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- Gathering clouds and a sequencing storm
- Nature Biotechnology 28(1):1 (2010)
Why cloud computing could broaden community access to next-generation sequencing. - As Genzyme flounders, competitors and activist investors swoop in
- Nature Biotechnology 28(1):3-4 (2010)
Introduction Genzyme's contamination woes have fueled headlines for the past 12 months. Just as the company seemed to have resolved the viral contamination at its Allston, Massachusetts plant, a new problem arose in the fall: steel, rubber and fiber fragments were found in vials from the same facility. As the company was forced to withdraw or scale back affected products for people with rare, life-threatening conditions, other companies have moved quickly to fill the vacuum. The US Food and Drug Administration (FDA) took steps to accelerate approval of Gaucher's and Fabry's disease treatments, made by Genzyme's main competitors. In November, as the gloom deepened, Genzyme's CEO Henri Termeer sold a noticeable chunk of his stock through an automatic sale. The series of black eyes for Genzyme has not only opened some of the company's key products up to competition earlier than anticipated, but also thrashed the stock and dented the image of the Cambridge, Massachusetts–based company, once known mainly for its innovation and remarkably profitable approach in developing drugs for rare diseases. Genzyme's serial manufacturing deficiencies have sparked questions about whether the management is competent or the company is just a victim of bad luck. Similar contamination problems have occurred at several other companies, but the double whammy of viral and particulate contamination have raised some eyebrows. The FDA has been tightening the reins on biotech manufacturers, and Genzyme's situation may just be a reflection of that. Alan Burns, of Sartorius Stedim Biotech in Concord, California, points out one of the challenges with biotech drugs is that the manufacturing processes are so varied. "Some of the processes under which biotech drugs are made are not as well-controlled as what you see in a typical pharmaceutical company, where most of the products are similar with respect to their manufacturing process," says Burns, whose company sells equipment and services for biomanufacturing. During the early days of the industry, the FDA had to "allow more variability within biotech production processes," he notes, or biotech drugs would not have been able to be made at all. But as the agency has become stricter about manufacturing standards, companies have been standardizing procedures and putting in more rigorous quality control measures. The goal is that even if contamination does occur, the affected product never reaches the public. "The FDA has shown a new interest in contamination, and this was a little bit initiated by other cases," says Huub Schellekens of the Department of Pharmaceutical Sciences at Utrecht University in The Netherlands. "Contamination is more or less a general problem, and I think it was just Genzyme's turn." For Genzyme, the trouble started last February when the FDA sent a warning letter detailing "significant objectionable conditions" at the Allston plant, which has six bioreactors. These issues were expected to take several months to address. Then, four months later, Genzyme announced vesivirus 2117 had been detected in a bioreactor producing Cerezyme (imiglucerase; recombinant human (rh) β-glucocerebrosidase) for treating Gaucher's disease. Production for Cerezyme and another drug Fabrazyme (agalsidase β; rh α-galactosidase A), for Fabry's disease, had recently been cut so that Myozyme (alglucosidase alfa; rh alpha-glucosidase), for treating Pompe's disease, could be added to the plant's schedule. As a result, manufacturing of all three products ended up being severely compromised when the plant was shut down to be disinfected. This is not Genzyme's first encounter with vesivirus: in 2008, the virus had contaminated the Allston plant and the company's brand new manufacturing plant in Geel, Belgium. There is no evidence that the virus harms people; rather, it diminishes the productivity of the cell lines used to pump out recombinant proteins. Because these are drugs for extremely rare and life-threatening diseases, patients and their doctors quickly became frantic as supplies plummeted. Europe's Committee for Medicinal Products for Human Use reduced the amount of Cerezyme given to each member nation by 80%. The medical advisory board of the National Gaucher Foundation in Tucker, Georgia, recommended that patients with the most advanced disease should get priority access to the drug and that others should receive lower doses to stretch out the small supply. It is not clear yet how this shortage has affected any patient's wellbeing. But the ramifications for Genzyme are not good either way: if patients were harmed by the temporary shortage, it's a tragedy; if the very low doses worked, demand for Cerezyme might go down, even when the company restores its manufacturing facility to full capacity. In addition, over the past few months, the FDA has given rivals Shire, located in Basingstoke, England, and Protalix Biotherapeutics of Carmiel, Israel, a major boost by accelerating review of, and facilitating early access for patients to, competing products that are not yet formally approved. Shire's velaglucerase alfa for Gaucher's and Replagal for Fabry's disease, and Protalix's Uplyso (taliglucerase alfa) for Gaucher's are all moving much more quickly thanks to the Allston debacle. Reports suggest that relatively few patients were switched to these still-experimental drugs, but, at the very least, Genzyme's problems have helped to increase patient and physician awareness about these rival products. In December, Pfizer even jumped into the fray, inking a major deal with Protalix for the plant-generated Uplyso, including a $60 million upfront payment. One of the key steps Genzyme has taken to upgrade its manufacturing processes is to assign Sandra E. Poole head of the Allston facility. Poole is a senior vice president and for the past few years oversaw the construction and European approval process for the company's new manufacturing facility in Geel, Belgium. Genzyme also developed a new test to detect vesivirus, which the company says was introduced by culture materials used in the manufacturing process. The Allston plant was back in operation by last August, but November heralded reports of more contamination. This time, "foreign particles," steel and other materials, were uncovered in less than 1% of product vials packaged at the Allston plant. No patients appear to have been harmed by these foreign particles, and because some of the affected drugs were the only treatments available, the FDA did not demand a recall. Instead, the agency issued a warning cautioning physicians to carefully inspect any vials of drugs produced at the plant before using them. Shortly after, Genzyme also announced that the agency had completed its review of Allston and had "provided Genzyme with a Form-483 outlining remaining deficiencies, which were mainly related to the fill/finish capabilities at the facility." It's not uncommon to see visible particles in some types of biotech products, mainly due to protein aggregation. But via e-mail, Patricia Hughes, from the Division of Manufacturing and Product Quality at the FDA's Center for Drug Evaluation and Research noted that, "According to the USP [United States Pharmacopeia], all parenterally administered articles [e.g., Genzyme's recombinant products] must be prepared in [a] manner designed to exclude particulate matter." Certain types of contaminants, such as fibers or metal shavings, can also indicate "poorly controlled operations or inadequate maintenance," she added. If a company is getting that kind of debris in the product, "Some part of your downstream filling system may not be set up right," says Bill Bees, senior vice president of operations at Cangene in Toronto, Ontario, which has a fill finish facility in Baltimore. For example, if a piece of equipment has been improperly assembled, metal shavings can arise wh! en the ill-fitting pieces rub together. Biomanufacturing experts acknowledge that contamination is a widespread concern in the industry, but many were disconcerted by the comments of Genzyme's senior vice president Geoff McDonough in the media. In an interview with the Boston Globe newspaper, McDonough stated that Genzyme's particle contamination rate was "within industry standards." The response of one manufacturing expert, speaking off the record, was "With that comment, they threw us all under the bus." ADVERTISEMENT Genzyme CEO Termeer responded to the crisis by announcing changes to operating procedures and a new focus on quality in manufacturing. But the biggest changes yet may be foisted on the company by activist investors. On December 10, The Wall Street Journal reported Genzyme had named an independent director to its board after pressure from stockholder Relational Investors of San Diego. This new director is Robert Bertolini, who was chief financial officer at Kenilworth, New Jersey-based Schering-Plough when it pulled off a remarkable turnaround in 2008. According to the Wall Street Journal, Relational Investors head, Ralph Whitworth, who is renowned for activism, wants to see even more changes at Genzyme. The good news finally seems to be trickling through. In December, the company announced the first new shipments of Cerezyme since the Allston plant was closed for cleaning. Shipping of Fabrazyme was also imminent as Nature Biotechnology went to press. Also in December the company announced an agreement with the FDA on a regulatory path for the long-delayed Lumizyme (a form of Myozyme for adults). The firm predicts its manufacturing capacity will increase fourfold from 2006 to 2012, both through new facilities and expansion of established plants. But it's going to take a massive effort for the company to undo all the damage. "They are taking the right steps by minimizing Allston's role while it's remediated," says Josh Schimmer, managing director and biotechnology analyst at Leerink Swann of Boston, "but they are having to scramble because they have done irreparable harm to the franchise." Schimmer approves of Bertolini's appointment and the fact that Genzyme is final! ly responding to shareholders' wishes. "The organization can be structured in such a way that these problems don't recur," he says. - Sarkozy's great biotech loan
- Nature Biotechnology 28(1):4 (2010)
Introduction President Nicolas Sarkozy has approved the national 'Grand Emprunt', French for 'big loan', a 35 ($73.7 billion) economic stimulus package to fund French industry and infrastructure. The borrowing scheme unveiled December 16 is heavily focused on education, research and innovation, with at least 5.5 billion ($7.9 billion) flowing into the life sciences, biotech, clean-tech and academic research. The Grand Emprunt is by far the biggest, though not the first, government-driven plan to benefit the biotech sector. In November, the Kurma Biofund was launched, as a joint partnership between the public financing body Caisse des Depots et Consignations (CDC) Entreprises, Paris, and venture capital group Natexis Private Equity, Paris. The 50 million ($71.5 million) fund, which will increase to 100 million ($143 million) next year, is open to newly-created biotech companies spinning off European academic centers. InnoBio, announced in October, is a 139 million ($199 million) fund aime! d at boosting the development of small-to-medium enterprises working in drug discovery and related technology platforms such as imaging, diagnostics and bioproduction. This dedicated biotech fund was created by the government's Strategic Fund for Innovation (FSI), which will contribute 52 million ($74.4 million), with the rest provided by nine corporate pharma partners, including 25 million ($35.8 million) pledged by Paris-based Sanofi Aventis and London-based GlaxoSmithKline. That the national CDC deposit fund is part of these financial investment instruments shows the French government's resolve to push biotech onto its agenda. But André Choulika, France Biotech President, laments the small sums invested. "InnoBio represents the cost of ten days of R&D in big pharma," he says, "nevertheless it could act as a catalyst to attract additional private funding." Existing schemes coupled with the 'Grand Emprunt' could signal a turning point for the biotech industry. Acc! ording to presidential advisors Arnold Munnich, head of pediat! rics, Necker Hospital, Paris, and economist Bernard Belloc, University of Toulouse, the French government understands that long-term growth depends on bridging the gap between academia and industry and is putting its muscle behind public-private partnerships to ensure university tech transfer and research evaluation are upgraded and professionalized. Ramin Chaybani from Novoptim, a Paris-based business development consultancy for European biotechs, points out, "The diagnosis is correct. Now we need to wait and see whether these measures have a catalytic effect." - Optimism in public biotech rises as credit crunch recedes
- Nature Biotechnology 28(1):5-6 (2010)
Introduction deCODE genetics, the public biotech company based in Iceland that served as the poster child for genetics-driven drug discovery, filed for Chapter 11 bankruptcy in November 2009. Riding the hype around the Human Genome Project, deCODE's stock once traded above $25 per share. The demise of deCODE says as much about the inadequacy of biotech investment models to sustain the development of new drugs from novel biology as it does about the current financial climate. But observed from a distance, the bankruptcy looks like just another biotech casualty of the credit crunch. In this respect, all is not gloom and doom. A survey of the cash status of 294 public biotechs by Nature Biotechnology reveals the sector has been more resilient to the credit shortfall than initial predictions might have suggested (Nat. Biotechnol. 27, 493, 2009). As Nature Biotechnology went to press, 22 biotech firms had filed for bankruptcy since January 2008, including 10 in 2009, according to figures from the Biotechnology Industry Organization in Washington, DC. Nine companies, though not officially bankrupt, have also closed business this year. Delistings of public companies from the exchanges have also remained common: 21 healthcare companies were delisted from the NASDAQ in 2009 through November, whereas 22 were delisted in 2008. But our analysis of the 294 public biotech filings to the end of September reveals that financing conditions have also started to ease over the past year. Roughly 28% of all biotechs were operating with less than one year's cash reserves on September 30, an improvement from an earlier analysis showing 39% based on a mix of 4Q 2008 and 1Q 2009 filings. One thing has not changed, however: microcap and small cap firms have been the hardest hit (Fig. 1). Even here, though, the outlook is improving, with 41% of microcap firms operating with less than a year's cushion compared with 50% last year (see Nat. Biotechnol. 27, 493, 2009). Strong merger and acquisition (M&A) activity has provided a lifeline for several companies, and the resurgent stock market may mean that access to public financing could improve. At the time of writing, the NASDAQ Biotechnology Index had climbed some 20 points since early March. This has observers predicting better days. "There is a lot more hope on the horizon now than there was a year ago, when there was none at all," says Chris Wasden, managing director at PricewaterhouseCoopers in New York. Financing figures back up that hope. Through November, the biotech industry had raised in 2009 $6.6 billion through public offerings, initial or otherwise—a tremendous improvement over the $2.25 billion raised through public offerings in all of 2008. A month-by-month breakdown of those figures (Table 1) shows that the surge came in the second half. That reverses the trend from 2008, when the public markets withered as the year progressed. There is also brightening news regarding employment. After a staggering 52 companies reduced their workforce in the first quarter, restructuring and downsizing activity tapered off significantly (Table 2); indeed, 2009 could end up resembling 2008 in totality—a victory of sorts. In this regard, M&A activity has hampered job growth, Wasden says, as merging companies create redundancies, and thus pink slips, and it usually takes months before those people find their way to new jobs or start-ups. Even if the crisis is passing, opinions vary on what sort of rebound biotech will see. When the economy retracts as strongly as it did in 2008, history suggests a recovery of similar slant—a 'V-shaped' recovery, as opposed to a 'W' shape, wherein the economy would surge and fall again. Wasden thinks the recovery will fall somewhere in between. ADVERTISEMENT "The general view is that the worst is behind us," he says. "And I'm actually more optimistic than a lot of people. I see it as more of a 'U' recovery." This means slower, gradual growth, which might not give much comfort to those firms treading water or in danger of slipping beneath the waves. But given the way 2009 began, any signs of recovery are fueling optimism. - New EU states ranked
- Nature Biotechnology 28(1):6 (2010)
Introduction The biotech industry in most of the EU's new member states lags behind that of their Western European neighbors, despite many declaring biotech a national priority. The 14 allbio report produced by EuropaBio and Zurich-based Venture Valuation is the first to gather data on the state of the biotech industry in the 12 new member states and 2 candidate countries. The report identifies 260 biotech companies—70% are in the service sector—operating in these countries and at least 18 therapeutic products in development. Hungary, Poland, the Czech Republic and Estonia lead the group, although the report found no correlation between a country's gross domestic product and the strength of its biotech sector. According to Patrik Frei of Venture Valuation who authored the report, despite a highly educated workforce, these countries lack support structures for small and medium-sized enterprises and funding for intellectual property and technology transfer. "It is essential to get th! ese fundamentals right because private equity and venture capital will not invest without them," Frei notes. Erno Duda, who heads the Hungarian Biotechnology Association, notes that the Hungarian biotech sector has grown from 10 to 110 companies in only a few years. "Hungary has a strong science base, especially in medicinal chemistry," he says. "The biggest obstacle now is lack of management knowledge. But we are beginning to have the critical mass of companies to make a cluster." - 15 states sue Amgen
- Nature Biotechnology 28(1):6 (2010)
Introduction New York and 14 other states have filed a lawsuit alleging that Amgen offered doctors illegal kickbacks to increase sales of its blockbuster anemia drug. The multi-state case charges Thousand Oaks, California–based Amgen of overfilling vials of erythropoietin-stimulating agent Aranesp (darbepoetin alfa) by 16–19% to provide medical practices with free product for which they could then bill insurers. An ex-employee turned whistleblower, who first filed a complaint in 2006, alleges that Amgen's sales force promoted the overfill and the revenue it would bring from third-party payers such as Medicaid. Drug wholesaler ASD Healthcare and drug-purchasing International Nephrology Network, both based in Frisco, Texas, are also named in the suit. The plaintiffs are requesting treble damages, which could amount to several billions of dollars; the defendants deny the charges. Wells Wilkinson, director of the Boston-based consumer watchdog Prescription Access Litigation, calls the sc! heme a creative variation on a widespread marketing tactic of inducing doctors to inflate drug prices on reimbursement. "Recent lawsuits have been seeking increasingly larger fines from drug companies," he notes. "These are encouraging signs that the federal government is going to take a stronger stand against prescription drug fraud." Until the penalties are sufficiently severe, companies will continue to use these types of "egregious" marketing ploys, he predicts. - The biotech Stradivarius
- Nature Biotechnology 28(1):6 (2010)
Introduction Thanks to a 'biotech' intervention, the modern fiddle in the picture fooled more than 100 listeners in a blind test. Professor Francis Schwarze of the Swiss Federal Laboratory for Materials Testing and Research treated Norwegian spruce and sycamore with two fungi to recreate the effects of cold climate thought to cause the superior quality of the wood used by Antonio Stradivari in the 17th century. Schwarze commissioned violin craftsman Michael Rhoneimer of Baden, Switzerland to build an instrument which was tested alongside untreated fiddles and a $2 million Stradivarius. Listeners were asked to identify the Strad, and while 113 picked the biotech fiddle, only 39 correctly identified the Strad. - Report concludes industry–academia partnerships on the wane
- Nature Biotechnology 28(1):7-8 (2010)
Introduction A survey published in the November issue of the journal Health Affairs reports that academic researchers' links with industry are on the ebb (Health Affairs 28, 1814–1825, 2009). The survey's results contrast with a growing perception in the media and political circles that industry's influence on academic research is on the increase—claims that have been fueled by high-profile cases in which researchers have failed to fully disclose corporate ties. An ongoing investigation by US Senate Finance Committee member Chuck Grassley into federally funded-researchers who flout the rules on ties with drug makers adds to such views. The data in the study showed that of the 3,080 scientists interviewed, 52.8% reported some kind of relationship with industry within the past three years. Overall, 20% of research faculty received industry funding, a drop from the 28% faculty who took part in a similar survey in 1995. "Universities and academia are eager to form relationships with industry, and politicians expect it. And yet at the same time, we keep finding complaints about conflicts." Art Caplan, professor of bioethics at University of Pennsylvania and director of its Center for Bioethics, describes the inherent contradictions in the situation. "It's almost as if the people we elect as public officials say 'get married to industry', but then our ethics say 'be careful about consummating the marriage'." The report's respondents were drawn randomly from life science departments at the top 50 US National Institutes of Health (NIH)-funded universities. Industry ties included consulting, paid speaking, research funding through a grant or contract as the principal investigator, and sitting on scientific advisory boards. A subset focusing on scientists working in biotech found industry collaborations to be 17%, compared with 23% in 1985 and 21% in 1995. Over the three year period covered in the report, industry supplied an average of $33,477 in research funds, excluding overheads, per respondent, a figure which constitutes 8.7% of all research funds received by faculty. Clinical faculty members received a greater proportion of their funds from industry than did non-clinical faculty members (10.5% versus 2.5%). Industry funding was significantly higher within clinical departments than in nonclinical departments (47.3% versus 26.3%). Of the faculty with industry support, the median amount of industry funding in 2006 was $99,000—similar to the (Consumer Price Index–Medical adjusted) value of $91,500 in 1996. One explanation for the drop may be the fallout from a series of scandals that have rocked the medical community and adversely affected public opinion. Grassley's probe into irregularities in disclosures of industry ties has damaged the reputations of several high-profile academics, including Stanford University's Alan Schatzberg, Brown University's Martin Keller and Emory University's Charles Nemeroff (Nat. Biotechnol. 27, 411–414, 2009). Such scandals are nothing new: almost a decade ago, University of Pennsylvania researcher Jim Wilson was enveloped by accusations of malfeasance when he failed to disclose a stake in Sharon Hill, Pennsylvania-based Genovo, the company that developed the ornithine decarboxylase gene therapy used in Wilson's trial that led to the death of teenager Jesse Gelsinger. In that case, even though Genovo provided no direct sponsorship or support for Wilson's trial, the perceived bias still severely damaged his reputation. Such cases thus not only ! have led to a tightening in ethical oversight of industry–faculty interactions, but also may have increased reticence on the part of academics to partner with companies. The customary solution for such conflicts of interest (COI) is disclosure and transparency. But a report published in November by the US Department of Health and Human Services states that >90% of universities rely on professors to disclose their own conflicts, rather than file reports with the NIH as required, a factor that may tacitly encourage under-reporting. Universities are reluctant to force NIH-funded researchers to disclose financial relationships with drug makers for fear that they may lose those researchers—along with the researchers' star power and associated revenue for the university—to other institutions with fewer restrictions. If many agree that oversight of COI in academia is inadequate, only a few have offered clear proposals for improving the situation. A report by the Washington, DC-based Institute of Medicine published last April (http://www.iom.edu/en/Reports/2009/Conflict-of-Interest-in-Medical-Research-Education-and-Practice.aspx) calls on health research centers, journals, professional societies and others to strengthen their COI policies through greater transparency, by rejecting gifts and by insisting that advisory boards do not themselves have members with industry ties. "You want experts making decisions," says Bernard Lo, Director of the Program in Medical Ethics at the University of California, San Francisco, who chaired the Institute of Medicine committee. "But the burden should be on those who say we can't find a qualified expert who doesn't have significant conflicts." Some universities and a few states have attempted to address complaints about ethics in industry–faculty relationships by implementing new, tighter laws and regulations. An acknowledged problem with these tougher policies is that they tend to restrict productive interactions. "Some relationships are desirable," says Lo. "They benefit the public and industry as well as academia and should be fostered." Minnesota is among a handful of states that require drug and device makers to disclose payments to clinicians. Minnesota's 1993 laws restricting interactions between industry and academic scientists have become a model for other states and may be emulated at the federal level. Last October, however, Michael Gonzalez-Campoy, an endocrinologist from Sunfish Lake, Minnesota, gave testimony about the effect of the 16-year-old legislation on the practice of medicine in the state. According to Gonzalez-Campoy, the legislation has led to a decline in medical education, confusion among patients and damage to the reputations of academics, who are forced to report relationships with industry in a manner that suggests it is always unethical. "Entire practices have closed their doors to the marketing side of industry. Some of these include prominent institutions, such as Allina, Mayo Clinic, Fairview and Park Nicollet. In turn, pharmaceutical companies have trimmed their local sales forces and several would rather not do business in Minnesota—they are gone from the state," Gonzalez-Campoy said. Gonzalez-Campoy testified, he did not, however, offer any information about patient outcomes. In fact, there are no studies that address how patients are affected by COI issues. The activist group PharmedOut has submitted an open letter to Francis Collins, director of the NIH, signed by a large group of scientists, physicians and ethicists, asking that the NIH fund studies on medical ethics, COI in medicine and research and prescribing behavior (http://www.pharmedout.org/NIHLetter.pdf) The issue has ruffled the feathers of many academics who work in translational research. Some feel under attack for their interactions with industry and characterize regulators and ethicists as a group of pencil pushers out of touch with the realities of science and patient care. "Conflict of interest is a meaningless term. It implies malignancy...If I have an interest in a company, I want that company to succeed, and that company is interested in me because of my objectivity and reputation and scientific integrity. If I compromise that, I'm of no use to anybody," says Thomas Stossel, professor of medicine at Harvard Medical School. According to Stossel, attempts made by universities to eliminate or reduce COI tend to stifle beneficial relationships. For example, Harvard's current policy prohibits a researcher from owning equity interest in a company and at the same time receiving money from the company. Stossel, who has equity interests in ZymeQuest of Beverly, Massachu! setts. and Critical Biologics Corporation (CBC) of Cambridge, Massachusetts, believes that equity is a positive incentive for scientists. "So here we have a rule that's predicated on the assumption that [...] the inventor intends to cheat, lie or steal. That's really disrespectful." Harvard University is undergoing a comprehensive review of its COI policy, and it declined to comment for this article. At other universities, similar policies seek to protect the integrity of education of graduate and postdoctoral students—essentially, to prevent the university from becoming a branch of the research and development department of grant-funding companies. However, for an early-stage biotech company, offering stocks in lieu of cash for consulting is an easy way to stretch a startup budget. If such liaison makes later sponsorship of the same scientist's research difficult or impossible, it could become an obstacle to product commercialization. Taking the industry's perspective, Paul Pomerantz, of the Drug Information Association, based in Horsham, Pennsylvania, notes, "No doubt the current scrutiny of the drug industry–academic relations has had a chilling effect on the dollars that are available to academia." He adds that strong ties are desirable to ensure clinical studies benefit from academic rigor. ADVERTISEMENT There could be a completely different explanation for the findings reported in Health Affairs: a drop in industry funding associated with the economy. Lila Feisee, who is the resident expert on these issues at BIO, believes this is unlikely because academic–industry licensing activity is holding steady. "We do hear that maybe sometimes, when companies work with universities, it could be a smoother process. Some tech transfer offices are more savvy than others." A consensus on the subject is unlikely, at least until more data are made available. Until then, Eric G. Campbell, the lead author of the Health Affairs paper and director of research at the Institute for Health Policy, Harvard Medical School, thinks that relationships with drug makers will continue to shrink. "Industry is less viable as a long-term funding source," he says. Its funding "tends to be small in amount and short in duration—and it's getting smaller." - China's GM rice first
- Nature Biotechnology 28(1):8 (2010)
Introduction Chinese officials have approved a strain of genetically engineered rice, placing the country in position to be first in the world to produce biotech rice on a commercial scale. China's Ministry of Agriculture in December said it had issued safety certificates for the rice but that additional production trials are required before full commercialization can begin. The trials may take two to three years. The rice variety, engineered to fend off pests with toxins from the bacterium Bacillus thuringiensis (Bt) was developed by scientists at Huazhong Agricultural University in Wuhan, China. News of the approval came in November, only a week after Chinese officials had announced approval of the country's first transgenic maize. The feed crop is engineered to produce phytase, an enzyme that helps animals better utilize phosphorus in maize. China's most widely grown transgenic crop, Bt cotton, was approved in 1997. China isn't the first nation to approve biotech rice, but it may be t! he first to commercialize it. US regulatory officials in 1999 approved, or deregulated, Bayer CropScience's transgenic herbicide-tolerant rice, but the North Carolina-based company never commercialized it. "Farmers are concerned that it will hurt their export markets," in countries that don't allow transgenic rice, says Doug Gurian-Sherman, a senior scientist at Cambridge, Massachusetts–based Union of Concerned Scientists. Farmers' fears were realized in 2006 when an unapproved transgenic rice variety contaminated US commercial rice, resulting in lost exports. - Pea trials flee to US
- Nature Biotechnology 28(1):8 (2010)
Introduction Field trials of transgenic peas developed by a European university may relocate overseas to ensure a biotech-friendly environment. The University of Hannover in Germany is eyeing North Dakota as a safe place to evaluate several genetically modified (GM) pea lines intended as animal feed, under field conditions, marking the first time that EU-funded plant research has been forced to emigrate. "Vandals are seen as heroes by some media. [Field trial] locations have to be disclosed precisely so that the eco-terrorists can program their GPS," says Hans-Jörg Jacobsen, whose laboratory engineered the GM peas to express one or more antifungal genes. The relocation will be part of a scientific collaboration still under negotiation with the North Dakota State University (NDSU). Pollen flow is not a problem because peas are self-fertilizing plants, but in Germany, field testing could get into trouble anyway, and Jacobsen predicts there is an 80% chance the fields would be destroye! d. "We face a militant resistance, which is extremely difficult to handle by a scientist which usually has only a small budget and limited personnel," sympathizes Jens Katzek from BIO Mitteldeutschland, a cluster promoting biotech. US trials are not expected to begin before 2011 for logistical reasons and will be performed ensuring "the highest level of containment and separation from commercial pea production channels," says Kevin McPhee a plant geneticist at NDSU. - Investor volatility plagues drug companies on new Chinese exchange
- Nature Biotechnology 28(1):9-10 (2010)
Introduction Small and medium-sized companies listing on ChiNext, a new Chinese stock market launched six weeks ago in Shenzhen, have been buffeted by investor volatility and insider trading. Despite the roller coaster ride, proponents say the exchange will offer a much-needed exit for Chinese domestic companies that generate profits. Indeed, the four Chinese drug companies that have so far floated on the exchange all achieved high initial valuations (Table 1). Even so, it will likely be some time before the new exchange will offer a bona fide alternative to more traditional markets, such as the New York–based NASDAQ exchange, let alone attract companies and investors from beyond China's borders. The ChiNext market, also called the China Growth Enterprise Market (GEM), has been in the making for more than eight years, says Hui-Hsing Ma of German venture capital (VC) firm TVM Capital, of Munich. Chinese domestic companies have been clamoring for such an exchange, says Ma, because government 'offshoring' restrictions have prohibited them from listing on foreign bourses. The long time from inception to launch is primarily a result of caution on the part of the Chinese authorities, who are anxious to avoid any risk of failure for domestic investors and are also ploughing money into startup funds for biotech (see Box 1). This cautious approach initially appeared to have paid off: during ChiNext's first day of trading on October 30, all 28 listed companies soared in price. Intense broker speculation even forced regulators to step in and suspend trading at one point. Over the next two weeks, shares rose by 10%, reaching a trading limit of 88.1 yuan ($12.9) for Sichuan Jifeng Agricultural Machinery Chain, located in the southwest Sichuan Province. On December 4, however, state regulators ordered that same company to close its trading account over alleged share price manipulation. Investors panicked, share prices plunged and more than two-thirds of the listed equities ended far below their starting prices. Twenty of them dropped by the maximum daily limit of 10%, triggering another suspension of trading, with Tianjin-based Chase Sun Pharmaceutical among the ten worst performers. ChiNext is centered on a range of high-tech businesses, from electronics and clean energy to software, robot design and biotech. Four biotech/pharma companies are listed on the exchange (Table 1)—Chongqing Lummy Pharmaceutical in the Chongqing municipality, Anhui Anke Biotechnology in Anhui province, Beijing Beilu Pharmaceutical and Chase Sun in Tianjin municipality—as developers of innovative drugs rather than the traditional generics or device firms. To qualify for ChiNext, companies must generate at least ¥50 million ($7.4 million) in the previous fiscal year, and made profits of at least ¥5 million in that year, or ¥10 million in two years. This excludes most high-risk, development-stage biotech companies, which have no products on the market. Despite the restrictions on company eligibility, the immaturity of the Chinese market and signs that local investors are looking to turn a quick profit, several analysts are upbeat. The new exchange will provide not only investment opportunities but also a new financing vehicle for fledgling Chinese companies. "Despite irrational near-term market performance, long-term prospects are rosy," says Zhang Yuanda, deputy secretary-general of China Association for SMEs (small and medium-sized enterprises). Indeed, although Ma says it is very early days, the high initial valuation achieved "is a definite incentive for this exit/financing option," indicating that ChiNext could be an important source of capital for the Chinese biotech industry at least. That said, when Chinese biopharmaceutical firm Nuokang announced in November it wanted to raise up to $69 million from an initial public offering (IPO) (it raised $32.9M in the end), it chose to file it on the NASDAQ rather than in China, even though Nuokang is profitable and thus would easily qualify for a ChiNext listing. The strict eligibility requirements for ChiNext also offer advantages, according to Ma. "This makes it less risky than other pre-revenue exchanges in the region, like the Tokyo's MOTHERS and Korea's KOSDAQ," says Ma. However, the need for profitability means that the exchange will be unlikely to provide another source of funds for cash-hungry Western biotech firms or for their backers looking for a better-value exit than selling up to big pharma or a rival biotech firm. The regulatory, financial and language hurdles of the Chinese markets continue to be too daunting: "China is a difficult place to figure out", says Drew Senyei, managing director of VC firm Enterprise Partners in La Jolla, California. In any case, many venture capitalists think that a return of the US or European IPO market is the only real hope for cash-hungry biotechs. "We are cautiously optimistic about the US IPO market for biotech, but are much less so about the other markets," says Jamie Topper, general partner at Frazier Healthcare Ventures, of Menlo Park, California. ADVERTISEMENT Markus Hosang, general partner at VC firm BioMedPartners in Basel, is also unenthusiastic about the idea of a Chinese float. "We do look for M&A exits for our companies on a global basis, but an exit through IPO would probably have to take place on one of the European stock markets," he says. David Seemungal of Cubase Consulting, London, reckons the more successful Western biotech companies will probably shy away from the Chinese market until they perceive that more robust intellectual property enforcement is in place. And far from benefiting from China's accelerating move into biotech, the West could even lose out, says Seemungal. "There could be a brain drain of biotech expertise from ailing Western biotechs to Chinese-based biotech companies newly established on the back of Chinese state funding," he says. - GM crop biosafety lab folds
- Nature Biotechnology 28(1):10 (2010)
Introduction A fully equipped laboratory for studying pathogen-resistant transgenic plants will close its doors by the year's end. The International Centre for Genetic Engineering and Biotechnology (ICGEB) Biosafety Outstation in Ca'Tron di Roncade, Treviso, Italy, was set up to study potential risks concerning genetically modified crops and plant pathogens of importance to the developing world. The outstation's facilities, part of the ICGEB, were refurbished with financing from Treviso-based Cassamarca Foundation, supported by banking group Unicredit. But the bank's financial woes have prevented the foundation from renewing the 4-million ($5.7 million), 5-year contract, says Mark Tepfer, leader of the outstation's Plant Virology group. Tepfer will transfer some his projects to his permanent appointment at the French National Institute for Agricultural Research in Paris. "I'm fairly optimistic that we'll find a way to continue," he adds. The ICGEB operates under a treaty signed by 59! countries within the United Nations system to conduct research and education in biomedicine, crop improvement, environmental remediation and biopharmaceutical and biopesticide production throughout the developing world. ICGEB administrator Decio Ripandelli hopes to shift some of the outstation's research and education programs to the Trieste and New Delhi groups. Ripandelli says he lobbied the Cassamarca Foundation to put the facilities, including a high-containment greenhouse, into a "pharmacological coma" to avoid restarting from scratch but the foundation is noncommittal. Ripandelli says, "It's really a pity and a scandal if the facilities are not used." - Plant genomics' ascent
- Nature Biotechnology 28(1):10 (2010)
Introduction Grants supporting plant genome research in the US have reached an all-time high. Over 2009, the National Science Foundation (NSF) doled out nearly $102 million, the largest sum since the annual grant program began in 1998. The funding aims to increase understanding of plant gene function and the interaction of plant genomes and the environment. "This funding lets you tackle bigger problems," says David Salt, a former grant recipient and plant biologist at Purdue University. "It lets you devise more integrated and collaborative projects." The NSF chose 32 projects focused on "economically important crop plants" ranging from West African cultivated rice to poplar trees, according to the foundation. The largest award, worth more than $10.4 million over four years, went to a proposal to help complete the international effort to sequence the tomato genome. James Giovannoni at Cornell University's Boyce Thompson Institute for Plant Research in Ithaca, New York, leads t! he project. The NSF also chose for the first time a switchgrass research project. With a grant worth more than $4.5 million, Thomas Juenger and his team at the University of Texas at Austin will explore over the next four years how switchgrass responds to drought and other stresses caused by climate change, to expand the knowledge needed to develop switchgrass as a biofuel crop. - Roger Beachy
- Nature Biotechnology 28(1):11-12 (2010)
Plant scientist Roger Beachy has joined the Obama administration to lead the National Institute of Food and Agriculture (NIFA), the new research funding arm of the US Department of Agriculture (USDA). Beachy, whose research led to the first transgenic crop, was previously the long-time head of the not-for-profit Donald Danforth Plant Science Center in St. Louis. Emily Waltz talks to Beachy about his plans for the new agency. - Up in a cloud?
- Nature Biotechnology 28(1):13-15 (2010)
Cloud computing offers solutions for companies wrestling with large-scale data sets, but security issues will likely continue to restrict its use to precompetitive or nonconfidential data. Clare Sansom reports. - Backing your brand
- Nature Biotechnology 28(1):16-19 (2010)
- Harmonizing biosecurity oversight for gene synthesis
- Nature Biotechnology 28(1):20-22 (2010)
Introduction To the Editor: As highlighted in your December issue, commercial gene synthesis companies routinely sell long strands of made-to-order DNA to researchers around the world. Observers have long speculated that individuals, terrorist organizations and governments could potentially use this DNA to create pathogens and other biosecurity threats. Last November, two separate industry groups—the International Association Synthetic Biology (IASB) and the International Gene Synthesis Consortium (IGSC)—issued competing standards1, 2 specifying the precautions that companies should take before they provide artificial DNA to customers. So far, roughly a dozen gene synthesis companies in the US, Europe and China have promised to follow one or the other of these standards. More recently, the US Department of Health and Human Services has similarly announced its own draft 'Framework Guidance' recommending steps that commercial gene synthesis providers should take to screen incoming orders3. Readers wh! o follow private sector 'standards wars' will immediately recognize that the current situation is unstable and only one of these three standards is likely survive in the long term. Furthermore, the prevailing standard will almost certainly set security policy in this area for many years. As we explain below, the choices are profound. On the one hand, the US government's draft Guidance embraces an automated 'Best Match' approach that defines threats based on how closely they resemble the so-called Select Agent list. We argue that this procedure is clearly less capable (but also less expensive) than either private standard, both of which require human experts to investigate gene function any time a customer sequence resembles a pathogen or toxin found in government's enormously larger Genbank database. On the other hand, the two private standards—despite their strong substantive similarities—also present an important choice. This is because the IASB standard was developed! openly in public meetings, whereas the IGSC standard was writ! ten behind closed doors by five large companies. For better or worse, the winning standard will almost certainly have a profound impact on future transparency both within the gene synthesis industry and in its dealings with the wider public. Since 1999, when suppliers started making DNA to order, industry observers understood that artificial DNA could potentially be used to 'resurrect' pathogens such as smallpox that are no longer found in nature, build genetically engineered weapons similar to those pursued by the Soviet Union in the 1980s or exploit the new science of synthetic biology to create artificial pathogens. Within a few years, most gene synthesis companies had developed and implemented programs to screen incoming orders for security threats. Most companies did this by comparing customer-submitted sequences against GenBank (http://www.ncbi.nlm.nih.gov/Genbank/). They then paid human experts to determine whether the closest homologs encoded functions that could be used to make weapons. Where the answer was problematic, companies would conduct a further investigation to make sure that the customer existed, had a legitimate use for the DNA and had thought through any safety or biosecurity issues. Today, ! most current and proposed screening protocols follow this same basic structure. The problem is that each DNA synthesis company imiplements this system differently. This means that across the industry, practices are highly nonuniform, with a few firms paying relatively little attention to biosecurity. Things would be better, industry observers agreed, if companies could be persuaded to converge on a uniform (and hopefully high) standard. In principle, there are two ways to accomplish this. The first and most familiar method is government regulation. In late 2006, the US government's National Science Advisory Board for Biosecurity (Washington, DC) asked the federal government to prepare formal guidance on how gene synthesis companies should screen incoming orders4. Shortly afterward, the US government convened a formal interagency task force to develop this vision into formal guidelines. However, there is also a second path: private agreement. In April 2008, Europe's leading gene synthesis industry trade association, the IASB, hosted a meeting in Munich where leading companies from the United States and Europe discussed what they could do to improve biosecurity at the grassroots level5. Participants quickly agreed to develop a new code of conduct. By mid-2008, both industry and government were hard at work developing screening standards. As it turned out, the private track was slightly faster. IASB produced a first draft "Code of Conduct for Best Practices in Gene Synthesis" in late 2008, which members continued to comment on into the first half of 2009. In keeping with the practice at most companies, this Code of Conduct required commercial gene synthesis providers to compare incoming orders against GenBank and use human experts to determine what the closest GenBank matches encoded. If the GenBank match was problematic—most notably, if it encoded a protein associated with virulence—members would have to conduct additional customer investigations before filling the order. On November 3, IASB held a meeting in Cambridge, Massachusetts, USA, to produce the final text of IASB's Code2. In the course of these discussions, participants agreed to narrow the draft Code so that members would only have to investigate sequences that corresponded to known pathogens. (The compromise was based on a judgment that c! urrent technology is incapable of making threats from the DNA found in other organisms.) Seven companies, including four European and one Chinese gene synthesis companies, had signed this final Code by late November. IASB's US counterpart trade association, SynBIA (http://www.synbia.org/), also announced its support. Alas, industry standard-setting is a messy business. Shortly after IASB announced plans to finalize its draft, two gene synthesis companies, DNA2.0 (Menlo Park, CA, USA) and Geneart (Regensburg, Germany), put together their own, competing proposal6. Unlike IASB's code of conduct, the DNA2.0/Geneart method did not require companies to screen against GenBank or pay human experts to determine what the closest matches encoded. Instead, the companies argued that commercial DNA providers should compare customer sequences against a predefined list of threats. The main advantage of this method, its authors pointed out, is that it can be done by computer and so promises to be both "fast" and "cheap." At the same time, a really exhaustive threat list would have to be coextensive with GenBank—and such a thing will not be possible for many years. This makes the Geneart/DNA2.0 approach far less capable than systems that rely on human experts. By October, it was obvious that DNA2.0 and Geneart were quietly reaching out to companies around a new and possibly revised standard. Nothing happened, however, until several weeks after IASB finalized its code of conduct. Then, on November 19, five companies—DNA2.0, Geneart, Blue Heron (Bothell, WA, USA), IDT (Coralville, IA, USA) and Genscript (Piscataway, NJ, USA)—announced that they had formed the IGSC and developed a "Harmonized Screening Protocol" to guide the industry3, 7. Encouragingly, this new document tracked the IASB's code in almost every detail. Indeed, it even dropped DNA2.0/Geneart's previous suggestion that screening should be based on predefined lists. Instead, like IASB, the IGSC code states that companies should "screen the complete DNA sequence of every synthetic gene order... against all entries found in one or more of the internationally coordinated sequence reference databanks (i.e., NCBI/GenBank, EBI/EMBL or DDBJ)." It goes on to state th! at when this procedure identifies "a potential pathogen or toxin sequence," orders should receive further review "by a human expert." Many industry observers find this family resemblance between the IASB and IGSC standards puzzling. After all, IASB's Cambridge meeting had been open, and two IGSC companies (Blue Heron and Geneart) had actually attended. Why write an entirely new Protocol when IASB's Code of Conduct already existed? The reason, we think, is that IGSC membership is limited to large companies or, as one IDT representative recently put it, companies that operate a "significant business in gene synthesis"7. As they dominate the DNA-to-order market, the five IGSC members preferred to write their own Protocol behind closed doors. Joining IASB—which is open to all gene synthesis companies, regardless of size—would dilute their control. IGSC has also indicated in its protocol that members may change the text in the future. As Nature Biotechnology goes to press, the world's gene synthesis companies thus have two voluntary standards from which to choose. As in most private sector 'standards wars'—think of the battle between VHS and Betamax video formats—the winner is likely to be decided quickly. And that will set up the endgame. Everyone knows that big pharma and other large customers are bound to embrace the winning standard. Once that happens, gene synthesis companies from Iowa to Shanghai will have to adopt it if they want to stay in business. By late last year, the US government regulation process was also in its final stages. One might have thought that the government would have been happy to endorse the high standards adopted by IASB and IGSC. Instead, on November 27, it published draft guidelines1 that call for a very different approach. Under this 'Best Match' method, companies would only perform a follow-up investigation if a customer's sequence were "more closely related to a Select Agent or Toxin sequence than to a non-Select Agent or Toxin Sequence." Like earlier suggestions based on predefined lists, Best Match is easy to automate and therefore fast and cheap. But it is also less capable. Indeed, even the guidelines admit that the "non-Select Agents or Toxins" that Best Match ignores "may pose a biosecurity threat." This is very different from the IASB and IGSC approaches, which require human experts to examine all pathogen and toxin matches. (The federal draft guidelines do point out that co! mpanies "may [emphasis supplied] choose to investigate such sequences as part of their best practices," but this is only a suggestion.) Clearly, commercial gene synthesis has come to a crossroads. For many years, the idea of a common, industry-wide screening standard was either theoretical or left to the indefinite future. Now, suddenly, policymakers have three to choose from. How should society approach this embarrassment of riches? For now, the US government's draft guidelines pose the most pressing issue. The problem is obvious: if the US government thinks that Best Match is sufficient, why should any company pay human experts to carry out the IASB or IGSC standards? And indeed, several IGSC members have already said that they think Best Match is sufficient8. In truth, this is a cost-benefit judgment and no one can be sure that having human experts investigate GenBank matches is worth the effort. Nevertheless, it seems strange for government to tell companies that current screening programs are, in effect, too ambitious. Given that most companies have already volunteered for a high standard, government should do no less. Probably the simplest way to do this will be to revise the draft guidelines so that companies practice both Best Match and human investigation each time GenBank searches turn up pathogen and toxin genes. Readers interested in the issue should e-mail comments on the guidelines to e-mai! l: asprfrcorrespondence@hhs.gov on or before January 26, 2010. In the long run, society will also need to choose between the IASB and IGSC standards. We have already argued that the only key difference concerns openness. This matters for several reasons. First, we see no good reason why small gene synthesis companies should not have a voice in setting their own standards. To the extent that standards affect competitiveness, they should be fair to all. Moreover, synthetic biology as an industrial field is rapidly developing, so that today's small gene synthesis company could easily be tomorrow's large biofuels player or contract research organization. In this context, it seems arbitrary to limit IGSC's membership based on current (and possibly transient) market share. The second reason for openness has to do with public trust. Openness—and inviting criticism—were key in showing the public that the IASB's Code of Conduct had been carefully designed. This openness will be needed again. For example, the IASB, IGSC and draft US federal guidelines say relatively little about how companies should investigate their customers. What should companies do for the handful of orders—estimated to be one or two per thousand9—where a customer (i) seeks a potentially dangerous sequence and (ii) is an individual or else is affiliated with an unknown start-up company? Suggestions based on computerized checks against, say, Dun and Bradstreet listings—which are notoriously subject to fraud10—strike us as clearly insufficient. But when human intervention is needed, companies must have detailed guidance as to which methods are and are not acceptable. These are hard questions that must not only be solved correctly but also shown to the public to have ! been solved correctly. ADVERTISEMENT Finally, openness is efficient. IASB and one of us (S.M.M.) at the University of California, Berkeley's Goldman School of Public Policy are now collaborating on pilot software for a proposed online forum (VIREP) where experts who investigate genes in the course of screening will be able to deposit their research. Sharing these data will save companies the trouble of investigating the same genes over and over again. Nothing will happen, however, unless companies are open with one another. It is difficult to see how this can happen under standards that are set by a few self-described 'significant' companies. The high standards set forth in the IASB and IGSC standards could still collapse. And even if they don't, no one can be sure whether future standards will be set in an open and transparent way. Still, gene synthesis companies have come a long way since IASB members first agreed to pursue an industry-wide Code of Conduct. The goal is in reach. - Correcting the record
- Nature Biotechnology 28(1):22-23 (2010)
Introduction To the Editor: As executive director, and on behalf, of the International Life Sciences Institute (ILSI; Washington, DC), I write to correct certain statements regarding ILSI made by David Schubert in a letter published in the September issue1. In suggesting that University of Georgia Professor Wayne Parrott was incorrectly characterized in a news article as a "public sector" scientist, Schubert accurately noted that Parrott is a scientific advisor to ILSI, but failed to acknowledge he was not speaking in any capacity relating to ILSI. Schubert then proceeded inaccurately to characterize ILSI as a "lobby group" and repeated a claim—made in an anonymous article on a Wikipedia-style website—that ILSI has a "hidden agenda to protect the interests of the food, chemical, and drug industries." Schubert further claimed that ILSI had been "banned from participating in World Health Organisation [WHO; Geneva] activities." These statements are both derogatory and untrue. First, ILSI has no "hidden agenda." ILSI is a respected world leader in scientific inquiry relating to nutrition, food safety, toxicology, risk assessment and the environment. ILSI has achieved this status through its tripartite operating model of bringing together scientists from academia, government and industry, which, in addition to producing broadly informed scientific output, also helps to ensure that ILSI's work is balanced and directed toward the public good rather than the commercial interests of its members. ILSI also publishes the results of its work, irrespective of whether it could be considered beneficial or harmful to its members' interests. Second, ILSI is not a "lobby group"; it is a public charity exempt from taxation under US Internal Revenue Code § 501(c)(3) and, as such, is prohibited by law from attempting to influence legislation as a substantial part of its activities. Since its inception, ILSI has gone beyond this legal prohibition and has refrained from lobbying. ILSI's board of trustees has always endorsed this stance. The most recent (March 2009) articulation of this tenet is found in the International Life Sciences Institute Code of Ethics and Organizational Standards of Conduct (available on the ILSI website; http://www.ilsi.org/documents/code%20of%20ethics%20(2009).pdf). This document states that, "Advocacy of any kind is strictly limited to promotion of the use of evidence-based science as an aid in decision-making. ILSI does not conduct lobbying activities." Thus, although ILSI does, from time to time, provide scientific information to public decision-making bodies, we do not endorse s! pecific public policy outcomes other than the application of evidence-based science ADVERTISEMENT Finally, WHO has not "banned" ILSI from participating in its activities. Schubert stated inaccurately that WHO has "banned" ILSI from taking part in its activities. It is true that in 2005, certain interest groups and labor unions wrote to the WHO to complain about the fact that ILSI receives industry funding, and expressed concern, among other things, that an ILSI-WHO scientific workshop scheduled for the spring of 2006 could "influence recommendations for the WHO on its Guidelines for Drinking Water Quality due in 2008." A subsequent report of the WHO Board Standing Committee on Nongovernmental Organizations (NGOs) clarified that WHO's collaboration with ILSI was intended to harness ILSI's technical expertise but did not include participation in "normative activities," such as setting microbiological or chemical standards for food and water. Schubert incorrectly implies that the WHO barred ILSI from participation in any of its activities because of doubts a! bout its scientific integrity. However, the truth is that ILSI had never participated in the standard-setting matters in question because the WHO had consistently reserved the right to set such standards without direct collaboration with outside organizations. Moreover, the WHO continues to recognize ILSI as an accredited NGO and continues to work with ILSI, as it has since 1991. On the basis of the above evidence, the derogatory statements made about ILSI in Schubert's letter go well beyond the mere expression of opinion, and instead constitute assertions of fact that are simply untrue. - Reply to Correcting the record
- Nature Biotechnology 28(1):23 (2010)
Introduction David Schubert replies: Suzanne Harris has four concerns about my letter in the September 2009 issue of Nature Biotechnology1. She claims that I implied Parrott's comments were made as a representative of the International life Sciences Institute (ILSI), that I misstated the ILSI agenda and lobbying status, and that I incorrectly stated that ILSI was banned from World Health Organization activities. The first is simply not true. Nowhere was this implied, for my only goal was to demonstrate that Parrott is not an unbiased academic observer in the transgenic food debate because he has associations with industry-sponsored institutions, such as ILSI. He has, in fact, in the past co-authored letters with industry-backed scientists to Nature Biotechnology similar to that of Harris2. The remaining concerns relate to the legal definition of lobbying or are subjective in nature. With respect to the latter, I will only furnish a few additional references, from which interested readers can make up their own minds. With respect to the agenda of ILSI, although I may be wrong, it seems logical to me that an organization that is heavily funded by the world's largest food, tobacco and transgenic seed companies is going to promote the interests of their support group. Although I did quote a referenced website regarding another group's assessment of the ILSI 'agenda', I recommend an examination of additional documents that some may say reach a similar conclusion. These include citations relating to ILSI activities in "Integrity in Science"3 published by the Center for Science in the Public Interest (CSPI; Washington, DC) and an article by Michael Jacobson4 that outlines the various ways industry is able to manipulate science and public health policy. With respect to lobbying, I was not aware of the legal definition of a lobbying group, and in this context both my cited source for this claim and I misused the word. I apologize for this mistake. It should be pointed out, however, that there are many ways to influence policy independently of formal lobbying, including those outlined by Jacobson4, as well as the 'sound science' approach promoted by Newt Gingrich and the Bush administration5. ADVERTISEMENT Finally, with respect to the ban of ILSI from WHO activities, I did not claim that they were banned from all WHO activities. Because of space limitations, I cited a text that was heavily referenced regarding the details of the WHO incident. Additional references include the Associated Press6 and CSPI3. My conclusion that Wayne Parrott is not simply a public sector plant biologist and should not have been introduced as such remains the same and was in fact confirmed by Nature Biotechnology7. However, it should be the responsibility of Nature Biotechnology to document these conflicts of interest, not a concerned reader, such as myself. A similar conflict with industry-funded plant biologists representing themselves as neutral commentators in the transgenic food debate was documented in these pages many years ago8. - International trade and the global pipeline of new GM crops
- Nature Biotechnology 28(1):23-25 (2010)
Introduction To the Editor: In a previous issue, Paul Christou and colleagues1 highlighted the patchwork of laws and regulations governing tolerance levels for approved genetically modified (GM) material in non-GM food and in the labeling and traceability of GM products. A related but different problem is that of 'asynchronous approval' of new GM crops across international jurisdictions, which is of growing concern due to its potential impact on global trade. Different countries have different authorization procedures and, even if regulatory dossiers are submitted at the same time, approval is not given simultaneously (in some cases, delays can even amount to years). For instance, by mid-2009 over 40 transgenic events were approved or close to approval elsewhere but not yet approved—or not even submitted—in the European Union (EU; Brussels) (for more details, see Supplementary Data). Yet, like some other jurisdictions, the EU also operates a 'zero-tolerance' policy to even the smallest traces of na! tionally unapproved GM crops (so-called low-level presence). The resultant rejection of agricultural imports has already caused high economic losses and threatens to disrupt global agri-food supply chains2, 3, 4, 5, 6, 7, 8. To assess the likelihood of future incidents of low-level presence of unapproved GM material in crop shipments and to understand related impacts on global trade and the EU's agri-food sector, we compiled a global pipeline of new GM crops. Our motivation was to obtain a realistic estimate of how many new GM crops will be commercialized in the next years, by whom and in which countries—and when these new crops will be authorized by the different trading partners of the EU. In this context, we invited a select panel of national regulators, industry representatives, experts from national and international research institutes and actors from the global food and feed supply chain to a workshop organized at the Institute for Prospective Technological Studies of the European Commission's Joint Research Centre in November 2008 to discuss for the first time the issue of low-level presence in view of a growing global pipeline of new GM crops. (For more details, see Supplementary Note! s.) On the basis of this workshop and subsequent desk research, we predict that by 2015 there could be over 120 different transgenic events in commercialized GM crops worldwide—compared with around 30 GM events in commercially cultivated GM crops in 2008 (Fig. 1)9. Although the currently common traits in GM crops (insect resistance and herbicide tolerance) will continue to be the most common traits in 2015, optimized crop composition is expected to gain increasing importance (Table 1). Moreover, we expect that about half the new transgenic events that could be brought to market until 2015 will have been developed by players in Asia (33 in India, 20 in China, 5 in the rest of Asia) and Latin America, with the other half coming from companies in the United States and the EU. (For more details, see Supplementary Data.) Apart from the implication that a quadrupling of the number of transgenic events in commercialized GM crops between 2008 and 2015 is likely to increase the negative impact of low-level presence on international trade (if no fundamental change takes place in the way new GM crops are currently approved in different countries), our study also indicates that new transgenic events are likely to be introduced and that new crops will be targeted. Even so, the current crops dominating the GM landscape (soybeans, maize, cotton and canola) will continue to dominate the picture in 2015 (Fig. 1). Likewise, the long-anticipated product quality traits are likely to come forth only slowly: of a total of 91 new GM crops that are expected to be commercialized between 2009 and 2015, only 18 represent quality innovations (Table 1). This conclusion is supported by a survey reported in the August issue, where Graff et al.10 sought to answer the question of why quality-improving innovations from ! agbiotech have not been more readily forthcoming, and through a survey carried out in 2004 they identified 49 quality innovations, which they expected to be commercialized by 2015 (21 of those between 2010 and 2015). More importantly, though, what our present study indicates is that an increasing number of GM crops are being developed by new players outside the United States or Europe (in particular, by actors in Asia). These new players develop the crops for their population-rich home markets and may therefore be less affected by the marketability of the crops abroad. Just in November, for example, China took a major step towards endorsing the use of a major staple crop, GM rice11. However, as has been seen in the recent cases where traces of GM maize in soybeans led to the rejection of the soybean shipments7, under certain regulatory settings (in particular zero tolerance towards low-level presence) the cultivation of one type of crop may even affect the marketability of other types of crops. This means that if third countries want to authorize GM varieties of crops that are welfare-enhancing for their societies, in future they may also consider the potential impact of 'cross low-level! presence' in different, but export-relevant, crops. The extent to which this situation shapes the approval and development of future agbiotech innovations remains to be seen. Unfortunately, past experience with the use of GM crops shows that irrational fear of export losses represents a significant impediment to biosafety policymaking12. ADVERTISEMENT Disclaimer: The views expressed are purely those of the authors and may not in any circumstances be regarded as stating an official position of the European Commission. Note: Supplementary information is available on the Nature Biotechnology website. - High-density resequencing DNA microarrays in public health emergencies
- Nature Biotechnology 28(1):25-27 (2010)
Introduction To the Editor: Despite epidemiological intelligence and microbiological surveillance systems or programs, virus emergence mostly occurs by surprise. Influenza A virus offers a paradigm of such a situation: the world was focusing on a threat due to highly pathogenic (H5N1) avian influenza A virus in Asia1. Instead, it faced a novel reassortant swine-origin H1N1 influenza A virus (H1N1pdm) with pandemic potential on the American continent2. Seasonal influenza surveillance and pandemic preparedness are potent incentives to develop rapid, specific, sensitive and robust diagnostic tools for laboratories, particularly the World Health Organization's (WHO; Geneva) National Influenza Centers and other laboratories in different countries specialized in epidemic responses. Here, we describe the use of random non-PCR–based nucleic acid amplification and high-density resequencing DNA microarrays to rapidly identify reassorted influenza A virus strains of swine origin. Such an approach could prove us! eful for public health authorities attempting to detect and identify reassortment events in future outbreaks. Worldwide, laboratories have developed or implemented identification assays targeting A(H5N1), A(H7N7), A(H9N2) and sometimes A(H2N2) viruses besides seasonal human influenza viruses A(H1N1) and A(H3N2). Very few anticipated that, one day, there would be a need for the detection of A(H1N1) with swine virus–derived components. Therefore, when the global alert spread worldwide about a new influenza A(H1N1) virus with a novel genetic make-up on April 24, 2009 (ref. 2), all frontline laboratories were abruptly faced with the task of rapidly identifying samples—in the case of our laboratory, as early as two days after the initial global alert. For national health authorities across the world, it was critical that local laboratories were able not only to identify H1N1 viruses but also to differentiate seasonal human H1N1 viruses from swine-like H1N1 strains. Despite prompt dissemination of a specific real-time reverse transcriptase (RT)-PCR set of protocols by the US Centers for Disease Control (CDC; Atlanta) and the very rapid availability of viral sequences on the Global Initiative on Sharing Avian Influenza Databank website (GISAID; http://platform.gisaid.org/dante-cms/live/struktur.jdante?aid=1131/), delays imposed by primer and probe manufacturers prevented immediate implementation of specific H1N1 assays in many centers across the world. Several national influenza centers resorted to performing RT-PCR of the influenza M (matrix) segment followed by sequencing of amplicons. Our laboratory, which focuses on the early identification of microbiological threats but is not specialized in influenza in particular, found another solution. We first used random non-PCR–based nucleic acid amplification of the samples3 followed by high-density resequencing on DNA microarrays (PathogenID v2.0) to identify and characterize four genes o! f the novel reassortant influenza virus from swine origin. We designed the PathogenID v2.0 microarray with a total of 126 viral sequences from a whole range of viruses. It was engineered to detect and describe four genes in order to type and subtype influenza viruses from a large diversity of natural and permanent hosts (humans, birds, horses and pigs) with a minimum of sequences tiled on the array (Leclercq et al., unpublished data; see Supplementary Data for PathogenID v2.0 microarray design). The possibility of using consensus sequences was one of the hypotheses tested in the design of the new version of the microarray. For each of the four genes, from 12 to 148 different sequences were first aligned. From the alignments, a small number of clusters gathering sequences with <15% variation were determined. For each cluster, one to three consensus sequences were computed and used for tiling (see Supplementary Table 1). The H1N1pdm virus that emerged in Mexico in 2009 resulted from a reassortment between the triple reassortant swine influenza virus that had caused considerable problems for pig farmers for several years and a Eurasian swine lineage. The eight segments of the resulting virus were thus from different host origins (that is, (i) avian (for PB2 and PA genes), (ii) human (PB1) and (iii) classic (H1, NP and NS) or avian-like (M, N1) swine viruses)4. From the start of the outbreak, our laboratory faced the urgent need to investigate several suspected cases of human infection by the novel virus. Among the samples processed during the outbreak, some of the isolates (for example, sample 70; designated as A/Paris/2618/2009 (H1N1)) were identified as seasonal human influenza viruses, whereas others (for example, sample 49, designated as A/Paris/2590/2009 (H1N1)) were clearly harboring genes different from those of viruses previously known to circulate in humans. Six original clinical specimens were tested with our PathogenID v2.0 resequencing microarray (Supplementary Methods). Four of the six tested samples were correctly identified as H1N1pdm virus (3/5) or seasonal H1N1 influenza virus (1/1) by BLASTN analysis of all viral sequences obtained (Supplementary Table 2). A low viral load in the original clinical specimens was thought to explain why only two viral segments (M and H1) were detected and identified in the case of sample 49, and no sequence at all was detected in the remaining two samples (data not shown). In these two cases, a quantification by real-time RT-P! CR specific for the M gene showed that they were under the detection limit by the DNA resequencing microarray, which has been estimated to be around 2.5 × 108 viral genomes copies after amplification3. As positive controls, we have successfully tested one prototype human strain A/Bayern/7/95 (H1N1)5 and two strains isolated from pigs, one representing the classical lineage A/Swine/England/117316/86 (H1N1)6 and one representing the Eurasian lineage (also called avian-like) A/Swine/England/195852/92 (H1N1)6, 7. Amplification products of viral RNA of A/Bayern/7/95 (H1N1) cell culture supernatant and of A/Paris/2618/2009 (H1N1) isolate both hybridized with one of the H1 consensus sequences tiled on the array. The BLASTN analysis of the sequences reconstructed by the PathogenID v2.0 microarray showed these strains were seasonal human influenza viruses (data not shown). For the isolate of the novel reassortant A/Paris/2590/2009 (H1N1), all sequences reconstructed from the microarray are presented in Supplementary Figure 1. The hemagglutinin (HA) sequence was reconstructed by hybridization to a H1 tiled consensus sequence that is different from the previous H1 consensus to which ! the seasonal strains hybridized. This shows that the method is useful as a discriminating diagnostic. BLASTN analysis allowed the determination of the segment origin for PB2 (which encodes subunits of viral RNA polymerase), H1 and N1 genes, which were derived from avian, classic swine virus and avian-like swine virus respectively (Table 1). Data on the M gene are not shown because this gene (only represented by one sequence on the chip) has been chosen to provide detection of influenza viruses and identification of their types and not further characterization. Geographical and host origins of PB2 and H1 segments were visualized by a phylogenetic tree generated with a wide range of prototype influenza A viruses (Fig. 1). A reassortment between this novel H1N1pdm and the highly pathogenic avian (H5N1) virus would be a pivotal event as it could generate a new virus with increased pathogenicity and transmissibility. Another event of reassortment leading to the transfer of the neuraminidase (NA) of current seasonal (H1N1) influenza strains to the pandemic prone H1N1pdm would very probably generate a new virus with partial surface antigen shift (on the HA only) but with a high level of resistance to oseltamivir (Tamiflu), a specific and effective drug against influenza8. This would have major consequences for public health and it would be paramount to detect such a reassortment as soon as possible, should it occur. As in many detection algorithms, the first set of protocols made available worldwide by the CDC, NA detection and characterization is generally not performed by first-line laboratories. In-depth characterization is therefore delayed until diagnostic confirmation and is undertaken by wo! rld-level reference centers. The avian strain A/Duck/Cambodia/D4(KC)/2006 (H5N1) on its own was successfully tested for PB2, HA and NA by the DNA microarray (data not shown). Various mixtures of equivalent amounts of RNA of influenza viruses belonging to the same subtype (H1N1) or in combination with different subtypes (H3N2 or H5N1) were then processed and hybridized onto the PathogenID v2.0 microarray. In all tested cases, all segments of H1N1pdm virus were detected and identified after a BLASTN analysis. The generated sequences were not affected by the presence of other viral sequences, even within the same molecular subtype. This strategy allowed a large viral genetic diversity to be covered and proved to be discriminating, even in the presence of a mixture of viral RNAs (see Table 1 and Supplementary Table 3). Non-PCR amplification systems, such as loop-mediated isothermal PCR, nucleic acid sequence-based amplification and rolling circle amplification, are used for viral diagnosis, but all these approaches need specific primers. Random PCR-based amplification processes are available but although random priming can amplify an unknown target, it often yields lower amounts of DNA than specific primers, which can reduce the overall sensitivity of the process. In previous studies, we showed that Phi29-based multiple displacement amplification is much more sensitive than random PCR3 because amplification is random and thus independent of any specific or orientated process (unlike quantitative RT-PCRs9 or specific hybridization DNA microarrays10 that can be developed only after a new viral strain is identified). ADVERTISEMENT Taken together with the advantages of our amplification protocol, we feel the PathogenID v2.0 DNA microarray offers several advantages over existing diagnostics for detecting novel pathogens. First, the microarray is able to generate sequences that are not already tiled. Second, PathogenID v2.0 is ready for use (indeed, its deployment in analyzing field strains might have enabled earlier identification of the novel H1N1 virus when it first emerged, which is thought to have been several months before the outbreak was officially recognized)4. Using PathogenID v2.0, any laboratory around the world could potentially carry out rapid and accurate viral identification. In addition, there would be no lag time between public health authorities issuing an alert and laboratories around the world implementing tests. Although high-throughput pyrosequencing technologies, such as the 454 FLX system marketed by Roche Diagnostics (Basel), can also be deployed for in-depth characterization of! novel viruses, the cost of sequencing instrumentation and reagents, as well as the delay in interpreting the data, makes these systems less useful to public health authorities seeking the first occurrence of a novel virus in a given country. Although the sequence information provided by resequencing microarrays are more limited than those produced by high-throughput pyrosequencing technologies, their ability to generate results as early as 24 h after the beginning of the experiment is a substantial advantage. The versatility, the rapidity and the high discriminating power of the PathogenID v2.0 microarray could prove critical to detect and identify reassortment events and therefore prompt health authorities to take efficient decisions for patient treatment and for outbreak management. Note: Supplementary information is available on the Nature Biotechnology website. - Clinical comparability and European biosimilar regulations
- Nature Biotechnology 28(1):28-31 (2010)
Clinical trials required by European regulators to compare biosimilar products with corresponding biologic brands are surplus to requirements and may even be a barrier for the development of biosimilars of more complicated biologics. - The intellectual property landscape for gene suppression technologies in plants
- Nature Biotechnology 28(1):32-36 (2010)
Reviewing the major features in the patent landscape of RNA-mediated gene suppression may aid the development of patent strategies that will support the next generation of genetically modified crops. - Recent patent applications in induced pluripotent stem (iPS) cells
- Nature Biotechnology 28(1):37 (2010)
Introduction Recent patent applications in induced pluripotent stem (iPS) cells Table 1 - Putting the lid on phosphodiesterase 4
- Nature Biotechnology 28(1):38-40 (2010)
Structural insights into the regulation of phosphodiesterase 4 lead to the discovery of allosteric modulators with reduced side effects. - Enriching quantitative proteomics with SIN
- Nature Biotechnology 28(1):40-42 (2010)
A new metric called the normalized spectral index (SIN) provides a simple way to quantify and compare label-free proteomics data. - Small but not simple
- Nature Biotechnology 28(1):42 (2010)
Introduction Even for the simplest organisms that can be grown in laboratory media, such as bacteria of the mycoplasma family, we are far from understanding all of the design principles and essential functions needed to sustain life. For instance, more than a quarter of the 370 essential protein-coding genes of Mycobacterium genitalium have no known function1. Three recent papers in Science2, 3, 4, by a consortium of research groups led by Peer Bork, Luis Serrano and Anne-Claude Gavin, illustrate the complexity of Mycobacterium pneumoniae through comprehensive analyses of its transcriptome2, proteome3 and metabolome4. M. pneumoniae has one of the smallest known genomes of a self-replicating bacterium, comprising 816 kb and encoding just 689 proteins, only 8 of which are predicted to be transcription factors. The observation that 89 of the 117 new transcripts identified are antisense to annotated genes reveals a hitherto unappreciated level of gene regulation2. Moreover, many genes were f! ound to produce more than one transcript2. Proteome analysis showed that at least 90% of the proteins studied are part of at least one of the 178 protein complexes identified3. More than half of these complexes had not been described previously. Reconstruction of the metabolic network revealed that many redundancies and branched pathways common to other organisms are not present in M. pneumoniae4. However, despite its low number of metabolic enzymes and transcriptional regulators, the bacterium is able to perform a large variety of metabolic reactions and to adapt quickly to changes in the environment. The former can be explained by the large fraction of multifunctional enzymes, whereas the latter suggests a level of regulation different from that of bacteria with larger genomes. Taken together, the papers highlight the complexity of even the simplest bacteria and underscore the challenges in understanding and reconstructing minimal life forms. More information can be found! in commentaries by Venter and colleagues1 and Ochman and Ragh! avan5. - Genome sequencing on nanoballs
- Nature Biotechnology 28(1):43-44 (2010)
Advances in technology deliver cheaper human genome sequencing. - Research highlights
- Nature Biotechnology 28(1):45 (2010)
Introduction Short-read genome assembler A novel algorithm lies behind recent insights into the genomes of the giant panda (Nature, published online 13 December 2009, doi:10.1038/nature08696), the cucumber (Nat. Genet., 41, 1275–1281, 2009) and new versions of two human genomes (p. 57–62). Wang and colleagues developed an approach, called SOAPdenovo, to assemble short sequencing reads (~35–75 bp) of large genomes into multikilobase sized chunks without needing a reference genome, a process termed de novo assembly. The approach combines efficient data structures for representing short reads with methods for correcting sequencing errors before genome assembly. Together, these advances enabled two human genomes to be assembled so that half of all bases are contained in stretches of sequence at least 5.9–7.4 kb long compared to 1.5 kb for the previous best de novo assembly methods. Although this size was smaller than the 20–100 kb achieved using Sanger sequencing (which generates longer reads), it was long en! ough to discover fragments containing novel coding regions of the human genome. And with the help of long-insert paired-end libraries, the sequences could be arranged into linear genome scaffolds hundreds of kilobases long, which is closer in size to assemblies derived from Sanger sequencing. As these studies suggest, de novo assembly of large mammalian and plant genomes from next-generation sequencing technology is now feasible. (Genome Res., published online December 17, 2009, doi:10.1101/gr.097261.109) CM Discrete logic models signaling With the advent of ever more detailed maps of cellular signaling pathways, it has become apparent that sophisticated analysis methods are needed to understand the behavior of the whole system. Approaches based on differential equations require measuring or estimating a multitude of parameters. A simpler method, discrete logic modeling, which represents the signaling networks as a series of interconnected 'on' and 'off' switches, only requires knowledge of protein-protein interactions and whether they activate or inhibit each other. Although this modeling strategy has been successfully applied in some cases, so far no general approach to optimizing the model using experimental data had been developed. Now, Sorger and colleagues present an algorithm that can modify an input signaling network to optimize the fit to experimental results. By introducing a tunable parameter that balances goodness of fit with model complexity, the authors avoid overfitting and optimize the predicti! ve power of the model. This is validated by constructing a model of HepG2 cell signaling and optimizing it with experimental data of phosphorylation cascades after different stimulations. Several predictions of the model have already been validated in the literature. (Mol. Syst. Biol. 5, 331, 2009) ME Taking down hepatitis C Chronic infection with hepatitis C virus (HCV) remains a public health problem, as current therapies work in only half of the 170 million people infected worldwide, many of whom will develop serious complications. Lanford and colleagues show that in chronically infected primates, targeting an endogenous, highly expressed liver microRNA results in an enduring reduction in viral load. The target, microRNA (miR)-122, upregulates HCV replication by binding to the viral 5´-untranslated end. Four chimpanzees were given 12 weekly intravenous injections of a locked nucleic acid–modified oligonucleotide directed against that region. In animals given the highest dose, circulating virus as well as liver HCV RNA was reduced by almost three orders of magnitude. Two lines of experiments showed that resistance to treatment did not develop: there was no viral rebound during treatment and deep sequencing did not reveal any mutations in samples taken throughout and after treatment. As vira! l loads took several months to rebound to pretreatment levels after therapy was stopped, the approach shows therapeutic promise. (Science, published online December 3, 2009; doi:10.1126/science.1178178) LD Receptor-selective aglycosylated Abs The ability of antibodies to bind all six members of the Fc gamma receptor (FcγR) family is essential for many aspects of adaptive immunity, including the antibody-dependent cell-mediated cytotoxicity (ADCC) response that underlies the effects of IgG-based therapeutics, such as the anticancer drug trastuzumab (Herceptin). Although the critical dependence of FcγR engagement on IgG glycosylation has restricted the manufacture of therapeutic antibodies to mammalian expression systems, Sazinsky et al. (Proc. Natl. Acad. Sci. USA 105, 20167–20171, 2008) demonstrated the ability to uncouple FcγR binding from antibody glycosylation by mutation of the Fc region. Jung et al. now further demonstrate the utility of microbial systems for antibody engineering by identifying mutants of aglycosylated trastuzumab that bind the high-affinity FcγR1 receptor with affinity similar to that of their glycosylated counterparts. Importantly, however, the mutant antibodies bind none of the five! other FcγRs, including the inhibitory FcγRIIb receptor that is well documented to prevent dendritic cell activation. Accordingly, mutant aglycosylated trastuzumab—but neither clinical-grade trastuzumab nor glycosylated mutant trastuzumab—potentiate the killing of HER2-overexpressing cancer cells in vitro by potent activation of dendritic cells. Although these effects have yet to be tested in vivo, they suggest that the efficacy of therapeutic antibodies might be enhanced by engineering aglycosylated variants to mediate more potent ADCC. (Proc. Natl. Acad. Sci. USA, published online December 18, 2009, doi:10.1073/pnas.0908590107) PH Haploid genetic screens for human cells The haploid genetic screens routinely used by yeast researchers to recognize recessive mutations have long been the envy of those working with multicellular eukaryotes. RNA interference–based strategies never silence gene expression completely and are often fraught with undesired off-target effects. Moreover, knockout strategies with diploid cells are complicated by the fact that most mammalian genes require disruption of both alleles to confer a phenotype different from the wild-type condition. To address this problem, Carette et al. use gene-trap retroviruses for large-scale gene disruption and tagging in a previously described derivative of the KBM7 chronic myeloid leukemia cell line that is haploid for all chromosomes except chromosome 8. Their efforts to screen gene trap–mutagenized KBM7 cells for resistance to influenza virus, cytolethal distending toxin and ADP-ribosylating toxins identify previously uncharacterized genes required for the actions of several intens! ively studied pathogens. This strategy should be amenable to screens that assay modulation of any reporter gene of interest. (Science 326, 1231–1235, 2009) PH - Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library
Lam HY Mu XJ Stütz AM Tanzer A Cayting PD Snyder M Kim PM Korbel JO Gerstein MB - Nature Biotechnology 28(1):47-55 (2010)
Structural variants (SVs) are a major source of human genomic variation; however, characterizing them at nucleotide resolution remains challenging. Here we assemble a library of breakpoints at nucleotide resolution from collating and standardizing ~2,000 published SVs. For each breakpoint, we infer its ancestral state (through comparison to primate genomes) and its mechanism of formation (e.g., nonallelic homologous recombination, NAHR). We characterize breakpoint sequences with respect to genomic landmarks, chromosomal location, sequence motifs and physical properties, finding that the occurrence of insertions and deletions is more balanced than previously reported and that NAHR-formed breakpoints are associated with relatively rigid, stable DNA helices. Finally, we demonstrate an approach, BreakSeq, for scanning the reads from short-read sequenced genomes against our breakpoint library to accurately identify previously overlooked SVs, which we then validate by PCR. A! s new data become available, we expect our BreakSeq approach will become more sensitive and facilitate rapid SV genotyping of personal genomes. - Building the sequence map of the human pan-genome
Li R Li Y Zheng H Luo R Zhu H Li Q Qian W Ren Y Tian G Li J Zhou G Zhu X Wu H Qin J Jin X Li D Cao H Hu X Blanche H Cann H Zhang X Li S Bolund L Kristiansen K Yang H Wang J Wang J - Nature Biotechnology 28(1):57-63 (2010)
Here we integrate the de novo assembly of an Asian and an African genome with the NCBI reference human genome, as a step toward constructing the human pan-genome. We identified ~5 Mb of novel sequences not present in the reference genome in each of these assemblies. Most novel sequences are individual or population specific, as revealed by their comparison to all available human DNA sequence and by PCR validation using the human genome diversity cell line panel. We found novel sequences present in patterns consistent with known human migration paths. Cross-species conservation analysis of predicted genes indicated that the novel sequences contain potentially functional coding regions. We estimate that a complete human pan-genome would contain ~19–40 Mb of novel sequence not present in the extant reference genome. The extensive amount of novel sequence contributing to the genetic variation of the pan-genome indicates the importance of using complete genome sequencing ! and de novo assembly. - Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety
Burgin AB Magnusson OT Singh J Witte P Staker BL Bjornsson JM Thorsteinsdottir M Hrafnsdottir S Hagen T Kiselyov AS Stewart LJ Gurney ME - Nature Biotechnology 28(1):63-70 (2010)
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (Imax ~ 80–90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site–directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for ! therapeutic benefit. - Chimeric mouse tumor models reveal differences in pathway activation between ERBB family– and KRAS-dependent lung adenocarcinomas
Zhou Y Rideout WM Zi T Bressel A Reddypalli S Rancourt R Woo JK Horner JW Chin L Chiu MI Bosenberg M Jacks T Clark SC Depinho RA Robinson MO Heyer J - Nature Biotechnology 28(1):71-78 (2010)
To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFRL858R and KRASG12V chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category. - Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle
Asokan A Conway JC Phillips JL Li C Hegge J Sinnott R Yadav S Diprimio N Nam HJ Agbandje-McKenna M McPhee S Wolff J Samulski RJ - Nature Biotechnology 28(1):79-82 (2010)
Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders. - Label-free, normalized quantification of complex mass spectrometry data for proteomic analysis
Griffin NM Yu J Long F Oh P Shore S Li Y Koziol JA Schnitzer JE - Nature Biotechnology 28(1):83-89 (2010)
Replicate mass spectrometry (MS) measurements and the use of multiple analytical methods can greatly expand the comprehensiveness of shotgun proteomic profiling of biological samples1, 2, 3, 4, 5. However, the inherent biases and variations in such data create computational and statistical challenges for quantitative comparative analysis6. We developed and tested a normalized, label-free quantitative method termed the normalized spectral index (SIN), which combines three MS abundance features: peptide count, spectral count and fragment-ion (tandem MS or MS/MS) intensity. SIN largely eliminated variances between replicate MS measurements, permitting quantitative reproducibility and highly significant quantification of thousands of proteins detected in replicate MS measurements of the same and distinct samples. It accurately predicts protein abundance more often than the five other methods we tested. Comparative immunoblotting and densitometry further validate our method! . Comparative quantification of complex data sets from multiple shotgun proteomics measurements is relevant for systems biology and biomarker discovery. - Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum
Hu G Cabrera A Kono M Mok S Chaal BK Haase S Engelberg K Cheemadan S Spielmann T Preiser PR Gilberger TW Bozdech Z - Nature Biotechnology 28(1):91-98 (2010)
Functions have yet to be defined for the majority of genes of Plasmodium falciparum, the agent responsible for the most serious form of human malaria. Here we report changes in P. falciparum gene expression induced by 20 compounds that inhibit growth of the schizont stage of the intraerythrocytic development cycle. In contrast with previous studies, which reported only minimal changes in response to chemically induced perturbations of P. falciparum growth, we find that ~59% of its coding genes display over three-fold changes in expression in response to at least one of the chemicals we tested. We use this compendium for guilt-by-association prediction of protein function using an interaction network constructed from gene co-expression, sequence homology, domain-domain and yeast two-hybrid data. The subcellular localizations of 31 of 42 proteins linked with merozoite invasion is consistent with their role in this process, a key target for malaria control. Our network ma! y facilitate identification of novel antimalarial drugs and vaccines. - Executive pay goes up at private life sciences companies despite tumultuous economic climate
- Nature Biotechnology 28(1):99-100 (2010)
Compensation to top executives at private life sciences companies continued along its upward trajectory, standing in stark contrast to flat pay levels at technology firms. - People
- Nature Biotechnology 28(1):102 (2010)
Introduction Michael Moore (right) has been named nonexecutive chairman of Oxford BioTherapeutics (Oxford, UK). Moore brings several decades of senior management experience in the biotech sector and joins the board after five years as CEO of Piramed Ltd. Previously, he was CSO and research director of Xenova Group. In addition, Oxford BioTherapeutics recently announced the appointment of Jim Cornett as COO, Mike Gresser as CSO and Jon Terrett as vice president, oncology, to lead its US R&D operations. Moore comments, "I am delighted to join Oxford BioTherapeutics at this exciting time in the company's development." Xencor (Monrovia, CA, USA) has named Bruce Carter (right) chairman of the board. Carter joined ZymoGenetics in 1986 as vice president of R&D. After Novo Nordisk acquired the company, he was promoted to corporate executive vice president and CSO for Novo Nordisk. He led the negotiations that spun out ZymoGenetics as an independent company in 2000 and most recently served as ZymoGenetics' CEO. He continues to serve as chairman of the board of ZymoGenetics. Mirna Therapeutics (Austin, TX, USA) has named Chris Earl, Corey S. Goodman and Evan Melrose as outside directors to its board. Earl was the first president and CEO of BIO Ventures for Global Health and also served as managing director of Perseus Capital and the Perseus-Soros BioPharmaceutical Fund. Goodman is currently an adjunct professor at the University of California, San Francisco, and most recently served as president of Pfizer's Biotherapeutics & Bioinnovation Center. Melrose is the founder of PTV Sciences and was formerly a director with Burrill & Company. Hana Biosciences (S. San Francisco, CA, USA) has announced the appointment of Howard Furst to its board. Furst has over 20 years of experience in the healthcare industry and is currently a partner at Deerfield Management. Hana also announced the departure of Arie Belldegrun from the board after six years of service. The BioIndustry Association (London) has announced the appointment of Nigel Gaymond as its new CEO. Gaymond began in sales and marketing at IBM in the UK and moved to the British Consulate-General in Boston, where he ran the commercial department in assisting the UK's biotech, healthcare and agriculture exports. Upon his departure, he established the consultancy Gaymond International. Millipore (Billerica, MA, USA) has named Robert S. Langer to the company's board of directors, replacing Daniel Bellus, a Millipore director since 2000, who will retire from the board on March 8, 2010. Langer is the David H. Koch Institute Professor at the Massachusetts Institute of Technology. He serves on the board of MIT's McGovern Institute and the Whitehead Institute. Affymetrix (Santa Clara, CA, USA) has named Andrew J. Last as chief commercial officer. He was previously vice president, global marketing and strategic planning of BD Biosciences' cell analysis unit and general manager of Pharmingen. Pepscan Holding (Lelystad, The Netherlands) has appointed Wim E.M. Mol as CEO. He brings more than 20 years of experience in the pharma industry, most recently at Schering Plough where he was vice president responsible for the global scientific development and commercial strategy of a phase 3 project in an alliance with a subsidiary of Merck-Serono. Gary Palmer, who most recently served as vice president of medical affairs at Genomic Health, has been appointed chief medical officer at On-Q-ity (Waltham, MA, USA), a diagnostics company developing products to improve cancer therapy effectiveness. Infinity Pharmaceuticals (Cambridge, MA, USA) has announced that Adelene Q. Perkins will become the company's president and CEO and join the board of directors in accordance with an existing management succession plan. Founder, CEO and current chairman Steven H. Holtzman will continue full-time involvement with the company as executive chair of the board. Perkins joined Infinity in 2002 and currently serves as president and chief business officer. Privately held NormOxys (Wellesley, MA, USA) has appointed Martin Tolar president and CEO. Tolar has held senior positions in pharma and biotech, most recently at CoMentis, where he served as CSO and later executive vice president and chief business officer. In addition, NormOxys announced the appointment of David Clark as its first chief medical officer. Clark previously served in Pfizer's clinical development division. Diagnostics company Vermillion (Fremont, CA, USA) has named William C. Wallen to its board of directors. Wallen is CSO and senior vice president, R&D for IDEXX Laboratories. Dennis Winger has been appointed to serve on the board of directors of Nektar Therapeutics (San Carlos, CA, USA). He is currently a director of Vertex Pharmaceuticals, Cephalon and Accuray, having retired in 2008 from Applera where he served as senior vice president and CFO. ADVERTISEMENT Vertex Pharmaceuticals (Cambridge, MA, USA) has announced the appointment of Nancy J. Wysenski as executive vice president and chief commercial officer. Wysenski previously held the position of COO at Endo Pharmaceuticals and she was a co-founder, president and CEO of EMD Pharmaceuticals. William D. Young, formerly chairman and CEO of Monogram Biosciences, has been named chairman of the board of Biogen Idec (Cambridge, MA, USA), succeeding Bruce R. Ross, who has retired from the board. Young previously served as Genentech's COO. Biogen Idec also announced that Marijn E. Dekkers, a director since May 2007, has stepped down from the board. Dekkers is the incoming CEO of Bayer HealthCare.
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