Latest Articles Include:
- China calling
- Nat Biotech 29(2):89 (2011)
Nature Biotechnology | Editorial China calling Journal name:Nature BiotechnologyVolume: 29,Page:89Year published:(2011)DOI:doi:10.1038/nbt.1784Published online07 February 2011 The Chinese market is a big draw for biotech investors, but overreliance on central control and insular vision could derail the sector. View full text Additional data - Testing times for gene test regulators
- Nat Biotech 29(2):90 (2011)
Nature Biotechnology | Editorial Testing times for gene test regulators Journal name:Nature BiotechnologyVolume: 29,Page:90Year published:(2011)DOI:doi:10.1038/nbt.1787Published online07 February 2011 The Obama administration's hint at regulatory rollback may make stricter oversight of direct-to-consumer (DTC) genetic testing less inevitable, particularly as fresh evidence on consumer attitudes suggests buyers can handle the information. View full text Additional data - Industry gives cautious welcome to NIH translational center
- Nat Biotech 29(2):91-92 (2011)
Nature Biotechnology | News Industry gives cautious welcome to NIH translational center * Jeffrey L Fox1Journal name:Nature BiotechnologyVolume: 29,Pages:91–92Year published:(2011)DOI:doi:10.1038/nbt0211-91Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Bloomberg NIH Director Francis Collins, who has championed translational research at the agency, is leading the creation of the National Center for Advancing Translational Sciences (NCATS). In December, top officials at the National Institutes of Health (NIH) led by director Francis Collins announced plans to establish a center focused on translational research. The ambition is to overcome obstacles that keep therapeutics from reaching the marketplace, a goal that has generated skepticism in some quarters and concerns from academic researchers that their resources could be undercut. Biotech and pharma companies, however, are greeting these plans with considerable enthusiasm. Industry sources agree that new efforts to encourage collaborations and marshal available resources towards translational goals could well yield tangible benefits. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Synthetic biology go ahead
- Nat Biotech 29(2):92 (2011)
Nature Biotechnology | News Synthetic biology go ahead * Michael EisensteinJournal name:Nature BiotechnologyVolume: 29,Page:92Year published:(2011)DOI:doi:10.1038/nbt0211-92Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. J.Craig Venter Institute M. mycoides, the first synthetic bacterial cell. Synthetic biologists see freedom to operate in the new guidelines from the Presidential Commission for the Study of Bioethical Issues (PCSBI) published on 16 December 2010. "Measured" is the word being used by many researchers to describe the 18 recommendations put forward in New Directions: The Ethics of Synthetic Biology and Emerging Technologies (http://www.bioethics.gov/documents/synthetic-biology/PCSBI-Synthetic-Biology-Report-12-16-10.pdf). The new report relies on existing regulations while remaining vigilant for technological developments in this still-young field. Most current research in synthetic biology still resembles conventional genetic engineering, with typical commercial efforts focused on modification of cellular biosynthetic pathways. As such, it should be business as usual for companies such as Berkeley, California–based Bio Architecture Lab (BAL), which is reprogramming algae for biofuel production. "We have a lot of control, and the guidelines a! re very well articulated for industrial microbiology and industrial fermentation," explains co-founder Yasuo Yoshikuni, "so we don't see many obstacles." The response from scientists in academia and industry has been broadly positive. J. Craig Venter, whose headline-earning production of a Mycoplasma bacterium with a synthetically constructed genome this past May (Science329, 52–56, 2010) was a major driver for the PCSBI efforts, praised the report's findings as "wise, warranted and restrained" in a recent press release. Keeping guidelines current, however, will be a challenge in this rapidly moving area. Indeed, more than a third of the PCSBI recommendations are concerned with reviewing progress in the field over the next 18 months and the suitability of existing guidelines by scientists and policymakers, with the results to be made public. "At least in the present state of the field, the hype is far outpacing our capabilities," says James Collins, a resear! cher at Harvard's Wyss Institute for Biologically Inspired Eng! ineering and one of dozens of guest speakers who gave presentations to the PCSBI, "and I think the Commission did a very good job of assessing current capabilities." Many see such efforts at transparency and combating hype—key themes of the report—as essential to the future of the field. Jay Keasling, of the University of California at Berkeley, says: "Scientists can't be so naive to think there won't be a possibility of bad things happening, but I think the public will grow to accept synthetic biology if we're able to talk about all of the great things that can be done with it." View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - RNAi momentum fizzles as pharma shifts priorities
- Nat Biotech 29(2):93-94 (2011)
Nature Biotechnology | News RNAi momentum fizzles as pharma shifts priorities * Charles Schmidt1Journal name:Nature BiotechnologyVolume: 29,Pages:93–94Year published:(2011)DOI:doi:10.1038/nbt0211-93Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Santaris Santaris Pharma (Danish headquarters pictured above) recently received $14 million from Pfizer to extend a locked nucleic acid technology collaboration for RNAi targeting initiated by Wyeth. Shock waves continue to reverberate around the RNA interference (RNAi) commercial sector following announcements last year from Basel-based drug giants Novartis and Roche that they were curtailing their programs in this technology. In September, Novartis terminated its partnership with Cambridge, Massachusetts–based RNAi flagship Alnylam; in mid-November, Roche also killed its entire RNAi program after ploughing $500 million into the area over three years. Although it wasn't all bad news for the field—RNAi company Dicerna of Watertown, Massachusetts, signed a $1.4 billion agreement with Japanese firm Kyowa Hakko Kirin—concerns linger over the ability of RNAi technology to deliver new drugs to the clinic in the next few years, even in niche indications. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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, Maine * Charles Schmidt Author Details * Charles Schmidt Search for this author in: * NPG journals * PubMed * Google Scholar - ReNeuron and StemCells get green light for neural stem cell trials
- Nat Biotech 29(2):95-97 (2011)
Nature Biotechnology | News ReNeuron and StemCells get green light for neural stem cell trials * George S Mack1Journal name:Nature BiotechnologyVolume: 29,Pages:95–97Year published:(2011)DOI:doi:10.1038/nbt0211-95Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. ReNeuron's potential off-the-shelf neural stem cell therapeutic ReN001(CTX0E03). Persistence has paid off for UK biotech ReNeuron. After five years of repeated regulatory rebuffs, in December the Guildford, UK–based company began treating patients with ReN001, a genetically engineered neural stem cell line. This is the first time genetically engineered neural stem cells will be evaluated in people with disabling ischemic stroke, and the first stem-cell trial has got the go-ahead from the UK's Gene Therapy Advisory Committee (GTAC; Nat. Biotechnol., 303, 2010). Also in the same month, StemCells of Palo Alto, California, received approval from Swiss regulatory agency Swissmedic for a phase 1 clinical trial with human neural stem cells, also in stroke. Two other companies, Geron of Menlo Park, California, and Neuralstem of Rockville, Maryland, moved into the clinic last year to tackle brain disorders and spinal paralysis using a human embryonic stem cell (hESC)-derived oligodendrocyte precursor cell therapy and a human neural stem cell line, respectively ! (Table 1). Table 1: Selected stem cell therapies entering the clinic Full table StemCells' product candidate (HuCNS-SC) is a purified population of human neural stem cells, derived from human fetal (16–20 weeks) brain tissue, sorted using the CD133 marker and expanded in culture. The company has already completed a phase 1 clinical trial in the US in the rare and fatal neurodegenerative disease infantile neuronal ceroid lipofuscinosis, or Batten's disease. Early this year, StemCells plans another phase 1 trial in which this same cell line will be implanted into patients with chronic spinal cord injury and paralysis. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Columbia, South Carolina * George S Mack Author Details * George S Mack Search for this author in: * NPG journals * PubMed * Google Scholar - Germany caps drug prices
- Nat Biotech 29(2):96 (2011)
Nature Biotechnology | News Germany caps drug prices * Peter MitchellJournal name:Nature BiotechnologyVolume: 29,Page:96Year published:(2011)DOI:doi:10.1038/nbt0211-96aPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Germany has enacted a law imposing price controls on newly licensed medicines. In the new system, the manufacturer's launch price will be valid for one year only. After that, the amount paid by health insurers will be capped at a nationally determined level, based on a preliminary assessment of the medicine's benefits. If it has no extra therapeutic benefit, reimbursement will be set at the same level as a medicine already on the market. The Medicines Market Restructuring Act, or AMNOG, will apply to most novel biotherapeutics, except orphan drugs where no comparable existing therapies exist, and whose annual sales remain below 50 ($64.5) million. According to Germany's Association of Research Pharmaceutical Manufacturers (VFA), in Berlin, AMNOG could cut 2 ($2.6) billion a year from the industry's revenues. "This is the biggest crisis ever faced by the industry," says VFA chief executive Cornelia Yzer. But Doris Pfeiffer, chief executive of the Association of Statutory ! Health Insurance Funds, in Berlin, says AMNOG would weaken the ability of individual health insurers to negotiate their own volume discounts, thus softening the blow to drug manufacturers. The UK also intends to introduce compulsory, value-based pricing of branded drugs starting in 2014. And this year Italy will enforce medicine price reductions totaling 1.3 ($1.7) billion. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Peter Mitchell Search for this author in: * NPG journals * PubMed * Google Scholar - Imperial's £140 million boost
- Nat Biotech 29(2):96 (2011)
Nature Biotechnology | News Imperial's £140 million boost * Jennifer RohnJournal name:Nature BiotechnologyVolume: 29,Page:96Year published:(2011)DOI:doi:10.1038/nbt0211-96bPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Imperial Innovations is growing beyond its humble origins as Imperial College London's in-house tech-transfer department to an investment group encompassing the UK's four leading research universities. Imperial Innovations announced its intention to raise £140 ($223) million in equity through rights (whereby two new shares are issued for three existing shares) to expand investment in companies founded or based on technology from Oxford and Cambridge Universities, University College London and Imperial College. Susan Searle, its CEO, said they expect to invest about £60 million a year. Although Imperial Innovations invests in businesses in various scientific disciplines, Searle says that healthcare biotech can expect to receive about half the new funds. Mature biotech companies already in its stable may gain further, for instance, Circassia of Oxford, and London-based Polytherics, Myotec and Cell Medica. Searle says about 60% of the new funds are earmarked for investment op! portunities presented by the new university collaborators. Mark Larche, founder of allergy vaccine company Circassia, now a consultant, says that although £140 million is a relatively small amount, when you multiply it by the venture capital investment that Imperial Innovations has skillfully brought in, it becomes quite substantial. He added, "Innovations meets a real unmet need, especially in the current economic climate when finding pre-seed funding is particularly difficult and VCs [venture capitalists] just aren't interested." View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Jennifer Rohn Search for this author in: * NPG journals * PubMed * Google Scholar - Cephalon splashes out on mesenchymal stem cells
- Nat Biotech 29(2):97 (2011)
Nature Biotechnology | News Cephalon splashes out on mesenchymal stem cells Journal name:Nature BiotechnologyVolume: 29,Page:97Year published:(2011)DOI:doi:10.1038/nbt0211-97aPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. As mesenchymal stem cell (MSC) transplantation has yet to deliver a commercial product, it takes a certain amount of chutzpah to forge a $1.7 billion deal around the approach. In early December, Frazer, Pennsylvania–based Cephalon made an up-front payment of $130 million to Melbourne, Australia–based Mesoblast to develop and commercialize adult mesenchymal precursor cell therapies for a multitude of disorders, ranging from congestive heart failure and neurodegenerative diseases to cancer. The collaboration will provide funding for Mesoblast to run a phase 2a trial; Cephalon will oversee phase 2b and 3 trials if the MSC therapy is taken forward and retain global commercialization rights. Cephalon has also paid $220 million for a 19.99% equity stake and a seat on the board of Mesoblast. In its due diligence process, Cephalon had access by a confidential agreement to data from a randomized placebo-controlled phase 2 congestive heart failure trial of 60 patients who had rece! ived injections of Revascor, Cephalon's adult allogeneic off-the-shelf MSC therapy. The product, delivered through a catheter to the ischemic myocardium, reduced the overall monthly rate of major adverse cardiac events by 84% compared with controls. "We had a great deal of difficulty in explaining that data away," says new Cephalon CEO Kevin Buchi. "It had a placebo, and all the endpoints seemed to be moving in the same direction," he says. Cephalon's $350 million cash investment, with milestone payments potentially adding up to $1.7 billion, is certainly substantial for an early-stage platform, but one specialty pharma analyst, who wants to remain anonymous, calls it a "smallish transaction" that won't really produce any meaningful phase 3 data until some years away. Venture capitalist and managing partner Daphne Zohar of Boston-based PureTech Ventures also stops short of saying the deal is too rich. "But the up-front payment is higher than most we're seeing," she says. "Most recent deals are structured as earnouts that are more backloaded, but Cephalon must have thought it was worth it." The big question is whether Mesoblast's phase 2 efficacy data will translate to larger trials. Another company, Osiris Therapeutics of Columbia, Maryland, also had compelling phase 2 efficacy data for its MSC therapy, Prochymal, in severe refractory graft-versus-host disease (GvHD), but failed to translate that efficacy into phase 3. In 2009, on the basis of the phase 2 data, Genzyme of Cambridge, Massachusetts, struck a deal with the Maryland biotech, paying $130 million up-front for rights to Osiris' MSC products: Prochymal for GvHD and Crohn's disease, and Chondrogen for knee cartilage repair (Nat. Biotechnol.27, 966–967, 2009). It should be noted, however, that although Osiris' and Mesoblast's products are both MSC therapies, the target indications and heterogeneity of the clinical populations studied are different. The methods of preparation for the two companies' products are also different: Osiris' cells are prepared by density gradient separation of bone marrow mon! onuclear cells and then purified on the basis of the (>90%) presence of CD73, CD90 and CD105 markers and absence of CD34, CD45, CD14 and CD3 markers (The Lancet, 1553–1554, 2008). Mesoblast's MSCs are CD34+CD117+ cells obtained by sorting granulocyte colony stimulating factor-mobilized bone marrow–derived cells (Nat. Med.7, 430–436, 2001). View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Fabry drug march-in denied
- Nat Biotech 29(2):97 (2011)
Nature Biotechnology | News Fabry drug march-in denied * Mark RatnerJournal name:Nature BiotechnologyVolume: 29,Page:97Year published:(2011)DOI:doi:10.1038/nbt0211-97bPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Three people affected by shortages in Genzyme's drug for Fabry disease failed to convince the National Institutes of Health (NIH) to use 'march-in rights' to break manufacturing patents held by the Cambridge, Massachusetts–based biotech and grant a new license to third parties to deal with the problem. The enzyme replacement therapy Fabrazyme (agalsidase β; rh α-galactosidase A) is the only treatment available for individuals with this disorder, and ongoing manufacturing problems at Genzyme's plants (Nat. Biotechnol., 681, 2009) have curtailed supplies for over a year. March-in right is granted to the government under the Bayh-Dole Act to issue a new license or revoke an existing patent in cases where a federally funded invention has not been adequately developed. Two of the drug's patents, owned by Mt. Sinai Hospital School of Medicine in New York, are based on inventions funded by NIH and exclusively licensed to Genzyme. But in December, NIH declined to hold a hearing ! on the issue, stating that a march-in proceeding would not increase the supply of Fabrazyme in the short term. Given that Genzyme expects to return patients to normal dosing during the first half of 2011, the real interest of the petitioners may lie more in inducing the biotech to lower the price of Fabrazyme, which costs hundreds of thousands of dollars per patient per year. That strategy succeeded for Knowledge Ecology International (KEI), a nongovernmental organization dealing with intellectual property issues related to public health, based in Washington, DC. KEI obtained a march-in hearing on the antiviral drug ritanovir in 2004. Although they lost the case, "Abbott Labs did make concessions," says KEI director James Love, who assisted the Fabrazyme plaintiffs. "But these Fabry's patients will never have their day in court and won't be able to push Genzyme." The plaintiffs are appealing the decision. Opening up the Mt. Sinai patent license could spur developmen! t of a biosimilar, which would put price pressure on Fabrazyme! . But in the 30 years since Bayh-Dole was enacted, NIH has never asserted march-in rights. "It's often perceived that one of the missions of the NIH is to keep the biotech community as happy as possible, so innovation continues," says Love. But when taxpayers put up the money for research, not industry, "patent law protection is not relevant," he contends. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Mark Ratner Search for this author in: * NPG journals * PubMed * Google Scholar - Trade secrets in balance as agencies issue new transparency rules
- Nat Biotech 29(2):98-99 (2011)
Nature Biotechnology | News Trade secrets in balance as agencies issue new transparency rules * Gunjan Sinha1Journal name:Nature BiotechnologyVolume: 29,Pages:98–99Year published:(2011)DOI:doi:10.1038/nbt0211-98Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Custom Medical Stock Photo/Newscom High profile court cases, such those brought against Roche for suspected links between anti-acne drug Accutane use and suicidal thoughts, pressured the EMA to reevaluate its transparency rules. The London-based European Medicines Agency (EMA) has responded to public demand for increased transparency by introducing a new policy regarding the medicines it approves. The public will now have broader access to market authorization dossiers of human and animal medicines than ever before. Both public health advocates and industry commend the new policy but questions remain over exactly how the EMA will balance demands to be more open with the need to protect commercially sensitive information. Also, some fear that because the EMA will, when in doubt, consult the sources, the rules may lack the necessary muscle to be useful from a public health point of view. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Berlin * Gunjan Sinha Author Details * Gunjan Sinha Search for this author in: * NPG journals * PubMed * Google Scholar - First public-private vaccine
- Nat Biotech 29(2):99 (2011)
Nature Biotechnology | News First public-private vaccine * Nidhi SubbaramanJournal name:Nature BiotechnologyVolume: 29,Page:99Year published:(2011)DOI:doi:10.1038/nbt0211-99aPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. The first new vaccine developed as a public-private partnership, and prequalified by the World Health Organization (WHO) of Geneva, made its debut in December. Twelve million children and young adults across Burkina Faso, Mali and Niger were inoculated with MenAfriVac a new conjugate vaccine against meningitis A (group A Neisseria meningitides). Group A epidemics occur every 7 to 14 years in sub-Saharan Africa and in 2001, the nonprofit PATH, of Seattle, and the WHO set up the Meningitis Vaccine Project (MVP) to introduce an affordable vaccine specific for Africa. With $70 million in seed funding from the Bill and Melinda Gates Foundation in Seattle, the partners developed a vaccine priced at $0.50 a dose. Development took less than a decade and cost less than one-tenth the $500 million usually required to bring a new vaccine to market. Success depended on forging key collaborations: Amsterdam-based Synco Bio Partners provided the polysaccharide ingredient, the Serum Institu! te of India in Pune contributed the tetanus toxoid and affordable manufacturing, and the US Food & Drug Administration laboratories in Bethesda, Maryland, licensed a technology for conjugating vaccine components. The WHO approved MenAfriVac in June 2010. Marc LaForce, MVP global program leader, is pleased with the "outstanding" 95% vaccination coverage. "It speaks to the high level of acceptance on the part of the population," he says. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Nidhi Subbaraman Search for this author in: * NPG journals * PubMed * Google Scholar - Mobile vaccine factories
- Nat Biotech 29(2):99 (2011)
Nature Biotechnology | News Mobile vaccine factories * Susan AldridgeJournal name:Nature BiotechnologyVolume: 29,Page:99Year published:(2011)DOI:doi:10.1038/nbt0211-99bPublished online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. GE Healthcare and G-Con Manufacturing of College Station, Texas, have signed a collaboration to produce a low-cost, flexible, good manufacturing practices (GMP) vaccine-manufacturing facility to meet the needs of developing countries and as a swift response to pandemic situations. The quick-to-build vaccine manufacturing station will combine Buckinghamshire, UK–based GE's single-use bioprocessing technologies with G-Con's modular, portable, clean-room technology. The facility is equipped to grow cell lines up to 1,000 liters and is easier to operate than existing technologies. Catarina Flyborg, general manager of bioprocess products at GE Healthcare's Life Sciences unit, explains that the stations will use GE's ReadyToProcess range of disposables, and G-Con's mix and match modules. Other companies offering single-use GMP bioreactors are Xcellerex of Marlborough, Massachusetts, and Pharmadule of Nacka, Sweden. Miriam Monge, vice president, global key accounts Biopharm Servi! ces in Buckinghamshire, UK, a specialist in the disposable technology arena, commented, "During the last flu pandemic many developing countries realized how ill-equipped to face the situation they were. The combination of portable facilities, disposable technologies that can be rapidly deployed and GE's global infrastructure appears an ideal solution for delivering rapid response manufacturing to these developing countries." View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 * Susan Aldridge Search for this author in: * NPG journals * PubMed * Google Scholar - Drug pipeline: Q410
- Nat Biotech 29(2):101 (2011)
Nature Biotechnology | News | Data Page Drug pipeline: Q410 * Wayne Peng1Journal name:Nature BiotechnologyVolume: 29,Page:101Year published:(2011)DOI:doi:10.1038/nbt.1776Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. The first recombinant human protein made in transgenic rabbit milk was approved in October by the European Medicines Agency. Proof-of-efficacy data in human phase 2 studies were obtained for several nucleic acid therapies: OncoGenex Pharmaceuticals' custirsen and Hemispherx Biopharma's Ampligen (rintatolimod) met their endpoints, whereas Antisense Pharma's trabedersen showed only a clinical benefit. Elsewhere, results were positive for Vertex Pharmaceuticals' VX-770 in a phase 2 trial of cystic fibrosis patients. Top ten disease grouped by pipeline size Oncology drugs dominate the development pipeline. Top 10 disease grouped by pipeline size Box 1: Top 10 disease grouped by pipeline size Full box Notable trial results (September–December 2010) 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 * Wayne Peng is Emerging Technology Analyst, Nature Publishing Group Author Details * Wayne Peng Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - 2010—bumper year for big biotech
- Nat Biotech 29(2):102 (2011)
Nature Biotechnology | News | Data Page 2010—bumper year for big biotech * Walter Yang1Journal name:Nature BiotechnologyVolume: 29,Page:102Year published:(2011)DOI:doi:10.1038/nbt.1777Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. The biotech industry raised $36.2 billion last year, excluding partnership monies—the most since the genomics bubble of 2000. The tally was helped by several large debt deals, with eight companies raising >$1 billion each and a total raised of $22.4 billion—up 131% from 2009. Initial public offerings also heated up, with 31 biotechs raising $1.6 billion versus 10 raising $928 million in 2009. Stock market performance Box 1: Stock market performance Full box Global biotech venture capital investment 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 * Walter Yang is Research Director at BioCentury Author Details * Walter Yang Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Natural-born eaters
- Nat Biotech 29(2):103-106 (2011)
Nature Biotechnology | News | News Feature Natural-born eaters * Jeffrey L. Fox1Journal name:Nature BiotechnologyVolume: 29,Pages:103–106Year published:(2011)DOI:doi:10.1038/nbt.1770Published online07 February 2011 With information on the Deepwater Horizon oil spill in the Gulf of Mexico still coming in, more is being learned about the role of indigenous bacteria in cleaning the spill. Meanwhile, efforts are under way to enlist new genomic technologies to improve outcomes. Jeffrey L. Fox reports. View full text Additional data Affiliations * Washington, DC * Jeffrey L. Fox Author Details * Jeffrey L. Fox Search for this author in: * NPG journals * PubMed * Google Scholar - Something new under the skin
- Nat Biotech 29(2):107-109 (2011)
Nature Biotechnology | News | News Feature Something new under the skin * Michael Eisenstein1Journal name:Nature BiotechnologyVolume: 29,Pages:107–109Year published:(2011)DOI:doi:10.1038/nbt.1768Published online07 February 2011 One-size-fits-all intravenous delivery of biologics may be giving way to alternate delivery routes that enable safer and more efficient drug administration. Michael Eisenstein reports. View full text 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 Excel files * Supplementary Text and Figures (22K) Supplementary Table Additional data Affiliations * Brooklyn, New York * Michael Eisenstein Author Details * Michael Eisenstein Search for this author in: * NPG journals * PubMed * Google Scholar - Streamlining your business for success
- Nat Biotech 29(2):110-112 (2011)
- The 2010 Eurobarometer on the life sciences
- Nat Biotech 29(2):113-114 (2011)
Nature Biotechnology | Opinion and Comment | Correspondence The 2010 Eurobarometer on the life sciences * George Gaskell1 * Agnes Allansdottir2 * Nick Allum3 * Paula Castro4 * Yilmaz Esmer5 * Claude Fischler6 * Jonathan Jackson1 * Nicole Kronberger7 * Jurgen Hampel8 * Niels Mejlgaard9 * Alex Quintanilha10 * Andu Rammer11 * Gemma Revuelta12 * Sally Stares1 * Helge Torgersen13 * Wolfgang Wager7 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:113–114Year published:(2011)DOI:doi:10.1038/nbt.1771Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. To the Editor: Since 1991, the triennial Eurobarometer survey has assessed public attitudes about biotech and the life sciences in Europe. The latest 2010 Eurobarometer survey on the Life Sciences and Biotechnology (http://ec.europa.eu/research/science-society/document_library/pdf_06/europeans-biotechnology-in-2010_en.pdf), based on representative samples from 32 European countries, hints at a new era in the relations between science and society. We see less criticism of technology based on distrust in government and industry; more enthusiasm for novel technologies; and a more sophisticated appraisal of what technologies offer in terms of benefits, safety and sustainability. Europeans want regulation in the public interest and want a voice in such regulation when social values are at stake; we highlight an emerging European landscape of social value differences that shape people's views of technologies. That sustainability is framing perceptions of technology is illustrated in Europeans' overwhelming support for the second-generation biofuels, as well as their optimism about the contribution of different technologies to improving our way of life. Respondents were asked about a number of technologies. From their answers, we have created an index of technological optimism: the more positive the score, the higher the ratio of optimists to pessimists. Figure 1 shows the impact of rising concerns about climate change and sustainability. Wind and solar energy, the sustainable options, are in the same league as the ubiquitous computers and information technology. These green energies have also drawn increasing support over the past five years. Nuclear power shows a similar increase, albeit still attracting an equal number of pessimists as optimists. By contrast, all the non–energy-related technologies show declines in optimism; it is possible that this is due to their lack of re! levance to the sustainability agenda rather than to a change in attitudes. Of note is that support for biotech has returned to the level seen in 1993 (before the controversies over agrifood biotechnologies of the mid to late 1990s). Figure 1: Index of optimism about six technologies. The more positive the score, the higher the ratio of optimists to pessimists. The countries included in each score for "Europe" (weighted according to their relative population sizes) reflect the expanding membership of the EU; thus, 1991 and 1993 scores are for the original 12 member states, 1996–2002 for EU15, 2005 for EU25 and 2010 for EU27. * Full size image (39 KB) A rebuilding of public trust in regulators and industry from the nadir of the 1990s is in evidence. On an index capturing trust surplus (the percentage trusting minus the percentage not trusting), we find national governments at 46% (up 13% since 2005), the European Union (EU; Brussels) at 56% (up 14%) and industry at 50% (up 9%). On this index, university scientists maintain a trust surplus of around 80%. 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 * London School of Economics and Political Science, London, UK. * George Gaskell, * Jonathan Jackson & * Sally Stares * University of Siena, Siena, Italy. * Agnes Allansdottir * University of Essex, Colchester, UK. * Nick Allum * ISCTE-Lisbon University Institute, Portugal. * Paula Castro * Bahcesehir University, Istanbul, Turkey. * Yilmaz Esmer * Ecole des Hautes Etudes en Science Sociales, Paris, France. * Claude Fischler * Johannes Kepler University of Linz, Linz, Austria. * Nicole Kronberger & * Wolfgang Wager * Stuttgart University, Stuttgart, Germany. * Jurgen Hampel * Aarhus University, Aarhus, Denmark. * Niels Mejlgaard * Institute for Molecular and Cell Biology, Porto, Portugal. * Alex Quintanilha * Tartu University, Tartu, Estonia. * Andu Rammer * University Pompeu Fabra, Barcelona, Spain. * Gemma Revuelta * Institute of Technology Assessment, Austrian Academy of Sciences, Vienna, Austria. * Helge Torgersen Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * George Gaskell Author Details * George Gaskell Contact George Gaskell Search for this author in: * NPG journals * PubMed * Google Scholar * Agnes Allansdottir Search for this author in: * NPG journals * PubMed * Google Scholar * Nick Allum Search for this author in: * NPG journals * PubMed * Google Scholar * Paula Castro Search for this author in: * NPG journals * PubMed * Google Scholar * Yilmaz Esmer Search for this author in: * NPG journals * PubMed * Google Scholar * Claude Fischler Search for this author in: * NPG journals * PubMed * Google Scholar * Jonathan Jackson Search for this author in: * NPG journals * PubMed * Google Scholar * Nicole Kronberger Search for this author in: * NPG journals * PubMed * Google Scholar * Jurgen Hampel Search for this author in: * NPG journals * PubMed * Google Scholar * Niels Mejlgaard Search for this author in: * NPG journals * PubMed * Google Scholar * Alex Quintanilha Search for this author in: * NPG journals * PubMed * Google Scholar * Andu Rammer Search for this author in: * NPG journals * PubMed * Google Scholar * Gemma Revuelta Search for this author in: * NPG journals * PubMed * Google Scholar * Sally Stares Search for this author in: * NPG journals * PubMed * Google Scholar * Helge Torgersen Search for this author in: * NPG journals * PubMed * Google Scholar * Wolfgang Wager Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Balancing open source stem cell science with commercialization
- Nat Biotech 29(2):115-116 (2011)
Nature Biotechnology | Opinion and Comment | Correspondence Balancing open source stem cell science with commercialization * Aidan Courtney1 * Paul de Sousa1 * Carol George2 * Graeme Laurie2 * Joyce Tait3 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:115–116Year published:(2011)DOI:doi:10.1038/nbt.1773Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. To the Editor: UKSCB The principles of open access currently stipulated in the UKSCB license terms and Code of Practice (pictured) are likely compromising the commercialization of stem cell–derived therapies. Experience has shown that early-stage choices made in setting up regulatory systems in the life sciences can, in unanticipated ways, determine the eventual scope for innovation and the delivery of public benefits from scientific discoveries1, 2. An example is stem cell science and regenerative medicine therapies where, although the UK regulatory system has succeeded in facilitating basic stem cell research, downstream development of therapies must navigate an increasingly challenging regulatory system. 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 * Roslin Cells Ltd., Roslin, Midlothian, UK. * Aidan Courtney & * Paul de Sousa * School of Law, University of Edinburgh, Edinburgh, UK. * Carol George & * Graeme Laurie * Innogen Centre, University of Edinburgh, Edinburgh, UK. * Joyce Tait Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Joyce Tait Author Details * Aidan Courtney Search for this author in: * NPG journals * PubMed * Google Scholar * Paul de Sousa Search for this author in: * NPG journals * PubMed * Google Scholar * Carol George Search for this author in: * NPG journals * PubMed * Google Scholar * Graeme Laurie Search for this author in: * NPG journals * PubMed * Google Scholar * Joyce Tait Contact Joyce Tait Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - MutaDATABASE: a centralized and standardized DNA variation database
- Nat Biotech 29(2):117-118 (2011)
Nature Biotechnology | Opinion and Comment | Correspondence MutaDATABASE: a centralized and standardized DNA variation database * Sherri Bale1 * Martijn Devisscher2 * Wim Van Criekinge3 * Heidi L Rehm4 * Frederik Decouttere2 * Robert Nussbaum5 * Johan T Den Dunnen6 * Patrick Willems7 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:117–118Year published:(2011)DOI:doi:10.1038/nbt.1772Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. To the Editor: The field of molecular diagnostics for genetic disease is entering a new era of whole-genome sequencing. The unprecedented speed and scale with which human sequence variants are being identified is presenting the diagnostics community with practical logistical problems in retrieving, collecting, sharing and depositing clinical and molecular information on genetic disease. In response to this problem, a large consortium of diagnostic testing laboratories in Europe, the United States, Australia and Asia have recently joined efforts to create a central database that provides a repository of DNA variations and allows open access to the whole community. Here, we outline the main features of this universal database, referred to as MutaDATABASE (Fig. 1; http://www.MutaDATABASE.org). Figure 1: Organization and structure of MutaDATABASE. () As new variations are discovered in human genes, experts in the field ('MutaCURATORS') will collect and review all information from the literature and other gene databases, together with information entered by labs and clinicians ('MutaCLINICIANS'). Molecular and clinical information can be submitted into MutaDATABASE directly or through specifically designed 'MutaREPORTER' software, which allows users to circulate all information and questions in community groups centering around a given disease gene ('MutaCIRCLES'). Reviews ('MutaREVIEWS') on specific genes, their variants and associated phenotypes will be published online and will be freely available. () A screenshot of the MutaREPORTER software. * Full size image (77 KB) There are several reasons why the finding of a pathogenic DNA variation is important for an individual affected with a genetic disease and for his or her family. A molecular diagnosis may offer confirmation of a clinically or biochemically suspected disease, carrier detection, disease risk assessment, prenatal diagnosis, management guidance and/or long-term prognosis and may also facilitate genetic counseling of family members. 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 * GeneDx, Gaithersburg, Maryland, USA. * Sherri Bale * GENOHM, Ghent, Belgium. * Martijn Devisscher & * Frederik Decouttere * BIOBIX, University of Ghent, Ghent, Belgium. * Wim Van Criekinge * Harvard Medical School, Cambridge, Massachusetts, USA. * Heidi L Rehm * Institute of Human Genetics, University of California, San Francisco, San Francisco, California, USA. * Robert Nussbaum * Leiden University Medical Center, Leiden, The Netherlands. * Johan T Den Dunnen * GENDIA, Antwerp, Belgium. * Patrick Willems Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Patrick Willems Author Details * Sherri Bale Search for this author in: * NPG journals * PubMed * Google Scholar * Martijn Devisscher Search for this author in: * NPG journals * PubMed * Google Scholar * Wim Van Criekinge Search for this author in: * NPG journals * PubMed * Google Scholar * Heidi L Rehm Search for this author in: * NPG journals * PubMed * Google Scholar * Frederik Decouttere Search for this author in: * NPG journals * PubMed * Google Scholar * Robert Nussbaum Search for this author in: * NPG journals * PubMed * Google Scholar * Johan T Den Dunnen Search for this author in: * NPG journals * PubMed * Google Scholar * Patrick Willems Contact Patrick Willems Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Learning from (others') experience
- Nat Biotech 29(2):119 (2011)
Nature Biotechnology | Book Review Learning from (others') experience * Shreefal Mehta1, 1Journal name:Nature BiotechnologyVolume: 29,Page:119Year published:(2011)DOI:doi:10.1038/nbt.1779Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Building the Case for Biotechnology: Management Case Studies in Science, Laws, Regulations, Politics, and Business Mark J. AhnMichael A. AlvarezArlen D. MeyersAnne S. York Logos Press, 2010 416 pp. pages, paperback/hardcover, $79.95/$99.95 ISBN: Hardcover ISBN: 978-1-934899-16-8 Buy this book: USUKJapan Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg When teaching biotechnology management courses, a bulk of the material usually covers the complex path for commercializing biomedical technologies—navigating the patent, regulatory and reimbursement pathways—in order to understand how to get a product to market. These are critical, informational topics for engineers and scientists with an interest in management or entrepreneurship as well as students approaching careers in this industry from the business perspective. All these types of students are typically present in biotech management electives or in executive courses in the industry, in which good scientists are now being elevated to management positions. View full text Author information Affiliations * Shreefal Mehta is CEO of The Paper Battery Company and an adjunct faculty member at Rensselaer Polytechnic Institute, Troy, New York, USA. shreefal@scientist.com Competing financial interests The author declares no competing financial interests. Author Details * Shreefal Mehta Contact Shreefal Mehta Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Gene therapy finds its niche
- Nat Biotech 29(2):121-128 (2011)
Nature Biotechnology | Feature Gene therapy finds its niche * Cormac Sheridan1Journal name:Nature BiotechnologyVolume: 29,Pages:121–128Year published:(2011)DOI:doi:10.1038/nbt.1769Published online07 February 2011 Gene therapy is finally poised to make a contribution to the treatment of debilitating, highly penetrant genetic diseases that have proved intractable to other regimens. View full text Figures at a glance * Figure 1: Different types of gene therapy vector. (Modified from O'Connor, T.P. & Crystal, R.G.Nat. Rev. Genet., 261–276 (2006).) * Figure 2: Breakdown of vectors used in gene therapy trials. (Source: The Journal of Gene Medicine, Wiley and Sons). 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 * Cormac Sheridan is a freelance writer based in Dublin Author Details * Cormac Sheridan Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - The 'real world' utility of miRNA patents: lessons learned from expressed sequence tags
- Nat Biotech 29(2):129-133 (2011)
Nature Biotechnology | Feature | Patents The 'real world' utility of miRNA patents: lessons learned from expressed sequence tags * Bonnie W McLeod1 * Mark L Hayman1 * Angela L Purcell1 * Joshua S Marcus1 * Erich Veitenheimer1 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:129–133Year published:(2011)DOI:doi:10.1038/nbt.1765Published online07 February 2011 Strategies are needed for drafting miRNA patent applications, in light of the existing patent landscape and genomic patent strategies of the past decades. 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 * Bonnie W. McLeod and Erich Veitenheimer are partners, Mark L. Hayman is an associate attorney and Angela L. Purcell and Joshua S. Marcus are patent agents at Cooley LLP, Washington, DC, USA. Competing financial interests MiRagen, a company active in the microRNA space, is a Cooley patent prosecution client; and B.V.M. and E.V. previously represented the Carnegie Institution of Washington for the Andrew Fire/Craig Mello portfolio directed to RNAi. Corresponding author Correspondence to: * Bonnie W McLeod Author Details * Bonnie W McLeod Contact Bonnie W McLeod Search for this author in: * NPG journals * PubMed * Google Scholar * Mark L Hayman Search for this author in: * NPG journals * PubMed * Google Scholar * Angela L Purcell Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua S Marcus Search for this author in: * NPG journals * PubMed * Google Scholar * Erich Veitenheimer Search for this author in: * NPG journals * PubMed * Google Scholar Additional data - Recent patent applications in synthetic biology
- Nat Biotech 29(2):134 (2011)
Nature Biotechnology | Feature | Patents Recent patent applications in synthetic biology Journal name:Nature BiotechnologyVolume: 29,Page:134Year published:(2011)DOI:doi:10.1038/nbt.1782Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - TALEs of genome targeting
- Nat Biotech 29(2):135-136 (2011)
Nature Biotechnology | News and Views TALEs of genome targeting * Jens Boch1Journal name:Nature BiotechnologyVolume: 29,Pages:135–136Year published:(2011)DOI:doi:10.1038/nbt.1767Published online07 February 2011 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. New tools for site-specific genome targeting in human cells are generated from TALE proteins. 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 * Jens Boch is in the Department of Genetics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Jens Boch Author Details * Jens Boch Contact Jens Boch Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - A mucosal gateway for vaccines
- Nat Biotech 29(2):136-138 (2011)
Nature Biotechnology | News and Views A mucosal gateway for vaccines * Jerry R McGhee1Journal name:Nature BiotechnologyVolume: 29,Pages:136–138Year published:(2011)DOI:doi:10.1038/nbt.1766Published online07 February 2011 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. The use of a natural IgG transport system to deliver a mucosal vaccine is a step toward needle-free immunization. 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 * Jerry R. McGhee is at the Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. Competing financial interests The author declares no competing financial interests. Corresponding author Correspondence to: * Jerry R McGhee Author Details * Jerry R McGhee Contact Jerry R McGhee Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Sequencing for the cream of the crop
- Nat Biotech 29(2):138-139 (2011)
Nature Biotechnology | News and Views Sequencing for the cream of the crop * Jer-Ming Chia1 * Doreen Ware2 * Affiliations * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:138–139Year published:(2011)DOI:doi:10.1038/nbt.1756Published online07 February 2011 Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Sequencing technologies are poised to transform conventional strategies for crop improvement. 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 * Jer-Ming Chia and Doreen Ware are at the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. * Doreen Ware is with the US Department of Agriculture, Agricultural Research Service, USA. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Doreen Ware Author Details * Jer-Ming Chia Search for this author in: * NPG journals * PubMed * Google Scholar * Doreen Ware Contact Doreen Ware Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$18Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - Research highlights
- Nat Biotech 29(2):140 (2011)
Nature Biotechnology | Research Highlights Research highlights Journal name:Nature BiotechnologyVolume: 29,Page:140Year published:(2011)DOI:doi:10.1038/nbt.1786Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. Stretching microparticle circulation Micron-sized particles used for medical imaging or drug delivery are physically filtered out of the blood by the microvasculature of organs such as the lungs, liver and spleen. Merkel et al. show that making particles that mimic the ability of red blood cells to deform can extend their half-life in the circulatory system of mice. The authors mold hydrogel (red) into discoid-shaped particles using a template with wells (green) and a sheet of material (gray) that wicks away excess liquid from the mold surface, a technique they had developed previously. By varying the amount of cross-linker in the hydrogel from 1–10%, the authors create red blood cell–sized particles having an elastic modulus of 7.8–63.9 kPa. Mouse red blood cells have a modulus of 26 ±7 kPa. The authors observe that the most elastic particles had a half-life of >3 days when injected intravenously into mice, up to 30 times longer than the least elastic ones, as estimated by pharmacokinetic models and mea! sured using blood draws. Although these studies highlight elasticity as a tunable parameter of microparticles, much work remains to reduce this observation to practical benefit. (Proc. Natl. Acad. Sci. USA, 586–591, 2011) CM Artificial proteins to the rescue A new study asks whether the proteins constituting today's organisms are functionally optimal or whether unnatural diversity can be mined to find others that can substitute. To answer these questions, Fisher et al. construct a protein library of 1.5 × 106 proteins, each 102 residues long, that fold into alpha-helices, and test their ability to rescue Escherichia coli auxotrophs. Surprisingly, 15% (4/27) of the auxotrophs are rescued, and in all but one of these, more than one unnatural protein can substitute. Detailed analysis of the rescuing proteins shows that they fold as designed and have no natural homologs. The researchers eliminate several ways in which the synthetic protein might allow growth of the mutants (e.g., they direct the synthesis of the end-product, upregulate an endogenous E. coli protein that provides missing function or induce a stress response). How the synthetic proteins rescue the mutants, however, remains unknown; the authors cannot detect expected ! enzymatic activities in vivo or in vitro, which they attribute to low activity of the synthetic proteins. All rescued transformants grow less well than wild-type cells, suggesting that further selection might identify better-performing proteins. (PLoS ONE, e15364, 2011) LD View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - David Roos
- Nat Biotech 29(2):141-142 (2011)
Nature Biotechnology | Computational Biology | Profile David Roos * H. Craig Mak1Journal name:Nature BiotechnologyVolume: 29,Pages:141–142Year published:(2011)DOI:doi:10.1038/nbt.1774Published online07 February 2011 Reflecting on the growth of bioinformatics over the past decade, the University of Pennsylvania's David Roos highlights the increasing diversity of large-scale data sets, changing paradigms for data release and the emergence of new career opportunities. View full text Figures at a glance * Figure 1: David Roos is responsible for the Plasmodium Genome Database, which his lab used to characterize anti-malarial drug targets and has since grown into an informatics resource that covers dozens of eukaryotic pathogens and is used by thousands of researchers around the world. * Figure 2: The team behind the Eukaryotic Pathogen Genome Database. Additional data Affiliations * H. Craig Mak is Associate Editor, Nature Biotechnology Author Details * H. Craig Mak Search for this author in: * NPG journals * PubMed * Google Scholar - A TALE nuclease architecture for efficient genome editing
- Nat Biotech 29(2):143-148 (2011)
Nature Biotechnology | Research | Article A TALE nuclease architecture for efficient genome editing * Jeffrey C Miller1, 2 * Siyuan Tan1, 2 * Guijuan Qiao1 * Kyle A Barlow1 * Jianbin Wang1 * Danny F Xia1 * Xiangdong Meng1 * David E Paschon1 * Elo Leung1 * Sarah J Hinkley1 * Gladys P Dulay1 * Kevin L Hua1 * Irina Ankoudinova1 * Gregory J Cost1 * Fyodor D Urnov1 * H Steve Zhang1 * Michael C Holmes1 * Lei Zhang1 * Philip D Gregory1 * Edward J Rebar1 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:143–148Year published:(2011)DOI:doi:10.1038/nbt.1755Received15 November 2010Accepted14 December 2010Published online22 December 2010 Abstract * Abstract * 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 Nucleases that cleave unique genomic sequences in living cells can be used for targeted gene editing and mutagenesis. Here we develop a strategy for generating such reagents based on transcription activator–like effector (TALE) proteins from Xanthomonas. We identify TALE truncation variants that efficiently cleave DNA when linked to the catalytic domain of FokI and use these nucleases to generate discrete edits or small deletions within endogenous human NTF3 and CCR5 genes at efficiencies of up to 25%. We further show that designed TALEs can regulate endogenous mammalian genes. These studies demonstrate the effective application of designed TALE transcription factors and nucleases for the targeted regulation and modification of endogenous genes. View full text Figures at a glance * Figure 1: Structure and DNA-binding specificity of TALE proteins. () Sketch of a TALE from Xanthomonas. Red rectangles indicate the central array of tandem repeats that mediate DNA recognition. A typical repeat sequence is provided above, with a box highlighting the RVD (positions 12 and 13) that determines base preference. Gray regions indicate flanking protein segments, which often contain 288 and 278 residues (left and right segments, respectively). Δ152 indicates a truncation point that disrupts TALE transport into plant cells but preserves other functions32, and which was used as the N terminus for all constructs in these studies. N and C denote N and C termini. () Base sequence preferences of four common RVDs23, 24, which have been used in recent studies to make TALEs with new specificities23, 30. () RVDs (top row of letters) and predicted target bases (second row of letters) for the natural protein TALE13. RVDs are listed in repeat order (1 through 13), whereas the predicted target site is provided with the 5′ on the left. * deno! tes repeats that contain 33 amino acids, instead of the more typical 34. For exact repeat sequences see Supplementary Figure 1. () Graphical depiction of a SELEX-derived base frequency matrix for a fragment of TALE13 containing the repeat region. (See Online Methods for more details.) At each matrix position, the frequency of the predicted target base is shown above the x axis, whereas the remaining base frequencies are shown below the x axis. Note that the N-terminal flanking segment specifies the 5′ thymine base23, 24. * Figure 2: Activation of the endogenous human NTF3 gene by engineered TALE transcription factors. () Sketch of the proteins used in this study and their target in the NTF3 promoter. The designed TALE NT-L or a truncated variant that retained 95 residues of the C-terminal flanking region (NT-L+95) were linked to the VP16 activation domain and expressed in HEK293 cells. (For construct and protein sequences see Supplementary Methods.) The sequence at bottom shows the promoter-proximal region of human NTF3. Underlined bases indicate the target site for the NT-L TALE repeat domain. The hooked arrow shows the start site of native NTF3 transcription. N denotes the N terminus of each protein. () Relative NTF3 mRNA levels in HEK293 cells expressing either NT-L or NT-L+95 fused to the VP16 activation domain. GFP indicates cells transfected with a control plasmid that expresses enhanced GFP. Measurements were performed in quadruplicate and error bars indicate s.d. () Levels of NT-3 protein (encoded by NTF3) secreted from HEK293 cells expressing either NT-L or NT-L+95 fused to the V! P16 activation domain. Measurements were performed in duplicate and error bars indicate s.d. Neg. indicates cells transfected with an empty vector control. () RVDs (top row of letters) and expected binding site (second row of letters) for NT-L and NT-L+95. For the design of NT-L and all other TALEs in this study, we used the four common and well-characterized RVDs23, 24 listed in Figure 1b, plus one additional design—NK—as an alternative for recognition of guanine24. () Graphical depiction of a SELEX-derived base frequency matrix for NT-L+95. For additional detail see legend to Figure 1d. * Figure 3: Modification of the endogenous NTF3 locus in human cells. () Sketch of the designed TALENs NT-L and NT-R bound to their target sites (boxed bases) in the NTF3 promoter. The hooked arrow shows the start site of NTF3 transcription. Ovals indicate the cleavage domain from wild-type FokI, which was the catalytic domain used for all TALENs in these studies. N denotes the N terminus of each protein. () Surveyor nuclease assay for minor insertions and deletions. Top, sketch of the amplicon used for this assay. The NT-L/NT-R cleavage target is centered at bp 46 of the 272-bp amplicon. Arrows indicate PCR primers. Bottom, annotated assay gels. Lane headings indicate the TALEN dimer used for modification of each sample, where +28 and +63 refer to the C-terminal truncation variant of NT-L or NT-R. GFP indicates negative control samples from cells transfected with a plasmid expressing enhanced GFP. The arrow indicates the larger fragment produced by a Surveyor nuclease digest of amplicons bearing a mismatch at the site of NT-L/NT-R cleavage (t! he smaller fragment was not visible on this gel). Numbers beneath each lane indicate the percentage of modified alleles. Example lane traces are provided in Supplementary Figure 6. () Mutated alleles identified from sequence analysis of 84 cloned amplicons from cells that expressed NT-L+28 and NT-R+63 at 30 °C. Underlines highlight binding sites for NT-L and NT-R. Dashes indicate deleted bases. Uncropped gels are shown in Supplementary Figure 12. * Figure 4: Modification of endogenous human CCR5. () Target names and sequences of the TALENs tested in this study. Targets are aligned with the corresponding region of CCR5 (double-stranded sequence at center). Each target is named according to whether it is a left or right target (L or R) and the position of its 3′ base in the CCR5 open reading frame (e.g., L532 is a target for a left TALEN and the 3′ T of this target is bp 532 of the CCR5 open reading frame). The underlined segment of CCR5 sequence indicates bases deleted in the Δ32 variant. For more detail regarding our choice of target sites see Supplementary Methods. () Gene modification levels induced by the +63/+63 versions of all 16 nuclease combinations as gauged by the Surveyor nuclease assay. The left grid provides modification levels whereas the right grid indicates the separation distance (or 'spacer') between nuclease target sites. An entry of "<1" indicates that modification levels were below the detection limit of 1%. In both grids, pairs showing d! etectable activity are shaded gray. () Average gene modification activities for +28/+28 and +63/+63 TALEN pairs from this study and one additional study (Supplementary Fig. 9), binned according to the spacer length between TALEN targets. Max. and Min. indicate the longest and shortest target separation distance (in bp) in each bin. The number of data points in each bin was for 5–9 bp: N = 4; 10–11 bp: N = 4; 12 bp: N = 3; 13 bp: N = 3; 14–16 bp: N = 5; 17–19 bp: N = 4; 20–23 bp: N = 3; and 24–27 bp: N = 2. Error bars indicate s.e.m.. * Figure 5: TALEN-mediated gene editing by HDR. () Experimental overview. HDR using the indicated repair template transfers a 46-bp insert bearing a BglI restriction site into the targeted locus. PCR amplification, followed by BglI digestion, allows detection and quantification of the gene editing event. Arrows indicate PCR primers. () Annotated assay gel. Arrows indicate the fragments generated by BglI digestion. Lane headings indicate which TALENs were used (pair 1, pair 2; see Supplementary Fig. 9 for details), as well as whether the resultant amplicons were treated with BglI. Uncropped gels are shown in Supplementary Figure 12. * Figure 6: Base preferences of the five RVDs used in this study, as determined by averaging SELEX-derived base preferences for NT-L (Fig. 2e) and NT-R (Supplementary Fig. 5), as well as two additional designed TALEs "VEGF-1" and "CCR5-1" (Supplementary Fig. 10). For each RVD (listed at top), the average frequency of its preferred target base is shown above the x axis, whereas frequencies of the remaining bases are shown below the x axis. Author information * Abstract * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Jeffrey C Miller & * Siyuan Tan Affiliations * Sangamo BioSciences, Inc., Richmond, California, USA. * Jeffrey C Miller, * Siyuan Tan, * Guijuan Qiao, * Kyle A Barlow, * Jianbin Wang, * Danny F Xia, * Xiangdong Meng, * David E Paschon, * Elo Leung, * Sarah J Hinkley, * Gladys P Dulay, * Kevin L Hua, * Irina Ankoudinova, * Gregory J Cost, * Fyodor D Urnov, * H Steve Zhang, * Michael C Holmes, * Lei Zhang, * Philip D Gregory & * Edward J Rebar Contributions J.C.M. and S.T. designed studies, performed experiments and analyzed data. G.Q., K.A.B., J.W., D.F.X., X.M., D.E.P., K.L.H., and G.J.C. performed studies. S.T, G.Q., E.L., S.J.H., G.P.D., L.Z., and I.A. developed new procedures and assembled constructs. F.D.U., H.S.Z, M.C.H., L.Z., P.D.G. and E.J.R. supervised studies and designed experiments. J.C.M., P.D.G. and E.J.R. wrote the manuscript. Competing financial interests All authors are current or past full-time employees of Sangamo BioSciences, Inc. Corresponding author Correspondence to: * Edward J Rebar Author Details * Jeffrey C Miller Search for this author in: * NPG journals * PubMed * Google Scholar * Siyuan Tan Search for this author in: * NPG journals * PubMed * Google Scholar * Guijuan Qiao Search for this author in: * NPG journals * PubMed * Google Scholar * Kyle A Barlow Search for this author in: * NPG journals * PubMed * Google Scholar * Jianbin Wang Search for this author in: * NPG journals * PubMed * Google Scholar * Danny F Xia Search for this author in: * NPG journals * PubMed * Google Scholar * Xiangdong Meng Search for this author in: * NPG journals * PubMed * Google Scholar * David E Paschon Search for this author in: * NPG journals * PubMed * Google Scholar * Elo Leung Search for this author in: * NPG journals * PubMed * Google Scholar * Sarah J Hinkley Search for this author in: * NPG journals * PubMed * Google Scholar * Gladys P Dulay Search for this author in: * NPG journals * PubMed * Google Scholar * Kevin L Hua Search for this author in: * NPG journals * PubMed * Google Scholar * Irina Ankoudinova Search for this author in: * NPG journals * PubMed * Google Scholar * Gregory J Cost Search for this author in: * NPG journals * PubMed * Google Scholar * Fyodor D Urnov Search for this author in: * NPG journals * PubMed * Google Scholar * H Steve Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Michael C Holmes Search for this author in: * NPG journals * PubMed * Google Scholar * Lei Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Philip D Gregory Search for this author in: * NPG journals * PubMed * Google Scholar * Edward J Rebar Contact Edward J Rebar Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Abstract * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Figs. 1–12 and Supplementary Methods Additional data - Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription
- Nat Biotech 29(2):149-153 (2011)
Nature Biotechnology | Research | Letter Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription * Feng Zhang1, 2, 3, 5, 7, 8 * Le Cong2, 3, 4, 8 * Simona Lodato5, 6 * Sriram Kosuri2, 3 * George M Church2, 3 * Paola Arlotta5, 6 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:149–153Year published:(2011)DOI:doi:10.1038/nbt.1775Received18 November 2010Accepted12 January 2011Published online19 January 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg The ability to direct functional proteins to specific DNA sequences is a long-sought goal in the study and engineering of biological processes. Transcription activator–like effectors (TALEs) from Xanthomonas sp. are site-specific DNA-binding proteins that can be readily designed to target new sequences. Because TALEs contain a large number of repeat domains, it can be difficult to synthesize new variants. Here we describe a method that overcomes this problem. We leverage codon degeneracy and type IIs restriction enzymes to generate orthogonal ligation linkers between individual repeat monomers, thus allowing full-length, customized, repeat domains to be constructed by hierarchical ligation. We synthesized 17 TALEs that are customized to recognize specific DNA-binding sites, and demonstrate that they can specifically modulate transcription of endogenous genes (SOX2 and KLF4) in human cells. View full text Figures at a glance * Figure 1: Design and construction of customized artificial TALEs for use in mammalian cells. () Schematic representation of the native TALE hax3 from Xanthomonas campestris pv. armoraciae depicting the tandem repeat domain and the two repeat variable di-residues (red) within each repeat monomer. These di-residues determine the base recognition specificity. The four most common naturally occurring di-residues used for the construction of customized artificial TAL effectors are listed together with their proposed major base specificity. NLS, nuclear localization signal; AD, activation domain of the native TAL effector. () Schematic of the hierarchical ligation assembly method for the construction of customized TALEs. Twelve separate PCRs are done for each of the four types of repeat monomers (NI, HD, NG and NN) to generate a set of 48 monomers to serve as assembly starting material. Each of the 12 PCR products for a given monomer type (e.g., NI) has a unique linker specifying its programmed position in the assembly (color-coded digestion and ligation adapters). After ! enzymatic digestion with a type IIs restriction endonuclease (e.g., BsaI), orthogonal overhangs are made by recoding each amino acid in the junction to use an alternative codon. The unique overhangs facilitate the positioning of each monomer in the ligation product. The ligation product was PCR amplified subsequently to yield the full-length repeat regions, which were then cloned into a backbone plasmid containing the N and C termini of the wild-type TALE hax3. () Schematic representation of the fluorescence reporter system for testing TALE-DNA recognition. The diagram illustrates the composition of the tandem repeat for a TALE and its corresponding 14-bp DNA-binding target in the fluorescent reporter plasmid. VP64, synthetic transcription activation domain; 2A, self-cleavage peptide. () 293FT cells co-transfected with a TALE plasmid and its corresponding reporter plasmid showed considerably greater mCherry expression compared with the reporter-only control. Scale bars, 200! μm. * Figure 2: Functional characterization of the robustness of TALE-DNA recognition in mammalian cells and truncation analysis of TALE N- and C-termini. () Thirteen TALEs were tested with their corresponding reporter constructs. Customized repeat regions and binding site sequences are shown on the left. The activities of the TALEs on target gene expression are shown on the right as the fold induction of the mCherry reporter gene. Fold induction was determined by flow cytometry analysis of mCherry expression in transfected 293FT cells, and calculated as the ratio of the total mCherry fluorescence intensity of cells transfected with and without the specified TALE, normalized by the GFP fluorescence to control for transfection efficiency differences (Online Methods). () The N- and C-terminal amino acid sequence of wild-type TAL effector hax3 showing the positions of all N- and C-terminal truncation constructs tested in 293FT cells. N0 to N8 designates N-terminal truncation positions (N0 retains the full-length N terminus), and C0 to C7 designate C-terminal truncations. Amino acids representing the nuclear localization signal an! d the activation domain in the native hax3 protein are underlined. () Relative activity of each N-terminal TALE truncation construct compared to the TALE (N0-C0). TALE truncation positions are indicated in . Error bars indicate s.e.m.; n = 3. TALE-TALE relative activity was calculated by dividing the fold induction of the construct by the fold induction of the reporter gene. Fold induction calculated as in . () Relative activity of each C-terminal truncation compared to TALE(N1,C0). * Figure 3: Activation of endogenous genes in human cells by TALEs. () TALEs designed to target the genes SOX2, KLF4, c-MYC and OCT4 facilitate activation of mCherry reporter in 293FT cells. The target sites are selected from the 200-bp proximal promoter region. Fold induction was determined by flow cytometry analysis using the same methodology as in Figure 2 and detailed in Online Methods. () Images of TALE-induced mCherry reporter expression in 293FT cells. Scale bar, 200 μm. () Levels of SOX2 and KLF4 mRNA in transfected 293FT cells, as determined by quantitative RT-PCR. Mock-treated cells received the transfection vehicle. TALE1 was used as a negative control. Error bars indicate s.e.m.; n = 3. *** indicates P < 0.005. Author information * Author information * Supplementary information Primary authors * These authors contributed equally to this work. * Feng Zhang & * Le Cong Affiliations * Society of Fellows, Harvard University, Cambridge, Massachusetts, USA. * Feng Zhang * Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA. * Feng Zhang, * Le Cong, * Sriram Kosuri & * George M Church * Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts, USA. * Feng Zhang, * Le Cong, * Sriram Kosuri & * George M Church * Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA. * Le Cong * Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. * Feng Zhang, * Simona Lodato & * Paola Arlotta * Center for Regenerative Medicine and Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. * Simona Lodato & * Paola Arlotta * Present address: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; McGovern Institute for Brain Research, MIT, Cambridge, Massachusetts, USA; and Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts, USA. * Feng Zhang Contributions F.Z. and L.C. conceived the study. F.Z., L.C., S.L. and S.K. designed, performed and analyzed all experiments. P.A. supervised the work of S.L. and G.M.C. supervised the work of F.Z., L.C. and S.K. G.M.C., P.A. and F.Z. provided support for this study. F.Z., L.C. and P.A. wrote the manuscript with support from all authors. G.M.C and P.A. equally contributed to this work. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Feng Zhang or * Paola Arlotta Author Details * Feng Zhang Contact Feng Zhang Search for this author in: * NPG journals * PubMed * Google Scholar * Le Cong Search for this author in: * NPG journals * PubMed * Google Scholar * Simona Lodato Search for this author in: * NPG journals * PubMed * Google Scholar * Sriram Kosuri Search for this author in: * NPG journals * PubMed * Google Scholar * George M Church Search for this author in: * NPG journals * PubMed * Google Scholar * Paola Arlotta Contact Paola Arlotta Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (808K) Supplementary Tables 1–3, Supplementary Figs. 1–3, Supplementary Methods and Supplementary Sequences Additional data - Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
- Nat Biotech 29(2):154-157 (2011)
Nature Biotechnology | Research | Letter Expression of therapeutic proteins after delivery of chemically modified mRNA in mice * Michael S D Kormann1, 3 * Günther Hasenpusch1 * Manish K Aneja1 * Gabriela Nica1 * Andreas W Flemmer2 * Susanne Herber-Jonat2 * Marceline Huppmann2 * Lauren E Mays3 * Marta Illenyi1 * Andrea Schams1 * Matthias Griese1 * Iris Bittmann4 * Rupert Handgretinger3 * Dominik Hartl3 * Joseph Rosenecker1 * Carsten Rudolph1 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:154–157Year published:(2011)DOI:doi:10.1038/nbt.1733Received05 October 2010Accepted17 November 2010Published online09 January 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Current viral vectors for gene therapy1, 2, 3 are associated with serious safety concerns, including leukemogenesis4, and nonviral vectors are limited by low gene transfer efficiency5. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days. View full text Figures at a glance * Figure 1: Modification of mRNA enhances transgene expression and decreases immune responses by reducing immunoreceptor binding. () RNA immunoprecipitation (RIP). PBMCs were transfected with 5 μg red fluorescent protein (RFP) mRNA, and the recovery ratios were determined by RIP using TLR3, TLR7, TLR8 and RIG-I specific antibodies. Boxes represent medians ± IQR (interquartile range). Whiskers represent the minimum and maximum observations. *, P < 0.05, **, P < 0.01 versus the unmodified RFP group. () Modifications of RFP mRNA inhibit immune responses in vivo after intravenous administration. Data represent the mean ± s.e.m. after 24 h (n = 4 each). s2U(0.5), modified mRNA with 50% 2-thiouridine (s2U) incorporation; s2U(0.25)m5C(0.25), modified mRNA with 25% s2U and 25% 5-methylcytidine (m5C) incorporation. (,) A549 cells () and MLE12 cells () were transfected with 200 ng RFP mRNA. Transfection efficiency (blue and orange bars) and RFP mean fluorescence intensity (MFI) (small blue bars) were determined by flow cytometry (medians ± IQR are shown). *, P < 0.05 versus the unmodified RFP group. Total RF! P expression (small red bars) was calculated as proportion of RFP-positive cells multiplied by MFI, given as arbitrary units. All experiments were performed twice in duplicates. Data represent the mean ± s.e.m. * Figure 2: Dual-modification of mEpo mRNA reduces binding to innate immune receptors, prevents immune responses and prolongs transgene expression in vivo. () Human PBMCs were transfected with 5 μg of unmodified and modified mEpo mRNA, and the recovery ratios were determined by RIP using TLR3, TLR7, TLR8 and RIG-I specific antibodies. Boxes represent medians ± IQR. Whiskers represent the minimum and maximum observations. *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus the unmodified mEpo mRNA group. () 5 μg unmodified and modified mEpo mRNA were injected into mice intramuscularly (n = 4 each) and cytokines were measured after 8 h in serum. (,) 5 μg of unmodified and modified mEpo were injected into mice intramuscularly (n = 4 each). () At days 14 and 28 mEpo was quantified in the serum with ELISA. () Hematocrit was determined in whole blood of the mice of the same experiment. Data represent mean ± s.e.m. *, P < 0.05 versus the untreated group of a respective time point; †, P < 0.05 versus the unmodified mEpo group of a respective time point. * Figure 3: Rescue of SP-B deficient mice with repeated doses of modified SP-B mRNA. () Application scheme of control and SP-B mRNA. () Life expectancy of SP-B−/− mice withdrawn from doxycycline at day 0 that were treated with modified EGFPLuc control mRNA (green line, n = 10), s2U(0.25)m5C(0.25) SP-B mRNA twice (orange line, n = 10), or continuously, twice a week, for 28 d (blue line, n = 13). Kaplan-Meier survival curves were plotted and statistical analysis (Wilcoxon-Gehan test) was performed. () Cell-free BALF supernatant (10 μg of total protein per lane) from mice on Doxy, continuously treated with SP-B mRNA, and control mRNA was blotted against specific SP-B antibody. Two representative blots are shown. () Typical expression of SP-B (brown) in lung tissue from mice described in . Scale bar, 20 μm. (,) Typical lung histology and BALF cytospin preparations (stained with May-Grünwald/Giemsa) of the same mice described in . Scale bar, 20 μm. () Cytokine levels at the time of necropsy were quantified in mice BALF by ELISA (mean ± s.e.m.); *P < 0.05! versus the untreated group. () Lung compliance over time. () Early cytokine levels were quantified in mice BALF by ELISA 8 h after administration (mean ± s.e.m.); 20 μg (50 μl) unmodified, s2U(0.25)m5C(0.25) SP-B mRNA and SP-B pDNA was delivered to the mice lungs (n = 4 each); Doxy, doxycycline; Pfc, perfluorocarbon. *, P < 0.05 versus the untreated group. Author information * Author information * Supplementary information Affiliations * Department of Pediatrics, Ludwig Maximilian's University Munich, Munich, Germany. * Michael S D Kormann, * Günther Hasenpusch, * Manish K Aneja, * Gabriela Nica, * Marta Illenyi, * Andrea Schams, * Matthias Griese, * Joseph Rosenecker & * Carsten Rudolph * Division of Neonatology, Children's Hospital and Perinatal Center, Grosshadern, Ludwig Maximilian's University Munich, Munich, Germany. * Andreas W Flemmer, * Susanne Herber-Jonat & * Marceline Huppmann * Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Tübingen, Germany. * Michael S D Kormann, * Lauren E Mays, * Rupert Handgretinger & * Dominik Hartl * Institute for Pathology, Diakonien Hospital Rotenburg (Wümme) LTD, Rotenburg (Wümme), Germany. * Iris Bittmann Contributions M.S.D.K. designed research, conceived and performed experiments, and wrote the manuscript. G.H., A.W.F. and S.H.-J. conceived and performed animal experiments. M.K.A. performed animal experiments and cloning. M.H. contributed to animal experiments. G.N. performed cloning. M.I. and A.S. performed in vitro experiments. L.E.M., D.H., M.G. and R.H. contributed materials and support in drafting the manuscript. I.B. performed histology. C.R. and J.R. designed and supervised the research and composed and wrote the manuscript. Competing financial interests C.R. recently founded a company, ethris GmbH, dedicated to the clinical translation of the technology described in this paper. The other authors declare that they have no competing financial interests. Corresponding authors Correspondence to: * Carsten Rudolph or * Michael S D Kormann Author Details * Michael S D Kormann Contact Michael S D Kormann Search for this author in: * NPG journals * PubMed * Google Scholar * Günther Hasenpusch Search for this author in: * NPG journals * PubMed * Google Scholar * Manish K Aneja Search for this author in: * NPG journals * PubMed * Google Scholar * Gabriela Nica Search for this author in: * NPG journals * PubMed * Google Scholar * Andreas W Flemmer Search for this author in: * NPG journals * PubMed * Google Scholar * Susanne Herber-Jonat Search for this author in: * NPG journals * PubMed * Google Scholar * Marceline Huppmann Search for this author in: * NPG journals * PubMed * Google Scholar * Lauren E Mays Search for this author in: * NPG journals * PubMed * Google Scholar * Marta Illenyi Search for this author in: * NPG journals * PubMed * Google Scholar * Andrea Schams Search for this author in: * NPG journals * PubMed * Google Scholar * Matthias Griese Search for this author in: * NPG journals * PubMed * Google Scholar * Iris Bittmann Search for this author in: * NPG journals * PubMed * Google Scholar * Rupert Handgretinger Search for this author in: * NPG journals * PubMed * Google Scholar * Dominik Hartl Search for this author in: * NPG journals * PubMed * Google Scholar * Joseph Rosenecker Search for this author in: * NPG journals * PubMed * Google Scholar * Carsten Rudolph Contact Carsten Rudolph Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (2M) Supplementary Figures 1–3 Additional data - Efficient mucosal vaccination mediated by the neonatal Fc receptor
- Nat Biotech 29(2):158-163 (2011)
Nature Biotechnology | Research | Letter Efficient mucosal vaccination mediated by the neonatal Fc receptor * Lilin Ye1 * Rongyu Zeng1 * Yu Bai1 * Derry C Roopenian2 * Xiaoping Zhu1, 3 * Affiliations * Contributions * Corresponding authorJournal name:Nature BiotechnologyVolume: 29,Pages:158–163Year published:(2011)DOI:doi:10.1038/nbt.1742Received18 October 2010Accepted01 December 2010Published online16 January 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Almost all infectious diseases are initiated at mucosal surfaces, yet intramuscular or subcutaneous vaccination usually provides only minimal protection at sites of infection owing to suboptimal activation of the mucosal immune system. The neonatal Fc receptor (FcRn) mediates the transport of IgG across polarized epithelial cells lining mucosal surfaces. We mimicked this process by fusing a model antigen, herpes simplex virus type-2 (HSV-2) glycoprotein gD, to an IgG Fc fragment. Intranasal immunization, together with the adjuvant CpG, completely protected wild-type, but not FcRn knockout, mice after intravaginal challenge with virulent HSV-2 186. This immunization strategy induced efficient mucosal and systemic antibody, B- and T-cell immune responses, with stable protection for at least 6 months after vaccination in most of the immunized animals. The FcRn-IgG transcellular transport pathway may provide a general delivery route for subunit vaccines against many mucosal path! ogens. View full text Figures at a glance * Figure 1: FcRn-targeted mucosal vaccination induces enhanced gD-specific antibody and T-cell responses. Either PBS or 20 μg of gD-Fc/wt, gD-Fc/wt/KO, gD-Fc/mut or gD were administered i.n. to wild-type (WT) or FcRn knockout (KO) mice together with 20 μg CpG. () Measurement of anti-HSV-2 gD-specific IgG antibody titers in serum before and after the boost immunization. Anti-HSV-2 gD-specific IgG antibody at the indicated days was measured in serum by ELISA. Immunization conditions are indicated on the right. The curves represent mean values for each group (± s.e.m.). Black line for PBS is overlapped with x axis due to negative IgG titer in PBS. Values marked with asterisk in this and subsequent figures: *, P < 0.05; **, P < 0.01. () Test of neutralizing activity in the immunized sera. Sera were heat inactivated, diluted tenfold, then in twofold steps in MEM with 2% FBS. HSV-2 (50 p.f.u.) was added and incubated at 37 °C for 1 h. Finally, the mixture was removed and washed, overlaid with 0.8% methylcellulose in 2% FBS containing DMEM and further incubated for 72 h at 37 °C. ! The titers were expressed as the reciprocal of the twofold serial dilution preventing the appearance of the cytopathic effects (CPE) over control sera. Each assay was done in triplicate. () The percentage of IFN-γ–producing T cells in the spleen 4 d after the boost. Spleen cells from the immunized mice were stimulated for 10 h with purified gD or medium control. Lymphocytes were gated by forward and side scatter and T cells labeled with anti-CD3 and identified by their respective surface markers CD4 and CD8 and intracellular IFN-γ staining. Immunization conditions are displayed on the bottom. Numbers represent the percentage of IFN-γ+ CD3+ CD4+ (left panel) or IFN-γ+ CD3+ CD8+ (right panel) T cells. Isotype controls included FITC-mouse-IgG1 with baseline response. () Cytokine secretions from the stimulated spleen T cells. Spleen cells were collected on day 4 after the boost. Cells were stimulated in vitro specifically with different multiplicities of infection (MOI) o! f inactivated HSV-2 virus as indicated for 24 h. Cytokines IFN! -γ, IL-2 and IL-4 in the culture supernatant were detected by ELISA. Data are representative of three experiments with three immunized mice pooled in each group. * Figure 2: Local immune responses induced by FcRn-targeted mucosal immunization. () Accumulation of activated B cells in germinal centers in the mediastinal lymph nodes (MeLN) and spleen. Representative flow cytometric analyses of germinal center B cells among CD19+ B220+ B cells in the MeLNs and spleen 10 d after the boost. B220+ PNAhigh cells are B cells that exhibit the phenotypic attributes of germinal center B cells. The germinal center staining in spleen was used as a positive control. Numbers are the percentage of activated germinal center B cells (PNA+ FAS+) among gated B cells and are representative of three independent experiments. () Germinal center formation and presence of activated B cells following immunizations as indicated. Frozen MeLN sections at day 10 from the immunized mice were co-stained with biotin-PNA (developed with avidin-FITC) and Alexa647 labeled anti-IgD. Scale bars represent 50 μm. () Quantitative analysis of germinal centers following immunization. The dynamics of the frequency of germinal center B cells (FAS+ PNA+, gated! on CD19+ B220+ cells) were plotted on days 10, 22 and 35 after the boost. Data indicate the mean and S.E.M., n = 5 mice. () The formation of inducible bronchus-associated lymphoid tissue (iBALT). Frozen serial sections of the lung were stained with biotin-PNA (germinal center, red) and anti-B220 (B cells, green), followed by Alexa 488-conjugated IgG of corresponding species and Alexa 555-Avidin. The nucleus is stained with DAPI (blue). A germinal center-like structure is shown in the merged panel by the white color. The data are representative of sections from at least three independent mice. Images were originally obtained at 10× magnification. Scale bars, 100 μm. (,). Presence of HSV-2 gD-specific T lymphocytes in the lung () and MeLNs (). Lung or MeLN cells were collected from mice 4 d after the boost. Lymphocytes were gated based on their forward scatter (FSC) versus side scatter (SSC) profile. Intracellular staining for IFN-γ was performed after surface staining of! CD4 and CD8 molecules. The profiles shown are representative ! of five mice from three separate experiments. Numbers indicate percentages of IFN-γ–producing T lymphocytes from gated CD4+ and CD8+ T cells. * Figure 3: FcRn-targeted mucosal immunization provides protective immunity to intravaginal challenge with virulent HSV-2 186. () Mean survival following genital HSV-2 challenge. Four weeks after the immunization, groups of five mice were challenged intravaginally with 1 × 104 p.f.u. of HSV-2 strain 186. Percentage survival on the indicated days is calculated as the number of mice surviving divided by the number of mice in each group and represented three similar experiments. () Mean of viral titers following HSV-2 challenge. Virus titers were measured from vaginal washes by taking swabs on the indicated days after HSV-2 inoculation based on a plaque assay on Vero cell monolayers. () Increased presence of HSV-specific T lymphocytes in the vaginal epithelium after challenge. Lymphocytes were harvested from collagenase-digested vaginal tissues 4 d after intravaginal inoculation with virus. Intracellular staining for IFN-γ expression on CD4+ and CD8+ T cells was analyzed after gating on viable CD3+ lymphocytes. The numbers in each column show the percentage of IFN-γ–positive T lymphocytes from the! gated CD4+ or CD8+ T cells. Data shown are representative of three experiments, using three mice per experiment. * Figure 4: Increased memory immune response in FcRn-targeted mucosal immunization. () Induction of gD-specific memory B cells in the spleen. The frequency of gD-specific memory B cells was assessed 6 months after the boost. Memory B cells, defined as B220+ gD-surface+, were analyzed 6 months after the boost by FACS. Purified gD proteins were labeled with Alexa Fluro647. Spleen cells (2 × 106) were incubated with the 1 μg Alexa Fluro647-labeled gD proteins and B220 antibody. Numbers in the quadrants are the percentage of gD-specific memory B lymphocytes. () Long-lived HSV gD-specific antibody-secreting cells in the bone marrow. Bone marrow cells (BMC) removed 6 months after the boost were placed on gD-coated plates and quantified by ELISPOT analysis of IgG-secreting plasma cells. Data were pooled from two separate experiments with five mice in each experiment. The graphs were plotted based on the average ELISPOT for replicate wells. Values marked with asterisks are significantly greater (P < 0.01) from the gD-Fc/wt protein-immunized mice than those of oth! er groups as indicated. () Durability of HSV-2 gD-specific serum IgG response. In two separate experiments, HSV-2 gD-specific IgG was quantified by ELISA in serum by endpoint titer from five mice at 6 months after the boost. HSV-specific IgG antibody was not detected in PBS-immunized mice. () Long-lived gD-specific T cell memory to FcRn-targeted mucosal vaccination. Spleen cells were isolated from the immunized mice 6 months after the boost, stained with CFSE and stimulated in vitro with 20 μg/ml of purified gD for 4 d. Data are expressed in CFSE histograms of fluorescence intensity versus the number of fluorescing cells, indicating the percentage of the cell population positive for CD4 and CD8 antigen. Numbers in the quadrants are the percentage of CD4+ and CD8+ proliferating T cells. Representative flow cytometry profiles of two similar experiments with three mice per group are shown. Immunization conditions are displayed on the top. () Mean survival following genital HS! V-2 challenge 6 months following the boost. The immunized mice! were challenged intravaginally with 1 × 104 p.f.u. of HSV-2. Percentage of mice protected on the indicated days is calculated as the number of mice surviving divided by the number of mice in each group (n = 5). () Proposed model of FcRn-mediated mucosal vaccine delivery. The Fc-fused antigens are transported by FcRn and targeted to the mucosal antigen-presenting cells (APC), such as dendritic cells. Antigen is taken up by pinocytosis or FcγRI-mediated endocytosis in APCs, then processed and presented to T cells. Author information * Author information * Supplementary information Affiliations * Laboratory of Immunology, Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, USA. * Lilin Ye, * Rongyu Zeng, * Yu Bai & * Xiaoping Zhu * The Jackson Laboratory, Bar Harbor, Maine, USA. * Derry C Roopenian * Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. * Xiaoping Zhu Contributions L.Y. and X.Z. designed and performed experiments, analyzed data and wrote the paper. R.Z. and Y.B. conducted experiments. D.C.R. interpreted data and made editorial suggestions. Competing financial interests The authors declare no competing financial interests. Corresponding author Correspondence to: * Xiaoping Zhu Author Details * Lilin Ye Search for this author in: * NPG journals * PubMed * Google Scholar * Rongyu Zeng Search for this author in: * NPG journals * PubMed * Google Scholar * Yu Bai Search for this author in: * NPG journals * PubMed * Google Scholar * Derry C Roopenian Search for this author in: * NPG journals * PubMed * Google Scholar * Xiaoping Zhu Contact Xiaoping Zhu Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (1M) Supplementary Figs. 1–10 Additional data - Regulation of transcription by unnatural amino acids
- Nat Biotech 29(2):164-168 (2011)
Nature Biotechnology | Research | Letter Regulation of transcription by unnatural amino acids * Chang C Liu1, 2 * Lei Qi1 * Charles Yanofsky3 * Adam P Arkin1, 4, 5 * Affiliations * Contributions * Corresponding authorsJournal name:Nature BiotechnologyVolume: 29,Pages:164–168Year published:(2011)DOI:doi:10.1038/nbt.1741Received23 July 2010Accepted01 December 2010Published online16 January 2011 Article tools * Full text * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg Small-molecule regulation of gene expression is intrinsic to cellular function and indispensable to the construction of new biological sensing, control and expression systems1, 2. However, there are currently only a handful of strategies for engineering such regulatory components and fewer still that can give rise to an arbitrarily large set of inducible systems whose members respond to different small molecules, display uniformity and modularity in their mechanisms of regulation, and combine to actuate universal logics3, 4, 5, 6, 7, 8. Here we present an approach for small-molecule regulation of transcription based on the combination of cis-regulatory leader-peptide elements with genetically encoded unnatural amino acids (amino acids that have been artificially added to the genetic code). In our system, any genetically encoded unnatural amino acid (UAA) can be used as a small-molecule attenuator or activator of gene transcription, and the logics intrinsic to the network def! ined by expanded genetic codes can be actuated. View full text Figures at a glance * Figure 1: A representative molecular recognition network of expanded genetic codes, its integration with cis-regulatory leader-peptide elements and some possible uses of this platform. Solid lines signify productive recognition between the connected components. The UAA-specific aaRS/tRNA pairs represented in this figure are the result of efforts to expand the genetic codes of organisms. This has lead to the successful encoding of ~70 UAAs that encompass a wide range of chemical structures. As we do not discuss the expanded genetic code field in detail, please refer to reference 11. * Figure 2: Behavior of UAA-controlled transcriptional switches. Fluorescence of cells grown in the presence or absence of para-acetylphenylalanine (5 mM) is shown. GFP expression is shown in background-subtracted relative fluorescence units (RFUs) normalized to optical density (OD); excitation at 485 nm, emission at 510 nm. Background autofluorescence was determined by measuring the RFU/OD of similarly grown cells containing plasmid pCCL-000, a control plasmid that does not encode GFP. Experiments were conducted in triplicate (error bars are ± s.d.) on the same day. Data were collected using a fluorescence plate reader (Online Methods). () Transcriptional OFF switch. () Transcriptional ON switch. * Figure 3: Control of transcriptional OFF and transcriptional ON switches with multiple UAAs. GFP expression is shown in background-subtracted relative fluorescence units (RFUs) normalized to optical density (OD); excitation at 485 nm, emission at 510 nm. Background autofluorescence was determined by measuring the RFU/OD of similarly grown cells containing plasmid pCCL-000, a control plasmid that does not encode GFP. Experiments were conducted in triplicate (error bars are ± s.d.) on the same day. Data were collected using a fluorescence plate reader (see Online Methods). (,) Fluorescence of cells grown in the presence or absence of para-azidophenylalanine (1 mM), 4-boronophenylalanine (1 mM) or para-iodophenylalanine (1 mM). () NOR behavior: cells containing pCCL-006 and pEVOL-Dual-pAcF/pAzF grown in the absence of UAAs, presence of para-acetylphenylalanine (5 mM), presence of para-azidophenylalanine (5 mM), or presence of para-acetylphenylalanine (2.5 mM) and para-azidophenylalanine (2.5 mM). See Supplementary Figure 6a for a mechanistic schematic. () OR behavior:! cells containing pCCL-016 and pEVOL-Dual-pAcF/pAzF grown in the absence of UAAs, presence of para-acetylphenylalanine (5 mM), presence of para-azidophenylalanine (5 mM), or presence of para-acetylphenylalanine (2.5 mM) and para-azidophenylalanine (2.5 mM). See Supplementary Figure 6b for a mechanistic schematic. Author information * Author information * Supplementary information Affiliations * Department of Bioengineering, University of California at Berkeley, Berkeley, California, USA. * Chang C Liu, * Lei Qi & * Adam P Arkin * Miller Institute for Basic Research in Science, Berkeley, California, USA. * Chang C Liu * Department of Biological Sciences, Stanford University, Stanford, California, USA. * Charles Yanofsky * Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. * Adam P Arkin * QB3: California Institute for Quantitative Biological Research, University of California at Berkeley, Berkeley, California, USA. * Adam P Arkin Contributions C.C.L. conceived of the study and C.Y. and A.P.A. advised. All authors were involved in designing the experiments. C.C.L. and L.Q. performed the experiments and interpreted the data. C.C.L. and A.P.A. wrote the manuscript. All authors discussed results and commented on the manuscript. Competing financial interests The authors declare no competing financial interests. Corresponding authors Correspondence to: * Chang C Liu or * Adam P Arkin Author Details * Chang C Liu Contact Chang C Liu Search for this author in: * NPG journals * PubMed * Google Scholar * Lei Qi Search for this author in: * NPG journals * PubMed * Google Scholar * Charles Yanofsky Search for this author in: * NPG journals * PubMed * Google Scholar * Adam P Arkin Contact Adam P Arkin Search for this author in: * NPG journals * PubMed * Google Scholar Supplementary information * Author information * Supplementary information PDF files * Supplementary Text and Figures (5M) Supplementary Discussion, Supplementary Sequences, Supplementary List of Plasmids and Supplementary Figs. 1–6 Additional data - Fourth-quarter biotech job picture
- Nat Biotech 29(2):169 (2011)
Nature Biotechnology | Careers and Recruitment Fourth-quarter biotech job picture * Michael Francisco1Journal name:Nature BiotechnologyVolume: 29,Page:169Year published:(2011)DOI:doi:10.1038/nbt.1778Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. 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 * Michael Francisco is a Senior Editor at Nature Biotechnology Author Details * Michael Francisco Search for this author in: * NPG journals * PubMed * Google Scholar Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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 - People
- Nat Biotech 29(2):170 (2011)
Nature Biotechnology | Careers and Recruitment | People People Journal name:Nature BiotechnologyVolume: 29,Page:170Year published:(2011)DOI:doi:10.1038/nbt.1781Published online07 February 2011 Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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. (below, right) has been appointed CEO of Orexo (Uppsala, Sweden), succeeding . Lundström joins the company from Biogen Idec, where he was most recently head of that company's hemophilia unit. He previously served as head of Biogen Idec's international commercial operations, responsible for worldwide sales and marketing. "Orexo has been successful in developing commercially attractive products. This was most recently demonstrated by the US approval of Abstral (fentanyl). Orexo also has significant partnerships with Boehringer Ingelheim, Ortho-McNeil Janssen and Janssen Pharmaceutica, and Novartis. I am looking forward to leading the company through its next stage, in building a competitive product portfolio that we can commercialize on our own in Europe or the US," says Lundström. Cephalon (Frazer, PA, USA) has announced the passing of company cofounder, chairman and CEO , from leukemia on December 16, 2010. Baldino was a biotech industry pioneer who helped found Cephalon in 1987. He had been on a leave of absence for medical reasons since August 2010. To succeed him, Cephalon's board of directors has appointed as CEO and a member of the company's board. The board will address the role of company chairman in the future. Buchi, who has been with Cephalon for almost 20 years, assumed day-to-day chief executive responsibilities for the company in August while serving as COO and CFO. ShangPharma (Shanghai) has named as CFO. , ShangPharma's CFO and COO, will become president and COO. Dai previously served as CFO of China Nepstar Chain Drugstore, and CFO and vice chair of the executive committee at MicroPort Medical Co. Genelux (San Diego) has appointed president, succeeding company founder , who will continue to serve as CEO and chairman of the board. Most recently, Devlin served as vice president at Abbott Laboratories, where she led global pipeline marketing for all therapeutic areas. has been elected to Alkermes' (Waltham, MA, USA) board of directors. She has more than 30 years of experience in the biopharmaceutical industry, most recently serving as chief marketing officer and president of global marketing for Bristol-Myers Squibb. Cardioxyl Pharmaceuticals (Chapel Hill, NC, USA) has announced the appointment of as chief medical officer. Gilbert served most recently in the same capacity at Archemix, and was previously vice president of clinical development, cardiovascular/inflammation at Millennium Pharmaceuticals. has been appointed vice president of business development at Momenta Pharmaceuticals (Cambridge, MA, USA). He was most recently senior director, business development at Biogen Idec, and before that, he identified and invested in early-stage life science companies at Advanced Technology Ventures. Optimer Pharmaceuticals (San Diego) has appointed to its board of directors. Formerly chairman and CEO of Pfizer, McKinnell is currently chairman of the Accordia Global Health Foundation, an organization dedicated to fighting infectious diseases in Africa, and is a member of the boards of Moody's, Angiotech Pharmaceutical and Emmaus Medical. Affymax (Palo Alto, CA, USA) president has been selected to succeed as CEO and a member of the board of directors. Morris will remain a consultant to Affymax until September 2011. has joined venture capital firm Advent Venture Partners (London) as a partner. Pfost has more than 25 years of experience as a life science entrepreneur and CEO, including serving as founding CEO and chairman of Orchid BioSciences, founding CEO and chairman of Acuity Pharmaceuticals, cofounder and CEO of Oxford GlycoSciences and CEO of Receptor BioLogix. AiCuris (Wuppertal, Germany) has named chief medical officer. She has over 24 years of experience in the pharmaceutical industry, including stints as vice president of clinical development at Sanofi Pasteur France and senior director for anti-infectives at GlaxoSmithKline in the UK. Crescendo Biologics (Cambridge, UK) has named as CEO. Romanos has been CSO of the company since May 2009, after spending the last ten years holding senior global positions leading major parts of GlaxoSmithKline's discovery unit. has been appointed vice president and chief business officer of Topaz Pharmaceuticals (Horsham, PA, USA). Most recently, he served as chief business officer of Trevena. has been appointed CFO of Epigenomics (Berlin) effective April 1, 2011, succeeding . Taapken joins the company from Biotie Therapies, where he has served as CFO since 2008. Previously he was an investment partner at DVC Deutsche Venture Capital and Burrill & Company. Trius Therapeutics (San Diego) has named (right) to the newly created role of chief commercial officer. Thompson has more than 18 years of pharma marketing and sales experience. Before joining Trius, he was vice president of marketing for Pfizer's specialty care business unit. View full text Read the full article * Instant access to this article: US$32Buy now * Subscribe to Nature Biotechnology for full access: SubscribeLogin for existing subscribers Additional access options: * Use a document delivery service * Rent this article from DeepDyve * Login via Athens * Purchase a site license * Institutional access * 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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