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- Unbottling the genes
- Nature Biotechnology 27(12):1059 (2009)
The ability to plug and play synthetic genes into minimized genomes promises to transform biological engineering.
- Federal stimulus adds momentum to sequencing stampede
- Nature Biotechnology 27(12):1061-1062 (2009)
Introduction The biomedical research community will soon see nearly $10 billion in new funding pouring into laboratories courtesy of the Obama administration's decisions over how to spend funds authorized as part of the American Recovery & Reinvestment Act (ARRA) of 2009 stimulus package. Suppliers of reagents, arrays and sequencing instruments are likely to receive a substantial boost from this cash injection at the US National Institutes of Health (NIH), which amounts to almost $1.5 billion earmarked for genomics research. Although a fraction of the funds will go directly to companies, the great bulk of funding is going to their clientele—researchers at academic and medical institutes. Thus, many companies foresee a bumper year in sales of sequencing and genomics technologies. "The NIH budget went down prior to the stimulus, and there was a general pall over the community," recalls Clifford Reid, who is chairman, president and CEO of Complete Genomics in Mountain View, California. "The stimulus package completely reversed that mood from grave concern to great optimism. This is a big deal for us." Federal ARRA funds affect companies doing genomics in several ways. The first and most direct is that a few companies are being awarded substantial funds to advance specific sequencing technologies (Table 1). For instance, this October the National Human Genome Research Institute (NHGRI) at NIH awarded $2.9 million to Helicos BioSciences in Cambridge, Massachusetts, to improve its single-molecule sequencing technology and $1.9 million to Pacific Biosciences of Menlo Park, California, to pursue its development of single-molecule sequencing as well as its specific, single base pair, DNA methylation sequencing analysis. "It's a nice grant, and it helps," says Helicos president Steve Lombardi. "But it's minor compared to what our customers received—they have the bigger part of it." For instance, deans at medical schools are now thinking about buying sequencing technology, he adds; in the previous financial climate, such technology was prohibitive in cost for many institutions. Though the instrumentation is still onerous, the newly funded research programs back the sequencing approach to studying disease. Ordinary grants and stimulus money from NHGRI and "virtually all the other institutes" within NIH are expanding genomic sequencing programs into "more applied, medical bellwether" areas, he says. "It's a perfect time from our perspective. We're the first out of the gate with third-generation technology." "The grants have an impact on the field; that's certainly true," says Steve Turner, founder and chief technology officer for Pacific Biosciences. But he views the "ripple effect" as far more important. "The Administration was savvy in emphasizing this strong shot for American technology development, and sequencing and genomics will be a strong economic driver—with estimates of it being a $50-billion market within a decade. Pacific Biosciences will benefit directly as this expanding ripple heats the field generally." Another slightly less-direct component of the ARRA package delivers funding to researchers in academic settings who work closely with particular companies and tend to license specific breakthroughs very quickly to their corporate partners, according to Jeffrey Schloss, program director of technology development at NHGRI. Thus, for example, $1.8 million in stimulus funds going to researchers at the University of California, Santa Cruz, and to Harvard University in Cambridge, Massachusetts, will support projects to develop nanopore-based sequencing technologies, with another $1.7 million slated for a team at Arizona State University in Tempe. Although this sequencing approach is not yet available commercially, Oxford Nanopore Technologies in Oxford, UK, is working in that direction and is expected to benefit from these and other grants that are part of the stimulus package, Schloss says. Similarly, a $2.5-million grant for developing an electron microscopy–based approach for sequencing DNA molecules will directly support George Church and his group at Harvard Medical School in Boston, but is likely also to benefit Halcyon Molecular, a sequencing startup near San Francisco. The stimulus is also stirring up excitement among investors in the life-sciences tool space, says Marshall Urist, a vice president for Morgan Stanley Research in New York. "This sector can expect large inflows over the next few years, and the stimulus is an important part of that," he adds. In the short term, there are questions as to which institutions will most benefit from ARRA funds, and there is also a built-in lag with grant reviews and spending that will play out over several years, he adds. Spending for instruments and similar equipment is on a relatively fast track, and companies like Waltham, Massachusetts–based ThermoFisher Scientific and Life Technologies in Carlsbad, California, are bellwethers, Urist says. For companies selling "consumables," such as reagents, business will "gain speed and gather steam more slowly." Many of these companies "were hot without the stimulus," and "some large projects were attracting funding anyway," he adds. "Yet, the net benefit will be positive." Instrument sales first, reagents later—that is indeed the early pattern that has followed the stimulus package announcement, according to Greg Lucier, chairman and CEO of Life Technologies, and Bernd Brust, president and chief commercial operations officer, who described how federal stimulus funds are affecting their business during a third-quarter earnings call. "To capture that revenue, we are bringing in a significant number of additional sales resources in the US next year [to] focus on larger academic accounts that are the recipients of these funds," Brust says. In terms of the purchasing being done by academic or comparable sequencing centers, 454 Life Sciences, a division of Roche, in Branford, Connecticut; Illumina in San Diego; and Applied Biosystems, a division of Life Technologies, are currently the three biggest players, with Helicos BioSciences and Pacific Biosciences, likely filling the next tier, according to Schloss, who is careful not to endorse any particular commercial approach. "The Institute's [NHGRI] goal is to see [that] these technologies are developed and useful, and we are agnostic as to whether it's by academics or companies," Schloss says. If a promising technology "is being commercialized, we don't want to stand in the way." "I am not sure the stimulus money will have any differential effect on the companies, but it certainly will add a few extra orders into their systems," says Jonathan Eisen of the Genome Center at the University of California, Davis. "That would not have happened otherwise. But as for which ones get the money, that will still come down to which ones are better." Another important point is that the stimulus package is "democratizing sequencing" Schloss says, such that "producing sequence data is no longer a bottleneck." An expert panel recently recommended that NHGRI "fund larger numbers of smaller centers, and we're using the stimulus money to do some of that. In the early days, genome centers chose one of two [commercial sequencing] platforms, but we're not seeing that now. It's still volatile, but it is a good thing to see diversity and competition." ADVERTISEMENT "We sell data, not instruments," says Complete Genomics's Reid. The company tracks grant proposals, reconnecting with potential clients once projects are funded and sequencing expertise and services are sought. "We anticipated that many of those funded proposals will turn into projects for us to drive our very large sequencing center and to grow our business," he says. Although it is too "early for us to measure in terms of transactions, the numbers of grants we read give us a lot of confidence that we should continue to invest and expand." The stimulus money will probably trigger a buying spree, as the lag between submission and funding of NIH research proposals has shrunk. This accelerated buying could, however, strain some companies to meet customer demand. "We're going to double the size of our group," says Reid. "Stimulus or no stimulus, it puts our company in the position of satisfying orders, our biggest challenge for 2010 when we release our first product. But you'll hear no complaints from me on this."
- ARRA boosts cancer programs but impact on personalized medicine unclear
- Nature Biotechnology 27(12):1062 (2009)
Introduction The cancer field is poised to thrive under ARRA, but support for diagnostic firms that could further the goal of personalizing cancer therapeutics has been less forthcoming. According to the Office of the Director, the National Cancer Institute received $1.26 billion of the NIH's ARRA monies, including $731 million in grants, $494 million in R&D contracts for the academic community, $6 million for intramural funding and $25 million of support. Eighteen of the 37 challenge grants NCI sent to NIH are being funded to the tune of $17.7 million; plus NIH is putting up $38 million to cover 41 additional high-priority NCI grants. There's also $36 million going to fund 37 early-phase clinical trials of compounds that, according to NCI director John Niederhuber, "we hope will soon expand our ability to provide targeted, personalized medicine." Nonetheless, according to some observers, ARRA's impact on personalized medicine and cancer treatment, where the bulk of such research is focused, could be greater. One reason is the holdup in the anticipated change to the Small Business Innovative Research (SBIR) program that would allow a flow of ARRA funds to venture capital–backed companies (see page 1065). Notes David Parkinson, CEO of Nodality in S. San Francisco, California, "Anticipating that the law would change, we applied for an SBIR grant, negotiated a budget, but then had to withdraw from what would have been an award because of the failure of Congress to reconcile the SBIR law." ADVERTISEMENT Even more importantly, diagnostics companies like Nodality, which is using flow cytometry to measure many signaling pathways concurrently to gain greater insight into why individuals respond or don't respond to particular therapeutic approaches, are not yet on the radar screen of policy makers. "Largely because the diagnostics companies have not been at the table, there's been little discussion of how to help the application of these new technologies to patient characterization," Parkinson says. "Much of the allocation of stimulus money from NCI was for support of upstream biology, such as genomic sequencing. I thought there would be value to looking strategically at the application of this kind of funding to the downstream interface between all this new biology and information." That view is echoed by Stephen Friend, the founder of Sage, a not-for-profit initiative located in Seattle that is developing biological networks to model disease across tissues and organs. There's nothing in the NIH system or in pharma, he suggests, that advances the Obama administration's goal of ascertaining who's getting what care and whether that care is working. "I feel there is still a real opportunity for the government to increase transparency in the care of patients. Not just for us or for companies like Nodality. There's a real interest that hasn't been tapped and, more importantly, hasn't been funded."
- Brazil and India access pharma vaccine know-how
- Nature Biotechnology 27(12):1063-1064 (2009)
Introduction Two innovative tech transfer initiatives in Brazil and India promise to provide these countries with access to state-of-the-art technologies and expertise, spurring local vaccine R&D. Brazil's major vaccine producer, the state-owned Oswaldo Cruz Foundation (known as Fiocruz), of Rio de Janeiro, has entered a tech transfer deal with London-based GlaxoSmithKline (GSK), which will enable local researchers to produce GSK's Synflorix pneumococcal vaccine as well as develop vaccines against dengue fever, yellow fever and malaria. In India, Merck of Whitehouse Station, New Jersey, and the London-based charity Wellcome Trust will invest equally in a not-for-profit joint venture focused on developing affordable vaccines for diseases that commonly affect developing countries. The MSD Wellcome Trust Hilleman Laboratories (MWTHL) will be set up near New Delhi with a combined cash contribution of $130 million over seven years, with the focus on vaccine R&D, taking projects to proof-of-co! ncept stage. Though the GSK-Fiocruz deal was announced in September by Brazil's health minister, José Temporão, and GSK's CEO, Andrew Witty, the contract was originally signed back in August 2008 by Fiocruz's president, Paulo Gadelha, and the senior vice president for global clinical R&D and chief medical officer of GSK Biologicals, Thomas Breuer. The deal builds on decades of experience at the state-owned Fiocruz in negotiating tech transfer agreements, starting in 1937, when Fiocruz first signed a deal with The Rockefeller Foundation in New York to locally produce yellow fever vaccines (today, Brazil provides 80% of the world's supply). Vaccines against meningococcus types A and C produced by Fiocruz's technical-scientific unit, the Immunobiologicals Technology Institute in Rio de Janeiro (Bio-Manguinhos), which develops vaccines, reagents and diagnostic kits, have also originated from research spurred by technology acquired from the French Mérieux Institute in Paris in the 1970s. Later deals with the Japanese Biken Institute of Osaka University and the Japan Poliomyelitis Research Institute in Tokyo have helped Fiocruz build expertise in both measles and polio vaccinology. In addition, Bio-Manguinhos currently produces vaccines against Haemophilus influenzae type B, diphtheria, tetanus, whooping cough and measles/! mumps/rubella. "Whenever there is a gap in the development of technology, we try to use the buying power of the state to be able to develop products, like vaccines and diagnostic kits, quicker than the market would," says Artur Roberto Couto, director of Bio-Manguinhos. "The pneumococcal vaccine is a brand new one, it is new technology, which knocks down the idea that companies would only transfer old technology," he adds. The 1.5 ($2.2) billion contract calls for Brazil to commit to first buy, and later produce, the pneumococcal vaccine over a period of roughly eight years. This will provide GSK with an entry into the large Brazilian market, with the bonus that the deal spans a much longer period than is customary for vaccines, and also preempts losing to rival low-cost generic vaccines. For Brazil, the deal entitles locals to purchase the vaccine at a discount price, which will continue to fall over time. The price starts at 11.50 ($17) a dose and should drop to 5 ($7.50) in the final years (in Europe the vaccine sells for 35–40 ($52–60) a dose). The Bio-Manguinhos director stresses that the terms of the partnership deal were paramount in choosing to close the deal with GSK and not another vaccine maker. Brazilian personnel have already gone to GSK Biologicals in Rixensart, Belgium, to become acquainted with the production facilities so that they can plan space and equipment needs in their Rio de Janeiro facility. The deal calls for Brazil to establish local production for Synflorix, a 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine. "Two of the serotypes—1 and 5—are particularly widespread in Brazil," says Antonio Barbosa, vice director for production at Bio-Manguinhos. "It is the most complex vaccine in the world today in technological terms," he adds. "Each of the ten conjugate components involve a complex manufacturing process," says Marcos Freire, vice director for technological development at Bio-Manguinhos. It is also hoped that the partnership will extend beyond pneumococcal vaccine to the development of other vaccines. For example, Brazil currently faces a widespread epidemic of dengue fever, with insect vectors and infections in all of the federation's states. Although GSK will benefit from access to the huge Brazilian market, local scientists anticipate benefits in terms of transfer of technological expertise and knowledge. "The dengue vaccine will give us the know-how of doing technological development, things like antigen selection, quality control, or even keeping books and documents," says Freire. If development proceeds as planned, human trials of the dengue vaccine could begin in 2012. GSK and Fiocruz will share any patents. Likewise, the tech transfer deal might extend to a vaccine against malaria or the development of a new yellow fever vaccine (the current vaccine for which is over 70 years old and has been associated, albeit rarely, with serious adverse events). GSK is already testing in Africa a malaria vaccine against Plasmodium falciparum, the common etiological agent of African malaria. Fiocruz would like to be a partner in a version that could target the more prevalent plasmodium species causing the disease in Brazil: Plasmodium vivax. "Ideally, a vaccine should target both [species]," says Freire Technology transfer and the use of local expertise in vaccine production is also a focus of the Indian not-for-profit joint venture announced by Wellcome and Merck. As Altaf Lal, MWTHL's CEO, points out, the goal of the new venture is to leverage local skills, not to compete. Indeed, most local firms are supportive of the venture. Rajesh Jain, joint managing director of Panacea Biotec in New Delhi says, "We do not expect competition as the Hilleman Lab intends to deliver products for diseases where the big pharma companies do not focus." Varaprasad Reddy, managing director of Hyderabad-based vaccine manufacturer Shantha Biotech, recently acquired by Paris-based Sanofi-Aventis (Nat. Biotechnol. 27, 879, 2009), is also upbeat: "We have to applaud their initiative." Virologist Jacob John of the Christian Medical College in Vellore hopes MWTHL will actually galvanize local vaccine research. "If my reading is correct, they would go for vaccines requiring new technologies. In that case, they will fill gaps rather than duplicate." He says India needs affordable pneumococcal conjugate vaccine and vaccines for dengue, malaria and tuberculosis. Although India currently produces and exports many vaccines, none was developed within the country, except a version of the recombinant hepatitis B vaccine developed by Shantha, admits Govindarajan Padmanabhan, a biochemistry professor at the Indian Institute of Science in Bangalore. "Indian biotech companies do not usually invest to develop a new vaccine unless success is ensured," says K.N. Vinayak, president of biopharmaceuticals research at Panacea. Once MWTHL develops a vaccine to proof-of-concept stage, the business model is that a local Indian biotech firm will take it forward on the understanding that the vaccine will be sold at an affordable price, he says. Some, including Sanjay Singh, who left the US National Institutes of Health to head Gennova Biopharmaceuticals in Pune, are skeptical. "India is already producing world-class vaccines at affordable cost and Sanofi's acquisition of Shantha Biotech proves this," he says. It is also unclear to Singh whether the MWTHL will help introduce new technologies into local vaccine firms. Sujay Shetty, associate director of the pharmaceutical and life sciences practice at PriceWaterhouseCoopers in Bangalore, says that Wellcome's presence means that discoveries made in MWTHL will be open source and available to other firms. The MWTHL facilities are slated to open by March 2010 and are expected to attract further corporate partners. Krishna Ella, CEO of Hyderabad-based Bharat Biotech, is also skeptical about inexpensive vaccines but says the joint venture will definitely boost research on vaccines for neglected diseases. ADVERTISEMENT More not-for-profit deals like that of Merck and the Wellcome Trust are likely to be emulated. In fact, Gennova and PATH-Malaria Vaccine Initiative in Bethesda, Maryland, have already created a dedicated facility in Pune to manufacture promising recombinant protein–based malaria vaccines for testing in clinical trials. According to Bhan, the Indian government's Department of Biotechnology in New Delhi is engaged in partnership with the Seattle-based Bill and Melinda Gates Foundation, PATH and others to develop a rotavirus and malaria vaccine. Discussions are also taking place with the New York-based, International AIDS Vaccine Initiative for a joint venture in India. In the meantime, Indian Department of Biotechnology secretary Maharaj Kishan Bhan remains guardedly optimistic about MWTHL. "We welcome it because its intention is to develop and promote affordable health technology. Only time will tell how successful this venture is, but in our view, the Merck-Wellcome joint venture is a positive step."
- Gates pours cash into agriculture
- Nature Biotechnology 27(12):1064 (2009)
Introduction The Bill and Melinda Gates Foundation has announced $120 million in grants to promote sustainable agriculture, a move intended to spur another Green Revolution, this time tailored to the needs of the poorest farmers. The Foundation will support crop research and agricultural projects that increase productivity and food security in low-income countries. The nine new grants announced in October, which will focus on homegrown crops from sub-Saharan Africa and South Asia, include $18 million for developing high-yielding varieties of sorghum and millet, $21 million for developing stress-tolerant sweet potatoes and $19 million to improve nitrogen fixation in legumes, such as soybean and cowpea. "The foundation believes that helping the poorest smallholder farmers grow more and get it to market is the world's single most important lever for reducing hunger and poverty. We're taking a comprehensive approach—from investing in improved seeds to supporting effective farm management! practices," says Lawrence Kent, senior program officer for the Gates Foundation's agricultural development initiative. Kent adds that biotech will be used where it has the potential to help farmers confront drought, flooding, disease or pests faster or more effectively than conventional breeding alone does—roughly 5% of the total funds. Seeds developed through foundation-supported research will be licensed royalty-free to seed distributors so that they can be sold to African farmers without extra charge. Although better known for its investments in health, the Gates Foundation has donated over $1.2 billion to agricultural development efforts since 2006 as part of its ongoing global development program, with a third of those funds designated for "science and technology." One of the current grantees is the African Agricultural Technology Foundation (AATF), based in Nairobi, Kenya, which last year launched its $48 million public-private partnership project, water-effi! cient maize for Africa, to develop new varieties of drought-to! lerant maize. Field trials are expected to start next year. St. Louis-based Monsanto, one of the project partners, is providing germplasm produced by conventional breeding, as well as a molecular breeding platform and drought-resistant transgenes. "If we were to start from zero, without any materials that had been bred and focused towards drought, normal plant breeding would take about ten years. Here we are getting materials which are already almost proven," says AATF's executive director, Daniel Mataruka.
- Congress punts on SBIR reauthorization
- Nature Biotechnology 27(12):1065-1066 (2009)
Introduction Efforts to reform and reauthorize the Small Business Innovative Research (SBIR) and related Small Business Technology Transfer (STTR) programs have failed, at least for now, leaving biotech companies unsure whether they will continue to qualify for this source of early-stage funding. The programs have been on the verge of permanent expiration since September 2008, when their statutory authority ran out, and they've been living hand-to-mouth via a series of continuing resolutions intended to give Congress time to enact formal reauthorization. The fifth such extension came in late October, continuing the programs to January 30, 2010. Created in 1982, the SBIR program provides grants to small, for-profit businesses through a portion of the extramural research budgets of 11 US government agencies, most notably the National Institutes of Health in Bethesda, Maryland, and the Department of Defense (DoD) in Washington, DC. Tangible progress was made this past July, when both houses of Congress passed reauthorization bills (S. 1233 and H.R. 2965). But the two bills differ significantly, and legislators haven't been able to craft a single compromise bill that can be signed into law. One of the chief controversies between the two bills concerns the involvement of venture capital–backed companies in the SBIR program. Since 2003, many small businesses that are majority owned by venture capital firms (as many young biotechs are) were prohibited from receiving SBIR grants under the assertion that these businesses do not qualify as 'small'. Since its inception the SBIR program has enabled federal agencies to award grants to small businesses defined as having fewer than 500 employees. Although the Senate bill would loosen those restrictions somewhat, the House version, favored by organizations such as the Biotechnology Industry Organization (BIO) and the National Venture Capital Association, both located in Washington, DC, would essentially lift all limits. BIO, in particular, has been outspoken on the issue. "We believe these innovations should be judged on the science and not the capital structure," says Ellen Dadisman, a spokeswoman at BIO. Advocacy groups like the National Small Business Association in Washington, DC, on the other hand, note that many venture-backed companies already do qualify for the program—either because they are not majority owned by venture capitalists or because the majority owner has fewer than 500 total employees in its portfolio of companies—and that limits are necessary to assure that grants go to legitimate small businesses rather than, for example, subsidiaries and spin-outs of large corporations. Another element of the House bill that would affect biotechs increases grant awards while allowing agencies to skip earlier phase 1 programs and proceed directly to larger phase 2 grants. Such a provision could lead to fewer, richer grants and cut off a source of early-stage capital to companies too small to receive traditional venture investment, suggests Jere Glover, executive director of the Small Business Technology Council, an arm of the National Small Business Association, who calls eliminating the phase 1 requirement "risky and dangerous." ADVERTISEMENT The level of disagreement on these issues caused the House and Senate Armed Services committees to attempt to independently reauthorize the DoD portions of the SBIR, STTR and Commercialization Pilot programs, the latter of which is intended to advance mature SBIR projects, for a period of 14 years. But disputes over jurisdiction on the programs limited the DoD portions to a one-year extension, through September 30, 2010. Observers noted that the attempted reauthorization of the DoD sections was adopted in the Senate rather than the House version of the bill, but it's unclear whether that will carry any weight in the ongoing debate. The actions of the Armed Services committees do, however, make it clear that the program, at least in some form, has a future. "If it's not reauthorized within the next year by the small business and science committees, then I think you'll see DoD doing it on its own," says Glover.
- Epigenomic colon cancer kit
- Nature Biotechnology 27(12):1066 (2009)
Introduction A blood-based epigenetic test for colon cancer has been launched in Europe, a diagnostic tool that could boost screening compliance and lead to significant cost savings. The Epi proColon test from Berlin-based Epigenomics detects methylation patterns in cell-free DNA in blood plasma. The assay converts all nonmethylated cytosine residues into thymine followed by PCR, which amplifies a region of the gene septin 9—specifically methylated in colon cancer—for quantitative assessment. The company hopes that its noninvasive assay is easier to use than stool-based fecal occult blood tests (FOBTs), currently the mainstay for early detection, but it does not see it replacing colonoscopy for a definitive diagnosis. The test is the first epigenetic diagnostic to be sold as a kit to laboratories; other epigenetic-based tests on the market, including cancer diagnostics and a test to predict how brain-tumor patients will respond to treatment, are run in the diagnostics makers' laborat! ories. The Epi proColon test, which consistently identifies 70% of cancers, could potentially lead to significant savings for healthcare providers by reducing screening costs and the cost of treating advanced cancers. But Durado Brooks, director of prostate and colorectal cancers at the American Cancer Society in Atlanta, has his concerns. "If it has to be done on a population basis once a year, frankly there's going to be no cost savings whatsoever," he said, citing cheaper annual FOBT and decadal colonoscopy costs.
- GSK adopts antisense
- Nature Biotechnology 27(12):1066 (2009)
Introduction GlaxoSmithKline (GSK)'s recent collaboration with Prosensa on therapeutics for Duchenne muscular dystrophy (DMD) is another sign that large pharma is willing to focus on niche markets. DMD is a childhood neuromuscular disease caused by a mutation in the dystrophin gene, the normal product of which is necessary for proper muscle formation. It affects 1 in 3,500 newborn boys, causing muscle weakness that often leads to respiratory or cardiac failure. Under the alliance, announced in October, GSK licenses Leiden, The Netherlands–based Prosensa's PRO051, an antisense RNA oligonucleotide that skips exon 51 of the gene dystrophin, allowing for production of a functional protein. The compound is scheduled to enter phase 3 trials early next year. The London-based pharma is paying $25 million upfront for the program, which also includes options on three other compounds targeting different exons (the mutation addressed by PRO051 is responsible for only 13% of DMD cases), and will fu! nd clinical development. The deal "fits squarely in with our current strategy of diversifying into other broader disease areas, accepting that it won't have anywhere near the return of a blockbuster," says Shelagh Wilson, vice president and head of GSK's European Center of Excellence for External Drug Discovery. "It RNA-targeting drugs appear to be uniquely suited to treat disorders caused by expression of mutant proteins, protein overproduction or misfolding" (Nat. Biotechnol. 27, 874, 2009).
- Biotechs get $1 billion windfall in R&D tax credits
- Nature Biotechnology 27(12):1066 (2009)
Introduction A small amendment to US healthcare reform legislation may prove a big boon for bioscience companies. It would create a $1 billion "credit to encourage new therapies," allowing small companies (defined as under 250 employees) to write off half their R&D costs or, if they aren't profitable and don't pay taxes, to get an equivalent treasury grant. The amendment, introduced by Sen. Robert Menendez (D-NJ), is modeled after tax credits for alternative energy projects added to the US economic stimulus bill earlier this year. It has been attached by the Senate Finance Committee to the America's Healthy Future Act of 2009, which was introduced by Sen. Max Baucus (D-Mont.), and will become law only if this sweeping reform legislation is enacted. The Biotechnology Industry Organization (BIO) wanted the legislation in the stimulus bill but found legislators more receptive for its inclusion in healthcare reform. ADVERTISEMENT "We are thrilled that the committee chose to pass the amendment," says Alan Eisenberg, BIO's executive vice president for emerging companies and business development. With the Baucus bill passed out of the Finance Committee, the Menendez amendment is very likely to remain part of the language ultimately voted on by the full Senate, assuming the bill reaches a vote. Only R&D conducted in 2009 and 2010 is eligible for the program. The credits and grants apply only to qualified "therapeutic discovery" projects, which would be determined by the US Treasury Department, working in conjunction with the US Department of Health and Human Services. Qualifying programs must "show reasonable potential," with a focus on unmet medical needs, particularly cancer, and reduce healthcare expenditures. There is no specific limit on the credit any particular company can receive, which means $1 billion will be awarded on a first-come, first-served basis. There should be no limit on competition for the awards. Eisenberg notes that over 90% of BIO members fall under the definition of 'small companies' eligible for the program.
- FDA recruits prominent critics
- Nature Biotechnology 27(12):1067-1068 (2009)
Introduction The US Food and Drug Administration (FDA) has embraced yet another of its outspoken critics by appointing Peter Lurie as an advisor to the assistant commissioner for policy David Horowitz. Lurie most recently served as of Public Citizen's Health Research Group. At Public Citizen, where he served as deputy director, Lurie was a relentless critic of the pharmaceutical industry and at times the FDA itself. Lurie's move into the agency has struck a dissonant chord with biopharma executives who view him as anti-industry. But some see the silver lining to Lurie's appointment in that it addresses criticisms that FDA is too close to industry, while giving the agency a degree of control over its most zealous critics. "Lurie has earned the reputation of being an industry antagonist," says former FDA associate commissioner Peter Pitts, now at public relations company Porter Novelli in New York. "When you're at the FDA, you need to look at each individual circumstance agnostically. If you go into the job as an advocate, you are doing the agency and public health a disservice," he points out. But the general response to the most recent appointment is positive, even among those who don't necessarily agree with Lurie's positions. Don Hannaford, senior vice president of Levick Strategic Communications in Washington DC, says, "It can't hurt to have smart people—who may be a little controversial—in government. People [in government] can go into this deep inertia of making only small, incremental movement...you can take [Lurie's] energy and his desire to improve the process to help move things forward." Lurie, a physician, will be the third person with ties to Public Citizen to be engaged by the FDA. Sidney Wolfe, former head of Public Citizen's Health Research Group and editor of Worst Pills, Best Pills (http://worstpills.org/; Nat. Biotechnol. 26, 149, 2008) has been a member of the FDA Drug Safety and Risk Management Advisory Committee since 2008. Also Joshua Sharfstein, the FDA's current principal deputy commissioner, has early ties to Public Citizen from an internship in 1992. Before joining the FDA, Sharfstein developed a reputation as a reformer and an industry critic through his advocacy work in the field of HIV/AIDS and his efforts to limit marketing of pediatric cold remedies. Lurie's career includes academic studies in AIDS prevention (including epidemiology, economics and ethics), and activist work with Public Citizen focused on drugs, devices, occupational health and policy. Examples of his advocacy activities include filing a petition in June to the FDA to halt its review of Indianapolis-based Eli Lilly's anti-platelet drug Effient (prasugrel) due to safety concerns, and publishing a study showing that FDA advisory board members with conflicts of interest are 10% more likely to vote in favor of a drug reviewed by the agency than those without conflicts—although that study also showed financial conflicts do not alter the overall outcome of voting (J. Am. Med. Assoc. 295, 1921–1928, 2006). Also earlier in June, Lurie testified before the House Energy and Commerce Committee Health Subcommittee on the dangers of the FDA's approval process for Menaflex, a device for injured meniscus produced by the Hackensack, New Jersey–based ReGen. The approval boondoggle resulted in a product recall, the resignation of Daniel Schultz, director of the Center for Devices and Radiological Health, and a major review of the 510(k) premarket notification process. While at Public Citizen, Lurie, Wolfe and colleague Elizabeth Barbehenn released the monthly Worst Pills, Best Pills, a newsletter focused on the risks and safety aspects of approved drugs. The three-person project helped plug an acknowledged gap in post-market surveillance. Many of the drugs designated "Do Not Use" by the editors have subsequently been withdrawn from the market. Along with Lurie's appointment, several others were announced. These positions include: Meghan Scott, former campaign director for the union-backed group WakeUpWalmart.com of Washington, DC, as FDA's chief press officer; Vicki Seyfert-Margolis, CSO of nonprofit Immune Tolerance Network, as advisor to FDA chief scientist Jesse Goodman; and attorney John M. Taylor, III, as counselor to the FDA commissioner Margaret Hamburg. Companies are still getting their way more often than the science would merit. The number of outside critics brought into the agency is a signal that Hamburg is not so much cleaning house as building a team with the most interested and motivated people she can find. According to Frank Torti, former FDA chief scientist and principal deputy commissioner, who served as acting commissioner after Andrew von Eschenbach stepped down, "I think it's important and wise to actually engage people from a variety of viewpoints in thinking about the FDA, so that reaching out to advocacy groups is a smart and necessary piece of reflecting different viewpoints. It makes some sense to me." The new appointees, coupled with changes made in recent months, point at radical changes afoot. Hamburg is pushing for greater transparency in the approval process, increased scrutiny of apparent conflicts of interest, an overhaul of the device approval process, the strengthening of science and technology expertise at the agency, and a much-needed reform of the postmarket surveillance system. ADVERTISEMENT Some observers, however, are concerned that assigning a few new people to senior roles will not shake the agency enough. Diana Zuckerman, president of the National Research Center for Women and Families, Washington, DC, points out that Lurie's job description is vague, and as an advisor, he may have little direct decision-making power. "The FDA is enormous," says Zuckerman, "and two people—even two people at the highest levels, including a commissioner who is very committed to public health—still can't turn around an agency. There are layers of leadership in the hierarchy at the FDA which have created the problems of the last 6 to 8 years, and most of those leaders are still there." In the drug approval process, science ought to be used to weigh the risks and benefits of a new treatment. Political pressure or doctors' desires for more treatment choices are not supposed to play in. But this is not always what happens, according to Zuckerman. "What should be a very scientific process ends up being influenced by the leadership...when people are promoted not because of merit, but because of their willingness to please the companies whose products they're supposed to be regulating.... I think companies are still getting their way more often than the science would merit."
- Comparative effectiveness $100 million handout
- Nature Biotechnology 27(12):1068 (2009)
Introduction Up to $100 million is on offer for grants focused on comparative effectiveness research (CER) to study what medical interventions work best and for whom and under what circumstances. On November 16, the Agency for Healthcare Research and Quality, located in Rockville, Maryland, will begin accepting proposals to support large projects in the Clinical and Health Outcomes Initiative in Comparative Effectiveness. The grants are funded by appropriations from the American Recovery and Reinvestment Act of 2009, which contains $1.1 billion in federal funding for CER over the next two years (Nat. Biotechnol. 27, 211–212, 2009). Ten awards will be funded in FY2010, which may be up to three years with a grant not exceeding $10 million and no more than $4 million in any one year. CER is what Britain's National Institute for Health and Clinical Excellence (NICE) uses to advise the National Health Service on the cost effectiveness of new treatments. "Without such information, policy a! nd policy decisions tend to be ad hoc, based on individual expert perceptions and may be influenced by interests of individuals or groups," says Kalipso Chalkidou, director of NICE's International Programme. As the US contemplates healthcare reform, US policymakers should consider [establishing] CER systems, says Chalkidou. NICE has recently launched a nonprofit fee-for-service, in which client countries or donors pay for advice.
- REMS violations fines
- Nature Biotechnology 27(12):1068 (2009)
Introduction Companies that fail to follow Risk Evaluation and Mitigation Strategies (REMS) can face fines of up to $10 million, according to a new draft guidance released by the US Food and Drug Administration (FDA). The document released on September 30 is the most extensive guidance for industry regarding postmarket management of drug risks since REMS was established under the FDA Amendments Act of 2007 (FDAAA) (Nat. Biotechnol. 25, 1189–1190, 2007). The guidelines specify the content the agency expects companies to submit in a REMS proposal and the fines for not meeting REMS requirements, which can add up to $10 million. On a practical level, the new guidance has the potential to delay a drug's approval process. For BioDelivery Sciences, in Raleigh, North Carolina, the agency's request for a REMS program had a major impact. The legislation was enacted as the FDA was reviewing their first drug, Onsolis (fentanyl buccal), for the management of cancer pain. Complying with REMS require! ments delayed product approval for nearly a year. Nonetheless, Al Medwar, vice president of marketing and corporate development at BioDelivery says, "I completely support the FDA's ability to enforce this as necessary, including imposing fines on those who don't comply. For too long, the FDA has not had adequate ability to enforce the regulations put in place," he says.
- Lilac—the new blue?
- Nature Biotechnology 27(12):1069 (2009)
Introduction Whiskey maker Suntory (Tokyo) and Australian firm Florigene (Melbourne) took 20 years to make the first blue biotech roses by inserting the flavonoid 3′,5′-hydroxylase gene that leads to the synthesis of blue pigment delphinidin in pansies. The flowers have been sold at florists in Japan since November for up to $33 a stem—10 times more expensive that other roses. 'Blue gene technology' notwithstanding, the roses still lack the true Royal Blue touch.
- Sequencing firms' court battle
- Nature Biotechnology 27(12):1069 (2009)
Introduction Life Technologies has filed a patent infringement lawsuit against Illumina of San Diego and its Solexa subsidiary, to which the latter promptly responded with a countersuit. Life Technologies of Carlsbad, California, and its subsidiary Applied Biosystems (ABI) contend Illumina's Genome Analyzer products violate ABI patents describing nucleic acid amplification technology in which the clonal amplification products remain in a fixed location. Illumina and Solexa have denied all the allegations and are charging that Life Technologies' SOLiD sequencing system infringes four Solexa patents related to sample preparation, data gathering and genome analysis. "This is completely normal," says David Resnick of Nixon Peabody in Boston. "It's just the dance they do." The DNA sequencing companies have been engaged in this dance for some time already. In December 2006 ABI sued its former IP counsel, Stephen Macevicz, along with Illumina and Solexa, alleging he filed patents while ! working for Lynx Therapeutics (which later merged with Solexa) that he should have filed on behalf of ABI. In response, Illumina and Solexa charged that ABI's SOLiD system infringes several Solexa patents. Jury decisions thus far have fallen both ways suggesting little will change as a result of the latest litigations. In January, for example, a California jury reaffirmed Illumina's ownership of the disputed patent, whereas another jury pronounced that ABI did not infringe at least two other Solexa patents. The lawsuits are only likely to end, Resnick believes, "When they decide they've spent enough money on it."
- GSK hosts new biotech park
- Nature Biotechnology 27(12):1069 (2009)
Introduction London-based GlaxoSmithKline (GSK) is teaming up with the UK government, the East of England Development (EEDA) agency and the Wellcome Trust to pioneer a new model of open innovation. With an initial funding of almost £38 ($63) million, the biotech campus will be based at GSK's Stevenage site and aims to attract early-stage companies. GSK will invest £11 million, land and facilities; the government's Department of Business, Innovation and Skills will add nearly £12 million and the UK Technology Strategy Board, £5 million; the Wellcome Trust will put in around £6 million and EEDA, £4 million. Companies will have shared access to GSK's specialist skills, expertise and equipment, and operate on an open innovation model, with an emphasis on collaboration and knowledge sharing. "This will be the first open innovation campus in the pharma sector," Hunter said. "This initiative is not just for GSK's benefit," explained Jackie Hunter, the park's sponsor within GSK. �! �It is also about translating the UK's excellent science into bioscience companies." She added that all pharma companies now have the stated intention of having more collaboration with biotechs, and it is hoped that the new park will provide an attractive location. Several companies have already expressed an interest, and, when complete, the park will house around 1,500 scientists.
- Proteostasis Therapeutics
- Nature Biotechnology 27(12):1070 (2009)
Why protein homeostasis has investors excited.
- What's in a name?
- Nature Biotechnology 27(12):1071-1073 (2009)
Defining an emerging field can be challenging. Nature Biotechnology asked 20 experts for their views on the term 'synthetic biology'.
- Making green
- Nature Biotechnology 27(12):1074-1076 (2009)
Biofuels top the list of products for many biotech companies using advanced biological engineering. Cormac Sheridan examines the diverse commercial paths being taken to reach this goal.
- Biotech in the basement
- Nature Biotechnology 27(12):1077-1078 (2009)
Do it yourself 'biohackers' want to break down institutional barriers and bring science to the people. But good intentions are up against the hard realities of doing science. Joe Alper reports, with additional reporting by Laura DeFrancesco.
- Negotiation 2.0
- Nature Biotechnology 27(12):1079-1081 (2009)
- Medicare formulary coverage for top-selling biologics
- Nature Biotechnology 27(12):1082-1084 (2009)
Introduction To the Editor: 'Biologics' are therapeutics produced through recombinant DNA technology or other biological processes. The number of available biologics and expenditures for them have increased dramatically in recent years. Although insurance coverage policies must balance patient and societal needs of access and affordability, insurers may also adopt strategies to manage the use of these expensive drugs. Such strategies include a more complex tiered formulary (drugs are divided into "tiers," with the first tier typically representing generics at the lowest level of patient cost-sharing, and a higher tier requiring higher patient cost-sharing), prior authorization (requiring physicians to obtain approval from the health plan before prescription for coverage) and the use of specialty pharmacy vendors1, 2, 3. Despite the growing importance of biologics, little is known about their coverage, cost-sharing and management tools, or how they vary across drug characteristics. Current evidence ! is limited to studies of selected health plans2, 3, geographical areas4 or diseases5. We examined coverage, cost-sharing and utilization management for the top-selling biologics in 2006 and 2009 using nationally representative data from the US Medicare prescription drug plan formulary files as in Table 1. The unit of analysis was each Part D product (that is, at each organization and plan combination). Our research goal was to understand how common biologics were covered. We analyzed the top 20 biologics (per global sales in 2006) with three specific aims: first, baseline patterns in coverage, cost-sharing and utilization management for 2006; second, whether coverage varied by drug characteristics (presence of a 'black box' warning and monthly costs); and finally, trends in insurance coverage policies between 2006 and 2009. We analyzed Medicare Part D drug coverage for several reasons. First, this program has expanded coverage for patients and thus has had a strong impact on drug demand. Second, Medicare coverage policies often drive coverage decisions for private payers. Finally, Medicare formulary data are nationally representative. Analysis of the 2006 Medicare formularies provides a baseline understanding of coverage patterns found immediately after the implementation of this prescription drug benefit. The drugs examined represented ~75% of the global biotech drug market in 2006 (ref. 6). To investigate the trend over time, we compared the coverage patterns between 2006 and 2009. These findings are important to patients, insurers and policy makers, but also to manufacturers and developers of biologics, given a lack of consensus about how such expensive biologics should be covered and managed. Patterns of formulary coverage, tiers and the type of cost-sharing for top-selling biologics among Medicare prescription drug plans are summarized in Table 1. The baseline findings for 2006 demonstrate that the top-selling biologics were covered by most Medicare prescription drug plans but were placed in a tier with high patient cost-sharing and were subject to prior authorization. The percentage of Medicare prescription drug plans including these drugs in their formularies ranged from ~99% for Enbrel (etanercept), Betaseron (interferon beta-1b) and Remicade (infliximab) to 42% for Herceptin (trastuzumab) and 12% for Levemir (insulin detemir), the most recently approved drug in the sample (2005). However, some biologics may only be covered under Part B: when administered in a physician's office or infusion center (for example, Avastin (bevacizumab), Herceptin, Rituxan (rituximab) and Remicade)7 or other particular circumstances8. This may result in a lower coverage rate unde! r Part D. We found that patient cost-sharing was commonly used by these plans to manage the use of these biologics. Tiered formularies are used by health plans to encourage the use of lower-cost drugs. Most of these biologics were classified in tier 4, which requires the greatest cost-sharing, except for diabetes drugs (tiers 2 or 3) and Herceptin, a cancer drug (tier 2). The out-of-pocket cost to patients was as high as $60 for a 30-day supply purchased at preferred pharmacies with a copayment. We also found that the most common cost-sharing method for these drugs was coinsurance (with a rate most commonly 25%). Coinsurance requires Medicare beneficiaries to pay a percentage of the drug cost, which creates a greater financial burden than does a flat fee copayment. For example, patients on Aranesp ($1,098 per month) would face a monthly out-of-pocket cost of $275. Patterns of copayment and utilization management are summarized in Table 2. Excepting diabetes drugs, the reviewed biologics all required prior authorization. Drugs with greater coverage and within a higher cost-sharing tier (such as rheumatoid arthritis and anemia drugs) were more likely to be associated with prior authorization requirements than those within a lower cost-sharing tier (such as diabetes and cancer drugs). Other utilization management strategies were used less often. Fewer than one-third of drug plans imposed quantity limits for these biologics, and fewer than 10% of these plans used step therapy, which would require patients to try a first-line medication (generally the most cost-effective and safest drugs) before receiving coverage for a second-line medication (more costly or risky drugs). One interesting comparison of utilization management between biologics and small molecule drugs is provided by a recent study9 that investigated coverage of small molecul! e drugs, such as psychotropic drugs, in Medicare Part D. Their study concludes that only a minority of Part D plans imposed prior authorization for small molecules. In our study, coverage was found to vary both across and within drug classes (defined as therapeutic class or indication). Most plans covered at least one biologic in each drug class, ranging from 100% for diabetes drugs to 55.6% for cancer drugs. Within the same drug class, coverage varied. Therapeutics in some indications were covered similarly, irrespective of the drug. For example, the least-covered rheumatoid arthritis treatment was present in 91.9% of plans, whereas the most-covered was present in 99.6% of plans. Similarly, the least-covered cancer medication was present in 42.1% of plans, whereas the most-covered was in 45.9% of plans. In other indications, however, there was a much larger variation of coverage. Thus, the least-covered anemia medication was present in 65.8% of plans, whereas the most-covered was in 95.4%; the least-covered diabetes drug (Levemir) was present in only 11% of plans, whereas the most-covered drug (Lantus (insulin glargine)) was present in! nearly every (97.8%) plan. We also examined whether coverage varied by drug characteristics (data not shown but available upon request). Two drug characteristics were examined: presence of a black box warning and monthly costs. A black box warning is a labeling requirement imposed by the FDA indicating that a drug may cause serious adverse effects. In general, drugs with a black box warning and higher monthly costs were associated with less coverage, a higher cost-sharing tier, and prior authorization requirements by most Medicare prescription drug plans. Next, we investigated trends over time by comparing coverage patterns of 2006 and 2009 (Table 2). In general, we found that an increasing number of plans included these biologics in their formularies in 2009, especially for cancer drugs and Levemir (which was a new drug in 2006). However, in 2009, more plans have adopted coinsurance as the cost-sharing method of choice for these biologics (except diabetes drugs), increased the coinsurance rate (with a most common rate of 33% in 2009 versus 25% in 2006), and raised the copayment amount. Prior authorization and quantity limit also increased significantly for most of the biologics studied. ADVERTISEMENT In sum, top-selling biologics were covered by most Medicare prescription drug plans in 2006, but access to these biologics was limited by high patient cost-sharing and prior authorization requirements. In 2009, patient cost-sharing and utilization management requirements have increased still further. In addition, we found significant variations by drug, drug class and drug characteristics. Our findings serve as a first step toward understanding and addressing the coverage issues for these expensive biologics, with important implications for drug access, formulary decisions and strategic planning for drug development. The results on coverage, cost-sharing and prior authorization for biologics are in general consistent with other studies examining the specialty tiers broadly10, 11, 12. Further research is needed to understand the impact of policies that relate formulary placement, such as codifying protected drug classes, to model patient out-of-pocket expenditures under different cost-sharing scenarios.
- The facts about Stemedica
- Nature Biotechnology 27(12):1085 (2009)
Introduction To the Editor: The News Feature in the September issue by Jane Qiu1 entitled "Trading on Hope" highlights the lack of oversight in certain clinical centers now offering stem cell treatments. At Stemedica, we recognize and respect the role that research and approved clinical trials have in the advancement of the stem cell industry. However, as vice chairman & CEO of the company, I was extremely concerned to find references within Qiu's article about our company. These references are inaccurate and potentially damaging to Stemedica's image within the regulatory, medical and investment communities and need to be corrected. On p. 791 of the article, Qiu included Stemedica as one of the organizations in Table 1 "promoting unproven stem cell treatments." This is incorrect: Stemedica does not promote unproven stem cells treatments. Later, on the same page, Qiu references two basic bench researchers—Sorapop Kiatpongsan of the University of Bangkok and Douglas Sipp of the Riken Center for Developmental Biology in Kobe, Japan. Until a recent effort by Stemedica to engage these two researchers, neither had ever had direct contact with anyone at Stemedica. Had they visited our facilities or interviewed any of our personnel, they would have learned the facts about our position regarding the evolution of stem cell therapy and the importance we place in having such therapy conducted under strict clinical protocols and with full regulatory approval. ADVERTISEMENT I would also like to state that neither Qiu nor anyone else from Nature Biotechnology called Stemedica to confirm the facts or verify that the information in the article concerning Stemedica was accurate. Although Stemedica commends Qiu's attempt at disclosing misuses of stem cell treatment, we regret that inaccurate information was advanced about our company in the article. Interested readers are invited to visit our web site (http://www.stemedica.com/) to review articles and press releases on research, conference presentations and other information about Stemedica. We strive to do what is right and responsible and take exception to any inaccurate information about our company.
- Reply to The facts about Stemedica
- Nature Biotechnology 27(12):1085 (2009)
Introduction Nature Biotechnology replies: The current version of Stemedica's website (http://www.stemedica.com/) neither publicizes treatments in stem cell clinics nor promotes them. In the process of fact checking the Qiu article, Nature Biotechnology editors twice checked the Stemedica website in June and August. When the website was checked on June 24, 2009, wording was present on the website indicating that the company was still publicizing treatments in stem cell clinics at that time. A subsequent check of the website on August 24 was unsuccessful as the website was not working. Evidence from the Internet Archive—as recent as 2008—does indicate that Stemedica publicized treatments in the past on its website (http://web.archive.org/web/20080222212144/www.stemedica.com/treatmentcenters/; http://web.archive.org/web/20071008142206/www.stemedica.com/patients/application/).
- Biotech and gender issues in the developing world
- Nature Biotechnology 27(12):1085-1086 (2009)
Introduction To the Editor: The recent World Food Prize Symposium1 celebrated the life of Norman Borlaug and the work of laureate sorghum breeder Gebisa Ejeta. The star-studded cast of speakers was led by Bill Gates and included women CEOs of major multinational corporations. Gates described how his foundation came to the realization that to deal with issues of health there must be good food in the stomach and described their emphasis on dealing with agricultural issues of nutrition, drought, insects and diseases with a clear and resounding emphasis on biotech, where it could be helpful. Gates and many others addressed gender issues, with the emphasis on girls' education and health so that the best might enter the business world and academia. Unfortunately, very little was said about the vast majority of women, who, no matter how well educated, would return to their rural settings, relegated to mainly 'femanual' work: soil preparation, planting, weeding and more weeding. Not a single invited speaker (except the laureate) mentioned weeds, let alone how modern technology can help. Engineers have provided designs for more ergonomic hoes. Genetic engineers can do better. Already transgenic glyphosate-resistant maize has become a hit among women farming in South Africa, who can now spray down more weeds in a day than they could hoe in a backbreaking month. Weed control biotech is not limited to herbicide-resistant crops. Ejeta received the prize for his work intelligently combining genes that partially encode resistance to various stages of attack by the root-parasitic weed Striga (witchweed). It is not easy to transfer these 3 or 4 recessive genes scattered throughout the sorghum genome from locally adapted variety to variety by backcross breeding, even with marker-assisted selection. When the genes are finally isolated, they can be put in a single dominant cassette that could be engineered into one variety of sorghum and, one hopes, other Striga-susceptible crop species and easily backcrossed to any local variety, preserving crop biodiversity. ADVERTISEMENT In principle, genetic engineering could also be used to engineer the secretion of weed-suppressing allelochemicals from crop roots or to enhance the vitality, virulence and persistence of biocontrol agents ('bioherbicides') such that they might become commercially viable. Such efforts to use the tools of modern biotech to attack weeds would clearly reduce the inappropriate drudgery that most women are relegated to enduring in the developing world. Confucius is quoted as saying: "If language is incorrect, then what is said is not meant; if what is said is not what is meant, then what should be done remains undone." If it is not clearly stated with meaning that weeds are a major constraint on the quality of life of most women in the developing world, then what should be done remains undone, and gender issues have not been adequately addressed with biotechnology.
- First transgenic geminivirus-resistant plant in the field
- Nature Biotechnology 27(12):1086-1088 (2009)
Introduction To the Editor: The article by Lucioli et al.1 in last year's June issue states not only the drawbacks to the use of pathogen-derived resistance (PDR) for geminiviruses, but also that RNA interference (RNAi) thus far has not proved to be a robust technology for obtaining plants resistant to these viral pathogens. We present here data on the generation of two transgenic geminivirus-resistant common bean lines. On the basis of these results, we feel that the conclusions of Lucioli et al.1 are premature. The family Geminiviridae infects a wide range of economically important crop species (e.g., common bean, Phaseolus vulgaris; tomato, Solanum lycopersicum; cassava, Manihot esculenta; maize, Zea mays and cotton, Gossypium hirsutum) in tropical and subtropical regions and has become a major threat to agriculture worldwide. Bean golden mosaic virus (BGMV) belongs to the genus Begomovirus, whose genome is composed of two single-stranded DNA molecules, designated DNA-A and DNA-B, both of which are essential for infectivity. BGMV is transmitted by the whitefly Bemisia tabaci (Gennadius) in a persistent, circulative manner, causing golden mosaic in common bean. This disease is characterized by yellow-green mosaic of leaves, stunted growth and distorted pods, which may vary among genotypes. Similar diseases have been described in Puerto Rico, Guatemala, the Dominican Republic, Mexico and the United States2, 3. Phylogenetic studies and differences in biological properties, such as sa! p transmissibility, support the taxonomic separation of bean-infecting geminivirus isolates from Brazil (designated BGMV) and isolates from Central America, the Caribbean basin and Mexico (designated Bean golden yellow mosaic virus, BGYMV)3. Control practices have focused primarily on controlling the vector by contact or systemic high-toxicity insecticides, with the concomitant problems of development of pesticide-resistant forms, low cost-benefit ratio and environmental concerns. This disease is the heaviest constraint on bean production in Latin America, causing significant yield losses ranging from 40% to 100%2. Since 1972, Brazilian bean production has been severely reduced by the disease. The increasing seriousness of the disease has been attributed to growing whitefly populations associated with expansion of soybean production in bean-growing areas. Extensive screening of common bean germ plasm for resistance to BGMV has not yielded genotypes with high resistance to the virus. Indeed, of more than 20,000 accessions of P. vulgaris and some accessions of P. lunatus, P. acutifolius and P. coccineus evaluated under field and laboratory conditions, not a single accession has proven immune. Resistance is often u! nsatisfactory, and commercial cultivars are susceptible to early, moderate or severe infection2, 4. After the first demonstration of pathogen-derived resistance (PDR) in the pioneering work from Roger Beachy's lab describing coat protein–mediated resistance to tobacco mosaic virus5, several strategies have been used to genetically engineer tolerance or immunity to viruses in transgenic plants. These strategies are based on two broad classes: protein-mediated resistance and RNA silencing–mediated resistance. Now that we better understand the mechanisms of RNA interference (RNAi) and its biological functions, it is possible to look back on initial experiments from a new perspective. It is now known that plants naturally process viral RNAs to generate small sequences of a pathogen's genetic material that can be specifically used against that pathogen through the RNA-induced silencing complex. An RNA-silencing (post-transcriptional gene silencing) mechanism was recognized as being responsible for resistance to RNA viruses. This mechanism depends on the formation of double-stranded RNA (dsRNA) whose antisense strand is complementary to the transcript of a targeted gene. These discoveries led to the introduction of constructs to produce intracellular generation of small interfering RNA (siRNA)-like species in transgenic plants, inducing targeted gene silencing and virus resistance. This is an important tool in generating plants resistant to a broad range of viruses6. However, not all viral genes used in transgenic constructs render plants resistant to infection. The use of inverted repeat constructs, resulting in dsRNA transcripts, is the most efficient means of generating transformed lines showing effective gene knockdown or virus resistance7. The most likely reason for this is that dsRNAs are fed directly into the silencing pathway at the level of the RNaseIII-like enzyme Dicer, and therefore they are not reliant on the action of plant-encoded RNA-dependent RNA polymerase proteins. Nevertheless, most examples of RNAi-mediated virus resistance pertain to RNA plant viruses. Indeed, attempts to obtain robust PDR to geminiviruses have not been! as successful as those against RNA viruses, and development of geminivirus-resistant plants is considered a major challenge8. Because of the social and economic importance of common bean as a source of protein in the diet of over a billion people worldwide, we have been attempting since the early 1990s to obtain BGMV-resistant engineered lines of the common bean. We have studied the molecular biology and diversity of BGMV and have developed a bean transformation system that allows us to obtain transgenic plants with high efficiency. We first created transgenic lines that express BGMV coat protein gene—the primary choice for PDR in begomoviruses—but these failed to show resistance to the virus (D. Maxwell, unpublished data). We also explored a second strategy involving expression of the construct comprising the viral genes encoding replication initiator protein (rep; AC1), transactivator protein (TrAP; AC2), replication enhancer protein (REn; AC3) and movement protein (BC1) in an antisense orientation9. The resulting transgenic lines showed delayed and attenuated golden mosaic symptoms upon whitefly-mediated inoculation. Using the strategy of transdominance, we then obtained bean lines with a vector containing the mutated rep (AC1) gene. This mutated rep gene encodes a mutated AC1 (REP) protein with an amino acid change (D262R) in the putative NTP-binding motif (EGX4GKTX32DD). One of these lines showed resistance to the virus. After studying resistance for several generations, however, we determined that immunity to infection depended on the number of viral particles inoculated10. More recently, we have explored the concept of using RNAi constructs to silence the AC1 viral gene, which encodes the only protein strictly essential for viral genome replication. We hypothesized that silencing expression of the AC1 viral gene, by sequence-specific degradation of target mRNA interfering with viral replication, would reduce or prevent viral DNA accumulation and, consequently, appearance of symptoms. We obtained 22 lines with an intron-hairpin construct designed to induce post-transcriptional gene silencing of the AC1 gene. These lines were first evaluated under greenhouse conditions. Two of these lines (named 2.3 and 5.1) showed high resistance (~93% of the plants were symptom free) upon inoculation at high pressure (>300 viruliferous whiteflies per plant during the plant's entire life cycle) and at a very early stage of plant development11. In the field, 2–10 whiteflies per plant led to 100% virus infection of wild-type plants. Homozygous plants were cross! ed with nontransgenic plants to generate a hemizygous population. Both homozygous and hemizygous plants were inoculated using viruliferous whiteflies. Two weeks after inoculation, 100% of homozygous plants remained symptomless, whereas 28.7% of hemizygous (n = 164) plants showed mild symptoms, and all nontransgenic plants (n = 40) showed severe symptoms. It is well known that viral protein, initially identified as a mediator of synergistic viral disease, acts to suppress the establishment of both transgene-induced and virus-induced gene silencing, in which co-infection with two heterologous viruses leads to much more severe symptoms than does infection with either virus alone. Many such synergistic diseases involve a member of the Potyvirus group of plant viruses12. Thus, we examined possible resistance suppression by co-inoculating transgenic plants with the bean common mosaic necrotic potyvirus or bean rugose mosaic comovirus and the BGMV. In these experiments, all transgenic plants infected with bean common mosaic potyvirus or bean rugose mosaic comovirus maintained their immunity against the BGMV (n = 5). We then conducted studies on the behavior of transgenic common bean lines under field conditions. The first two field trials were carried out during the agricultural seasons of 2007 and 2007–2008 in the state of Goiás, Brazil. Results from these trials confirmed earlier greenhouse observations. Experimental plots with five replications (each replication with five 5-m rows and >300 plants), conducted in a random-block design under low and high B. tabaci pressure, resulted in no infected transgenic lines. The highest average incidence of infection in nontransgenic control plots was 18% in 2007 and 83% in 2008 (Fig. 1). Nontransgenic plants showed characteristic severe symptoms of the golden mosaic disease (yellow-green mosaic in leaves, stunted growth and distorted pods). Off-target effects were not apparent, and transgenic lines showed normal phenotypes (plant height, site of insertion of first pod, number of branches, internode length, foliar area and total number of flow! ers, flowering time and pods). We went on to select transgenic line 5.1 for agronomical evaluation in the field during the low-disease-incidence season in three distinct regions of Brazil (Paraná, 23° 11′ S, 51° 10′ W; Goiás, 16° 30′ S, 49° 17′ W; and Minas Gerais, 19° 26′ S, 44° 09′ W). In these trials, no significant differences were observed in the seed germination, initial plant height, width of the leaves, flowering time, yield, number of seeds per pod and 100-seed weight (Table 1). ADVERTISEMENT We are now conducting biosafety evaluations, taking into account the demands of the Brazilian Biosafety Committee and other regulatory authorities, with a view to obtaining authorization for commercial release of the first transgenic bean varieties. These studies are evaluating interactions of transgenic plants with microorganisms, insects and other plants from the agricultural and natural environment. In addition, the stability of foreign gene expression, gene flow and factors related to their interaction with the complex physiology of these plants exposed to natural stress in tropical environments are now under study. Furthermore, food biosafety analysis is being carried out by the Biosafety Network of Embrapa to determine differences in nutritional and antinutritional compounds as well as to verify the absence of toxic molecules. All risk assessment data generated so far have suggested no differences between transgenic lines and parental plants. In addition, as RNAi in eu! karyotes is a sequence-specific gene silencing mechanism, we are resequencing viruses isolated from several parts of Brazil and have observed no significant variations in the sequence of the rep gene. Molecular analysis of the 421-base-pair fragment from the BGMV genome used for the intron-hairpin construct showed isolates with 100% similarity or variants with one point polymorphism. We believe we are on the road to generating the first commercial transgenic plant produced in Latin America. This work is an example of a public sector effort to develop useful traits, such as resistance to a devastating disease in an 'orphan crop' cultivated by poor farmers throughout Latin America. It has the potential to become a milestone as one of the first 'homemade' biotech crop improvements performed in a non-G8 country as a result of the interaction between bench and field scientists. In addition, in the context of global food deficiency and high prices, where golden mosaic virus causes annual reductions in yields in the range of 90,000 to 280,000 tons, a geminivirus-resistant bean could boost production enough to feed an estimated extra 6 million to 20 million adults. In addition to the economic problems caused by yield reduction, this virus also brings other social consequences as it precludes common bean as a crop in family based agricultural systems. Approximate! ly 180,000 hectares are now unsuitable for common bean cropping in the dry season in Brazil due to the occurrence of BGMV. These areas can be recovered for bean cultivation after development of resistant cultivars. Finally, the success presented here demonstrates the feasibility of genetically engineering geminivirus-resistant plants, a technique that can also be applied to other devastating geminivirus diseases, such as those affecting maize and cassava in Africa and tomatoes worldwide.
- Reply to First transgenic geminivirus-resistant plant in the field
- Nature Biotechnology 27(12):1088-1089 (2009)
Introduction Lucioli & Tavazza reply: The focus of our letter of correspondence was protein-mediated resistance against geminiviruses (particularly tomato yellow leaf curl Sardinia virus; TYLCSV); in contrast, Aragão and Faria expand on the utility of RNA silencing–mediated resistance to geminiviruses. In our letter, we described the molecular mechanisms that form the basis for the ability of TYLCSV to overcome protein-mediated PDR. Using an anti-virus-induced transgene silencing strategy, we demonstrated that virus-induced gene silencing (VIGS) is an Achilles' heel for protein-mediated resistance. As we wrote in the original article, "if the transgenic protein does not stop viral expression and/or replication in the cells initially infected, then the virus will shut off transgenic expression, leading to a late-susceptible phenotype." We also proposed a simplified model to represent protein-mediated resistance to geminiviruses that takes into account the impact of VIGS. Our model suggests that strategies to avoid VIGS, while potentiating protein-mediated resistance to geminiviruses, may not generate virus-immune plants. In the final part of the correspondence, we expressed personal opinions as to the drawbacks of using PDR against geminiviruses. Drawbacks include the lack of robust evidence proving the effectiveness of RNA interference (RNAi) in obtaining geminivirus-resistant plants1, 2 (for reasons that remain unresolved), the possibility that PDR may be compromised by plant viruses encoding proteins that interfere with different steps of the RNA silencing pathway3 (a not unlikely scenario, given the prevalence of mixed viral infections) and the capacity of geminiviruses to evolve rapidly by mutation, recombination and pseudorecombination4 (potentially leading to the emergence of resistance within a short time). We think that a deeper investigation of the above aspects is still necessary for thorough exploitation of PDR against geminiviruses. ADVERTISEMENT With regards to RNAi, the current effectiveness and efficiency of this technology against geminiviruses still lag far behind those obtained against RNA viruses 9 years ago5. Moreover, in contrast to its use against RNA viruses, the use of transgene-derived siRNA targeted against particular geminivirus sequences is no guarantee of plant resistance1, 2. This does not rule out the possibility that this technology can produce plants of agronomic value. In this context, Aragão and coworkers6 recently reported that 1 out of 18 (6% of) transgenic lines, containing an intron-spliced RNA with a hairpin structure targeting BGMV, were resistant to the virus. In the discussion6, however, the authors concede that "the resistance frequency was very low when compared with those observed for RNA viruses" (90%–100%). As yet, no conclusive evidence has been presented outlining the features required in an RNAi construct that confers resistance to geminivirus infection. In this respect, ! the results reported here by Aragão and Faria do not significantly differ from their previous data6, which essentially confirm the demonstration by others2 that it is possible to use RNAi to confer geminivirus resistance, albeit at a low frequency. In conclusion, compared with transgenic PDR strategies against RNA viruses, PDR strategies against geminiviruses await conclusive proof of their robustness, applicability and utility. Many more molecular, agronomical and ecological studies are required for this technology to be validated as the biotechnological tool of choice for combating geminivirus infection. In the meantime, we think that alternative strategies are worth exploring.
- The changing economics of DNA synthesis
- Nature Biotechnology 27(12):1091-1094 (2009)
How are the economics of synthetic biology likely to develop in the coming years?
- Parts, property and sharing
- Nature Biotechnology 27(12):1095-1098 (2009)
Synthetic biology should look to other industries' models for ownership and open sharing.
- Building outside of the box: iGEM and the BioBricks Foundation
- Nature Biotechnology 27(12):1099-1102 (2009)
Innovative community efforts in academia and non-profits to engage student researchers, encourage open sharing of DNA constructs and new methodology as well as build a Registry of Standardized Biological Parts have been central to the emergence of synthetic biology.
- Our synthetic future
- Nature Biotechnology 27(12):1103-1105 (2009)
Two prominent ethicists provide their views on the ethical debates surrounding synthetic biology.
- Should moral objections to synthetic biology affect public policy?
- Nature Biotechnology 27(12):1106-1108 (2009)
Moral concerns as to the relationship of synthetic biology with nature do not provide a convincing basis for more stringent regulatory oversight of the field.
- From synthetic biology to biohacking: are we prepared?
- Nature Biotechnology 27(12):1109-1111 (2009)
The emergence of synthetic biology, and off-shoots such as DIYbio, make the need for a rigorous, sustained and mature approach for assessing, and preparing for, the broad range of associated dangers and risks all the more pressing.
- Engineering a new business
- Nature Biotechnology 27(12):1112-1120 (2009)
As the market for DNA on demand continues to grow, increases in the scale and efficiency of new genome engineering approaches promise to accelerate product discovery and even open up new commercial opportunities.
- The sorcerer of synthetic genomes
- Nature Biotechnology 27(12):1121-1124 (2009)
J. Craig Venter reflects on an effort spanning decades to create a living cell from chemically synthesized building blocks.
- The obviousness rejection as a barrier to biotech patent prosecution
- Nature Biotechnology 27(12):1125-1126 (2009)
An analysis of US Federal Circuit decisions shows the effects of the Supreme Court's decision in KSR v. Teleflex.
- Recent patent applications in synthetic biology
- Nature Biotechnology 27(12):1127 (2009)
Introduction Recent patent applications in synthetic biology Table 1
- Engineering direct conversion of CO2 to biofuel
- Nature Biotechnology 27(12):1128-1129 (2009)
Genetically engineered cyanobacteria harvest light energy to directly produce isobuteraldehyde and isobutanol.
- A first look at entire human methylomes
- Nature Biotechnology 27(12):1130-1132 (2009)
Complete maps of DNA methylation in human cells provide insight into the epigenetic regulation of pluripotency.
- Capturing global metabolism
- Nature Biotechnology 27(12):1132-1133 (2009)
Metabolite arrays sample the metabolic state of bacteria and complex microbial communities while aiding enzyme discovery.
- Research highlights
- Nature Biotechnology 27(12):1134 (2009)
Introduction Gene therapy learns its ABCDs A gene therapy tested on two seven-year-old boys with X-linked adrenoleukodystrophy has halted the progression of this fatal demyelinating disease. The treatment used autologous CD34+ peripheral blood mononuclear cells transduced ex vivo with a lentiviral vector carrying a normal copy of the defective gene, ABCD1. Earlier gene-therapy trials with γ-retroviral vectors had relied on an intrinsic selective advantage of the genetically corrected cells to ensure a sufficient level of engraftment. Because expression of ABCD1 does not confer a growth advantage, Cartier et al. used full myeloablative conditioning to 'make room' for the corrected cells. From previous studies, they expected that corrected hematopoietic stem cells infused into the blood would reconstitute hematopoiesis in the bone marrow, differentiate into myeloid precursors that migrate to the brain, and differentiate further into microglial cells that express ABCD1. At 20–30 months after transplantation, up to 14! % of several blood cell lineages and up to 18% of bone marrow CD34+ cells expressed the transgene. Progressive brain demyelination arrested at 14–16 months. Importantly, corrected cells isolated at 24 and 30 months were polyclonal, showing little evidence that a small subset of transduced cells had acquired a selective advantage through growth-promoting viral integrations. (Science 326, 818–823, 2009) KA Mapping drug promiscuity Off-target drug interactions have long been the bugaboo of drug developers. But multiple interactions—polypharmacology—is not only a fact of life, but might be beneficial. Absent structures of all human targets, in silico techniques for predicting interactions, off and on target, have been developed. Now, Keiser and colleagues have applied their similarity ensemble approach (SEA) first described in these pages (Nat. Biotechnol. 25, 197–206, 2007), to map out interactions between 3665 drugs (available or in development) against 65,000 ligands. SEA classifies targets by the similarity of compounds that bind to them, and reveals ligand-based similarities where they are not expected. Among 184 unprecedented interactions, thirty of which they verified experimentally, they found examples of new targets as the primary site of action, off-target binding that could explain side effects, and binding that was unrelated in sequence, structure or function. For example, the hallucin! ogen dimethyltryptamine was found to bind serotonergic receptors with a high probability, which suggests that what was believed to be the primary target (σ receptor) is probably incorrect. Some widely prescribed selective serum reuptake inhibitors like Paxil and Prozac were found to be β-blockers, which explains some of the side effects seen during rapid withdrawal. (Nature 462, 175–181, 2009) LD New DNA-binding motifs Transcription activator–like (TAL) effectors from plant pathogenic bacteria in the genus Xanthomonas contribute to many crop diseases by activating host genes. Moreover, certain crops have co-opted TAL effectors to trigger defense responses. Although the DNA-binding specificity of TAL effectors has long been known to be defined by a stretch of tandem imperfect amino acid repeats, the molecular basis of their interaction with DNA has remained enigmatic. Boch et al. and Moscou & Bogdanove independently report that the specificity of promoter activation by TAL effectors is determined by the ability of particular pairs of adjacent amino acids in each repeat to recognize a particular base pair in target DNA. Boch et al. demonstrate that the modular architecture of the specificity-determining domain enables the design of effectors with novel specificities. Moscou & Bogdanove show that the affinity of any repeat in a TAL effector, unlike zinc fingers, does not appear to be affect! ed by its neighbor. The potential for identifying plant genes either involved in resisting or promoting diseases is extended by the demonstration by Römer et al. that functionally distinct DNA motifs recognized by separate TAL effectors retain their function when combined into a single promoter. Novel resistance genes activated by multiple TAL effectors could enable engineering of broad spectrum and durable disease resistance. (Science, published online October 29, 2009; 10.1126/science.11788111; 10.1126/science.1178817; Proc. Natl. Acad. Sci. USA, published online November 12; doi: 10.1074/pnas.0908812106) PH Reprogramming for all When cultured fibroblasts are infected with viral vectors expressing the reprogramming genes Oct4, Sox2, Klf4 and c-Myc, only a few rare cells convert to induced pluripotent stem (iPS) cells. This low efficiency has been attributed to the variability of viral delivery: every cell does not take up all four vectors, and those that do may not express the transgenes at the required doses. To control for this variability, Jaenisch and colleagues previously devised a "secondary" reprogramming system that generates large numbers of somatic cells with an identical viral integration pattern selected by its competence to produce iPS cells (Nat. Biotechnol. 26, 916–924, 2008; Nat. Biotechnol. 27, 169–171, 2009). But even with this system, in which reprogramming is induced simply by adding doxycycline, only a small minority of cells became iPS cells. This puzzling result is explored in a new study from the Jaenisch group. Using secondary pre-B-cells carrying a Nanog-GFP reporter! , the authors cultured single cells in individual wells in the presence of doxycycline. After two weeks, cells in 3–5% of the wells expressed Nanog (a marker of iPS cells). But as the time in culture increased, the number of GFP+ wells continued to rise, reaching 92% of the wells at 18 weeks. The variation in the kinetics of reprogramming was independent of transgene expression levels and cell growth rates. These findings suggest that all somatic cells are amenable to reprogramming. (Nature advance online publication, doi: 10.1038/nature08592, November 8, 2009) KA Stackable paper cell culture Cells in the human body grow in the presence of molecular gradients of nutrients and signals. To mimic this environment, Derda et al. culture cells in extracellular matrix hydrogel supported by the fibers within a sheet of paper. Stacking sheets of paper permeated with cells creates a three-dimensional growth environment in which the concentration of nutrients within the stack can be controlled. Unstacking the sheets allows the properties of cells at each layer to be assayed. Using this system, Derda et al. demonstrate that cell growth, histological staining markers and gene expression patterns accurately reflect the oxygen gradient available to cells at different layers in the stack. Paper-based cell culture stacks could be optimized with different types of paper for specialized applications, formatted to fit in microtiter plates to enable high-throughput assays and synthesized with chemical compounds on the paper to enable drug screening. (Proc. Natl. Acad. Sci. USA 106, 1! 8457–18462, 2009) CM
- How does multiple testing correction work?
- Nature Biotechnology 27(12):1135-1137 (2009)
When prioritizing hits from a high-throughput experiment, it is important to correct for random events that falsely appear significant. How is this done and what methods should be used?
- Next-generation synthetic gene networks
- Nature Biotechnology 27(12):1139-1150 (2009)
Synthetic biology is focused on the rational construction of biological systems based on engineering principles. During the field's first decade of development, significant progress has been made in designing biological parts and assembling them into genetic circuits to achieve basic functionalities. These circuits have been used to construct proof-of-principle systems with promising results in industrial and medical applications. However, advances in synthetic biology have been limited by a lack of interoperable parts, techniques for dynamically probing biological systems and frameworks for the reliable construction and operation of complex, higher-order networks. As these challenges are addressed, synthetic biologists will be able to construct useful next-generation synthetic gene networks with real-world applications in medicine, biotechnology, bioremediation and bioenergy.
- Genome engineering
- Nature Biotechnology 27(12):1151-1162 (2009)
For more than 50 years, those engineering genetic material have pursued increasingly challenging targets. During that time, the tools and resources available to the genetic engineer have grown to encompass new extremes of both scale and precision, opening up new opportunities in genome engineering. Today, our capacity to generate larger de novo assemblies of DNA is increasing at a rapid pace (with concomitant decreases in manufacturing cost). We are also witnessing potent demonstrations of the power of merging randomness and selection with engineering approaches targeting large numbers of specific sites within genomes. These developments promise genetic engineering with unprecedented levels of design originality and offer new avenues to expand both our understanding of the biological world and the diversity of applications for societal benefit.
- Synthetic viruses: a new opportunity to understand and prevent viral disease
- Nature Biotechnology 27(12):1163-1172 (2009)
Rapid progress in DNA synthesis and sequencing is spearheading the deliberate, large-scale genetic alteration of organisms. These new advances in DNA manipulation have been extended to the level of whole-genome synthesis, as evident from the synthesis of poliovirus, from the resurrection of the extinct 1918 strain of influenza virus and of human endogenous retroviruses and from the restructuring of the phage T7 genome. The largest DNA synthesized so far is the 582,970 base pair genome of Mycoplasma genitalium, although, as yet, this synthetic DNA has not been 'booted' to life. As genome synthesis is independent of a natural template, it allows modification of the structure and function of a virus's genetic information to an extent that was hitherto impossible. The common goal of this new strategy is to further our understanding of an organism's properties, particularly its pathogenic armory if it causes disease in humans, and to make use of this new information to prot! ect from, or treat, human viral disease. Although only a few applications of virus synthesis have been described as yet, key recent findings have been the resurrection of the 1918 influenza virus and the generation of codon- and codon pair–deoptimized polioviruses.
- High-resolution analysis of DNA regulatory elements by synthetic saturation mutagenesis
Patwardhan RP Lee C Litvin O Young DL Pe'er D Shendure J - Nature Biotechnology 27(12):1173-1175 (2009)
We present a method that harnesses massively parallel DNA synthesis and sequencing for the high-throughput functional analysis of regulatory sequences at single-nucleotide resolution. As a proof of concept, we quantitatively assayed the effects of all possible single-nucleotide mutations for three bacteriophage promoters and three mammalian core promoters in a single experiment per promoter. The method may also serve as a rapid screening tool for regulatory element engineering in synthetic biology.
- Direct photosynthetic recycling of carbon dioxide to isobutyraldehyde
Atsumi S Higashide W Liao JC - Nature Biotechnology 27(12):1177-1180 (2009)
Global climate change has stimulated efforts to reduce CO2 emissions. One approach to addressing this problem is to recycle CO2 directly into fuels or chemicals using photosynthesis. Here we genetically engineered Synechococcus elongatus PCC7942 to produce isobutyraldehyde and isobutanol directly from CO2 and increased productivity by overexpression of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco). Isobutyraldehyde is a precursor for the synthesis of other chemicals, and isobutanol can be used as a gasoline substitute. The high vapor pressure of isobutyraldehyde allows in situ product recovery and reduces product toxicity. The engineered strain remained active for 8 d and produced isobutyraldehyde at a higher rate than those reported for ethanol1, hydrogen2 or lipid3 production by cyanobacteria or algae. These results underscore the promise of direct bioconversion of CO2 into fuels and chemicals, which bypasses the need for deconstruction of biomass.
- DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity
Henson JD Cao Y Huschtscha LI Chang AC Au AY Pickett HA Reddel RR - Nature Biotechnology 27(12):1181-1185 (2009)
Alternative lengthening of telomeres (ALT)1 is likely to be an important target for anticancer treatment as ~10% of cancers depend on this telomere maintenance mechanism for continued growth2, and inhibition of ALT can cause cellular senescence3. However, no ALT inhibitors have been developed for therapeutic use because of the lack of a suitable ALT activity assay and of known ALT-specific target molecules. Here we show that partially single-stranded telomeric (CCCTAA)n DNA circles (C-circles) are ALT specific. We provide an assay that is rapidly and linearly responsive to ALT activity and that is suitable for screening for ALT inhibitors. We detect C-circles in blood from ALT+ osteosarcoma patients, suggesting that the C-circle assay (CC assay) may have clinical utility for diagnosis and management of ALT+ tumors.
- A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner
Schellenberger V Wang CW Geething NC Spink BJ Campbell A To W Scholle MD Yin Y Yao Y Bogin O Cleland JL Silverman J Stemmer WP - Nature Biotechnology 27(12):1186-1190 (2009)
Increasing the in vivo residence times of protein therapeutics could decrease their dosing frequencies. We show that genetic fusion of an unstructured recombinant polypeptide of 864 amino acids, called XTEN, to a peptide or protein provides an apparently generic approach to extend plasma half-life. Allometric scaling suggests that a fusion of XTEN to the exenatide peptide should increase exenatide half-life in humans from 2.4 h to a projected time of 139 h. We confirmed the biological activity of the exenatide-XTEN fusion in mice. As extended stability might exacerbate undesirable side effects in some cases, we show that truncating the XTEN sequence can regulate plasma half-life. XTEN lacks hydrophobic amino acid residues that often contribute to immunogenicity and complicate manufacture. Based on data on XTEN fusions to exenatide, glucagon, GFP and human growth hormone, we expect that XTEN will enable dosing of otherwise rapidly cleared protein drugs at up to monthly ! intervals in humans.
- Exchange and transfer
- Nature Biotechnology 27(12):1191-1192 (2009)
International exchange programs for tech transfer aim to advance the field and build bridges.
- Nature Biotechnology 27(12):1194 (2009)
Introduction EMD Serono (Rockland, MA, USA) has named Howard Mayer chief medical officer for the US organization, with responsibilities including oversight of the US medical affairs group, US medical operations, US medical information, US product surveillance and quality assurance, and US regulatory affairs. Mayer joins the company from Pfizer's global R&D group, where he served as global virology worldwide clinical development and medical affairs disease area leader, focused on HIV and hepatitis. He previously worked in the infectious diseases clinical research group at Bristol-Myers Squibb Pharmaceutical Research Institute. Rosetta Genomics (Rehovot, Israel and Philadelphia) has named Kenneth A. Berlin president and CEO. He most recently served as worldwide general manager at Veridex, a Johnson & Johnson company. Berlin joined Johnson & Johnson in 1994, holding positions of increasing responsibility, including vice president, licensing and new business development in the pharmaceuticals group from 2001 to 2004 and worldwide vice president, franchise development, Ortho-Clinical Diagnostics from 2004 to 2007. Iris International (Chatsworth, CA, USA) has appointed Lawrence J. Blecka as vice president, R&D. From 1999 to 2009, he was group engineering manager for the BioPlex division of Bio-Rad Laboratories. Previously he served as corporate vice president, product development for Biocircuits. Dynavax Technologies (Berkeley, CA, USA) has named Francis R. Cano to the company's board of directors. Cano is president and founder of Cano Biotech, a consulting firm. Previously, he served as president and COO for Aviron. CellCyte Genetics (Eastgate, WA, USA) has appointed Douglas Cerretti CSO and director of business development. Cerretti served in positions ranging from staff scientist through scientific director at Immunex from 1984 to 2002, and after Immunex's acquisition in 2002, with Amgen until his retirement in 2007. He has since been involved with CellCyte as an independent consultant, helping the company refine its interim operating plan. ExonHit Therapeutics (Paris) has announced the appointment of Hervé Duchesne de Lamotte as CFO. He brings over 25 years of international financial experience to ExonHit, including 10 years in the biotech industry. He served as CFO of the IDM Group in France, Canada and the United States, and was subsequently appointed COO, France, at IDM Paris from 2006 to 2008. Most recently, he managed Cirrus Finance Management, a consultancy firm specializing in business and organizational strategies. John LaMattina has joined PureTech Ventures (Boston) as a senior partner and member of the board of directors. He was formerly president of Pfizer global R&D and senior vice president at Pfizer, and currently serves on the board of directors of Human Genome Sciences and Neurogen. In addition, PureTech has announced the promotions of Eric Elenko and Steve Muniz to partner. Elenko joined PureTech in 2005 from McKinsey & Company, and Muniz was a partner in the corporate department of Edwards, Angell, Palmer & Dodge before joining PureTech in 2007. Mirna Therapeutics (Austin, TX, USA) has named Paul Lammers president, CEO and member of the board of directors. Prior to joining Mirna, Lammers was most recently president of Repros Therapeutics. He also served for 6 years as chief medical officer for EMD Serono. Cytomedix (Rockville, MD, USA) has announced the appointment of Craig B. Mendelsohn to the company's board of directors, increasing the number of board members to seven. Mendelsohn is vice president and deputy general counsel for the American Red Cross and brings more than 15 years of healthcare industry experience as a regulatory attorney and medical director in the medical device and pharmaceutical industries. Hollings C. Renton has been appointed to the position of chairman of the board of directors at Affymax (Palo Alto, CA, USA), replacing Nick Galakatos, who served as lead board member since the company's initial public offering in 2006 and who will be resigning from the board at the end of 2009. Prior to joining Affymax's board in June 2009, Renton served as chairman of Onyx Pharmaceuticals from 2000 to 2008, where he also served as president and CEO from 1993 and as a director from 1992. Renton was previously president and COO officer of Chiron and CFO of Cetus. Tim Rothwell, former chairman of Sanofi-Aventis US, has been appointed to Emisphere Technologies' (Cedar Knolls, NJ, USA) board of directors, filling the vacancy created by Franklin Berger's recent resignation from the board. International Stem Cell Corporation (Oceanside, CA, USA) has announced the appointments of current board member and executive vice president Andrey Semechkin as CEO and Brian Lundstrom as president. Outgoing CEO Kenneth Aldrich will remain as chairman of the board and Jeffrey Janus will remain as senior vice president of ISCO and CEO of its subsidiary, Lifeline Cell Technology. Semechkin has more than 20 years of business experience, and has been an investor and advisor to ISCO since 2008. Amarin (Dublin) has named John F. Thero as the company's CFO. Thero has more than 20 years of senior financial and operational management experience, most recently as CFO at ViaCell. ADVERTISEMENT Jaye Thompson has been elected to the board of directors of Repros Therapeutics (The Woodlands, TX, USA), and as a member of the board's audit committee. Thompson was president and founder of Synergos, a full-service contract research organization acquired by inVentiv Health as a wholly owned subsidiary in 2006. In addition, Repros has announced that Nola E. Masterson, a board member since 2004, has been appointed as chair of the board of directors, effective immediately, and that Mark Lappe, the current chair, has resigned from the board, effective immediately, for personal reasons. Stefan Wohlfeil has been promoted from chief medical officer of TRIN Pharma (Appenzell, Switzerland) to CEO. Rudolf Reiter, who previously held the position of CEO in addition to his role as CEO of Ergonex, will now focus entirely on his responsibility for Ergonex.