We plan to have some sort of crowd-sourced peer review sometime in the future,” said Wu. Other platforms, such as FundaGeek, have discussion forums where potential donors are encouraged to debate the merits of a proposal. As crowdfunding does not involve spending large amounts of public money, it might be an ideal way to try out new forms of peer review. According to Curry, however, there are important aspects of academic peer review that cannot be provided by these systems. “The advantage of grant committees considering many applications in competition with one another is that it allows the best ones to be selected. Details of prior work and expected feasibility are necessary to judge a project,” he said.Crowdfunding is selling science to the crowd, and, just like in any outreach activity, there might be cases of conveying projects too optimistically or overstating their impact. Yet, a main advantage of crowdfunding is that it allows donors to stay involved in projects and that it encourages direct interaction between scientists and non-scientists [3]. If a crowdfunding project does not live up to its promises, the donors will find out. “Microryza is really about sharing the discovery process directly with the donors,” Wu explained. “Every time something happens in the lab scientists post an update and an email goes out to all donors.” Perlstein also maintains close contact with his backers, having met many of them in person. “If we accept their money we are going to give them front row seats to the science,” he said. Research is a labour-intensive, slow process that includes technical difficulties and reconsideration of hypotheses, a fact that might come as a surprise to non-scientists. “We are actually doing a service here to enlighten the non-scientists that this is the rhythm of basic science,” said Perlstein.Crowdfunding of science has exploded in recent years, with funding goals becoming increasingly ambitious; some projects have attracted US$10,000–20,000 or even moreCrowdfunding is by no means a gold mine, with most research projects raising only a few thousand dollars. Byrnes, however, is optimistic that it will grow and inspire a larger crowd to get involved. “Now you see $10 million projects in gaming technology and the arts. That took some years to happen. We will get there, but we still have a lot to learn. I think science crowdfunding is still in the early growth phase,” he said. As crowdfunding increases, scientists will find themselves confronted with some questions. The open sharing of the scientific process with a broader public is a key aspect of crowdfunded projects. In many cases, scientists make the primary record of a research project publicly available. What does this entail when it comes to publications or patents? “Most journals don''t have a policy on open notebooks,” acknowledged Wu. Filing of patents could also become difficult if scientists have already made all their work and results public.Crowdfunding also enables projects to be undertaken outside the academic system where rules and regulations are less well defined. uBiome, a citizen science start-up, draws on crowds not only for funding but also for providing data. The company collected more than US$300,000 through Indiegogo to sequence the microbiome of its donors (http://www.indiegogo.com/projects/ubiome-sequencing-your-microbiome). Whereas academic biomedical research involving humans has to be reviewed by an independent ethics committee, this requirement would not apply to the uBiome project. “[P]rojects that don''t want federal money, FDA approval, or to publish in traditional journals require no ethical review at all as far as we know,” Jessica Richman and Zachary Apte, cofounders of uBiome, wrote in an invited guest blog on Scientific American (http://blogs.scientificamerican.com/guest-blog/2013/07/22/crowdfunding-and-irbs-the-case-of-ubiome/). The researchers worked with an independent institutional review board to provide ethics oversight. Some crowdfunding websites, such as Microryza, make sure their researchers have approval from an institutional review board. Greater consistency is needed, however, to ensure that research is carried out according to ethics standards.Crowdfunding is not going to substitute public funding … rather, it would coexist as a more democratic form of philanthropyCrowdfunding is not a one-size-fits-all revenue stream for science. It might be easier to get support for ‘catchy'' topics than for investigation of molecular interactions or protein structures. Crowdfunding is not going to substitute public funding either; rather, it would coexist as a more democratic form of philanthropy. But for those who embrace it, crowdfunding can be a rewarding experience. “I had a lot of fun being part of #SciFund—I got to meet a lot of other interesting scientists, I raised some money, and I learned a bit about working with journalists and science writers to get my ideas and results disseminated to the public,” Killgrove said. Crowdfunding provides an opportunity for public engagement, raises public awareness, and gives scientists an incentive to communicate their research to a broader public. “In many cases, scientists do not receive any real incentive for doing outreach work” Byrnes said. “Crowdfunding can be seen as a means to reward them for their effort.”     

Should Informed Consent for Cancer Treatment Include a Discussion about Hospital Outcome Disparities?

Background to the debate: Several studies have found disparities in the outcome of medical procedures across different hospitals—better outcomes have been associated with higher procedure volume. An Institute of Medicine workshop found such a “volume–outcome relationship” for two types of cancer surgery: resection of the pancreas and esophagus (http://www.iom.edu/?id=31508). This debate examines whether physicians have an ethical obligation to inform patients of hospital outcome disparities for these cancers.     

InSilico DB genomic datasets hub: an efficient starting point for analyzing genome-wide studies in GenePattern,Integrative Genomics Viewer,and R/Bioconductor

Genomics datasets are increasingly useful for gaining biomedical insights, with adoption in the clinic underway. However, multiple hurdles related to data management stand in the way of their efficient large-scale utilization. The solution proposed is a web-based data storage hub. Having clear focus, flexibility and adaptability, InSilico DB seamlessly connects genomics dataset repositories to state-of-the-art and free GUI and command-line data analysis tools. The InSilico DB platform is a powerful collaborative environment, with advanced capabilities for biocuration, dataset sharing, and dataset subsetting and combination. InSilico DB is available from https://insilicodb.org.     

The 2015 Bioinformatics Open Source Conference (BOSC 2015)

The Bioinformatics Open Source Conference (BOSC) is organized by the Open Bioinformatics Foundation (OBF), a nonprofit group dedicated to promoting the practice and philosophy of open source software development and open science within the biological research community. Since its inception in 2000, BOSC has provided bioinformatics developers with a forum for communicating the results of their latest efforts to the wider research community. BOSC offers a focused environment for developers and users to interact and share ideas about standards; software development practices; practical techniques for solving bioinformatics problems; and approaches that promote open science and sharing of data, results, and software. BOSC is run as a two-day special interest group (SIG) before the annual Intelligent Systems in Molecular Biology (ISMB) conference. BOSC 2015 took place in Dublin, Ireland, and was attended by over 125 people, about half of whom were first-time attendees. Session topics included “Data Science;” “Standards and Interoperability;” “Open Science and Reproducibility;” “Translational Bioinformatics;” “Visualization;” and “Bioinformatics Open Source Project Updates”. In addition to two keynote talks and dozens of shorter talks chosen from submitted abstracts, BOSC 2015 included a panel, titled “Open Source, Open Door: Increasing Diversity in the Bioinformatics Open Source Community,” that provided an opportunity for open discussion about ways to increase the diversity of participants in BOSC in particular, and in open source bioinformatics in general. The complete program of BOSC 2015 is available online at http://www.open-bio.org/wiki/BOSC_2015_Schedule.Open in a separate window     

Discovery of protein phosphorylation motifs through exploratory data analysis

Background

The need for efficient algorithms to uncover biologically relevant phosphorylation motifs has become very important with rapid expansion of the proteomic sequence database along with a plethora of new information on phosphorylation sites. Here we present a novel unsupervised method, called Motif Finder (in short, F-Motif) for identification of phosphorylation motifs. F-Motif uses clustering of sequence information represented by numerical features that exploit the statistical information hidden in some foreground data. Furthermore, these identified motifs are then filtered to find “actual” motifs with statistically significant motif scores.

Results and Discussion

We have applied F-Motif to several new and existing data sets and compared its performance with two well known state-of-the-art methods. In almost all cases F-Motif could identify all statistically significant motifs extracted by the state-of-the-art methods. More importantly, in addition to this, F-Motif uncovers several novel motifs. We have demonstrated using clues from the literature that most of these new motifs discovered by F-Motif are indeed novel. We have also found some interesting phenomena. For example, for CK2 kinase, the conserved sites appear only on the right side of S. However, for CDK kinase, the adjacent site on the right of S is conserved with residue P. In addition, three different encoding methods, including a novel position contrast matrix (PCM) and the simplest binary coding, are used and the ability of F-motif to discover motifs remains quite robust with respect to encoding schemes.

Conclusions

An iterative algorithm proposed here uses exploratory data analysis to discover motifs from phosphorylated data. The effectiveness of F-Motif has been demonstrated using several real data sets as well as using a synthetic data set. The method is quite general in nature and can be used to find other types of motifs also. We have also provided a server for F-Motif at http://f-motif.classcloud.org/, http://bio.classcloud.org/f-motif/ or http://ymu.classcloud.org/f-motif/.     

Open Labware: 3-D Printing Your Own Lab Equipment

The introduction of affordable, consumer-oriented 3-D printers is a milestone in the current “maker movement,” which has been heralded as the next industrial revolution. Combined with free and open sharing of detailed design blueprints and accessible development tools, rapid prototypes of complex products can now be assembled in one’s own garage—a game-changer reminiscent of the early days of personal computing. At the same time, 3-D printing has also allowed the scientific and engineering community to build the “little things” that help a lab get up and running much faster and easier than ever before.Applications of 3-D printing technologies (Fig. 1A, Box 1) have become as diverse as the types of materials that can be used for printing. Replacement parts at the International Space Station may be printed in orbit from durable plastics or metals, while back on Earth the food industry is starting to explore the same basic technology to fold strings of chocolate into custom-shaped confectionary. Also, consumer-oriented laser-cutting technology makes it very easy to cut raw materials such as sheets of plywood, acrylic, or aluminum into complex shapes within seconds. The range of possibilities comes to light when those mechanical parts are combined with off-the-shelf electronics, low-cost microcontrollers like Arduino boards [1], and single-board computers such as a Beagleboard [2] or a Raspberry Pi [3]. After an initial investment of typically less than a thousand dollars (e.g., to set-up a 3-D printer), the only other materials needed to build virtually anything include a few hundred grams of plastic (approximately US$30/kg), cables, and basic electronic components [4,5].Open in a separate windowFig 1Examples of open 3-D printed laboratory tools. A ₁, Components for laboratory tools, such as the base for a micromanipulator [18] shown here, can be rapidly prototyped using 3-D printing. A _2, The printed parts can be easily combined with an off-the-shelf continuous rotation servo-motor (bottom) to motorize the main axis. B ₁, A 3-D printable micropipette [8], designed in OpenSCAD [19], shown in full (left) and cross-section (right). B ₂, The pipette consists of the printed parts (blue), two biro fillings with the spring, an off-the-shelf piece of tubing to fit the tip, and one screw used as a spacer. B ₃, Assembly is complete with a laboratory glove or balloon spanned between the two main printed parts and sealed with tape to create an airtight bottom chamber continuous with the pipette tip. Accuracy is ±2–10 μl depending on printer precision, and total capacity of the system is easily adjusted using two variables listed in the source code, or accessed via the “Customizer” plugin on the thingiverse link [8]. See also the first table.

Box 1. Glossary

Open source

A collective license that defines terms of free availability and redistribution of published source material. Terms include free and unrestricted distribution, as well as full access to source code/blueprints/circuit board designs and derived works. For details, see http://opensource.org.

Maker movement

Technology-oriented extension of the traditional “Do-it-Yourself (DIY)” movement, typically denoting specific pursuits in electronics, CNC (computer numerical control) tools such as mills and laser cutters, as well as 3-D printing and related technologies.

3-D printing

Technology to generate three-dimensional objects from raw materials based on computer models. Most consumer-oriented 3-D printers print in plastic by locally melting a strand of raw material at the tip (“hot-end”) and “drawing” a 3-D object in layers. Plastic materials include Acrylnitrile butadiene styrene (ABS) and Polylactic acid (PLA). Many variations of 3-D printers exist, including those based on laser-polymerization or fusion of resins or powdered raw materials (e.g., metal or ceramic printers).

Arduino boards

Inexpensive and consumer-oriented microcontroller boards built around simple processors. These boards offer a variety of interfaces (serial ports, I2C and CAN bus, etc.), μs-timers, and multiple general-purpose input-output (GPIO) pins suitable for running simple, time-precise programs to control custom-built electronics.

Single board computers

Inexpensive single-board computers capable of running a mature operating system with graphical-user interface, such as Linux. Like microcontroller boards, they offer a variety of hardware interfaces and GPIO pins to control custom-built electronics.It therefore comes as no surprise that these technologies are also routinely used by research scientists and, especially, educators aiming to customize existing lab equipment or even build sophisticated lab equipment from scratch for a mere fraction of what commercial alternatives cost [6]. Designs for such “Open Labware” include simple mechanical adaptors [7], micropipettes (Fig. 1B) [8], and an egg-whisk–based centrifuge [9] as well as more sophisticated equipment such as an extracellular amplifier for neurophysiological experiments [10], a thermocycler for PCR [11], or a two-photon microscope [12]. At the same time, conceptually related approaches are also being pursued in chemistry [13–15] and material sciences [16,17]. See also

Brothers in arms

The horrific injuries and difficult working conditions faced by military medical personnel have forced the military to fund biomedical research to treat soldiers; those new technologies and techniques contribute significantly to civilian medicine.War is the father of all things, Heraclitus believed. The military''s demand for better weapons and transportation, as well as tools for communication, detection and surveillance has driven technological progress during the past 150 years or so, producing countless civilian applications as a fallout. The military has invested heavily into high-energy physics, materials science, navigation systems and cryptology. Similarly, military-funded biomedical research encompasses the whole range from basic to applied research programmes (Fig 1), and the portion of military-funded research in the biological and medical fields is now considerable.Open in a separate windowFigure 11944 advertisement for Diebold Inc. (Ohio, USA) in support of blood donations for soldiers wounded in the Second World War. The military has traditionally been one of the greatest proponents of active research on synthetic blood production, blood substitutes and oxygen therapeutics for treating battlefield casualties. One recent approach in this direction is The Defense Advanced Research Projects Agency''s (DARPA''s) Blood Pharming programme, which plans to use human haematopoietic stem cells—such as those obtained from umbilical cord blood—as a “starting material to develop an automated, fieldable cell culture and packaging system capable of producing transfusable amounts of universal donor red blood cells” (http://www.darpa.mil/Our_Work/DSO/Programs/Blood_Pharming.aspx).War has always driven medical advances. From ancient Roman to modern times, treating the wounds of war has yielded surgical innovations that have been adopted by mainstream medicine. For example, the terrible effect of modern artillery on soldiers in the First World War was a major impetus for plastic surgery. Similarly, microbiology has benefited from war and military research: from antiseptics to prevent and cure gangrene to the massive production of penicillin during the Second World War, as well as more basic research into a wide range of pathogens, militaries worldwide have long been enthusiastic sponsors of microbiology research. Nowadays, military-funded research on pathogens uses state-of-the-art genotyping methods to study outbreaks and the spread of infection and seeks new ways to combat antibiotic resistance that afflicts both combatants and civilians.…military-funded biomedical research encompasses the whole range from basic to applied research programmes…The US Military Infectious Diseases Research Program (MIDRP) is particularly active in vaccine development to protect soldiers, especially those deployed overseas. Its website notes that: “Since the passing of the 1962 Kefauver–Harris Drug Amendment, which added the FDA requirement for proof of efficacy in addition to proof of safety for human products, there have been 28 innovative vaccines licenced in the US, including 13 vaccines currently designated for paediatric use. These 28 innovative vaccine products targeted new microorganisms, utilized new technology, or consisted of novel combinations of vaccines. Of these 28, the US military played a significant role in the development of seven licenced vaccines” (https://midrp.amedd.army.mil/). These successes include tetravalent meningococcal vaccine and oral typhoid vaccine, while current research is looking into the development of vaccines against malaria, dengue fever and hepatitis E.Similarly, the US Military HIV Research Program (MHRP) is working on the development of a global HIV-1 vaccine (http://www.hivresearch.org). MHRP scientists were behind the RV144 vaccine study in Thailand—the largest ever HIV vaccine study conducted in humans—that demonstrated that the vaccine was capable of eliciting modest and transient protection against the virus [1]. In the wake of the cautious optimism raised by the trial, subsequent research is providing insights into the workings of RV144 and is opening new doors for vaccine designers to strengthen the vaccine. In a recent study, researchers isolated four monoclonal antibodies induced by the RV144 vaccine and directed at a particular region of the HIV virus envelope associated with reduced infection, the variable region 2. They found that these antibodies recognized HIV-1-infected CD4(+) T cells and tagged them for attack by the immune system [2].In response to the medical problems military personnel are suffering in Iraq and Afghanistan, a recent clinical trial funded by the US Department of the Army demonstrated the efficacy of the aminoglycoside antibiotic paromomycin—either with or without gentamicin—for the topical treatment of cutaneous leishmaniasis, the most common form of infection by Leishmania parasites. Cutaneous leishmaniasis—which is endemic in Iraq and Afghanistan and rather frequent among soldiers deployed there—is transmitted to humans through the bite of infected sandflies: it causes skin ulcers and sores and can cause serious disability and social prejudice [3]. Topical treatments would offer advantages over therapies that require the systemic administration of antiparasitic drugs. The study—a phase 3 trial—was conducted in Tunisia and enrolled some 375 patients with one to five ulcerative lesions from cutaneous leishmaniasis. Patients, all aged between 5 and 65, received topical applications of a cream containing either 15% paromomycin with 0.5% gentamicin, 15% paromomycin alone or the control cream, which contained no antibiotic. The combination of paromomycin and gentamicin cured cutaneous leishmaniasis with an efficacy of 81%, compared with 82% for paromomycin alone and just 58% for control—the skin sores of cutaneous leishmaniasis often heal on their own. Researchers reported no adverse reactions to paronomycin-containing creams. Because the combination therapy with gentamicin is probably effective against a larger range of Leishmania parasitic species and strains causing the disease, it could become a first-line treatment for cutaneous leishmaniasis on a global scale the authors concluded [3].…military-funded research on pathogens uses state-of-the-art genotyping methods to study outbreaks and the spread of infectionNot surprisingly, trauma and regenerative and reconstructive medicine are other large areas of research in which military influence is prevalent. The treatment of wounds, shock and the rehabilitation of major trauma patients are the very essence of medical aid on the battlefield (Figs 2, ​,3).3). “Our experience of military conflict, in particular the medicine required to deal with severe injuries, has led to significant improvements in trauma medicine. Through advances in the prevention of blood loss and the treatment of coagulopathy for example, patients are now surviving injuries that 5–10 years ago would have been fatal,” said Professor Janet Lord, who leads a team investigating the inflammatory response in injured soldiers at the National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre (NIHR SRMRC) in Birmingham, UK (http://www.srmrc.nihr.ac.uk/).Open in a separate windowFigure 2Medical services in Britain, 1917. Making an artificial leg for a wounded serviceman at Roehampton Hospital in Surrey. This image is from The First World War Poetry Digital Archive, University of Oxford (www.oucs.ox.ac.uk/ww1lit). Copyright: The Imperial War Museum.Open in a separate windowFigure 3US soldiers use the fireman''s carry to move a simulated casualty to safety during a hyper-realistic training environment, known as trauma lanes, as part of the final phase of the Combat Lifesaver Course given by medics from Headquarters Support Company, Headquarters and Headquarters Battalion, 25th Inf. Div., USD-C, at Camp Liberty, Iraq, March 2011. Credit: US Army, photo by Sgt Jennifer Sardam.NIHR SRMRC integrates basic researchers at Birmingham University with clinicians and surgeons at the Royal Centre for Defence Medicine and University Hospital Birmingham to improve the treatment of traumatic injury in both military and civilian patients. As Lord explained, the centre has two trauma-related themes. The first is looking at, “[t]he acute response to injury, which analyses the kinetics and nature of the inflammatory response to tissue damage and is developing novel therapies to ensure the body responds appropriately to injury and does not stay in a hyper-inflamed state. The latter is a particular issue with older patients whose chance of recovery from trauma is significantly lower than younger patients,” she said. The second theme is, “[n]eurotrauma and regeneration, which studies traumatic brain injury, trying to develop better ways to detect this early to prevent poor outcomes if it goes undiagnosed,” Lord said.Kevlar helmets and body armour have saved the lives of many soldiers, but they do not protect much the face and eyes, and in general against blasts to the head. Because human retinas and brains show little potential for regeneration, patients with face and eye injuries often suffer from loss of vision and other consequences for the rest of their lives. However, a new stem cell and regenerative approach for the treatment of retinal injury and blindness is on the horizon. “Recent progress in stem cell research has begun to emerge on the possible exploitation of stem cell-based strategies to repair the damaged CNS (central nervous system). In particular, research from our laboratory and others have demonstrated that Müller cells—dormant stem-like cells found throughout the retina—can serve as a source of retinal progenitor cells to regenerate photoreceptors as well as all other types of retinal neurons,” explained Dong Feng Chen at the Schepens Eye Research Institute, Massachusetts Eye and Ear of the Harvard Medical School in Boston (Massachusetts, USA). In collaboration with the US Department of Defence, the Schepens Institute is steering the Military Vision Research Program, “to develop new ways to save the vision of soldiers injured on today''s battlefield and to push the frontier of vision technologies forward” (http://www.schepens.harvard.edu).“My laboratory has shown that adult human and mouse Müller cells can not only regenerate retina-specific neurons, but can also do so following induction by a single small molecule compound, alpha-aminoadipate,” Chen explained. She said that alpha-aminoadipate causes isolated Müller glial cells in culture to loose their glial phenotype, express progenitor cell markers and divide. Injection of alpha-aminoadipate into the subretinal space of adult mice in vivo induces mature Müller glia to de-differentiate and generate new retinal neurons and photoreceptor cells [4]. “Our current effort seeks to further elucidate the molecular pathways underlying the regenerative behaviour of Muller cells and to achieve functional regeneration of the damaged retina with small molecule compounds,” Chen said. “As the retina has long served as a model of the CNS, and Müller cells share commonalities with astroglial lineage cells in the brain and spinal cord, the results of this study can potentially be broadened to future development of treatment strategies for other neurodegenerative diseases, such as brain and spinal cord trauma, or Alzheimer and Parkinson disease.”The treatment of wounds, shock and the rehabilitation of major trauma patients are the very essence of medical aid on the battlefieldBrain injuries account for a large percentage of the wounds sustained by soldiers. The Defense Advanced Research Projects Agency (DARPA), an agency of the US Department of Defense, recently awarded US$6 million to a team of researchers to develop nanotechnology therapies for the treatment of traumatic brain injury and associated infections. The researchers are trying to develop nanoparticles carrying small interfering RNA (siRNA) molecules to reach and treat drug-resistant bacteria and inflammatory cells in the brain. Protecting the siRNA within a nanocomplex covered with specific tissue homing and cell-penetrating peptides will make it possible to deliver the therapeutics to infected cells beyond the blood–brain barrier—which normally makes it difficult to get antibiotics to the brain. The project has been funded within the framework of DARPA''s In Vivo Nanoplatforms programme that “seeks to develop new classes of adaptable nanoparticles for persistent, distributed, unobtrusive physiologic and environmental sensing as well as the treatment of physiologic abnormalities, illness and infectious disease” (www.darpa.mil).“The DARPA funding agency often uses the term ‘DARPA-hard'' to refer to problems that are extremely tough to solve. What makes this a DARPA-hard problem is the fact that it is so difficult to deliver therapeutics to the brain. This is an underserved area of research,” explained team leader Michael Sailor, from the University of California San Diego, in a press release (http://ucsdnews.ucsd.edu/pressrelease/darpa_awards_6_million_to_develop_nanotech_therapies_for_traumatic_brain_in).In the near future, DARPA, whose budget is set for a 1.8% increase to US$2.9 billion next year, will focus on another important project dealing with the CNS. The BRAIN Initiative—short for Brain Research through Advancing Innovative Neurotechnologies—is a new research effort whose proponents intend will “revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer''s, schizophrenia, autism, epilepsy and traumatic brain injury” (www.whitehouse.gov). Out of a total US$110 million investment, DARPA will obtain US$50 million to work on understanding the dynamic functions of the brain and demonstrating breakthrough applications based on these insights (Fig 4). In addition to exploring new research areas, this money will be directed towards ongoing projects of typical—although not exclusive—military interest that involve enhancing or recovering brain functions, such as the development of brain-interfaced prosthetics and uncovering the mechanisms underlying neural reorganization and plasticity to accelerate injury recovery.Open in a separate windowFigure 4The BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative infographic. A complete version can be downloaded at http://www.whitehouse.gov/infographics/brain-initiative.“[T]here is this enormous mystery waiting to be unlocked, and the BRAIN Initiative will change that by giving scientists the tools they need to get a dynamic picture of the brain in action and better understand how we think and how we learn and how we remember. And that knowledge could be—will be—transformative,” said US President Obama, presenting the initiative (http://www.whitehouse.gov/the-press-office/2013/04/02/remarks-president-brain-initiative-and-american-innovation).“The President''s initiative reinforces the significance of understanding how the brain records, processes, uses, stores and retrieves vast quantities of information. This kind of knowledge of brain function could inspire the design of a new generation of information processing systems; lead to insights into brain injury and recovery mechanisms; and enable new diagnostics, therapies and devices to repair traumatic injury,” explained DARPA Director Arati Prabhakar in a press release (http://www.darpa.mil/NewsEvents/Releases/2013/04/02.aspx).But BRAIN is also stirring up some controversy. Some scientists fear that this kind of ‘big and bold'' science, with a rigid top-down approach and vaguely defined objectives, will drain resources from smaller projects in fundamental biology [5]. Others ask whether the BRAIN project investment will really generate the huge return hinted at in Obama''s speech during the initiative''s launch, or whether a substantial amount of hype about the potential outcomes was used to sell the project (http://ksj.mit.edu/tracker/2013/04/obamas-brain-initiative-and-alleged-140).As these examples show, the most important player in military-funded biomedical research is the USA, with the UK following at a distance. But other countries with huge defence budgets are gearing up, although with less visibility. In July 2011, for instance, India and Kyrgyzstan opened the joint Mountain Biomedical Research Centre at the Kyrgyz capital Bishkek, to carry out research into the mechanisms of short- and long-term high-altitude adaptation. The institute will use molecular biological approaches to identify markers for screening people for high-altitude resistance and susceptibility to high-altitude sickness, and development of other mountain maladies. On the Indian side, the scientists involved in the new research centre belong to the Defence Institute of Physiology and Applied Sciences, and the money came from India''s defence budget.As mankind seems unlikely to give up on armed conflicts anytime soon, war-torn human bodies will still need to be cured and wounds healed. Whether the original impetus for military-funded biomedical research is noble or not, it nonetheless fuels considerable innovation leading to important medical discoveries that ultimately benefit all.     

In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile

Background

Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX.

Methods and Findings

We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial “up-front” in vivo MTX treatment (1 g/m²) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02).

Conclusions

Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL.Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00137111","term_id":"NCT00137111"}}NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).     

A Global Comparison of the Human and T. brucei Degradomes Gives Insights about Possible Parasite Drug Targets

We performed a genome-level computational study of sequence and structure similarity, the latter using crystal structures and models, of the proteases of Homo sapiens and the human parasite Trypanosoma brucei. Using sequence and structure similarity networks to summarize the results, we constructed global views that show visually the relative abundance and variety of proteases in the degradome landscapes of these two species, and provide insights into evolutionary relationships between proteases. The results also indicate how broadly these sequence sets are covered by three-dimensional structures. These views facilitate cross-species comparisons and offer clues for drug design from knowledge about the sequences and structures of potential drug targets and their homologs. Two protease groups (“M32” and “C51”) that are very different in sequence from human proteases are examined in structural detail, illustrating the application of this global approach in mining new pathogen genomes for potential drug targets. Based on our analyses, a human ACE2 inhibitor was selected for experimental testing on one of these parasite proteases, TbM32, and was shown to inhibit it. These sequence and structure data, along with interactive versions of the protein similarity networks generated in this study, are available at http://babbittlab.ucsf.edu/resources.html.     

Automatic figure ranking and user interfacing for intelligent figure search

Background

Figures are important experimental results that are typically reported in full-text bioscience articles. Bioscience researchers need to access figures to validate research facts and to formulate or to test novel research hypotheses. On the other hand, the sheer volume of bioscience literature has made it difficult to access figures. Therefore, we are developing an intelligent figure search engine (http://figuresearch.askhermes.org). Existing research in figure search treats each figure equally, but we introduce a novel concept of “figure ranking”: figures appearing in a full-text biomedical article can be ranked by their contribution to the knowledge discovery.

Methodology/Findings

We empirically validated the hypothesis of figure ranking with over 100 bioscience researchers, and then developed unsupervised natural language processing (NLP) approaches to automatically rank figures. Evaluating on a collection of 202 full-text articles in which authors have ranked the figures based on importance, our best system achieved a weighted error rate of 0.2, which is significantly better than several other baseline systems we explored. We further explored a user interfacing application in which we built novel user interfaces (UIs) incorporating figure ranking, allowing bioscience researchers to efficiently access important figures. Our evaluation results show that 92% of the bioscience researchers prefer as the top two choices the user interfaces in which the most important figures are enlarged. With our automatic figure ranking NLP system, bioscience researchers preferred the UIs in which the most important figures were predicted by our NLP system than the UIs in which the most important figures were randomly assigned. In addition, our results show that there was no statistical difference in bioscience researchers'' preference in the UIs generated by automatic figure ranking and UIs by human ranking annotation.

Conclusion/Significance

The evaluation results conclude that automatic figure ranking and user interfacing as we reported in this study can be fully implemented in online publishing. The novel user interface integrated with the automatic figure ranking system provides a more efficient and robust way to access scientific information in the biomedical domain, which will further enhance our existing figure search engine to better facilitate accessing figures of interest for bioscientists.     

Consent to ‘personal’ genomics and privacy

Direct-to-consumer genetic tests and population genome research challenge traditional notions of privacy and consentThe concerns about genetic privacy in the 1990s were largely triggered by the Human Genome Project (HGP) and the establishment of population biobanks in the following decade. Citizens and lawmakers were worried that genetic information on people, or even subpopulations, could be used to discriminate or stigmatize. The ensuing debates led to legislation both in Europe and the USA to protect the privacy of genetic information and prohibit genetic discrimination.Notions of genetic determinism have also been eroded as population genomics research has discovered a plethora of risk factors that offer only probabilistic value…Times have changed. The cost of DNA sequencing has decreased markedly, which means it will soon be possible to sequence individual human genomes for a few thousand dollars. Notions of genetic determinism have also been eroded as population genomics research has discovered a plethora of risk factors that offer only probabilistic value for predicting disease. Nevertheless, there are several increasingly popular internet genetic testing services that do offer predictions to consumers of their health risks on the basis of genetic factors, medical history and lifestyle. Also, not to be underestimated is the growing popularity of social networks on the internet that expose the decline in traditional notions of the privacy of personal information. It was only a matter of time until all these developments began to challenge the notion of genetic privacy.For instance, the internet-based Personal Genome Project asks volunteers to make their personal, medical and genetic information publicly available so as, “to advance our understanding of genetic and environmental contributions to human traits and to improve our ability to diagnose, treat, and prevent illness” (www.personalgenomes.org). The Project, which was founded by George Church at Harvard University, has enrolled its first 10 volunteers and plans to expand to 100,000. Its proponents have proclaimed the limitations, if not the death, of privacy (Lunshof et al, 2008) and maintain that, under the principle of veracity, their own personal genomes will be made public. Moreover, they have argued that in a socially networked world there can be no total guarantee of confidentiality. Indeed, total protection of privacy is increasingly unrealistic in an era in which direct-to-consumer (DTC) genetic testing is offered on the internet (Lee & Crawley, 2009) and forensic technologies can potentially ‘identify'' individuals in aggregated data sets, even if their identity has been anonymized (Homer et al, 2008).Since the start of the HGP in the 1990s, personal privacy and the confidentiality of genetic information have been important ethical and legal issues. Their ‘regulatory'' expression in policies and legislation has been influenced by both genetic determinism and exceptionalism. Paradoxically, there has been a concomitant emergence of collaborative and international consortia conducting genomics research on populations. These consortia openly share data, on the premise that it is for public benefit. These developments require a re-examination of an ‘ethics of scientific research'' that is founded solely on the protection and rights of the individual.… total protection of privacy is increasingly unrealistic in an era in which direct-to-consumer (DTC) genetic testing is offered on the internetAlthough personalized medicine empowers consumers and democratizes the sharing of ‘information'' beyond the data sharing that characterizes population genomics research (Kaye et al, 2009), it also creates new social groups based on beliefs of common genetic susceptibility and risk (Lee & Crawley, 2009). The increasing allure of DTC genetic tests and the growth of online communities based on these services also challenges research in population genomics to provide the necessary scientific knowledge (Yang et al, 2009). The scientific data from population studies might therefore lend some useful validation to the results from DTC, as opposed to the probabilistic ‘harmful'' information that is now provided to consumers (Ransohoff & Khoury, 2010; Action Group on Erosion, Technology and Concentration, 2008). Population data clearly erodes the linear, deterministic model of Mendelian inheritance, in addition to providing information on inherited risk factors. The socio-demographic data provided puts personal genetic risk factors in a ‘real environmental'' context (Knoppers, 2009).Thus, beginning with a brief overview of the principles of data sharing and privacy under both population and consumer testing, we will see that the notion of identifiability is closely linked to the definition of what constitutes ‘personal'' information. It is against this background that we need to examine the issue of consumer consent to online offers of genetic tests that promise whole-genome sequencing and analysis. Moreover, we also demonstrate the need to restructure ethical reviews of genetic research that are not part of classical clinical trials and that are non-interventionist, such as population studies.The HGP heralded a new open access approach under the Bermuda Principles of 1996: “It was agreed that all human genomic sequence information, generated by centres funded for large-scale human sequencing, should be freely available and in the public domain in order to encourage research and development and to maximise its benefit to society” (HUGO, 1996). Reaffirmed in 2003 under the Fort Lauderdale Rules, the premise was that, “the scientific community will best be served if the results of community resource projects are made immediately available for free and unrestricted use by the scientific community to engage in the full range of opportunities for creative science” (HUGO, 2003). The international Human Genome Organization (HUGO) played an important role in achieving this consensus. Its Ethics Committee considered genomic databases as “global public goods” (HUGO Ethics Committee, 2003). The value of this information—based on the donation of biological samples and health information—to realize the benefits of personal genomics is maximized through collaborative, high-quality research. Indeed, it could be argued that, “there is an ethical imperative to promote access and exchange of information, provided confidentiality is protected” (European Society of Human Genetics, 2003). This promotion of data sharing culminated in a recent policy on releasing research data, including pre-publication data (Toronto International Data Release Workshop, 2009).There is room for improvement in both the personal genome and the population genome endeavoursIn its 2009 Guidelines for Human Biobanks and Genetic Research Databases, the Organization for Economic Cooperation and Development (OECD) states that the “operators of the HBGRD [Human Biobanks and Genetic Research Databases] should strive to make data and materials widely available to researchers so as to advance knowledge and understanding.” More specifically, the Guidelines propose mechanisms to ensure the validity of access procedures and applications for access. In fact, they insist that access to human biological materials and data should be based on “objective and clearly articulated criteria [...] consistent with the participants'' informed consent”. Access policies should be fair, transparent and not inhibit research (OECD, 2009).In parallel to such open and public science was the rise of privacy protection, particularly when it concerns genetic information. The United Nations Educational, Scientific and Cultural Organization''s (UNESCO) 2003 International Declaration on Human Genetic Data (UNESCO, 2003) epitomizes this approach. Setting genetic information apart from other sensitive medical or personal information, it mandated an “express” consent for each research use of human genetic data or samples in the absence of domestic law, or, when such use “corresponds to an important public interest reason”. Currently, however, large population genomics infrastructures use a broad consent as befits both their longitudinal nature as well as their goal of serving future unspecified scientific research. The risk is that ethics review committees that require such continuous “express” consents will thereby foreclose efficient access to data in such population resources for disease-specific research. It is difficult for researchers to provide proof of such “important public interest[s]” in order to avoid reconsents.Personal information itself refers to identifying and identifiable information. Logically, a researcher who receives a coded data set but who does not have access to the linking keys, would not have access to ‘identifiable'' information and so the rules governing access to personal data would not apply (Interagency Advisory Panel on Research Ethics, 2009; OHRP, 2008). In fact, in the USA, such research is considered to be on ‘non-humans'' and, in the absence of institutional rules to the contrary, it would theoretically not require research ethics approval (www.vanderbilthealth.com/main/25443).… the ethics norms that govern clinical research are not suited for the wide range of data privacy and consent issues in today''s social networks and bioinformatics systemsNevertheless, if the samples or data of an individual are accessible in more than one repository or on DTC internet sites, a remote possibility remains that any given individual could be re-identified (Homer et al, 2008). To prevent the restriction of open access to public databases, owing to the fear of re-identifiability, a more reasonable approach is necessary; “[t]his means that a mere hypothetical possibility to single out the individual is not enough to consider the persons as ‘identifiable''” (Data Protection Working Party, 2007). This is a proportionate and important approach because fundamental genomic ‘maps'' such as the International HapMap Project (www.hapmap.org) and the 1000 Genomes project (www.1000genomes.org) have stated as their goal “to make data as widely available as possible to further scientific progress” (Kaye et al, 2009). What then of the nature of the consent and privacy protections in DTC genetic testing?The Personal Genome Project makes the genetic and medical data of its volunteers publicly available. Indeed, there is a marked absence of the traditional confidentiality and other protections of the physician–patient relationship across such sites; overall, the degree of privacy protection by commercial DTC and other sequencing enterprises varies. The company 23andMe allows consumers to choose whether they wish to disclose personal information, but warns that disclosure of personal information is also possible “through other means not associated with 23andMe, […] to friends and/or family members […] and other individuals”. 23andMe also announces that it might enter into commercial or other partnerships for access to its databases (www.23andme.com). deCODEme offers tiered levels of visibility, but does not grant access to third parties in the absence of explicit consumer authorization (www.decodeme.com). GeneEssence will share coded DNA samples with other parties and can transfer or sell personal information or samples with an opt-out option according to their Privacy Policy, though the terms of the latter can be changed at any time (www.geneessence.com). Navigenics is transparent: “If you elect to contribute your genetic information to science through the Navigenics service, you allow us to share Your Genetic Data and Your Phenotype Information with not-for-profit organizations who perform genetic or medical research” (www.navigenics.com). Finally, SeqWright separates the personal information of its clients from their genetic information so as to avoid access to the latter in the case of a security breach (www.seqwright.com).Much has been said about the lack of clinical utility and validity of DTC genetic testing services (Howard & Borry, 2009), to say nothing of the absence of genetic counsellors or physicians to interpret the resulting probabilistic information (Knoppers & Avard, 2009; Wright & Kroese, 2010). But what are the implications for consent and privacy considering the seemingly divergent needs of ensuring data sharing in population projects and ‘protecting'' consumer-citizens in the marketplace?At first glance, the same accusations of paternalism levelled at ethics review committees who hesitate to respect the broad consent of participants in population databases could be applied to restraining the very same citizens from genetic ‘info-voyeurism'' on the internet. But, it should be remembered that citizen empowerment, which enables their participation both in population projects and in DTC, is expressed within very different contexts. Population biobanks, by the very fact of their broad consent and long-term nature, have complex security systems and are subject to governance and ongoing ethical monitoring and review. In addition, independent committees evaluate requests for access (Knoppers & Abdul-Rahman, 2010). The same cannot be said for the governance of the DTC companies just presented.There is room for improvement in both the personal genome and the population genome endeavours. The former require regulatory approaches to ensure the quality, safety, security and utility of their services. The latter require further clarification of their ongoing funding and operations and more transparency to the public as researchers begin to access these resources for disease-specific studies (Institute of Medicine, 2009). Public genomic databases should be interoperable and grant access to authenticated researchers internationally in order to be of utility and statistical significance (Burton et al, 2009). Moreover, to enable international access to such databases for disease-specific research means that the interests of publicly funded research and privacy protection must be weighed against each other, rather than imposing a requirement that research has to demonstrate that the public interest substantially outweighs privacy protection (Weisbrot, 2009). Collaboration through interoperability has been one of the goals of the Public Population Project in Genomics (P³G; www.p3g.org) and, more recently, of the Biobanking and Biomolecular Resources Research Infrastructure (www.bbmri.eu).Even if the tools for harmonization and standardization are built and used, will trans-border data flow still be stymied by privacy concerns? The mutual recognition between countries of privacy equivalent approaches—that is, safe harbour—the limiting of access to approved researchers and the development of international best practices in privacy, security and transparency through a Code of Conduct along with a system for penalizing those who fail to respect such norms, would go some way towards maintaining public trust in genomic and genetic research (P3G Consortium et al, 2009). Finally, consumer protection agencies should monitor DTC sites under a regulatory regime, to ensure that these companies adhere to their own privacy policies.… genetic information is probabilistic and participating in population or on-line studies may not create the fatalistic and harmful discriminatory scenarios originally perceived or imaginedMore importantly in both contexts, the ethics norms that govern clinical research are not suited for the wide range of data privacy and consent issues in today''s social networks and bioinformatics systems. One could go further and ask whether the current biomedical ethics review system is inadequate—if not inappropriate—in these ‘data-driven research'' contexts. Perhaps it is time to create ethics review and oversight systems that are particularly adapted for those citizens who seek either to participate through online services or to contribute to population research resources. Both are contexts of minimal risk and require structural governance reforms rather than the application of traditional ethics consent and privacy review processes that are more suited to clinical research involving drugs or devices. In this information age, genetic information is probabilistic, and participating in population or online studies might not create the fatalistic and harmful discriminatory scenarios originally perceived or imagined. The time is ripe for a change in governance and regulatory approaches, a reform that is consistent with what citizens seem to have already understood and acted on.? Open in a separate windowBartha Maria Knoppers     

Dizeez: An Online Game for Human Gene-Disease Annotation

Structured gene annotations are a foundation upon which many bioinformatics and statistical analyses are built. However the structured annotations available in public databases are a sparse representation of biological knowledge as a whole. The rate of biomedical data generation is such that centralized biocuration efforts struggle to keep up. New models for gene annotation need to be explored that expand the pace at which we are able to structure biomedical knowledge. Recently, online games have emerged as an effective way to recruit, engage and organize large numbers of volunteers to help address difficult biological challenges. For example, games have been successfully developed for protein folding (Foldit), multiple sequence alignment (Phylo) and RNA structure design (EteRNA). Here we present Dizeez, a simple online game built with the purpose of structuring knowledge of gene-disease associations. Preliminary results from game play online and at scientific conferences suggest that Dizeez is producing valid gene-disease annotations not yet present in any public database. These early results provide a basic proof of principle that online games can be successfully applied to the challenge of gene annotation. Dizeez is available at http://genegames.org.     

CIBMAN: Database exploring Citrus biodiversity of Manipur

The rich wealth of Citrus genetic resources makes India to enjoy a remarkable position in the “Citrus belt of the world”. We have developed CIBMAN, a unique database on Citrus biodiversity of Manipur which comprises 33 accessions collected through extensive survey for more than three years. CIBMAN provides integrated access to Citrus species through sophisticated web interface which has following capabilities a) morphological details, b) socio-economic details, c) taxonomic details and d) geographical distribution. Morphological variability among Citrus accessions is due to variance in their genome which contributes to diverse agronomical traits and diverse bioactive compounds of high value. This diverse gene pool can be potential source for genetic improvement of existing cultivars and rootstocks. Systematic collection, characterization and conservation of the underutilized or lesser exploited varieties is required for incorporating in breeding program and conserve the germplasm from ever going on genetic erosion. This database will be useful for scientific validations and updating of traditional wisdom in bioprospecting aspects especially industrialization of Citrus found in the state. Further, the features will be suited for detailed investigation on potential medicinal and edible Citrus that make CIBMAN a powerful tool for sustainable management.

Availability

http://ibsd.gov.in/cibman     

Functional group and substructure searching as a tool in metabolomics

Background

A direct link between the names and structures of compounds and the functional groups contained within them is important, not only because biochemists frequently rely on literature that uses a free-text format to describe functional groups, but also because metabolic models depend upon the connections between enzymes and substrates being known and appropriately stored in databases.

Methodology

We have developed a database named “Biochemical Substructure Search Catalogue” (BiSSCat), which contains 489 functional groups, >200,000 compounds and >1,000,000 different computationally constructed substructures, to allow identification of chemical compounds of biological interest.

Conclusions

This database and its associated web-based search program (http://bisscat.org/) can be used to find compounds containing selected combinations of substructures and functional groups. It can be used to determine possible additional substrates for known enzymes and for putative enzymes found in genome projects. Its applications to enzyme inhibitor design are also discussed.