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- Nat Biotechnol 29(11):vii-viii (2011)
Article preview View full access options Nature Biotechnology | In This Issue In this issue Journal name:Nature BiotechnologyVolume: 29,Pages:vii–viiiYear published:(2011)DOI:doi:10.1038/nbt.2047Published online08 November 2011 siRNA curbs inflammation Many diseases, including arthritis, heart disease and cancer, have an inflammatory component. Nahrendorf, Weissleder and colleagues show that an optimized lipid nanoparticle can deliver short interfering RNA (siRNA) to inflammatory monocytes, a cell type involved in the innate immune responses needed to sustain inflammation. The localization of this monocyte subpopulation to the site of inflammation depends on the CC-motif chemokine receptor 2 (CCR2). When the authors systemically administer the lipid nanoparticle with a CCR2 siRNA, it is rapidly cleared from the bloodstream and accumulates in the spleen and the bone marrow, where it delivers the siRNA to monocytes. The degradation of the CCR2 mRNA inhibits the movement of the inflammatory monocytes to the sites of inflammation. The treatment shows therapeutic benefits in a diverse set of conditions such as coronary artery occlusion, atherosclerotic plaque formation, pancreatic islet transplantation and cancer. ME Kinase inhibitor selectivity Small-molecule inhibitors of protein kinases have already proved their mettle both as therapeutics and as probes for interrogating cellular signaling pathways. However, their tendency to promiscuously inhibit kinases other than their intended targets remains a critical obstacle to realizing their full potential for targeted clinical and research applications. Two complementary studies use different strategies to comprehensively evaluate these off-target interactions. Using the miniaturized assay of catalytic activity depicted, Peterson and colleagues measure the pairwise inhibition of 300 recombinant human protein kinases by 178 commercially available kinase inhibitors, including widely used research reagents and US Food and Drug Administration–approved therapeutics. In contrast with this functional readout, Zarrinkar and colleagues extend their previous studies involving a competition binding assay (Nat. Biotechnol.23, 329–336, 2005; Nat. Biotechnol.26, 127–132, 2008)! by reporting the affinities of 72 kinase inhibitors with 442 human kinases. Together, the findings should provide valuable leads to identify unusually selective inhibitors, drugs that inhibit kinases recalcitrant to targeting and molecules that selectively target multiple kinases of interest. [] PH Double take on macaque genomics Cynomolgus macaques are the reference nonhuman primate for drug safety testing, and Chinese rhesus macaques are an important model for HIV research. A team led by researchers from The South China Center for Innovative Pharmaceuticals and BGI-Shenzhen present the genome sequences of these two species. Each ~2.8-Gb genome was sequenced exclusively using short-read technology, assembled de novo, and compared with each other and with the previously published genome of the Indian rhesus macaque. The comparisons revealed single-nucleotide polymorphisms and larger chromosomal differences, some of which occur in genes with human homologs that are targeted by drugs. This catalog of genetic variants should be valuable for infectious disease and drug development research. Analysis of the two genomes also identified regions of introgression, where genes have been transferred from one species to another, and regions of selective sweeps, where variation among the macaques is reduced. Thes! e findings point to the value of the genomes for population genetics and other branches of primatology. [] CM Integrated sequence capture and priming Capturing and sequencing of genomic targets, such as exomes, involves complex workflows that hamper the application of the approach to clinical diagnostics and to surveying genetic variation across large populations. Ji and collaborators have developed a new approach that dramatically simplifies targeted resequencing. They modify an Illumina flow cell so that the lawn of oligonucleotides attached to the flow-cell surface are used as both genome capture probes and sequencing primers, in contrast to existing approaches in which separate sets of oligos perform these two functions. The oligonucleotides used in this process are designed to be complementary to target genomic sequences of interest and are custom synthesized. The authors resequence the exons of 10 genes using 366 column-synthesized oligos and the exons of 344 genes using 11,742 microarray-synthesized oligos. In both cases, >87% of captured reads were on-target. As the authors demonstrate, one immediate application i! s for resequencing candidate genes and identifying mutations from cancer patients because tumor tissue samples matched with normal tissue can be barcoded, multiplexed and processed together, thereby reducing sources of technical bias. [] CM Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data - Big ideas and grand challenges
- Nat Biotechnol 29(11):951 (2011)
Nature Biotechnology | Editorial Big ideas and grand challenges Journal name:Nature BiotechnologyVolume: 29,Page:951Year published:(2011)DOI:doi:10.1038/nbt.2048Published online08 November 2011 The US government's initiative to create a national blueprint for a 21st century bioeconomy is too narrowly drawn. A more expansive vision is needed. View full text Additional data - America Invents Act receives cautious welcome
- Nat Biotechnol 29(11):953-954 (2011)
Article preview View full access options Nature Biotechnology | News America Invents Act receives cautious welcome * Jeffrey L Fox1Journal name:Nature BiotechnologyVolume: 29,Pages:953–954Year published:(2011)DOI:doi:10.1038/nbt1111-953Published online08 November 2011 Jacquelyn Martin/AP Photo Legislators, business leaders and students gather to witness President Obama's signing of the America Invents Act at Thomas Jefferson High School for Science and Technology in Alexandria, Va. President Barack Obama signed the America Invents Act into law on September 16, praising it as a "much-needed reform," calling it "the most significant reform of the Patent Act since 1952" and predicting that it "will speed up the patent process so that innovators and entrepreneurs can turn a new invention into a business as quickly as possible." Amid widespread praise, some critics dispute those optimistic claims, saying that the new law might instead stifle university researchers and independent inventors. Others, although mostly happy with the central reforms, express pragmatic concerns—predicting confusion as components of the new statute are phased in and perhaps also a bit of accompanying mischief as new and, in some cases, untried features of the new law are implemented. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Affiliations * Washington, DC * Jeffrey L Fox Author Details * Jeffrey L Fox Search for this author in: * NPG journals * PubMed * Google Scholar - Larger companies dominate cancer companion diagnostic approvals
- Nat Biotechnol 29(11):955-957 (2011)
Article preview View full access options Nature Biotechnology | News Larger companies dominate cancer companion diagnostic approvals * Charles Schmidt1Journal name:Nature BiotechnologyVolume: 29,Pages:955–957Year published:(2011)DOI:doi:10.1038/nbt1111-955Published online08 November 2011 The novel B-Raf kinase inhibitor treatment for melanoma recently approved as Zelboraf was discovered by Plexxikon but developed by Roche. Two novel cancer drugs and their companion diagnostics to predict treatment response were given a go-ahead to market in quick succession. On August 17, the US Food and Drug Administration (FDA) approved Roche/Genentech's Zelboraf (vemurafenib) and multiplex PCR-based diagnostic for the BRAF V600E gene for individuals with advanced melanoma harboring the mutation. Approval of Pfizer's drug Xalkori (crizotinib) for non-small cell lung cancer (NSCLC) patients with tumors containing anaplastic lymphoma kinase (ALK) gene structural variants, together with a fluorescent in situ hybridization (FISH) test for detecting rearrangements of the ALK gene, followed nine days later. Both Basel-based Roche and New York–based Pfizer claim the companion diagnostics used to screen tissue samples for the drugs' target mutations—by narrowing patient populations to likely responders—sped clinical trials and accelerated FDA approval. But other companies considering the approach remain uncert! ain about the economic feasibility of co-developing medicines with companion diagnostics, as a study published last month attests (Nat. Rev. Drug. Discov.10, 1–17, 2011). The first generation of targeted therapeutics included anticancer drugs Herceptin (trastuzumab), which was approved in 1998 with Glostrup (HercepTest), Denmark-based DAKO's immunohistochemistry companion diagnostic for HER2 protein overexpression, and Gleevec (imatinib), which was initially approved for chronic myeloid leukemia without a companion diagnostic but added a c-KIT immunoassay to its label when approved for patients with gastrointestinal stromal tumors. These products have since turned into blockbusters for Roche and Basel-based Novartis, respectively. Sometimes, companies have found themselves with a drug-diagnostic pairing, even if they hadn't planned on it. In the case of Thousand Oaks–based Amgen's colorectal cancer treatment Vectibix (panitumumab), oncologists have increasingly adopted home-brew tests for the KRAS mutation, after it became clear certain variants of the encoded GTPase (G12A, G12N, G12V, G12C, G12S and G13D) predict a lack of drug response. Such testing has likely lowered Vectibix revenues as Amgen's pricing of the drug has not increased to reflect the narrower population. Although Herceptin's combined diagnostic and drug approval was a landmark, it did not open the floodgates to companion diagnostic approvals. Indeed, the risk, expense and complexity of taking both a drug and a diagnostic through regulatory oversight has deterred many smaller companies from developing such an approach, according to Kathleen Glaub, president of Plexxikon, in Berkeley, California. "Adding companion diagnostics makes the whole process nearly twice as expensive and twice as complex," she says. Glaub should know. Roche's Zelboraf (vemurafenib)—an oral drug that is active in melanoma patients with the BRAF V600E mutation in their tumors—originated with Plexxikon. The biotech partnered with Roche Molecular Systems (RMS), headquartered in Pleasanton, California, to develop the 'cobas 4800 BRAF V600 Mutation Test,' a PCR-based diagnostic. Plexxikon is the only biotech company of many queried by Nature Biotechnology that agreed to comment on companion diagnostics. Thus far, either diagnostics specialists, such as Deerfield, Illinois–based Vysis (now part of Abbott), DAKO or Salt Lake City, Utah–based Myriad Genetics, or diagnostic subsidiaries of pharma companies, such as RMS and Abbott Molecular Oncology, have dominated the companion diagnostic space. One exception is Clovis Oncology, a Boulder, Colorado–based company. The biotech recently teamed up with Roche and Ventana Medical Systems, in Tucson, Arizona, to develop companion diagnostics for Clovis' preclinical drug CO-1686. The small molecule targets T790M mutant forms of the epidermal growth factor receptor (EGFR) tyrosine kinase. Roche will be using the PCR-based diagnostic platform 'cobas 4800' to identify patients with the EGFR T790M mutation. Clovis is currently in S-1 filing with the US Securities and Exchange Commission and could not comment for this story. In terms of other small companies eyeing companion diagnostic options, "You're more likely to see startup biotechs approach startup diagnostics companies, but that's happening slowly," says Terry McGuire, a partner with Polaris Venture Partners, in Waltham, Massachusetts. For Martin Murphy, partner at MVM Life Science Partners, a venture capital firm in London, the promise of companion diagnostics in oncology is clear but he has reservations about biotech involvement. "Can smaller companies develop therapies and diagnostics hand in hand? It's a very capital-intensive process that I think is in range for these companies, but it's going to be challenging," he says. According to Glaub, Plexxikon sought out a diagnostic partnership when the compound was in phase 1 because only 50% of melanoma patients express the V600E mutation targeted by its small molecule, then called PLX4032. (The mutation also occurs in ~10% of all colorectal cancers and ~8% of solid tumors.) "We thought that if we could test the drug in a patient-specific way that we could accelerate development," Glaub says. At first, RMS wasn't convinced that Plexxikon had a viable compound. Moreover, the diagnostics company worried that modifying its PCR-based cobas platform to suit Plexxikon's paraffin-imbedded melanoma samples, where much of the DNA is degraded, would be onerous and time consuming. When RMS ultimately did partner with Plexxikon in 2005, Glaub says, it was only because of personal connections with Plexxikon's CEO, Peter Hirth. Development was slow at first, she adds, likely due to RMS's reluctance to invest until clinical signs showing that PLX4032 might be clinically useful first appeared. In 2006, Plexxikon signed with RMS's parent company, Roche, and Zelboraf and the cobas 4800 BRAF V600 Mutation Test emerged successfully from clinical testing five years later. Still, Hirth and Glaub say the landscape for biotech-diagnostics partnerships remains exceedingly challenging. What they're most critical of is a new FDA draft guidance recommending that therapeutic sponsors incorporate diagnostic development early in drug development plans, to boost chances for simultaneous approval (Box 1). This pressure—driven by what FDA claims is a need to ensure diagnostic accuracy in personalized medicine—places biotech companies in a bind, Glaub says. "It's very difficult to get diagnostic companies to invest in a compound that might not turn out to be a drug," she comments. "The alternative is that the companies wait for clinical proof of concept, but then diagnostic development lags behind the drug and you can't get approvals at the same time." Box 1: FDA circulates guidelines on companion diagnostics Full box Mark Capone, president of Myriad, says biotech and pharma companies alike worry that companion diagnostics add more risk to drug development and lower returns by shrinking target populations. But echoing a shared view in his industry, Capone counters that the tests boost chances of quick success in clinical trials, by deliberately excluding nonresponders. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Affiliations * Portland, Oregon * Charles Schmidt Author Details * Charles Schmidt Search for this author in: * NPG journals * PubMed * Google Scholar - Transatlantic PML
- Nat Biotechnol 29(11):956 (2011)
Article preview View full access options Nature Biotechnology | News Transatlantic PML * Lucas LaursenJournal name:Nature BiotechnologyVolume: 29,Page:956Year published:(2011)DOI:doi:10.1038/nbt1111-956Published online08 November 2011 The European Medicine Agency and US Food and Drug Administration (FDA) published in September the proceedings of a joint workshop held to address questions related to progressive multifocal leukoencephalopathy (PML), a rare and sometimes fatal brain disease that can occur as an adverse drug reaction to some therapeutics that affect immunological functions. The meeting attended by 170 regulators, academic scientists, funding bodies and clinical researchers, called for work on animal models, predictive biomarkers and long-term studies. "No one company is going to answer all the questions; they're going to be answered by research consortia," says co-convener and European Medicines Agency (EMA) pharmacovigilance head Peter Arlett. Five companies—Cambridge, Massachusetts–based Biogen Idec, New York–based Bristol-Myers Squibb, Elan of Dublin, Pfizer of New York and Roche of Basel—already fund basic research into drug-related PML through a nonprofit consortium. Concerns! over drug-related PML were prompted by patients receiving Biogen's multiple sclerosis therapy Tysabri (natalizumab) and other biologics such as Roche-Genentech's antibody Rituxan (rituximab) (Nat. Biotechnol.28, 105–106, 2010). By weakening patients' immune system, these treatments allow the reactivation of John Cunningham (JC) virus, which is normally latent, to infect the central nervous system and cause the disease. According to risk calculations that took into account duration of treatment, published by the FDA in April 2011, in an average sample of 3,333 people taking Tysabri, up to 5 could develop PML and of those one would die. In June 2011, the EMA released a more complete risk stratification algorithm, which also accounts for the presence of anti-JC virus antibodies and prior exposure to immunosuppresants. However, there is no treatment for JC virus or PML and even diagnosis is difficult. In addition to the consortium-funded research, Biogen is at work on two po! tential JC virus therapies that might help protect its large i! nvestment in Tysabri: one is a small molecule targeting the large T antigen on the JC virus and one is a neutralizing antibody against the JC virus. But the biggest result in the last year, says Biogen Idec senior vice president and global head of drug safety and risk management Carmen Bozic, is the improved quantification of risk factors for PML now available in the EMA label. As Nature Biotechnology went to press, Biogen was awaiting a decision from the FDA for a new label for Tysabri that would include anti-JC virus antibody status to help clinicians stratify the risk of PML. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Lucas Laursen Search for this author in: * NPG journals * PubMed * Google Scholar - 1,000 pediatric genomes
- Nat Biotechnol 29(11):957 (2011)
Article preview View full access options Nature Biotechnology | News 1,000 pediatric genomes * Karen CareyJournal name:Nature BiotechnologyVolume: 29,Page:957Year published:(2011)DOI:doi:10.1038/nbt1111-957aPublished online08 November 2011 Complete Genomics will sequence DNA from 500 tumor-normal pairs of childhood cancer cases as part of a National Cancer Institute (NCI) study designed to accelerate pediatric therapies. The Mountain View, California–based company, working for the NCI's contractor SAIC-Frederick of Frederick, Maryland, will provide whole genome sequences to uncover somatic mutations associated with specific tumor types. The initial focus is on acute lymphoblastic leukemia, acute myeloid leukemia, neuroblastoma, osteosarcoma and Wilm's tumor. Complete Genomics will receive $8 million to undertake the work, part of the NCI's TARGET (therapeutically applicable research to generate effective treatments) initiative, funded by the American Reinvestment and Recovery Act of 2009. The biotech will deposit the information in a database as a resource for NCI researchers. "Though the biological relevance of these mutations will be hard to establish, they represent a new unexplored frontier," says Co! mplete Genomics spokeswoman Jennifer Turcotte. Drug discovery efforts have largely avoided the pediatric space because of small sample sizes, varying pharmacokinetics and issues around informed consent. However, a spokesman for Johnson & Johnson Pharmaceutical R&D, of Raritan, New Jersey, points out that translating sequencing information into therapeutics will require "a lot of time and resources". Complete Genomics will also be sequencing 1,000 genomes of healthy elderly people between the ages of 80 and 108 to gather insights into the genetic variants that favor longevity, this time at their own expense. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Karen Carey Search for this author in: * NPG journals * PubMed * Google Scholar - Hedgehog inhibitor single arm
- Nat Biotechnol 29(11):957 (2011)
Article preview View full access options Nature Biotechnology | News Hedgehog inhibitor single arm * Karen CareyJournal name:Nature BiotechnologyVolume: 29,Page:957Year published:(2011)DOI:doi:10.1038/nbt1111-957bPublished online08 November 2011 Roche is aiming for accelerated approval of its Hedgehog antagonist vismodegib, a small molecule licensed from Curis, of Lexington, Massachusetts, based on an uncontrolled phase 2 trial. The Basel-based company submitted a new drug application to the US Food and Drug Administration for vismodegib in September undeterred by the agency's refuse-to-file letter issued last year for T-DM1 (trastuzumab-DM1, a conjugate of Herceptin and maytansine) for mid-stage breast cancer. "It really comes down to the question of, 'Is this addressing an unmet medical need?' and that's the crux of it," says analyst Joe Pantginis, of Roth Capital Partners in New York. Whereas for breast cancer several therapeutic options exist, vismodegib is targeted to patients with limited treatment options and no standard of care. "Unmet medical need is a prerequisite for accelerated approval based on single-arm trials," says analyst Jason Kantor, of RBC Capital Markets in San Francisco. Vismodegib shr! ank tumors or healed lesions in 43% of locally advanced and 30% of metastatic basal cell carcinoma in the pivotal study. The objective response rate was 60% and 46%, respectively, and progression-free survival for both was 9.5 months. If approved, analysts expect a launch next year with sales somewhere north of $150 million. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Karen Carey Search for this author in: * NPG journals * PubMed * Google Scholar - Priority voucher flops
- Nat Biotechnol 29(11):958 (2011)
Article preview View full access options Nature Biotechnology | News Priority voucher flops * Bethan HughesJournal name:Nature BiotechnologyVolume: 29,Page:958Year published:(2011)DOI:doi:10.1038/nbt1111-958aPublished online08 November 2011 Novartis Malaria drug Coartem. The first company to deploy a priority review voucher (PRV) received a complete response letter from the US Food and Drug Administration (FDA) provoking criticisms that the scheme has failed. The scheme was established in 2008 as an incentive for developers of drugs for neglected tropical diseases. Novartis of Basel recently used the only PRV issued so far—granted for the approval of the antimalarial drug Coartem (artemether/lumefantrine) in 2009—to have a 'priority' review of their supplemental biologics license application (sBLA) to the FDA for Ilaris (canakinumab). "We decided to utilize our PRV for ACZ885 (canakinumab) in gouty arthritis because of the significant unmet need that exists despite standard treatment options," says Eric Althoff, head of global media relations. Unfortunately, Novartis received a complete response letter from the FDA requesting additional clinical data to evaluate the benefit-risk profile for use of Ilaris in refractory patients. As No! vartis used their PRV (which cost an additional fee of $5,280,000 on top of the sBLA fee) but did not achieve approval of the supplementary indication for Ilaris, industry observers have been quick to suggest that use of this first PRV has been a failure. This is because the potential value of the PRV has been predicted based on additional sales revenue that a company would theoretically receive if approval was achieved at an earlier date. "Some studies have estimated the value of the voucher to be more than $300 million, others have estimated that it would provide a company with approximately four additional months of peak sales of a product," says Nick Cammack, head of GlaxoSmithKline's Tres Cantos Medicines Development Campus in Spain. However, as use of the first PRV has not resulted in increased sales revenues in the short term, many are questioning the voucher's value as an incentive to develop drugs for neglected tropical diseases. Nevertheless, Tim Wells, CSO of! the Medicines Malaria Venture in Geneva, remains optimistic o! f the voucher's value. "Even if only one in ten of the vouchers were deployed successfully, it would still have a book value of tens of millions of dollars. This is enough to help drive innovative clinical development." Cammack adds, "As only one PRV has been awarded, we believe it is too early to draw any conclusions on the effectiveness of PRVs as an incentive." Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Bethan Hughes Search for this author in: * NPG journals * PubMed * Google Scholar - European ruling raises specter of mandatory GM pollen tests on honey
- Nat Biotechnol 29(11):958 (2011)
Article preview View full access options Nature Biotechnology | News European ruling raises specter of mandatory GM pollen tests on honey * Emily Waltz1Journal name:Nature BiotechnologyVolume: 29,Page:958Year published:(2011)DOI:doi:10.1038/nbt1111-958bPublished online08 November 2011 Jaime R. Carrero/AP Photo A Europeam high court decision could force European honey sellers to test their products for the minute amounts of GM pollen stored by bees in the hive. Honey producers may be forced to test for exposure to genetically modified (GM) pollen after a decision from the high court of the European Union (EU) in Luxembourg. The court ruled in September that honey found to contain traces of pollen from GM corn must receive regulatory approval before it can be sold in Europe. If interpreted broadly, the decision could have widespread consequences for testing requirements for other agricultural products. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Affiliations * Nashville, Tennessee * Emily Waltz Author Details * Emily Waltz Search for this author in: * NPG journals * PubMed * Google Scholar - Industry leaders cite barriers to sequencing in trials
- Nat Biotechnol 29(11):959 (2011)
Article preview View full access options Nature Biotechnology | News Industry leaders cite barriers to sequencing in trials * Michael EisensteinJournal name:Nature BiotechnologyVolume: 29,Page:959Year published:(2011)DOI:doi:10.1038/nbt1111-959aPublished online08 November 2011 BSIP, CAVALLINI JAMES/SCIENCE PHOTO LIBRARY The Multiple Myeloma Research foundation recently launched a 1000-patient study tracking molecular profiles to improve understanding of clinical responses to new treatments. In September, the Norwalk, Connecticut–based Multiple Myeloma Research Foundation (MMRF) announced they will be partnering with Millennium, a wholly-owned Takeda subsidiary in Cambridge, Massachusetts, in an eight-year stratified medicine initiative to follow 1,000 individuals, characterize their genetic and molecular biomarkers, and track their molecular response to treatment. And more recently, Foundation Medicine of Cambridge, Massachusetts, announced that it will use its next-generation exome sequencing test in collaboration with the M.D. Anderson Cancer Center in Houston, to help match patients to experimental drugs. Despite these early steps, however, many still question whether the time is ripe to move towards broadly incorporating next- generation sequencing into the clinical trials Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Michael Eisenstein Search for this author in: * NPG journals * PubMed * Google Scholar - NIH tightens conflict rules
- Nat Biotechnol 29(11):959 (2011)
Article preview View full access options Nature Biotechnology | News NIH tightens conflict rules * Jim KlingJournal name:Nature BiotechnologyVolume: 29,Page:959Year published:(2011)DOI:doi:10.1038/nbt1111-959bPublished online08 November 2011 In a long anticipated move, the US National Institutes of Health tightened its disclosure requirements for funding applicants. The original rules established in 1995 called for disclosure when a researcher—or his/her spouse or children—received at least $10,000 in payments or 5% equity from companies or outside institutions. The new rules issued in August reduce that amount to $5,000 or any equity at all in a private company. Some are disappointed, however, that one rumored change was not included: the requirement for universities to post potential conflicts in publicly accessible web sites. Universities criticized the proposal. "That's a disappointment, because I do think it would be useful to have that information publicly available. I do think that awareness is higher and there will probably be more activity around disclosures," says Lisa Bero, professor of clinical pharmacy and health policy at the University of California San Francisco, Tom Stossel, professor at! Harvard Medical School, is a critic of the new policy. He says that no one has produced evidence that financial entanglements are harmful, and too much disclosure could lead to a witch hunt that undermines collaborations between academia and industry. "The old regulations didn't require very much. The new ones are going to open a Pandora's Box." Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Jim Kling Search for this author in: * NPG journals * PubMed * Google Scholar - Bispecific biologics rush
- Nat Biotechnol 29(11):959 (2011)
Article preview View full access options Nature Biotechnology | News Bispecific biologics rush * Josh P RobertsJournal name:Nature BiotechnologyVolume: 29,Page:959Year published:(2011)DOI:doi:10.1038/nbt1111-959cPublished online08 November 2011 In late August, Vancouver-based Zymeworks inked a deal worth up to $187 million plus royalties to advance bi-specific antibodies for Merck of Whitehouse Station, New Jersey. A week later Vienna-based f-star announced a collaboration with Merck Serono of Geneva to discover bi-specific IgGs against the pharma's targets, in a deal worth up to $676 million plus royalties. Such major deals in rapid succession suggest that bi-specific antibody platforms have matured enough to attract investment from big pharma. "Deals tend to come in lumps," says Carl Gordon, a partner at healthcare investment firm OrbiMed Advisors based in New York. Gordon points to a May publication (J. Clin. Oncol., 2386–2390, 2011) showing strong efficacy for Carlsbad, California–based Micromet's blinatumomab in a phase 2 trial for acute lymphocytic leukemia. Micromet's antibody is a bi-specific T-cell engager (BiTE), which binds CD19 on B cells and a CD3 site for T cells. "That is probably a proof o! f concept for the whole field," Gordon says. Zymeworks' platform consists of in silico–designed heterodimeric IgG scaffolds containing two different but complementary heavy chain subunits. f-star's bi-specific antibodies can be engineered with three antigen binding sites, so that they are heterovalent for one epitope and monovalent for another. The technology has matured enough to solve some inherent problems, and to generate "data that are interesting enough to get those deals," adds Jean-François Formela, partner at Atlas Venture in Cambridge, Massachusetts, and a member of f-star's board of directors. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Josh P Roberts Search for this author in: * NPG journals * PubMed * Google Scholar - Academia's $1,000 genome
- Nat Biotechnol 29(11):960 (2011)
Article preview View full access options Nature Biotechnology | News Academia's $1,000 genome * Gunjan SinhaJournal name:Nature BiotechnologyVolume: 29,Page:960Year published:(2011)DOI:doi:10.1038/nbt1111-960aPublished online08 November 2011 In August, the National Human Genome Research Institute (NHGRI) awarded $14 million in grants to support technologies that will enable rapid sequencing of a human genome for $1,000 or less by 2012. Grantees include seven university-based research groups and two companies—Electron Optica of Palo Alto, California, and Stratos Genomics of Seattle—that will undertake studies of new platforms and follow-on studies. Since 2004, NHGRI, part of the National Institutes of Health, has been spending between $18 and $22 million each year to bolster next-generation sequencing technologies, says Jeffery Schloss, program director of Technology Development Coordination at NHGRI. The goal is to ensure that genome sequencing will be easily available to researchers and healthcare providers. Technology supported by NHGRI has already brought the price down below $20,000, "but the data aren't yet of the quality we'd like to see," says Schloss. "The question is whether researchers can im! prove on these things." Many commercially successful sequencing technologies were supported by NHGRI grants at some point during development including Roche's 454, Oxford Nanopore's SOLiD, and Helicos' tSMS, says Jay Shendure, associate professor of genome sciences at University of Washington, Seattle, and a 2011 grant recipient. "This is a great example of the NIH supporting risky, innovative work that is explicitly technology development and also an example of how those bets can pay off." Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Gunjan Sinha Search for this author in: * NPG journals * PubMed * Google Scholar - China eyes Western biologics
- Nat Biotechnol 29(11):960 (2011)
Article preview View full access options Nature Biotechnology | News China eyes Western biologics * Hepeng JiaJournal name:Nature BiotechnologyVolume: 29,Page:960Year published:(2011)DOI:doi:10.1038/nbt1111-960bPublished online08 November 2011 Shenyang-based 3SBio forged a venture partnership with Taizhou Oriental to license biopharmaceuticals from Western companies for late-stage development or manufacturing in China. In August, the biotech formed 3SBio Ventures with an initial investment of RMB200 million ($31.3 million) from 3SBio and RMB50 million ($7.8 million) from Taizhou Oriental, the investment arm of an industrial park in the wealthy eastern Jiangsu province. The new fund will seek Chinese licensing rights to biologic therapeutics for use in oncology, nephrology and inflammatory diseases. The fund will allocate $3–5 million to each company, with the first investment expected this year. The 3SBio case is not unique. More than five years ago, the state-owned Beijing Pharmaceutical Group, set up a company in California to seek early-stage pharma products for further development in China. The economic downturn in the US and Europe and the booming development of the Chinese pharma sector, plus heavy governm! ent support and Chinese returnees trained in the West, have facilitated the process, according to Fang Hu, former president of Shanghai-based Sunway Bio, who is now operating a contract research organization to help small, innovative biotech firms develop clinical trials. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Author Details * Hepeng Jia Search for this author in: * NPG journals * PubMed * Google Scholar - Hemophilia market awaits next-generation therapies
- Nat Biotechnol 29(11):960 (2011)
Article preview View full access options Nature Biotechnology | News Hemophilia market awaits next-generation therapies * Cormac Sheridan1Journal name:Nature BiotechnologyVolume: 29,Page:960Year published:(2011)DOI:doi:10.1038/nbt1111-960cPublished online08 November 2011 Daniel Mihailescu/Newscom Water fountains in Bucharest coloured red by Romanian Hemophilia Association to draw attention to the disease. Recombinant coagulation factors control symptoms but the short duration of hemophilia products remains a major limitation. As Biogen Idec and Swedish Orphan Biovitrum prepare to report phase 3 data from a pivotal trial in hemophilia patients of their long-acting, recombinant version of the serum coagulation factor VIII (FVIII) next year, several next-generation hemophilia therapies are progressing in the clinic. In addition to Biogen/Biovitrum's product FVIII:Fc, a FVIII linked to the amino terminus of the Fc domain of IgG1, Recoly of Brussels, and its partner Bayer, of Leverkusen, Germany, have already filed for approval in undisclosed territories for LongAte, a liposome-formulated plasma-derived FVIII, with a recombinant-based counterpart (BAY-79-4980) in phase 2 studies. Several other companies are developing hemophilia products with half-life extension technologies, including Freising, Germany–based XL Protein, Amunix, of Mountain View, California, and Bagsværd, Denmark–based Novo Nordisk. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data Affiliations * Dublin * Cormac Sheridan Author Details * Cormac Sheridan Search for this author in: * NPG journals * PubMed * Google Scholar - The R&D partnership universe
- Nat Biotechnol 29(11):961 (2011)
Article preview View full access options Nature Biotechnology | News | Data Page The R&D partnership universe * Wayne Peng1Journal name:Nature BiotechnologyVolume: 29,Page:961Year published:(2011)DOI:doi:10.1038/nbt.2035Published online08 November 2011 Apart from a 2006 spike, the annual number of deals has remained relatively flat, with an average of ~440 deals per year; however, deal size has swollen tenfold. Licenses for small-molecule discovery/screening platforms, monoclonal antibody, oncology and infectious disease assets predominate, with drug delivery partnerships increasing, perhaps due to the rise of biobetters. Deals on hepatitis C virus NS5B polymerase inhibitors, a small molecule against all vascular endothelial growth factor receptor (VEGFR) subtypes and a biosimilar figure prominently this year. Historic total number and average value of biotech deals Box 1: Historic total number and average value of biotech deals Full box Historic number of deals by primary technology/modality Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Wayne Peng is Emerging Technology Analyst, Nature Publishing Group Author Details * Wayne Peng Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Biotech plummets in 3Q11
- Nat Biotechnol 29(11):962 (2011)
Article preview View full access options Nature Biotechnology | News | Data Page Biotech plummets in 3Q11 * Walter Yang1Journal name:Nature BiotechnologyVolume: 29,Page:962Year published:(2011)DOI:doi:10.1038/nbt.2036Published online08 November 2011 The US debt downgrade and Dendreon's lower than anticipated sales of Provenge (sipuleucel-T) conspired to torpedo the biotech markets. Funding also declined, with $4.1 billion excluding partnership monies, the lowest since 4Q08. Despite the poor quarter, biotechs have raised $27.6 billion so far this year, more than in 7 of the past 10 years. Public offerings were up 18% from a year ago but down 50% from 2Q11; debt and other funding deals were down from 3Q10, as were private biotech financings. Stock market performance Box 1: Stock market performance Full box Global biotech initial public offerings Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Walter Yang is Research Director at BioCentury Author Details * Walter Yang Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Hepatitis C: move over interferon
- Nat Biotechnol 29(11):963-966 (2011)
Nature Biotechnology | News Feature Hepatitis C: move over interferon * Ken Garber1Journal name:Nature BiotechnologyVolume: 29,Pages:963–966Year published:(2011)DOI:doi:10.1038/nbt.2031Published online08 November 2011 Following approval of hepatitis C virus protease inhibitors Incivek and Victrelis, companies are partnering to devise all-oral combination antiviral regimens without interferon α. But the virus is a long way from vanquished. Ken Garber investigates. View full text Additional data Affiliations * Ann Arbor, Michigan * Ken Garber Author Details * Ken Garber Search for this author in: * NPG journals * PubMed * Google Scholar - In vogue with venture
- Nat Biotechnol 29(11):967-970 (2011)
- A label we don't need
- Nat Biotechnol 29(11):971-972 (2011)
Article preview View full access options Nature Biotechnology | Opinion and Comment | Correspondence A label we don't need * Henry I Miller1 * Drew L Kershen2 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:971–972Year published:(2011)DOI:doi:10.1038/nbt.2027Published online08 November 2011 To the Editor: The United Nations (UN; New York) agency that sets food standards—the Codex Alimentarius (Latin for 'Food Code,' commonly called 'Codex' for short)—recently reached an impasse on the labeling of food containing products derived from recombinant DNA technology. It decided neither to recommend nor to establish compulsory labeling for foods with ingredients from recombinant DNA-modified organisms—but you'd never know that from the spin. The Codex was established in 1963 by two UN entities, the Food & Agricultural Organization (FAO; Rome) and the World Health Organization (WHO; Geneva). Operating through various committees, one of which is the Committee on Food Labeling (CCFL), Codex develops voluntary, consensus, international standards to promote consumer health and fair trade in food products in international commerce. Codex is important for another, unobvious reason. In accordance with specific language in the World Trade Organization's (WTO, Geneva) trade agreements, any country that incorporates the Codex standards into its domestic laws is automatically assumed to be acting in compliance with WTO strictures1. Thus, Codex provides a legal safe-haven for nations whose policies or actions may be challenged by WTO complaints. For almost two decades, the CCFL has dealt with the (unnecessarily) contentious issue of whether foods derived from crops modified with recombinant DNA technology should have to be labeled as such. The obvious question is whether these products are sufficiently unique or pose dangers that should require such labeling. The scientific community has known the answer for a very long time. As Nature editorialized in 1992, "the same physical and biological laws govern the response of organisms modified by modern molecular and cellular methods and those produced by classical methods....[Therefore] no conceptual distinction exists between genetic modification of plants and microorganisms by classical methods or by molecular techniques that modify DNA and transfer genes"2. The US Food and Drug Administration (FDA) has explicitly rejected the labeling of food to indicate that it contains ingredients produced with recombinant DNA technology, as is the case for other genetic modific! ation techniques3. During the deliberations at Codex, Europe has consistently argued for mandatory process-based labeling that reflects the use of certain techniques used in plant breeding, whereas Canada, the United States and other countries have consistently argued against such special labeling, instead endorsing labeling based on food content, safety and nutritional value. Since the early 1990s the issue has been unresolved, with the same arguments presented ad nauseam. The result was an impasse. In May 2011, in Quebec City, the CCFL reached a truce that had two components. First, nations agreed on the lack of consensus about compulsory labeling for foods derived from modern biotech, and the committee therefore agreed to discontinue further work on definitions and precise rules on this topic. Second, the nations agreed to the adoption of a document entitled "Compilation of Codex Texts Relevant to Labeling of Foods Derived from Modern Biotechnology." The CCFL sent this compilation to the Codex Alimentarius Commission itself, which met in Geneva in June. The commission accepted the CCFL's compilation document and its decision to discontinue further work. As this action was taken on a consent docket, Codex member nations took no vote; Codex simply accepted the CCFL's May 2011 impasse4, 5. Codex's action has been widely misreported, being variously interpreted as either condoning or condemning compulsory labeling of foods derived through the techniques of modern biotech6, 7, 8. It does neither; it is simply a compilation that was presented without any value judgments. As described therein, the purpose of the document was "only to recall and assemble in a single document some important elements of guidance from Codex texts, which are relevant to labeling of foods derived from modern biotechnology." The document further clarifies that "[d]ifferent approaches regarding labeling of foods derived from modern biotechnology are used. Any approach implemented by Codex members should be consistent with already adopted Codex provisions. This document is not intended to suggest or imply that foods derived from modern biotechnology are necessarily different from other foods simply due to their method of production." Far from presenting any new recommendations or requirements, the document notes that it contains only "citations to specific, already existing Codex texts relevant to labeling of foods"9. None of these texts specifically addresses labeling of biotech-derived foods. The document prompted prominent anti-biotech groups, such as Consumers International (London) and Greenpeace (Amsterdam), to immediately proclaim 'victory' in the labeling debate, claiming that Codex had adopted an international standard that protected nations from WTO challenges to mandatory labeling requirements. Consumers International also asserted that the compilation document reflects Codex support for countries in Africa and Latin America to adopt the European mandatory labeling approach7. The Codex compilation does no such thing: the document takes pains to make clear that it does not create an international standard for the labeling of biotech-derived foods. The document declares that "different approaches regarding labeling of foods derived from modern biotechnology are used" around the world but emphasizes that Codex does not intend "to suggest or imply that foods derived from modern biotechnology are necessarily different from other foods." The document then cites ten existing Codex standards that countries should comply with in food labeling. Therefore, nations with mandatory labeling laws that lack a scientific basis—which are prohibited by WTO rules—are still vulnerable to WTO challenges. Even the European Union joylessly informed its member states that mandatory labeling "has been on the [CCFL] agenda since 1996 and despite intense negotiations, the US and their allies have managed to prevent any real progress. The US's main motivation is to prevent the adoption of any Codex text which would encourage GM labelling and also make our GM labelling framework WTO compatible..."10. Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * The Hoover Institution, Stanford University, Stanford, California, USA. * Henry I Miller * University of Oklahoma, School of Law, Norman, Oklahoma, USA. * Drew L Kershen Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Henry I Miller Author Details * Henry I Miller Contact Henry I Miller Search for this author in: * NPG journals * PubMed * Google Scholar * Drew L Kershen Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Harnessing cloud computing with Galaxy Cloud
- Nat Biotechnol 29(11):972-974 (2011)
Nature Biotechnology | Opinion and Comment | Correspondence Harnessing cloud computing with Galaxy Cloud * Enis Afgan1 * Dannon Baker1 * Nate Coraor2 * Hiroki Goto2 * Ian M Paul3 * Kateryna D Makova2 * Anton Nekrutenko2 * James Taylor1 * Affiliations * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:972–974Year published:(2011)DOI:doi:10.1038/nbt.2028Published online08 November 2011 To the Editor: Continuing evolution of DNA sequencing has transformed modern biology. Lower sequencing costs coupled with novel sequencing-based assays have led to rapid adoption of next-generation sequencing across diverse areas of life sciences research1, 2, 3, 4. Sequencing has moved out of the genome centers into core facilities and individual laboratories where any investigator can access it for modest and progressively declining cost. Although easy to generate in tremendous quantities, sequence data are still difficult to manage and analyze. Sophisticated informatics techniques and supporting infrastructure are needed to make sense of even conceptually simple sequencing experiments, let alone the more complex analysis techniques being developed. The most pressing challenge facing the sequencing community today is providing the informatics infrastructure and accessible analysis methods needed to make it possible for all investigators to realize the power of high-throughput sequencing ! to advance their research. View full text Author information * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Departments of Biology and Mathematics & Computer Science, Emory University, Atlanta, Georgia, USA. * Enis Afgan, * Dannon Baker & * James Taylor * Center for Comparative Genomics and Bioinformatics, Penn State University, University Park, Pennsylvania, USA. * Nate Coraor, * Hiroki Goto, * Kateryna D Makova & * Anton Nekrutenko * Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania, USA. * Ian M Paul Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * James Taylor or * Anton Nekrutenko or * Kateryna D Makova Author Details * Enis Afgan Search for this author in: * NPG journals * PubMed * Google Scholar * Dannon Baker Search for this author in: * NPG journals * PubMed * Google Scholar * Nate Coraor Search for this author in: * NPG journals * PubMed * Google Scholar * Hiroki Goto Search for this author in: * NPG journals * PubMed * Google Scholar * Ian M Paul Search for this author in: * NPG journals * PubMed * Google Scholar * Kateryna D Makova Contact Kateryna D Makova Search for this author in: * NPG journals * PubMed * Google Scholar * Anton Nekrutenko Contact Anton Nekrutenko Search for this author in: * NPG journals * PubMed * Google Scholar * James Taylor Contact James Taylor Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Notes and Fig. 1 (194k) Harnessing cloud-computing for biomedical research with Galaxy Cloud Additional data - Going viral
- Nat Biotechnol 29(11):975 (2011)
Nature Biotechnology | Opinion and Comment | Commentary Going viral * Victor Bethencourt1 * Christopher Scott1 * AffiliationsJournal name:Nature BiotechnologyVolume: 29,Page:975Year published:(2011)DOI:doi:10.1038/nbt.2033Published online08 November 2011 Affymetrix was an early mover in the DNA microarray space that came to dominate the market, overcoming criticism from its users and a slew of cutthroat competitors. How did it do it? View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Victor Bethencourt is Associate Business Editor & Christopher Scott is Contributing Editor. Author Details * Victor Bethencourt Search for this author in: * NPG journals * PubMed * Google Scholar * Christopher Scott Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Theory of knowledge and biotech patents: worlds apart?
- Nat Biotechnol 29(11):977-978 (2011)
Nature Biotechnology | Feature | Patents Theory of knowledge and biotech patents: worlds apart? * Myriam M Altamirano-Bustamante1 * Adalberto de Hoyos2 * León Olivé3 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:977–978Year published:(2011)DOI:doi:10.1038/nbt.2026Published online08 November 2011 The development of original research requires tacit as well as explicit knowledge, which allows for the establishment of new epistemic trajectories with novel epistemic horizons. Much of the tacit knowledge involved in the innovation process can be transmitted as explicit knowledge through the patent document. View full text Author information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Myriam M. Altamirano-Bustamante is in the Research Unit of Metabolic Diseases and the Cross-Functional Group in Clinical Ethics, Century XXI Medical Center, Mexican Institute of Social Security, Mexico City, Mexico * Adalberto de Hoyos is in the Cross-Functional Group in Clinical Ethics, Century XXI Medical Center, Mexican Institute of Social Security, Mexico City, Mexico, and the Institute of Philosophical Research, National Autonomous University of Mexico, Mexico City, Mexico * León Olivé is in the Institute of Philosophical Research, National Autonomous University of Mexico, Mexico City, Mexico. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * León Olivé Author Details * Myriam M Altamirano-Bustamante Search for this author in: * NPG journals * PubMed * Google Scholar * Adalberto de Hoyos Search for this author in: * NPG journals * PubMed * Google Scholar * León Olivé Contact León Olivé Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Recent patent applications in antibody fragments: an academic update from the EU
- Nat Biotechnol 29(11):979 (2011)
Article preview View full access options Nature Biotechnology | Feature | Patents Recent patent applications in antibody fragments: an academic update from the EU * Julien Muzard1Journal name:Nature BiotechnologyVolume: 29,Page:979Year published:(2011)DOI:doi:10.1038/nbt.2039Published online08 November 2011 Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Julien Muzard is at the School of Chemistry & Chemical Biology, University College Dublin, Ireland. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Julien Muzard Author Details * Julien Muzard Contact Julien Muzard Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Interrogating the kinome
- Nat Biotechnol 29(11):981-983 (2011)
Article preview View full access options Nature Biotechnology | News and Views Interrogating the kinome * Chao Zhang1 * Gaston Habets1 * Gideon Bollag1 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:981–983Year published:(2011)DOI:doi:10.1038/nbt.2021Published online08 November 2011 Comprehensive studies of the kinome set the stage for discovering the next generation of kinase-directed drugs. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * 日本語要約 * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Chao Zhang, Gaston Habets and Gideon Bollag are at Plexxikon, Inc., Berkeley, California, USA. Competing financial interests The authors are employees of Plexxikon Inc., a member of the Daiichi Sankyo group. Corresponding author Correspondence to: * Gideon Bollag Author Details * Chao Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Gaston Habets Search for this author in: * NPG journals * PubMed * Google Scholar * Gideon Bollag Contact Gideon Bollag Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Primate genomes for biomedicine
- Nat Biotechnol 29(11):983-984 (2011)
Article preview View full access options Nature Biotechnology | News and Views Primate genomes for biomedicine * Steven E Bosinger1 * Zachary P Johnson1 * Guido Silvestri2 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:983–984Year published:(2011)DOI:doi:10.1038/nbt.2032Published online08 November 2011 Genome sequences are now available for two macaque species used in infectious disease research and drug safety testing. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * 日本語要約 * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Steven E. Bosinger and Zachary P. Johnson are at the Non-Human Primate Genomics Core, Yerkes National Primate Research Center, Robert W. Woodruff Health Sciences Center, Emory University, Atlanta, Georgia, USA * Guido Silvestri is at the Yerkes National Primate Research Center and the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Robert W. Woodruff Health Sciences Center, Atlanta, Georgia, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Guido Silvestri Author Details * Steven E Bosinger Search for this author in: * NPG journals * PubMed * Google Scholar * Zachary P Johnson Search for this author in: * NPG journals * PubMed * Google Scholar * Guido Silvestri Contact Guido Silvestri Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Road test for genetically modified mosquitoes
- Nat Biotechnol 29(11):984-985 (2011)
Article preview View full access options Nature Biotechnology | News and Views Road test for genetically modified mosquitoes * Todd Shelly1 * Don McInnis2 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:984–985Year published:(2011)DOI:doi:10.1038/nbt.2025Published online08 November 2011 Results from the first open-field trial of transgenic mosquitoes bode well for large-scale releases to fight infectious diseases. Article preview Read the full article * Instant access to this article: US$18 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Todd Shelly is at US Department of Agriculture-Animal and Plant Health Inspection, Waimanalo, Hawaii, USA * Don McInnis is based in Hilo, Hawaii, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Todd Shelly Author Details * Todd Shelly Contact Todd Shelly Search for this author in: * NPG journals * PubMed * Google Scholar * Don McInnis Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - How to apply de Bruijn graphs to genome assembly
- Nat Biotechnol 29(11):987-991 (2011)
Nature Biotechnology | Computational Biology | Primer How to apply de Bruijn graphs to genome assembly * Phillip E C Compeau1 * Pavel A Pevzner2 * Glenn Tesler1 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:987–991Year published:(2011)DOI:doi:10.1038/nbt.2023Published online08 November 2011 A mathematical concept known as a de Bruijn graph turns the formidable challenge of assembling a contiguous genome from billions of short sequencing reads into a tractable computational problem. View full text Figures at a glance * Figure 1: Bridges of Königsberg problem. () A map of old Königsberg, in which each area of the city is labeled with a different color point. () The Königsberg Bridge graph, formed by representing each of four land areas as a node and each of the city's seven bridges as an edge. * Figure 2: De Bruijn graph. The de Bruijn graph B for k = 4 and a two-character alphabet composed of the digits 0 and 1. This graph has an Eulerian cycle because each node has indegree and outdegree equal to2. Following the blue numbered edges in order from 1 to 16 traces an Eulerian cycle 000, 001, 011, 110, 100, 001, 010, 101, 011, 111, 111, 110, 101, 010, 100, 000. Recording the first character (in boldface) of each edge label spells the cyclic superstring . * Figure 3: Two strategies for genome assembly: from Hamiltonian cycles to Eulerian cycles. () An example small circular genome. () In traditional Sanger sequencing algorithms, reads were represented as nodes in a graph, and edges represented alignments between reads. Walking along a Hamiltonian cycle by following the edges in numerical order allows one to reconstruct the circular genome by combining alignments between successive reads. At the end of the cycle, the sequence wraps around to the start of the genome. The repeated part of the sequence is grayed out in the alignment diagram. () An alternative assembly technique first splits reads into all possible k-mers: with k = 3, ATGGCGT comprises ATG, TGG, GGC, GCG and CGT. Following a Hamiltonian cycle (indicated by red edges) allows one to reconstruct the genome by forming an alignment in which each successive k-mer (from successive nodes) is shifted by one position. This procedure recovers the genome but does not scale well to large graphs. () Modern short-read assembly algorithms construct a de Bruijn graph by ! representing all k-mer prefixes and suffixes as nodes and then drawing edges that represent k-mers having a particular prefix and suffix. For example, the k-mer edge ATG has prefix AT and suffix TG. Finding an Eulerian cycle allows one to reconstruct the genome by forming an alignment in which each successive k-mer (from successive edges) is shifted by one position. This generates the same cyclic genome sequence without performing the computationally expensive task of finding a Hamiltonian cycle. Author information * Author information * Supplementary information Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Phillip E. C. Compeau and Glenn Tesler are in the Department of Mathematics, University of California San Diego, La Jolla, California, USA * Pavel A. Pevzner is in the Department of Computer Science and Engineering, University of California San Diego, La Jolla, California, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Pavel A Pevzner Author Details * Phillip E C Compeau Search for this author in: * NPG journals * PubMed * Google Scholar * Pavel A Pevzner Contact Pavel A Pevzner Search for this author in: * NPG journals * PubMed * Google Scholar * Glenn Tesler Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Figure 1 and 2 (139k) De Bruijn graph from reads with sequencing errors Additional data - Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus
- Nat Biotechnol 29(11):993-1003 (2011)
Nature Biotechnology | Research | Perspective Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus * Ann D Kwong1 * Robert S Kauffman1 * Patricia Hurter1 * Peter Mueller1 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:993–1003Year published:(2011)DOI:doi:10.1038/nbt.2020Published online08 November 2011 Abstract * Abstract * Author information Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Infection with hepatitis C virus (HCV) is a major medical problem with over 170 million people infected worldwide. Substantial morbidity and mortality are associated with hepatic manifestations (cirrhosis and hepatocellular carcinoma), which develop with increasing frequency in people infected with HCV for more than 20 years. Less well known is the burden of HCV disease associated with extrahepatic manifestations (diabetes, B-cell proliferative disorders, depression, cognitive disorders, arthritis and Sjögren's syndrome). For patients infected with genotype 1 HCV, treatment with polyethylene glycol decorated interferon (peginterferon) α and ribavirin (PR) is associated with a low (40–50%) success rate, substantial treatment-limiting side effects and a long (48-week) duration of treatment. In the past 15 years, major scientific advances have enabled the development of new classes of HCV therapy, the direct-acting antiviral agents, also known as specifically targeted antiv! iral therapy for hepatitis C (STAT-C). In combination with PR, the HCV NS3-4A protease inhibitor telaprevir has recently been approved for treatment of genotype 1 chronic HCV in the United States, Canada, European Union and Japan. Compared with PR, telaprevir combination therapy offers significantly improved viral cure rates and the possibility of shortened treatment duration for diverse patient populations. Developers of innovative drugs have to blaze a new path with few validated sign posts to guide the way. Indeed, telaprevir's development was once put on hold because of its performance in a standard IC50 assay. Data from new hypotheses and novel experiments were required to justify further investment and reduce risk that the drug might fail in the clinic. In addition, the poor drug-like properties of telaprevir were a formidable hurdle, which the manufacturing and formulation teams had to overcome to make the drug. Finally, novel clinical trial designs were developed to! improve efficacy and shorten treatment in parallel instead of! sequentially. Lessons learned from the development of telaprevir suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success. View full text Figures at a glance * Figure 1: Important research and commercial milestones in telaprevir development. aref. 110; brefs. 49, 50; cref. 111; drefs. 54, 55; eref. 112; frefs. 71, 72; gref. 79; hrefs. 19, 85, 86; iref. 96; jrefs. 102, 103, 104. * Figure 2: From natural substrate to peptidomimetic: highlights in telaprevir medicinal chemistry strategy. () Evolution of protease inhibitor from a decamer peptide substrate to telaprevir. () Model of NS5A-5B peptide substrate (EDVVCCSMSY) bound to NS3 protease. The NS3 protease domain is shown in a salmon-colored cartoon diagram. The active site triad residues Ser139, His57 and Asp81 are highlighted as sticks (with carbons colored green, oxygen in red, nitrogen in blue). The NS4A co-factor peptide segment is shown as a cartoon in blue. The NS5A-5B peptide is shown in sticks representation (with carbons colored cyan, oxygen in red, nitrogen in blue). Telaprevir is also shown in line diagram (with carbons colored magenta, oxygen in red, nitrogen in blue). () Crystal structure of telaprevir bound to NS3-4A protease crystal structure. The NS3 protease domain is shown in a salmon-colored cartoon diagram. The active site triad residues Ser139, His57 and Asp81 are highlighted as sticks (with carbons colored green, oxygen in red, nitrogen in blue). The NS4A co-factor peptide segment is! shown as a cartoon in blue. Telaprevir is shown as a stick diagram (with carbons colored magenta, oxygen in red, nitrogen in blue). * Figure 3: Challenges in telaprevir formulation. The structure of telaprevir (1) leads to a molecule with challenging physicochemical properties for a drug intended for oral delivery. As shown in (2), the high polar surface area (PSA) makes telaprevir fall well outside the 'Egan Egg' for marketed orally delivered drugs that are known to be well absorbed113. It should be noted that the measured logP (octanol-water partition coefficient, a measure of hydrophobicity) for telaprevir is 4.0, significantly higher than the calculated value of 2.8 (the clogP (calculated logP) was used in the figure for all molecules including telaprevir, for consistency), which puts telaprevir toward the upper end of logP values relative to marketed oral drugs. As shown in (3), telaprevir is highly crystalline, with a high melting point (mp) of 246 °C, contributing to the extremely poor water solubility (Saq) of crystalline material (4.7 mg/ml). (4) The solubility of telaprevir is actually lower than that of marble. (5) Preliminary formulation at! tempts showed that solutions, crystalline suspensions and even a nanosuspension, resulted in very low oral exposure of telaprevir (%F is the absolute bioavailability). (6) It was found that formulating telaprevir as an amorphous spray dried dispersion (Tg is the glass transition temperature) substantially improved the kinetic solubility (Saqkin) in aqueous media, and thereby improved bioavailability. The choice of stabilizing polymer and surfactant is critical, as shown in (7). The early formulation used in toxicology and phase 1 studies was not as physically stable (that is, crystallization occurred more rapidly in aqueous media) as the final formulation. Stabilizing the dispersion led to substantially improved exposure (AUCinf), allowing the safety margin for telaprevir to be confidently established. * Figure 4: The role of telaprevir and PR in the treatment regimen. During telaprevir combination treatment, a triphasic viral RNA decline is observed. During the telaprevir and PR (TVR + PR) phase of treatment, HCV RNA levels drop quickly. In the second phase (PR alone), resistant variants begin to emerge. Once the telaprevir-sensitive variants are cleared, the slope of the curve decreases, as less sensitive HCV variants comprise the majority of the viral population and require more time to clear. A key role of PR in the regimen is to clear telaprevir-resistant variants. In patients who do not achieve SVR, any telaprevir-resistant variants are rapidly replaced by wild-type virus. Note that the definition of SVR is dependent on the lower limit of HCV RNA detection in the assay used. TVR: telaprevir; PR: peginterferon a and ribavirin. Author information * Abstract * Author information Affiliations * Vertex Pharmaceuticals, Cambridge, Massachusetts, USA. * Ann D Kwong, * Robert S Kauffman, * Patricia Hurter & * Peter Mueller Competing financial interests All authors are employees and stock owners of Vertex Pharmaceuticals, Inc. Corresponding author Correspondence to: * Ann D Kwong Author Details * Ann D Kwong Contact Ann D Kwong Search for this author in: * NPG journals * PubMed * Google Scholar * Robert S Kauffman Search for this author in: * NPG journals * PubMed * Google Scholar * Patricia Hurter Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Mueller Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Therapeutic siRNA silencing in inflammatory monocytes in mice
- Nat Biotechnol 29(11):1005-1010 (2011)
Nature Biotechnology | Research | Article Therapeutic siRNA silencing in inflammatory monocytes in mice * Florian Leuschner1, 11 * Partha Dutta1, 11 * Rostic Gorbatov1 * Tatiana I Novobrantseva2 * Jessica S Donahoe1 * Gabriel Courties1 * Kang Mi Lee3 * James I Kim3 * James F Markmann3 * Brett Marinelli1 * Peter Panizzi4 * Won Woo Lee5 * Yoshiko Iwamoto1 * Stuart Milstein2 * Hila Epstein-Barash2 * William Cantley2 * Jamie Wong2 * Virna Cortez-Retamozo1 * Andita Newton1 * Kevin Love6 * Peter Libby7 * Mikael J Pittet1 * Filip K Swirski1 * Victor Koteliansky2 * Robert Langer6, 8, 9 * Ralph Weissleder1, 10 * Daniel G Anderson6, 8, 9 * Matthias Nahrendorf1 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:1005–1010Year published:(2011)DOI:doi:10.1038/nbt.1989Received13 July 2011Accepted29 August 2011Published online09 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Inflammatory monocytes—but not the noninflammatory subset—depend on the chemokine receptor CCR2 for localization to injured tissue. Here we present an optimized lipid nanoparticle and a CCR2-silencing short interfering RNA that, when administered systemically in mice, show rapid blood clearance, accumulate in spleen and bone marrow, and localize to monocytes. Efficient degradation of CCR2 mRNA in monocytes prevents their accumulation in sites of inflammation. Specifically, the treatment attenuates their number in atherosclerotic plaques, reduces infarct size after coronary artery occlusion, prolongs normoglycemia in diabetic mice after pancreatic islet transplantati! on, and results in reduced tumor volumes and lower numbers of tumor-associated macrophages. View full text Figures at a glance * Figure 1: Nanoparticle-encapsulated siRNA is distributed to leukocytes. () Dynamic FMT-CT biodistribution imaging of siRNA shows major uptake in the spleen (dashed circle). The material is rapidly cleared from the blood pool (arrow) and excreted through the hepato-biliary route into the bowel (n = 5). () Immunofluorescence microscopy of the splenic red pulp shows colocalization of siRNA (red) and CD11b expression (green). Scale bar, 20 μm. () Profiling by flow cytometry reveals strong uptake of siRNA into cells of the mononuclear phagocyte system in the bone marrow, blood and the spleen. Representative dot-plots on the left illustrate the gating strategy (Lin: lineage markers). Histograms on the right illustrate the uptake of siRNA (red) in the respective cells (columns) and organs (rows). Blue indicates control fluorescence in cells harvested from noninjected mice. () Comparison of siRNA content in Ly-6Chigh monocytes retrieved from different organs (n = 3 mice per group). Mean ± s.d., *P < 0.05. AU, arbitrary unit. * Figure 2: Intravenous injection of nanoparticle-encapsulated siRNA results in knockdown in monocytes. () PCR analysis of FACS-sorted splenic Ly-6Chigh monocytes after intravenous administration of nanoparticle-encapsulated siRNA targeting CCR2 (siCCR2). siCON, control siRNA treatment. n = 3 per group. () Western blot analysis of Ly-6Chigh monocytes isolated from the spleen of mice that were either treated with siCCR2 or control. The reduced band in the siCCR2 lane confirms a lower expression of CCR2 receptor protein in splenic monocytes after intravenous treatment (experiment was done in triplicate, representative blot is cropped; the full-length blot is presented in Supplementary Fig. 6). () FACS analysis of CCR2 protein on splenic Ly-6Chigh monocytes. Representative histogram shows isotype antibody staining (black), control treatment (red) and siCCR2 treatment (blue). Bar graph of mean fluorescent intensity (MFI, y axis starts at mean fluorescence intensity of the isotype control; n = 6 per group). () Migration assay of sorted Ly-6Chigh monocytes using MCP-1 as chemoattrac! tant. Cells were harvested from mice injected with either siCCR2 or control siRNA (n = 3 per group). Stained membranes on the left, bar graph shows enumeration of migrated cells. Mean ± s.d., *P < 0.05. * Figure 3: Treatment with siCCR2 reduces ischemia reperfusion injury. () FACS of hearts 24 h after ischemia reperfusion injury (IRI). Dot-plots show a reduction of monocytes/macrophages (blue gate) in the infarct tissue after siCCR2 treatment. Right column of dot plots displays subset analysis with a drastically reduced Ly-6Chigh monocyte population in the lower right quadrant. () Cell tissue numbers for monocytes/macrophages (Mo/MΦ, left) and for Ly-6Chigh monocytes (n = 9 per group). () Fluorescence reflectance images display the area at risk, which is void of microspheres injected during ischemia (left column). TTC staining of the same myocardial short-axis slice (right column). The pale, unstained infarct is outlined by a dashed line. () Infarct size normalized to the nonperfused area at risk (n = 7–9 per group). (,) FACS of infarcts 24 h after permanent coronary ligation. Spleen "minus" indicates removal of the spleen at time of myocardial infarction. () Histogram of Ly-6Chigh monocytes in infarcts. () Number of Ly-6Chigh monocytes! in infarcts. () Number of monocytes/macrophages in infarcts. No statistically significant difference was detected between treatment groups (n = 4–8 per group). Mean ± s.d.; *, P < 0.05. * Figure 4: Treatment with siCCR2 reduces inflammation in atherosclerotic lesions in apoE−/− mice. () FACS analysis of cell suspensions retrieved from aortas after 3 weeks of treatment with siRNA targeting CCR2 (siCCR2) or control siRNA treatment (siCON). () Number of monocytes and macrophages (Mo/MΦ) and Ly-6Chigh monocytes in the aortas of apoE−/− mice (n = 10 per group). () Immunohistochemical analysis of aortic roots for CD11b and lesion size (n = 8–14 per group). ROI, region of interest; AU, arbitrary units. Mean ± s.d., *P < 0.05. * Figure 5: siCCR2 treatment prolongs survival of pancreatic islet allografts. Diabetic C57/BL/6 mice received BALB/c islets. () Survival curve of pancreatic islet transplants in untreated control (blue), control siRNA-treated (green) and siCCR2-treated (black) recipients. Rejection was defined as the return of hyperglycemia (blood glucose level >200 mg/dl on two consecutive measurements, n = 7–10 per group). P < 0.05. () H&E histology of a transplanted islet from a mouse treated with siCCR2. () Rejected islet from a control siRNA-treated mouse. Scale bar, 50 μm. * Figure 6: Treatment with siCCR2 reduces tumor size and the number of tumor-associated macrophages. () Tumor size measured by X-ray CT. Representative images from mice on day 10 after implantation of EL4-tumors (n = 7 per group). Top row displays cohort treated with control siRNA (siCON), bottom row shows siCCR2 treatment. The three-dimensional CT reconstruction shows tumor in red pseudocolor. () FACS analysis of tumors with monocyte/macrophage gate (blue box) after treatment with control siRNA (top) or siCCR2 (n = 5 per group). (–) Immunohistochemical evaluation of tumors for myeloid cells (, CD11b), vascular endothelial growth factor (, VEGF) and vessel density (, CD31). Bar graphs show quantification. FOV, field of view. Scale bars, 50 μm. Mean ± s.d.; *P < 0.05; n = 7 per group. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Florian Leuschner & * Partha Dutta Affiliations * Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. * Florian Leuschner, * Partha Dutta, * Rostic Gorbatov, * Jessica S Donahoe, * Gabriel Courties, * Brett Marinelli, * Yoshiko Iwamoto, * Virna Cortez-Retamozo, * Andita Newton, * Mikael J Pittet, * Filip K Swirski, * Ralph Weissleder & * Matthias Nahrendorf * Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. * Tatiana I Novobrantseva, * Stuart Milstein, * Hila Epstein-Barash, * William Cantley, * Jamie Wong & * Victor Koteliansky * Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA. * Kang Mi Lee, * James I Kim & * James F Markmann * Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, Alabama, USA. * Peter Panizzi * Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul, Korea. * Won Woo Lee * David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. * Kevin Love, * Robert Langer & * Daniel G Anderson * Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. * Peter Libby * Department of Chemical Engineering, MIT, Cambridge, Massachusetts, USA. * Robert Langer & * Daniel G Anderson * Division of Health Science Technology, MIT, Cambridge, Massachusetts, USA. * Robert Langer & * Daniel G Anderson * Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. * Ralph Weissleder Contributions F.L. and P.D. performed experiments, collected and analyzed the data and contributed to writing the manuscript, R.G. did surgeries and performed experiments, T.I.N. designed experiments and siRNA screens, analyzed data and contributed to writing the manuscript; K.M.L. did islet transplantations and analyzed data, J.S.D., G.C., J.I.K., J.F.M., B.M., P.P., W.W.L., Y.I., V.C.-R., A.N., W.C., J.W. performed experiments, imaging, collected, analyzed and discussed data, S.M., H.E.-B., K.L. formulated siRNA nanoparticles, P.L., M.J.P. and F.K.S. conceived experiments and discussed strategy and results; V.K., R.L., R.W., D.G.A. and M.N. designed experiments, developed siRNA delivery technology and in vivo imaging strategies and systems, and reviewed, analyzed and discussed data. M.N. and R.W. wrote the manuscript which was edited and approved by all co-authors. M.N. developed and supervised the project. Competing financial interests T.I.N., S.M., H.E.B., W.C., J.W. and V.K. are Alnylam Pharmaceuticals employees; K.L., R.L., and D.G.A. receive funding from Alnylam Pharmaceuticals. R.L. and D.G.A. are consultants with Alnylam. Corresponding authors Correspondence to: * Matthias Nahrendorf or * Ralph Weissleder Author Details * Florian Leuschner Search for this author in: * NPG journals * PubMed * Google Scholar * Partha Dutta Search for this author in: * NPG journals * PubMed * Google Scholar * Rostic Gorbatov Search for this author in: * NPG journals * PubMed * Google Scholar * Tatiana I Novobrantseva Search for this author in: * NPG journals * PubMed * Google Scholar * Jessica S Donahoe Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Courties Search for this author in: * NPG journals * PubMed * Google Scholar * Kang Mi Lee Search for this author in: * NPG journals * PubMed * Google Scholar * James I Kim Search for this author in: * NPG journals * PubMed * Google Scholar * James F Markmann Search for this author in: * NPG journals * PubMed * Google Scholar * Brett Marinelli Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Panizzi Search for this author in: * NPG journals * PubMed * Google Scholar * Won Woo Lee Search for this author in: * NPG journals * PubMed * Google Scholar * Yoshiko Iwamoto Search for this author in: * NPG journals * PubMed * Google Scholar * Stuart Milstein Search for this author in: * NPG journals * PubMed * Google Scholar * Hila Epstein-Barash Search for this author in: * NPG journals * PubMed * Google Scholar * William Cantley Search for this author in: * NPG journals * PubMed * Google Scholar * Jamie Wong Search for this author in: * NPG journals * PubMed * Google Scholar * Virna Cortez-Retamozo Search for this author in: * NPG journals * PubMed * Google Scholar * Andita Newton Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin Love Search for this author in: * NPG journals * PubMed * Google Scholar * Peter Libby Search for this author in: * NPG journals * PubMed * Google Scholar * Mikael J Pittet Search for this author in: * NPG journals * PubMed * Google Scholar * Filip K Swirski Search for this author in: * NPG journals * PubMed * Google Scholar * Victor Koteliansky Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Langer Search for this author in: * NPG journals * PubMed * Google Scholar * Ralph Weissleder Contact Ralph Weissleder Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel G Anderson Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias Nahrendorf Contact Matthias Nahrendorf Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Figures 1–12 Additional data - SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells
- Nat Biotechnol 29(11):1011-1018 (2011)
Nature Biotechnology | Research | Article SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells * Nicole C Dubois1 * April M Craft1 * Parveen Sharma2 * David A Elliott3 * Edouard G Stanley3 * Andrew G Elefanty3 * Anthony Gramolini2 * Gordon Keller1 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:1011–1018Year published:(2011)DOI:doi:10.1038/nbt.2005Received12 May 2011Accepted19 September 2011Published online23 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg To identify cell-surface markers specific to human cardiomyocytes, we screened cardiovascular cell populations derived from human embryonic stem cells (hESCs) against a panel of 370 known CD antibodies. This screen identified the signal-regulatory protein alpha (SIRPA) as a marker expressed specifically on cardiomyocytes derived from hESCs and human induced pluripotent stem cells (hiPSCs), and PECAM, THY1, PDGFRB and ITGA1 as markers of the nonmyocyte population. Cell sorting with an antibody against SIRPA allowed for the enrichment of cardiac precursors and cardiomyocytes from hESC/hiPSC differentiationcultures, yielding populations of up to 98% cardiac troponin T-positive cells. When plated in culture, SIRPA-positive cells were contracting and could be maintained over extended periods of time. These findings provide a simple method for isolating populations of cardiomyocytes from human pluripotent stem cell cultures, and thereby establish a readily adaptable technology for! generating large numbers of enriched cardiomyocytes for therapeutic applications. View full text Figures at a glance * Figure 1: Specification of the cardiovascular lineage from hESCs. () Outline of the protocol used to differentiate hESCs to the cardiac lineage (modified from ref. 3). () QPCR analysis of T, MESP1, ISLET1, NKX2-5, MYH6, MYH7, MYL2, MYL7, NEUROD1 and FOXA2 in HES2-derived embryoid bodies at different stages during differentiation. Day 0, hESCs; LV, human fetal left ventricle; LA, human fetal left atria; AH, human adult heart, Ed, hESC-derived endoderm14. Error bars represent s.e.m., n = 3. * Figure 2: Expression of the cell-surface receptor SIRPA during hESC differentiation. () Flow cytometric analysis of SIRPA on embryoid bodies derived from NKX2-5–GFP hESCs. d; day of differentiation. () Expression of SIRPA on HES2-derived embryoid body populations at the indicated times. () RT-qPCR analysis of expression of SIRPA and its ligand CD47 in HES2-derived embryoid bodies at different times of differentiation. Day 0, ESCs; LV, human fetal left ventricle; LA, human fetal left atrial; AH, human adult heart. Error bars represent s.e.m., n = 4. () Immunostaining for SIRPA and cTNI on cardiac monolayer cultures. Monolayers were generated from day 20 HES2-derived embryoid bodies. Scale bars, 50 μm. Rel., relative. * Figure 3: Enrichment of cardiomyocytes from hESC-derived cultures by cell sorting based on SIRPA expression. () Flow cytometric analysis of SIRPA expression in embryoid bodies at day (d)8, d12 and d20 of differentiation. FACS for SIRPA was performed at d8, d12 and d20. The unsorted, SIRPA+ and SIRPA− fractions from each time point were analyzed for cTNT expression by intracellular flow cytometry. The frequency of cTNT+ cells at d8, d12 and d20 was significantly higher in the SIRPA+ fraction (d8: 95.2% ± 1.9, d12: 94.4 ± 1.7, d20: 89.6 ± 3.6), compared to SIRPA− cells (d8: 13.0 ± 2.1, d12: 14.3 ± 3.9, d20: 15.7 ± 6.0, P ≤ 0.001). () Average enrichment of cTNT+ cells from three different cell separation experiments. Error bars represent s.e.m. Asterisks indicate statistical significance as determined by student's t-test, ***, P ≤ 0.001. () QPCR analysis of unsorted, SIRPA+ and SIRPA− cells. Expression of SIRPA, NKX2-5, MYH6, MYH7 and MYL7 was significantly higher in the SIRPA+ fraction compared to SIRPA− fraction at all stages analyzed (d8, d12 and d20). Expression ! of markers for the noncardiac lineages (PECAM and DDR2) segregated to the SIRPA− fraction. Error bars represent s.e.m. Asterisks indicate statistical significance as determined by student's t-test. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; n = 3. () Immunostaining of cTNI on monolayer cultures generated from unsorted, SIRPA+ and SIRPA− cells sorted on day 20. Scale bars, 200 μm. * Figure 4: Enrichment of cardiomyocytes from hiPSC-derived cultures by cell sorting based on SIRPA expression. () Flow cytometric analysis of SIRPA expression at d20 of differentiation on 38-2 and MSC-iPS1 hiPSC-derived cells. FACS for SIRPA was performed on d20 and the unsorted, SIRPA+ and SIRPA− fractions were analyzed for cTNT expression by intracellular flow cytometry. () The frequency of cTNT+ cells was significantly higher in the SIRPA+ fraction of both hiPSC-derived cultures (MSC-iPS1: 67.0 ± 3.6, 38-2: 71.4 ± 3.8), compared to SIRPA− cells (MSC-iPS1: 4.9 ± 2.1; 38-2: 6.2 ± 0.9). Error bars represent s.e.m. Asterisks indicate statistical significance as determined by student's t-test. **, P ≤ 0.01; ***, P ≤ 0.001; n = 3. () QPCR analysis of unsorted, SIRPA+ and SIRPA− cells isolated from MSC-iPS1 and 38-2 hiPSC-derived day 20 cultures. Expression of markers specific for the cardiac lineage (SIRPA, NKX2-5, MYH6, MYH7, MYL2 and MYL7) was significantly higher in the SIRPA+ compared to the SIRPA− fraction. Expression of markers for the noncardiac lineages (PDGFRB a! nd NEUROD1) segregated to the SIRPA− fraction and the PS cells. Error bars represent s.e.m. Asterisks indicate statistical significance as determined by student's t-test. *, P ≤ 0.05; **, P ≤ 0.01; ***, P ≤ 0.001; n = 5. * Figure 5: Expression of SIRPA on human fetal cardiomyocytes and in adult human heart. () RT-qPCR analysis for SIRPA in human fetal heart tissue and adult heart. LV, left ventricle; RV, right ventricle; AP, Apex; LA, left atria; RA, right atria, AVJ, atrioventricular junction; AH, adult heart; d20, day 20 embryoid bodies, day 0, hESCs; HEK, human embryonic kidney cells; RT, reverse transcriptase control. Error bars represent s.e.m., n = 6. () Immunostaining for SIRPA (green) on human fetal ventricular cells and staining with MitoTracker Red. () Flow cytometric analysis for SIRPA on human fetal heart tissue. () Intracellular flow cytometric analysis for cTNT on human fetal heart tissue. * Figure 6: Using SIRPA to predict cardiac differentiation efficiency. () Day 5 KDR/PDGFRA flow cytometry profiles of cells from cardiac differentiation cultures induced with varying combinations of activin A (A0, 3, 6, 9 ng/ml) and BMP4 (B10, 30 ng/ml). The KDR+PDGFRA+ population has been shown to contain cardiac mesoderm cells2. () Day 9 SIRPA flow cytometric analysis expression profiles of the cultures described in . () Day 20 cTNT profiles (intracellular flow cytometric analysis) of the cultures described in . () Quantification of –. Close correlation of expression of SIRPA on day 9 (green dots) and cTNT expression on day 20 (red rhombuses) illustrates the predictive potential of SIRPA for cardiac differentiation efficiency. * Figure 7: Enrichment of cardiomyocytes through negative selection. () Flow cytometric analysis of markers specifically expressed on nonmyocyte (SIRPA-negative) cells in day 20 differentiation cultures (HES2). () FACS for the combination of markers specifically expressed on nonmyocyte cells (in PE: CD31, CD90, CD140B, CD49A). () Flow cytometric analysis of the unsorted cells, PE-negative (LIN−) and PE-positive (LIN+) samples for SIRPA. () Quantification of nonmyocyte markers on day 20 of differentiation (as shown in ), n = 4. () Quantification of SIRPA+ cells in PS, LIN− and LIN+ fractions after cell sorting. Asterisks indicate statistical significance as determined by student's t-test, ***, P ≤ 0.001; n = 3. () QPCR analysis of the unsorted, LIN− and LIN+ samples for noncardiac markers (PECAM1, PDGFRB, THY1 and DDR2) and cardiac specific genes (SIRPA, NKX2-5, MYH6 and MYH7). Error bars represent s.e.m. Asterisks indicate statistical significance as determined by student's t-test, **, P ≤ 0.01; ***, P ≤ 0.001; n = 3. Expr., expre! ssion. Author information * Abstract * Author information * Supplementary information Affiliations * McEwen Centre for Regenerative Medicine, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada. * Nicole C Dubois, * April M Craft & * Gordon Keller * Department of Physiology, University of Toronto, Toronto, Ontario, Canada. * Parveen Sharma & * Anthony Gramolini * Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia. * David A Elliott, * Edouard G Stanley & * Andrew G Elefanty Contributions N.C.D. and G.K. designed the study and wrote the paper. N.C.D., A.M.C., P.S. and A.G. designed and performed experiments and analyzed the data. D.A.E., A.G.E. and E.G.S. generated and provided the NKX2-5–GFP hESC line. Competing financial interests G.K. is a paid consultant for, and N.B. and G.K. own stock in, VistaGen Therapeutics, which funded this study in part. N.C.B., A.M.C. and G.K. are employees of University Health Network, which has filed a patent application based on this study. Corresponding author Correspondence to: * Gordon Keller Author Details * Nicole C Dubois Search for this author in: * NPG journals * PubMed * Google Scholar * April M Craft Search for this author in: * NPG journals * PubMed * Google Scholar * Parveen Sharma Search for this author in: * NPG journals * PubMed * Google Scholar * David A Elliott Search for this author in: * NPG journals * PubMed * Google Scholar * Edouard G Stanley Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew G Elefanty Search for this author in: * NPG journals * PubMed * Google Scholar * Anthony Gramolini Search for this author in: * NPG journals * PubMed * Google Scholar * Gordon Keller Contact Gordon Keller Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Tables 1–3 and Supplementary Figs. 1–12 Movies * Supplementary Movie 1 (1.2M) Embryoid bodies at day 20 derived from NKX2-5-GFP HES3 cells * Supplementary Movie 2 (21M) Unsorted cardiac monolayer culture from HES2-derived EB's * Supplementary Movie 3 (27M) Cardiac monolayer cultures from SIRPA+ sorted populations at day 20 * Supplementary Movie 4 (8M) Cardiac monolayer cultures from SIRPA- sorted populations at day 20 Additional data - Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques
- Nat Biotechnol 29(11):1019-1023 (2011)
Nature Biotechnology | Research | Letter Open Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques * Guangmei Yan1, 2, 16 * Guojie Zhang3, 16 * Xiaodong Fang3, 16 * Yanfeng Zhang4, 16 * Cai Li3, 16 * Fei Ling5, 16 * David N Cooper6 * Qiye Li3, 5 * Yan Li7 * Alain J van Gool8 * Hongli Du5 * Jiesi Chen2 * Ronghua Chen9 * Pei Zhang3 * Zhiyong Huang3 * John R Thompson10 * Yuhuan Meng5 * Yinqi Bai3 * Jufang Wang5 * Min Zhuo5 * Tao Wang5 * Ying Huang3 * Liqiong Wei5 * Jianwen Li3 * Zhiwen Wang3 * Haofu Hu3 * Pengcheng Yang3 * Liang Le2 * Peter D Stenson6 * Bo Li3 * Xiaoming Liu11 * Edward V Ball6 * Na An3 * Quanfei Huang3 * Yong Zhang3 * Wei Fan3 * Xiuqing Zhang3 * Yingrui Li3 * Wen Wang4 * Michael G Katze12 * Bing Su4 * Rasmus Nielsen13 * Huanming Yang3 * Jun Wang3, 13, 14 * Xiaoning Wang1, 5, 15 * Jian Wang3 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:1019–1023Year published:(2011)DOI:doi:10.1038/nbt.1992Received08 March 2011Accepted31 August 2011Published online16 October 2011 Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The nonhuman primates most commonly used in medical research are from the genus Macaca1. To better understand the genetic differences between these animal models, we present high-quality draft genome sequences from two macaque species, the cynomolgus/crab-eating macaque and the Chinese rhesus macaque. Comparison with the previously sequenced Indian rhesus macaque reveals that all three macaques maintain abundant genetic heterogeneity, including millions of single-nucleotide substitutions and many insertions, deletions and gross chromosomal rearrangements. By assessing genetic regions with reduced variability, we identify genes in each macaque species that may have experienced positive selection. Genetic divergence patterns suggest that the cynomolgus macaque genome has been shaped by introgression after hybridization with the Chinese rhesus macaque. Macaque genes display a high degree of sequence similarity with human disease gene orthologs and drug targets. However, we iden! tify several putatively dysfunctional genetic differences between the three macaque species, which may explain functional differences between them previously observed in clinical studies. View full text Figures at a glance * Figure 1: Single nucleotide divergence between macaque species/subspecies. () Classification of single nucleotide divergence between macaque species. The ~20 million single nucleotide differences among macaques were classified into three subclasses. The overlapping regions represent heterozygous variants shared between two individuals or all individuals. U, unique heterozygous variations evident in each species; F, the number of fixed homozygous variations in each species. () Single nucleotide divergence between macaque species in 100-kb windows across the genome. Heterozygous variants were ignored in this calculation. The divergence of X chromosomes between the two rhesus macaque subspecies was a significant outlier (P < 0.05, Grubbs' test). CE, crab-eating macaque; CR, Chinese rhesus macaque; IR, Indian rhesus macaque. * Figure 2: Divergence rate and selective sweep regions. () The genetic distance between macaques (blue curve), human and macaques (red curve), and the distance between macaque species/subspecies (green curve for IR and CR; yellow curve for CR and CE) across chromosome 14. The dashed red line depicts the average genetic distance between human and macaque. The dotted blue line represents the average genetic distance between the macaques. The red bars at the bottom denote the candidate selective sweep regions, and the blue bars denote the putative introgression regions. The consecutive regions containing zero mutations in all species (such as the ~20 Mb region) are sequencing gaps or alignment gap regions. () A potential introgression region (shaded blue), which contains fewer variations between CE macaque and CR macaque than between the two rhesus macaques (IR macaque and CR macaque). () A selective sweep region, encompassing 400 kb, which contains only one gene. The red bar denotes the coding region of the SBF2 gene; the red shade! d box corresponds to the extent of the putative selective sweep. * Figure 3: Population study of the TRIM5 gene in the CR macaque and CE macaque populations. () Schematic of protein encoded by TRIM5 in macaque. Annotated functional domains are marked with the names of domains in the colored boxes. The positions of nonsynonymous polymorphisms and the two-amino-acid deletion (in red) are marked.() The frequencies of all the nonsynonymous polymorphisms and the two-amino-acid deletion in the CR macaque and CE macaque populations. The frequency is counted for the genotype that appears in the IR macaque reference. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions DNA Data Bank of Japan * AEHK00000000 * AEHL00000000 * AEHK01000000 * AEHL01000000 Gene Expression Omnibus * GSE29629 Sequence Read Archive * SRA023855 * SRA023856 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Guangmei Yan, * Guojie Zhang, * Xiaodong Fang, * Yanfeng Zhang, * Cai Li & * Fei Ling Affiliations * The South China Center for Innovative Pharmaceuticals, Guangzhou, China. * Guangmei Yan & * Xiaoning Wang * Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. * Guangmei Yan, * Jiesi Chen & * Liang Le * BGI-Shenzhen, Shenzhen, China. * Guojie Zhang, * Xiaodong Fang, * Cai Li, * Qiye Li, * Pei Zhang, * Zhiyong Huang, * Yinqi Bai, * Ying Huang, * Jianwen Li, * Zhiwen Wang, * Haofu Hu, * Pengcheng Yang, * Bo Li, * Na An, * Quanfei Huang, * Yong Zhang, * Wei Fan, * Xiuqing Zhang, * Yingrui Li, * Huanming Yang, * Jun Wang & * Jian Wang * State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. * Yanfeng Zhang, * Wen Wang & * Bing Su * School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, China. * Fei Ling, * Qiye Li, * Hongli Du, * Yuhuan Meng, * Jufang Wang, * Min Zhuo, * Tao Wang, * Liqiong Wei & * Xiaoning Wang * Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK. * David N Cooper, * Peter D Stenson & * Edward V Ball * College of Animal Science and Technology, Sichuan Agriculture University, Ya'an, Sichuan, China. * Yan Li * Translational Medicine Research Centre, Department of Exploratory and Translational Sciences, Merck Research Laboratories, Singapore. * Alain J van Gool * Molecular Informatics, Informatics-IT, Merck & Co., Inc., Boston, Massachusetts, USA. * Ronghua Chen * Department of Exploratory and Translational Sciences, Merck Research Laboratories, Rahway, New Jersey, USA. * John R Thompson * South-China Primate Research & Development Center, Guangdong Entomological Institute, Guangzhou, China. * Xiaoming Liu * Department of Microbiology, University of Washington School of Medicine, Seattle, Washington, USA. * Michael G Katze * Department of Biology, University of Copenhagen, Copenhagen, Denmark. * Rasmus Nielsen & * Jun Wang * The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. * Jun Wang * School of Life Science, General Hospital of PLA, Beijing, China. * Xiaoning Wang Contributions G.Y., G.Z., X.F., Yanfeng Zhang, C.L. and F.L. contributed equally to this work. G.Y., Jun Wang, X.W. and Jian Wang managed the project. H.D., X.Z., L.L., F.L., Jufang Wang, T.W. and L.W. prepared the DNA and performed sequencing and PCR-based experiments. G.Z., X.F., Yanfeng Zhang, C.L., Q.L., Yong Zhang, P.D.S., Yan Li, X.L., P.Z., Z.H., J.L., Y.M., Y.B., M.Z., T.W., J.C., L.W., J.L., Y.H., Z.W., C.L., H.H., B.L., N.A., Q.H., W.F., Y.L., D.N.C., R.N., M.G.K. and E.V.B. performed the genome assembly, gene annotation, and human disease gene, druggable domain, gene evolution, introgression and selective sweep analyses. R.C., J.R.T., A.J.v.G. and P.Y. coordinated the RNA sequencing and analysis. G.Y., G.Z. and X.F. wrote the manuscript while D.N.C., W.W., B.S., R.B., H.Y., Jun Wang, X.W. and Jian Wang revised the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Jian Wang or * Guangmei Yan or * Xiaoning Wang Author Details * Guangmei Yan Contact Guangmei Yan Search for this author in: * NPG journals * PubMed * Google Scholar * Guojie Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaodong Fang Search for this author in: * NPG journals * PubMed * Google Scholar * Yanfeng Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Cai Li Search for this author in: * NPG journals * PubMed * Google Scholar * Fei Ling Search for this author in: * NPG journals * PubMed * Google Scholar * David N Cooper Search for this author in: * NPG journals * PubMed * Google Scholar * Qiye Li Search for this author in: * NPG journals * PubMed * Google Scholar * Yan Li Search for this author in: * NPG journals * PubMed * Google Scholar * Alain J van Gool Search for this author in: * NPG journals * PubMed * Google Scholar * Hongli Du Search for this author in: * NPG journals * PubMed * Google Scholar * Jiesi Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Ronghua Chen Search for this author in: * NPG journals * PubMed * Google Scholar * Pei Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiyong Huang Search for this author in: * NPG journals * PubMed * Google Scholar * John R Thompson Search for this author in: * NPG journals * PubMed * Google Scholar * Yuhuan Meng Search for this author in: * NPG journals * PubMed * Google Scholar * Yinqi Bai Search for this author in: * NPG journals * PubMed * Google Scholar * Jufang Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Min Zhuo Search for this author in: * NPG journals * PubMed * Google Scholar * Tao Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Ying Huang Search for this author in: * NPG journals * PubMed * Google Scholar * Liqiong Wei Search for this author in: * NPG journals * PubMed * Google Scholar * Jianwen Li Search for this author in: * NPG journals * PubMed * Google Scholar * Zhiwen Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Haofu Hu Search for this author in: * NPG journals * PubMed * Google Scholar * Pengcheng Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Liang Le Search for this author in: * NPG journals * PubMed * Google Scholar * Peter D Stenson Search for this author in: * NPG journals * PubMed * Google Scholar * Bo Li Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoming Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Edward V Ball Search for this author in: * NPG journals * PubMed * Google Scholar * Na An Search for this author in: * NPG journals * PubMed * Google Scholar * Quanfei Huang Search for this author in: * NPG journals * PubMed * Google Scholar * Yong Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Wei Fan Search for this author in: * NPG journals * PubMed * Google Scholar * Xiuqing Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Yingrui Li Search for this author in: * NPG journals * PubMed * Google Scholar * Wen Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Michael G Katze Search for this author in: * NPG journals * PubMed * Google Scholar * Bing Su Search for this author in: * NPG journals * PubMed * Google Scholar * Rasmus Nielsen Search for this author in: * NPG journals * PubMed * Google Scholar * Huanming Yang Search for this author in: * NPG journals * PubMed * Google Scholar * Jun Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoning Wang Contact Xiaoning Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Jian Wang Contact Jian Wang Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Sections 1–9 Excel files * Supplementary Tables 17 and 26 (274K) Creative Commons Attribution-Noncommercial-Share Alike license This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence (http://creativecommons.org/licenses/by-nc-sa/3.0/), which permits distribution, and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation, and derivative works must be licensed under the same or similar license. Additional data - Efficient targeted resequencing of human germline and cancer genomes by oligonucleotide-selective sequencing
- Nat Biotechnol 29(11):1024-1027 (2011)
Nature Biotechnology | Research | Letter Efficient targeted resequencing of human germline and cancer genomes by oligonucleotide-selective sequencing * Samuel Myllykangas1, 3 * Jason D Buenrostro2, 3 * Georges Natsoulis1 * John M Bell2 * Hanlee P Ji1, 2 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:1024–1027Year published:(2011)DOI:doi:10.1038/nbt.1996Received19 April 2011Accepted08 September 2011Published online23 October 2011 Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We describe an approach for targeted genome resequencing, called oligonucleotide-selective sequencing (OS-Seq), in which we modify the immobilized lawn of oligonucleotide primers of a next-generation DNA sequencer to function as both a capture and sequencing substrate. We apply OS-Seq to resequence the exons of either 10 or 344 cancer genes from human DNA samples. In our assessment of capture performance, >87% of the captured sequence originated from the intended target region with sequencing coverage falling within a tenfold range for a majority of all targets. Single nucleotide variants (SNVs) called from OS-Seq data agreed with >95% of variants obtained from whole-genome sequencing of the same individual. We also demonstrate mutation discovery from a colorectal cancer tumor sample matched with normal tissue. Overall, we show the robust performance and utility of OS-Seq for the resequencing analysis of human germline and cancer genomes. View full text Figures at a glance * Figure 1: Overview of OS-Seq. Capture of targets, processing and sequencing are performed on an Illumina next-generation sequencer. Reads originating from each primer probe are target and strand specific. Shown here is the median coverage profile for OS-Seq-366. For step 1, target-specific oligonucleotides are used to modify flow cell primers to create 'primer probes'. Hybridized oligonucleotides are used as a template for DNA polymerase and D primers are extended. After denaturing, target-specific primer probes are randomly immobilized on the flow cell. For step 2, genomic targets in a single-adaptor library are captured using primer probes. These adapters incorporate sites for sequencing primers and immobilized flow cell primers. Targets in the single-adaptor library are captured during a high-heat hybridization step to their complementary primer probes. Captured single-adaptor library fragments are used as a template for DNA polymerase, and primer probes are extended. Denaturation releases template DN! A from immobilized targets. For step 3, immobilized captured targets are rendered to be compatible for DNA sequencing. During a low-heat hybridization step the single-adaptor tails of the immobilized targets hybridize to type C primers on the flow cell surface, which stabilizes a bridge structure. The 3′ ends of immobilized targets and C primers are extended using DNA polymerase, which creates two molecules capable of bridge PCR. After denaturation, bridge amplification and cluster processing, paired-end sequencing can be conducted. * Figure 2: Targeted sequencing coverage profile along the KRAS gene from the OS-Seq-366 assay. Base positions relative to the start of exon 1 are presented on the x axis and KRAS exons are marked in red on the x axis. Sequencing fold coverage is listed on the y axis. * Figure 3: Coverage assessment of OS-Seq. Uniformity assessment of primer-probe yields within column- and array-synthesized oligonucleotides. We compared the uniformity of capture between column-synthesized (blue, n = 366) and array-synthesized (red, n = 11,742) oligonucleotides. On the x axis, oligonucleotides are sorted by sequence capture yields, on the y axis is the normalized primer probe yield. To calculate normalized yield, we divided the yield of each oligonucleotide by the median yield from all oligonucleotides. Accession codes * Accession codes * Author information * Supplementary information Referenced accessions Sequence Read Archive * SRA036669 Author information * Accession codes * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Samuel Myllykangas & * Jason D Buenrostro Affiliations * Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. * Samuel Myllykangas, * Georges Natsoulis & * Hanlee P Ji * Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA. * Jason D Buenrostro, * John M Bell & * Hanlee P Ji Contributions The project was conceived and experiments planned by S.M., J.D.B. and H.P.J. S.M. and J.D.B. carried out all experiments. J.D.B., S.M., J.M.B., G.N. and H.P.J. performed data analysis. J.D.B., S.M., J.M.B. and H.P.J. wrote the manuscript, and all authors reviewed it. All aspects of the study were supervised by H.P.J. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Hanlee P Ji Author Details * Samuel Myllykangas Search for this author in: * NPG journals * PubMed * Google Scholar * Jason D Buenrostro Search for this author in: * NPG journals * PubMed * Google Scholar * Georges Natsoulis Search for this author in: * NPG journals * PubMed * Google Scholar * John M Bell Search for this author in: * NPG journals * PubMed * Google Scholar * Hanlee P Ji Contact Hanlee P Ji Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Accession codes * Author information * Supplementary information PDF files * Supplementary Text and Figures (890K) Supplementary Tables 1–3, Supplementary Methods and Supplementary Figures 1–8 * Supplementary Table 4 (1M) * Supplementary Table 5 (49K) Zip files * Supplementary Data Files (6K) OS-Seq programs Additional data - A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia
- Nat Biotechnol 29(11):1028-1033 (2011)
Nature Biotechnology | Research | Letter A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia * Lacramioara Ivanciu1 * Raffaella Toso1 * Paris Margaritis1, 2 * Giulia Pavani1 * Haein Kim1 * Alexander Schlachterman1 * Jian-Hua Liu1 * Valerie Clerin3 * Debra D Pittman3 * Rosalind Rose-Miranda3 * Kathleen M Shields3 * David V Erbe3 * James F Tobin3 * Valder R Arruda1, 2 * Rodney M Camire1, 2 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:1028–1033Year published:(2011)DOI:doi:10.1038/nbt.1995Received18 July 2011Accepted07 September 2011Published online23 October 2011 Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Effective therapies are needed to control excessive bleeding in a range of clinical conditions. We improve hemostasis in vivo using a conformationally pliant variant of coagulation factor Xa (FXaI16L) rendered partially inactive by a defect in the transition from zymogen to active protease1, 2. Using mouse models of hemophilia, we show that FXaI16L has a longer half-life than wild-type FXa and does not cause excessive activation of coagulation. Once clotting mechanisms are activated to produce its cofactor FVa, FXaI16L is driven to the protease state and restores hemostasis in hemophilic animals upon vascular injury. Moreover, using human or murine analogs, we show that FXaI16L is more efficacious than FVIIa, which is used to treat bleeding in hemophilia inhibitor patients3. FXaI16L may provide an effective strategy to enhance blood clot formation and act as a rapid pan-hemostatic agent for the treatment of bleeding conditions. View full text Figures at a glance * Figure 1: Effect of hFXaI16L on coagulation parameters. () HB mice (BALB/c) were injected with PBS (▪; n = 7) or hFXaI16L (▴, 225 μg/kg, n = 4; ▵, 450 μg/kg, n = 9). A modified one-stage aPTT was performed on processed mouse plasma at the time intervals indicated. Clotting times for WT mice (○, n = 7) are also indicated. () WT hFXa (•, 20 nM) or hFXaI16L (▴, 20 nM) were incubated in diluted HB (BALB/c) mouse plasma and residual activity was assessed by clotting assay. The solid lines were drawn after analysis of data sets to a single exponential decay with fitted half-lives of 0.15 ± 0.01 min and 5.3 ± 0.46 min for WT hFXa and hFXaI16L, respectively. These values have been appropriately adjusted for sample dilution. The data are representative of two to three similar experiments. (–) Markers of coagulation activation. HB mice (BALB/c) were injected with PBS (▪; n = 3–10) or hFXaI16L (▵, 450 μg/kg, n = 3–8). At the indicated time intervals, levels of fibrinogen (), platelets (), D-dimer () and thrombin-a! ntithrombin complex (TAT) () were measured. In and –, all measurements are presented as mean ± s.e.m. For statistical comparisons, treated animals are compared to HB-PBS controls at the same time point; **, P < 0.001; *, P < 0.05. * Figure 2: Blood loss following tail-clipping. () PBS (white column) or hFXaI16L (blue columns) was administered to HB mice (C57Bl/6) via tail vein at the indicated dosage 5 min before injury. Total blood loss (μl) was then measured after tail transection. () Tail clipping was performed on WT mice or HB mice (BALB/c) before protein infusion and blood was collected for 2 min (total blood loss at 2 min: WT mice: 17 ± 5.4 μl; HB: 49 ± 7.7 μl). Subsequently, PBS (white column) or hFXaI16L (blue columns) was administered to HB mice through a jugular vein cannulus at the indicated dosage; WT mice also received PBS (black column). Blood was collected for an additional 10 min in a fresh tube of saline and total blood loss (μl) was measured. Data in represent total blood loss subsequent to protein infusion. () PBS (white column) or hFVIIa (red columns) was administered to HB mice (C57Bl/6) by means of tail vein at the indicated dosage 5 min before injury. Total blood loss (μl) was then measured following tail transection. ! () PBS (white column), mFXaI16L (blue columns) or mFVIIa (red columns) was administered to HB mice (BALB/c) through tail vein at the indicated dosage 5 min before injury. Total blood loss (μl) was then measured following tail transection. In –, hemostatically normal mice of the appropriate strain infused with PBS (WT-PBS, black column) served as a control. In each panel, the number of animals per group is indicated and all measurements are presented as mean ± s.e.m. For statistical comparisons, treated animals are compared to HB-PBS controls. **, P < 0.001; *, P < 0.05. * Figure 3: Platelet and fibrin accumulation following laser-induced arteriole injury in WT mice and hFXaI16L-treated HB mice. In these experiments, PBS or protein was infused 5 min before vessel injury. () Digital composite fluorescence and brightfield images of representative thrombi in WT mice (+ PBS), HB (+PBS) and HB (+hFXaI16L, 10 μg/kg) mice before (0 s) and 30, 90 and 180 s after laser-induced injury of the blood vessel wall. Platelets (red) were detected by an Alexa555-labeled rat anti-CD41 F(ab)2 and fibrin (green) with Alexa488-labeled anti-fibrin antibody; areas of overlap are depicted in yellow. (,) Quantitative analysis of platelet and fibrin accumulation over time following laser injury in WT mice (black; 20 thrombi; n = 3 mice), HB (gray; 20 thrombi; n = 3 mice), and HB + hFXaI16L (blue; 20 thrombi; n = 3 mice; 10 μg/kg) treated mice. Median fluorescence intensity (MFI) for platelet () and fibrin () fluorescence are plotted versus time. For both platelet () and fibrin () accumulation, there is no statistically significant difference (P > 0.1) in MFI when comparing values between WT! mice and HB + hFXaI16L at every 30 s intervals by the Wilcoxon rank sum test. However, the MFI values (evaluated at 30 s intervals) between WT mice versus HB and HB + hFXaI16L versus HB are significantly different (P < 0.001). Author information * Author information * Supplementary information Affiliations * Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. * Lacramioara Ivanciu, * Raffaella Toso, * Paris Margaritis, * Giulia Pavani, * Haein Kim, * Alexander Schlachterman, * Jian-Hua Liu, * Valder R Arruda & * Rodney M Camire * The University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA. * Paris Margaritis, * Valder R Arruda & * Rodney M Camire * Pfizer Inc., Cambridge, Massachusetts, USA. * Valerie Clerin, * Debra D Pittman, * Rosalind Rose-Miranda, * Kathleen M Shields, * David V Erbe & * James F Tobin Contributions L.I. designed, coordinated and performed experiments; R.T., P.M., G.P., H.K., A.S., J.-H.L. and K.M.S. performed experiments; R.R.-M. coordinated and performed experiments; V.C. designed and analyzed experiments; D.D.P. interpreted data; J.F.T., D.V.E., V.R.A. and R.M.C. designed experiments and analyzed data. L.I. and R.M.C. wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests R.M.C. receives licensing fees and research funding from Pfizer. V.C., D.D.P., R.R.-M., K.M.S., D.V.E. and J.F.T. are employees of Pfizer, Inc. Corresponding author Correspondence to: * Rodney M Camire Author Details * Lacramioara Ivanciu Search for this author in: * NPG journals * PubMed * Google Scholar * Raffaella Toso Search for this author in: * NPG journals * PubMed * Google Scholar * Paris Margaritis Search for this author in: * NPG journals * PubMed * Google Scholar * Giulia Pavani Search for this author in: * NPG journals * PubMed * Google Scholar * Haein Kim Search for this author in: * NPG journals * PubMed * Google Scholar * Alexander Schlachterman Search for this author in: * NPG journals * PubMed * Google Scholar * Jian-Hua Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Valerie Clerin Search for this author in: * NPG journals * PubMed * Google Scholar * Debra D Pittman Search for this author in: * NPG journals * PubMed * Google Scholar * Rosalind Rose-Miranda Search for this author in: * NPG journals * PubMed * Google Scholar * Kathleen M Shields Search for this author in: * NPG journals * PubMed * Google Scholar * David V Erbe Search for this author in: * NPG journals * PubMed * Google Scholar * James F Tobin Search for this author in: * NPG journals * PubMed * Google Scholar * Valder R Arruda Search for this author in: * NPG journals * PubMed * Google Scholar * Rodney M Camire Contact Rodney M Camire Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (766K) Supplementary Table 1 and Supplementary Figures 1–8 Movies * Supplementary Movie 1 (4M) Representative movie depicting thrombus formation following laser injury in a wild-type mouse (Balb/c). Brightfield images of the cremaster muscle along with accumulating platelets and fibrin are shown. Platelets (red) were detected by an Alexa555-labeled rat anti- CD41 F(ab)2 and fibrin (green) with Alexa488-labeled anti-fibrin antibody; areas of overlap are depicted by yellow. A 10 μm scale bar is shown in the lower left corner and a time stamp in the upper right corner. For convenience, the speed of the movie is increased by 5-fold. Further details of the methodology can be found in Methods. * Supplementary Movie 2 (5M) Representative movie depicting thrombus formation following laser injury in an HB mouse (Balb/c) treated with FXaI16L (10 μg/kg) prior to laser injury. Platelets and fibrin accumulation were detected as described in Supplemental Movie 1 and in Methods. * Supplementary Movie 3 (16M) Representative movie depicting thrombus formation following laser injury in an HB mouse (Balb/c) treated with FXaI16L (30 μg/kg). In this experiment, the animal was injured and monitored for approximately 3.5 min. After this observation period, FXaI16L was infused via a jugular vein cannulus and thrombus formation was immediately monitored. The animal was not repositioned or reinjured. Platelets and fibrin accumulation were detected as described in Supplemental Movie 1 and in Methods. Additional data - Field performance of engineered male mosquitoes
- Nat Biotechnol 29(11):1034-1037 (2011)
Nature Biotechnology | Research | Letter Field performance of engineered male mosquitoes * Angela F Harris1, 2 * Derric Nimmo3 * Andrew R McKemey3 * Nick Kelly1 * Sarah Scaife3 * Christl A Donnelly4 * Camilla Beech3 * William D Petrie1 * Luke Alphey3, 5 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:1034–1037Year published:(2011)DOI:doi:10.1038/nbt.2019Received28 June 2011Accepted27 September 2011Published online30 October 2011 Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Dengue is the most medically important arthropod-borne viral disease, with 50–100 million cases reported annually worldwide1. As no licensed vaccine or dedicated therapy exists for dengue, the most promising strategies to control the disease involve targeting the predominant mosquito vector, Aedes aegypti. However, the current methods to do this are inadequate. Various approaches involving genetically engineered mosquitoes have been proposed2, 3, 4, including the release of transgenic sterile males5, 6, 7, 8, 9, 10. However, the ability of laboratory-reared, engineered male mosquitoes to effectively compete with wild males in terms of finding and mating with wild females, which is critical to the success of these strategies, has remained untested. We report data from the first open-field trial involving a strain of engineered mosquito. We demonstrated that genetically modified male mosquitoes, released across 10 hectares for a 4-week period, mated successfully with wild fe! males and fertilized their eggs. These findings suggest the feasibility of this technology to control dengue by suppressing field populations of A. aegypti. View full text Figures at a glance * Figure 1: Field site and larval fluorescence. () Aerial photomap illustrating the trial site in East End, Grand Cayman. The 10-ha release area is outlined; this area includes ~97 substantial buildings including 89 houses. Yellow circles indicate pupal release locations. The BG Sentinel adult trap locations are indicated by numbers 1–9 in boxes and the ovitraps by numbers 10–44. Trap numbers correspond with those in Tables 1 and 2. Additional traps were placed outside of the release area (not shown). Trapped eggs were hatched and scored for fluorescence. (,) Four wild-type and OX513A larvae, from left to right: wild type, OX513A, wild type, OX513A visualized in white light () or under conditions for fluorescence photomicroscopy (). OX513A shows a distinctive and readily identifiable punctate pattern of red fluorescence but is indistinguishable from wild type under normal light. * Figure 2: OX513A release and recapture data. () The wild mosquito population density in the release area was consistently high throughout the release period. Ovitrap index is the proportion of ovitraps containing at least one A. aegypti egg after a week in the field. () Pupae were placed in the field in release devices and the number of males exiting calculated for each of 12 releases. () Adult mosquitoes were trapped and the relative proportions of OX513A and wild-type males determined. () Eggs from wild females were obtained from ovitraps, hatched and scored for fluorescence to determine the relative OX513A and wild-type paternity. Author information * Author information * Supplementary information Affiliations * Mosquito Research and Control Unit (MRCU), Grand Cayman, Cayman Islands. * Angela F Harris, * Nick Kelly & * William D Petrie * Vector Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK. * Angela F Harris * Oxitec Limited, Oxford, UK. * Derric Nimmo, * Andrew R McKemey, * Sarah Scaife, * Camilla Beech & * Luke Alphey * MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, St Mary's Campus, London, UK. * Christl A Donnelly * Department of Zoology, University of Oxford, South Parks Road, Oxford, UK. * Luke Alphey Contributions L.A., A.R.M., C.B., A.F.H., D.N. and W.D.P. conceived and supervised the project. A.F.H., D.N., N.K. and S.S. conducted the experiments. A.R.M., C.A.D. and L.A. analyzed the data and wrote the paper. All authors discussed the results and commented on the manuscript. Competing financial interests D.N., A.R.M. S.S., C.B. and L.A. are employees of Oxitec Ltd. and have employment and/or equity interest in Oxitec. All other authors declare no competing financial interests. Oxitec and Oxford University hold patents and/or other intellectual property rights in areas related to the subject matter of this paper. Corresponding author Correspondence to: * Luke Alphey Author Details * Angela F Harris Search for this author in: * NPG journals * PubMed * Google Scholar * Derric Nimmo Search for this author in: * NPG journals * PubMed * Google Scholar * Andrew R McKemey Search for this author in: * NPG journals * PubMed * Google Scholar * Nick Kelly Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah Scaife Search for this author in: * NPG journals * PubMed * Google Scholar * Christl A Donnelly Search for this author in: * NPG journals * PubMed * Google Scholar * Camilla Beech Search for this author in: * NPG journals * PubMed * Google Scholar * William D Petrie Search for this author in: * NPG journals * PubMed * Google Scholar * Luke Alphey Contact Luke Alphey Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (233K) Supplementary Figure 1 Additional data - Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity
- Nat Biotechnol 29(11):1039-1045 (2011)
Nature Biotechnology | Research | Resources Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity * Theonie Anastassiadis1 * Sean W Deacon2 * Karthik Devarajan1 * Haiching Ma2 * Jeffrey R Peterson1 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:1039–1045Year published:(2011)DOI:doi:10.1038/nbt.2017Received01 September 2011Accepted23 September 2011Published online30 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Small-molecule protein kinase inhibitors are widely used to elucidate cellular signaling pathways and are promising therapeutic agents. Owing to evolutionary conservation of the ATP-binding site, most kinase inhibitors that target this site promiscuously inhibit multiple kinases. Interpretation of experiments that use these compounds is confounded by a lack of data on the comprehensive kinase selectivity of most inhibitors. Here we used functional assays to profile the activity of 178 commercially available kinase inhibitors against a panel of 300 recombinant protein kinases. Quantitative analysis revealed complex and often unexpected interactions between protein kinases and kinase inhibitors, with a wide spectrum of promiscuity. Many off-target interactions occur with seemingly unrelated kinases, revealing how large-scale profiling can identify multitargeted inhibitors of specific, diverse kinases. The results have implications for drug development and provide a resource fo! r selecting compounds to elucidate kinase function and for interpreting the results of experiments involving kinase inhibitors. View full text Figures at a glance * Figure 1: Large-scale kinase-inhibitor interaction analysis. () Distribution of the intended targets of the inhibitor library, by kinase family. () The distribution of kinases in the screening panel is represented by blue dots on a dendrogram representing the human kinome (kinome illustration was adapted and is reproduced courtesy of Cell Signaling Technology based on ref. 33). () Scatter plot of the kinase activity in replicate 1 versus replicate 2 for each kinase-inhibitor pair for which >20% inhibition of kinase activity was observed. () Two-way hierarchical clustering analysis of the entire kinase-inhibitor interaction map presented as a heat map of kinase activity. A fully labeled, high-resolution version of this heat map is presented in Supplementary Figure 2, as a data table in Supplementary Table 3 and via the Kinase Inhibitor Resource (KIR) online tool (http://kir.fccc.edu/). Ctrl, control. * Figure 2: Comparison of functional inhibition data generated in this study with previous kinase-inhibitor interaction profiling studies. (,) Scatter plots compare our results with studies that examined interactions of overlapping kinase-inhibitor pairs by a quantitative kinase-inhibitor binding assay1, 2 (), or an assay measuring resistance to thermal denaturation by kinases in the presence of individual inhibitors3 (). In , remaining kinase activity is plotted as a function of kinase-compound binding affinity (Kd) for 654 kinase-inhibitor pairs. The resulting data were fit to a sigmoidal dose-response curve (solid line) and can be compared with a theoretical curve (dotted line) for expected remaining kinase activity for an inhibitor of the given affinity. In remaining kinase activity is plotted against the change in Tm, relative to solvent control, caused by compound binding for 3,926 kinase-inhibitor pairs. The dashed vertical line denotes the Tm shift threshold used in ref. 3. The dashed horizontal line highlights the 50% threshold for inhibition of catalytic activity. The resulting upper right quadrant in! cludes compounds that showed significant thermal stabilization without inhibiting kinase activity whereas the lower left quadrant contains compounds which only marginally affect thermal stability yet show >50% inhibition of catalytic activity. Ctrl, control. * Figure 3: Kinase selectivity. A ranked bar chart of selectivity scores (S(50%)) for all tested kinases. This score corresponds to the fraction of all tested inhibitors that inhibit catalytic activity by >50%. Each bar represents the selectivity score of an individual kinase. Insets identify the 14 kinases that were not inhibited by any compound (left) and the seven most frequently inhibited kinases (right). The complete table is presented in Supplementary Table 4. * Figure 4: Kinase inhibitor selectivity. () A ranked list of kinase inhibitors sorted by Gini score15 as a measure of inhibitor selectivity. A Gini score of 0 indicates equal inhibition of all kinases (promiscuous inhibition) whereas a score of 1 indicates inhibition of only one kinase (selective inhibition). Left inset highlights the five compounds with the lowest Gini scores and the right inset, the five highest scoring compounds. The complete table is presented in Supplementary Table 5. Below, the selectivity of three representative compounds are presented on a dendrogram of all human kinases based on amino acid sequence similarity33. Spot color represents inhibitory potency: darkest, 0–10% remaining activity; lighter, 10–25% activity; lightest, 25–50% activity. The kinome dendrogram was adapted and is reproduced courtesy of Cell Signaling Technology. () Target spectrum of 4-(4-benzyloxyanilino)-6,7-dimethoxyquinazoline, a multitargeted inhibitor, highly selective for ErbB family members, a limited number ! of other tyrosine kinase targets and the serine/threonine kinase CHK2. Each bar corresponds to the percent remaining activity for an individual kinase. * Figure 5: Uni-specific kinase inhibitors. The left panel presents a graphical table of compounds ranked based on the compound's ability to inhibit a single kinase more potently than any other kinase tested. The left boundary of each horizontal bar depicts the potency with which the compound inhibits its most sensitive target and the right boundary reflects the potency with which the next most sensitive kinase is inhibited (% remaining kinase activity is shown in bins of 5%). Thus, the horizontal length of each bar reflects the differential activity of the corresponding inhibitor against its two most potently inhibited targets. Only compounds with a differential potency of at least 5% are shown. The central table identifies the compounds that showed at least 20% differential potency, their intended targets, and their most sensitive targets. Six compounds for which the most sensitive target is not the intended target are shown in gray. In the right panel, the effect of the individual compounds on each kinase in the pa! nel is shown in a ranked plot. *, SB 202474 is a negative control compound for the p38 MAP kinase inhibitor SB 202190. **, ATM kinase was not included in our test panel. Ctrl, control. Author information * Abstract * Author information * Supplementary information Affiliations * Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. * Theonie Anastassiadis, * Karthik Devarajan & * Jeffrey R Peterson * Reaction Biology Corporation, Malvern, Pennsylvania, USA. * Sean W Deacon & * Haiching Ma Contributions The study was conceived by J.R.P., S.W.D. and H.M., experimental data was collected by S.W.D., statistical analysis was performed by K.D., data were analyzed by T.A. and J.R.P. with input from S.W.D. and H.M., and the manuscript was written by J.R.P. with input from the other authors. Competing financial interests S.W.D. and H.M. are current employees of Reaction Biology Corporation. Corresponding author Correspondence to: * Jeffrey R Peterson Author Details * Theonie Anastassiadis Search for this author in: * NPG journals * PubMed * Google Scholar * Sean W Deacon Search for this author in: * NPG journals * PubMed * Google Scholar * Karthik Devarajan Search for this author in: * NPG journals * PubMed * Google Scholar * Haiching Ma Search for this author in: * NPG journals * PubMed * Google Scholar * Jeffrey R Peterson Contact Jeffrey R Peterson Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (11M) Supplementary Tables 1,2,4,5 and Supplementary Figures 1–5 Excel files * Supplementary Table 3 (991K) Complete pairwise kinase-compound activity dataset. Additional data - Comprehensive analysis of kinase inhibitor selectivity
- Nat Biotechnol 29(11):1046-1051 (2011)
Nature Biotechnology | Research | Resources Comprehensive analysis of kinase inhibitor selectivity * Mindy I Davis1, 2, 3 * Jeremy P Hunt1, 2, 3 * Sanna Herrgard1, 3 * Pietro Ciceri1, 2, 3 * Lisa M Wodicka1, 2 * Gabriel Pallares1, 2 * Michael Hocker1 * Daniel K Treiber1, 2 * Patrick P Zarrinkar1, 2 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:1046–1051Year published:(2011)DOI:doi:10.1038/nbt.1990Received10 May 2011Accepted30 August 2011Published online30 October 2011 Abstract * Abstract * Author information * Supplementary information Article tools * Full text * 日本語要約 * Print * Email * pdf options * download pdf * view interactive pdfpowered by ReadCube * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about c! ellular signaling. View full text Figures at a glance * Figure 1: Quantitative distribution of kinome-wide selectivity of compounds. A kinome selectivity score (S(3 μM)) was calculated for each compound as described in the text, and compounds were binned according to their scores. () Distribution of selectivity for the entire set of 72 compounds. () Distribution of selectivity for 37 compounds classified as type I inhibitors based on relative binding affinity for phosphorylated and nonphosphorylated variants of ABL1 (Supplementary Table 5). () Distribution of selectivity for 13 compounds classified as type II inhibitors based on relative binding affinity for phosphorylated and nonphosphorylated variants of ABL1 (Supplementary Table 5). * Figure 2: Quantitative distribution of compound selectivity of kinases. A selectivity score (Skinase(3 μM)) was calculated for each of the 442 kinases in the assay panel as described in the text, based on the number of compounds each kinase binds, and kinases binned according to their scores. * Figure 3: Selective inhibitors for primary targets. Each kinase on the y axis is a primary, intended target of one or more compounds in the set tested here (Supplementary Table 3). The most selective compound for each target is shown. () Relative selectivity. For each of these primary targets, the compound with the greatest relative selectivity for that target was identified by counting the number of kinases bound with a Kd within tenfold or better of the Kd for the primary target for each compound targeting the kinase. The number of kinases bound with Kd within tenfold of that for the primary target is shown for the most selective compound targeting each of the kinases shown. () Absolute selectivity. For each of the primary targets the compound with the greatest absolute selectivity for that target was identified, using the S(3 μM) as a measure of absolute selectivity (Supplementary Table 5). The S(3 μM) is shown for the most selective compound targeting each of the kinases shown. * Figure 4: Group-selective compounds. Compounds were divided into selectivity bins based on their overall selectivity (S(3 μM) 0–0.1, 0.1–0.2, 0.2–0.4, >0.4), and selectivity scores (S(3 μM)) were calculated for each compound for the kinase groups for which more than fifteen kinases are represented in the assay panel (thereby excluding atypical, lipid and CK1 kinases). Shown here are the kinase interaction maps and kinase group fingerprints for one group-selective and one non-group-selective compound from each selectivity bin. () Compounds from the S(3 μM) = 0–0.1 bin. () Compounds from the S(3 μM) = 0.1–0.2 bin. () Compounds from the S(3 μM) = 0.2–0.4 bin. () Compounds from the S(3 μM) > 0.4 bin. The interaction maps were generated using TREEspot software (http://www.kinomescan.com/) and display a circular representation of the kinase family tree based on kinase domain sequence. The bars in each bar graph indicate S(3 μM) for the individual kinase groups. Red bars indicate the kinase group co! ntaining the primary target for each compound. Dashed lines signify the overall S(3 μM) for each compound. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Mindy I Davis, * Jeremy P Hunt, * Sanna Herrgard & * Pietro Ciceri Affiliations * Ambit Biosciences, San Diego, California, USA. * Mindy I Davis, * Jeremy P Hunt, * Sanna Herrgard, * Pietro Ciceri, * Lisa M Wodicka, * Gabriel Pallares, * Michael Hocker, * Daniel K Treiber & * Patrick P Zarrinkar * Present addresses: National Institutes of Health, Bethesda, Maryland, USA (M.I.D.), KINOMEscan Division of DiscoveRx Corporation, San Diego, California, USA (J.P.H., P.C., L.M.W., G.P., D.K.T.) and Blueprint Medicines Corporation, San Diego, California, USA (P.P.Z.). * Mindy I Davis, * Jeremy P Hunt, * Pietro Ciceri, * Lisa M Wodicka, * Gabriel Pallares, * Daniel K Treiber & * Patrick P Zarrinkar Contributions M.I.D. coordinated development of the assay panel, J.P.H. developed technology to enhance the efficiency of compound screening, S.H. analyzed data, M.I.D., J.P.H., P.C. and L.M.W. developed binding assay technology and performed assay development, G.P. coordinated and executed the measurement of Kd values, M.H. synthesized compounds, D.K.T. conceived the technology, designed assay development strategies, and supervised technology and assay development, S.H. and D.K.T. contributed to preparation of the manuscript, P.P.Z. designed the study, supervised the project, analyzed data and wrote the manuscript. Competing financial interests All authors are former or current employees of Ambit Biosciences and were employed by Ambit during the course of the project described in the manuscript. J.P.H., P.C., L.M.W., G.P. and D.K.T. are current employees of Discoverx Corp. Discoverx has acquired the technology used for the project from Ambit Biosciences. Corresponding authors Correspondence to: * Patrick P Zarrinkar or * Daniel K Treiber Author Details * Mindy I Davis Search for this author in: * NPG journals * PubMed * Google Scholar * Jeremy P Hunt Search for this author in: * NPG journals * PubMed * Google Scholar * Sanna Herrgard Search for this author in: * NPG journals * PubMed * Google Scholar * Pietro Ciceri Search for this author in: * NPG journals * PubMed * Google Scholar * Lisa M Wodicka Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriel Pallares Search for this author in: * NPG journals * PubMed * Google Scholar * Michael Hocker Search for this author in: * NPG journals * PubMed * Google Scholar * Daniel K Treiber Contact Daniel K Treiber Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick P Zarrinkar Contact Patrick P Zarrinkar Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (3M) Supplementary Table 2 and Supplementary Figures 1–3 Excel files * Supplementary Table 1 (98K) List of 442 kinase domains in the assay panel and their calculated kinase selectivity scores. * Supplementary Table 3 (41K) Compounds tested, their primary targets, and comparison of published and measured activities. * Supplementary Table 4 (307K) Binding results (Kd's in nM) for 72 inhibitors vs 442 kinase assays. Blank fields indicate combinations that were tested, but for which binding was weak (Kd > 10 uM), or not detected in a 10 uM primary screen. * Supplementary Table 5 (33K) Compound selectivity scores. Additional data - Third-quarter biotech job picture
- Nat Biotechnol 29(11):1052 (2011)
Article preview View full access options Nature Biotechnology | Careers and Recruitment Third-quarter biotech job picture * Michael Francisco1Journal name:Nature BiotechnologyVolume: 29,Page:1052Year published:(2011)DOI:doi:10.1038/nbt.2037Published online08 November 2011 Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Author information Article tools * Print * Email * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Affiliations * Michael Francisco is a Senior Editor at Nature Biotechnology. Author Details * Michael Francisco Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - People
- Nat Biotechnol 29(11):1054 (2011)
Article preview View full access options Nature Biotechnology | Careers and Recruitment | People People Journal name:Nature BiotechnologyVolume: 29,Page:1054Year published:(2011)DOI:doi:10.1038/nbt.2045Published online08 November 2011 The 2011 Nobel Prize in medicine was awarded last month to three scientists for their discoveries about the immune system. Half of the $1.5 million prize went to and , and the other half was awarded to (right). In the 1970s, Steinman found dendritic cells that help regulate adaptive immunity. Beutler and Hoffmann were cited for their later discoveries of receptor proteins that can recognize bacteria and other microorganisms as they enter the body and activate the first line of defense in the immune system, known as innate immunity. These discoveries advanced the development of improved vaccines against infectious diseases. Beutler is professor of genetics and immunology at The Scripps Research Institute (San Diego) and Hoffmann is head of CNRS, the French National Research Agency at the University of Strasbourg. Steinman, who headed Rockefeller University's Center for Immunology and Immune Diseases since 1970, passed away on September 30, three days before the awards were an! nounced. Protea Biosciences (Morgantown, WV, USA) has announced that has joined the company as vice president and general manager. He brings over 25 years of experience in separation sciences and mass spectrometry. At PerkinElmer he held senior roles including senior director of their mass spectrometry business. Inspiration Biopharmaceuticals (Laguna Niguel, CA, USA) has named as CEO, replacing who has assumed the role of CSO and is retaining the title of president at Inspiration. Butler has more than 20 years of business experience, most recently from Genzyme where he served as president of the company's rare genetic diseases business. , a former president at both Eli Lilly and Genzyme, has been named to the board of directors of Oncobiologics (Cranbury, NJ, USA). A 30-year industry veteran, Canute was most recently head of global manufacturing and corporate operations for Genzyme. Immune Design Corp. (Seattle) has appointed as its new chief business officer. Most recently, he was vice president of business development and a member of senior management at Cardiome Pharma. Orexo (Uppsala, Sweden) has appointed as CSO. Since 2008 Edman has served as CSO and head of R&D at Sobi (Swedish Orphan Biovitrum). Before joining Sobi, he held various R&D positions at Pharmacia and AstraZeneca. He will assume his position on January 1, 2012. has been named vice president of finance, chief accounting officer and treasurer at Aastrom Biosciences (Ann Arbor, MI, USA), succeeding CFO , who is leaving the company for personal reasons. Gibson joined Aastrom in 2010 as controller after 10 years of progressive experience at PricewaterhouseCoopers. has joined Zafgen's (Cambridge, MA, USA) board of directors. She brings nearly 20 years of experience in pharma and biotech business development, licensing and legal affairs. Most recently, she served as executive vice president of business development at Exelixis Pharmaceuticals. Amgen (Thousand Oaks, CA, USA) has named executive vice president, global commercial operations. He joins Amgen after 16 years at Bristol-Myers Squibb where he was most recently senior vice president, commercial operations and president, United States, Japan and Intercontinental. In addition, Amgen announced the appointment of , its president and COO, to the company's board of directors. Bradway joined Amgen in 2006 as vice president, operations strategy. has joined Cubist Pharmaceuticals (Lexington, MA, USA) as senior vice president of regulatory affairs. She joins Cubist from Biogen Idec Hemophilia where she was vice president of regulatory affairs and clinical compliance. Panmira Pharmaceuticals (San Diego) has named as CEO. Kumar most recently served as chief business officer of Amira Pharmaceuticals. has been named this year's winner of The Economist's tenth annual Innovation Awards in the category of bioscience. Langer is a pioneer in the application of engineering principles to biology, notably in the fields of controlled drug delivery and tissue engineering. He is the David H. Koch Institute Professor at the department of chemical engineering at Massachusetts Institute of Technology (Cambridge, MA, USA). Article preview Read the full article * Instant access to this article: US$32 Buy now * Subscribe to Nature Biotechnology for full access: Subscribe * Personal subscribers: Log in Additional access options: * Login via Athens * Login via your Institution * Purchase a site license * Use a document delivery service * Rent this article from DeepDyve * British Library Document Supply Centre * Infotrieve * Thompson ISI Document Delivery * You can also request this document from your local library through inter-library loan services. Additional data
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