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Unformatted text preview: F E AT U R E Industrial biotechnology—a chance at redemption Stephan Herrera © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology Industrial biotechnology could boost biotech fortunes and help heal the planet. But there’s a giant gulf between here and there. Trend-spotters at the European Commission (Brussels), US Department of Energy (DOE; Washington, DC, USA), Organization for Economic Co-operation and Development (OECD, Paris) and McKinsey & Co. (Frankfurt, Germany) are just a sample of the growing legion of high-profile groups touting something called ‘industrial’ or ‘white’ biotechnology (the application of biotechnology to industrial production). Not so long ago, interest in things such as biodegradable plastics and enzyme efficiency was scant and industrial expertise limited primarily to chemical companies, which is why the scope of innovation was narrow and the time frame long. Today, interest in industrial biotechnology (IB) is coming from a diverse group of researchers and industries, which will help accelerate the pace that scientific knowledge accumulates and broaden the range of commercial applications for this science. However, although governments and a small collection of large companies around the world are waking up to the technology, on the whole, industry and investors have still not made the leap necessary to build the kind of momentum needed to upgrade the industrial complex. And until they do, this promising but still largely untested brand of biotechnology will remain underdeveloped and underused—its full potential unrealized. The vision The IB vision for the future is based on a rather old scientific curiosity that everything from medicines and fuels to clothing fibers and assorted other industrial raw materials can be made from plants and microorganisms. Indeed, ‘made better’, because unlike chemicals and fossil fuels, biologically based industrial ingredients and catalysts are made from infinitely greener, more renewable resources like corn, soybeans and bacteria. (Fig 1). These by-products don’t kill fish, contaminate soil or foul the air (but see Box 1). Just as the chemical industry evolved in the 1940s from a business based on inorganic mineral feedstocks to an organic, petroleum- Stephan Herrera is a freelance writer based in New York. Figure 1 Idealized biorefinery concept. (Image courtesy of Oak Ridge National Laboratory, Oak Ridge, TN, USA.) based platform, chemicals and other heavy industries have reached a new inflection point, one in which petroleum and chemistry will slowly be supplanted by renewable agricultural crops and biotechnology. McKinsey, for one, predicts that this transformation from fossil fuels and chemicals to plant ‘biofactories’ is not just imminent1. Rather, it believes that biotech had a hand in the production of at least $50 billion worth of products last year and could by 2010 contribute to $160 billion in sales in the chemical industry alone. The ethanol industry is another sector whose future will increasingly rely upon innovations made possible through IB. Royal Dutch/Shell (Rotterdam, The Netherlands) and the Canadian company Iogen (Ottawa, ON), are among those building ethanol refineries that rely upon so-called cel- NATURE BIOTECHNOLOGY VOLUME 22 NUMBER 6 JUNE 2004 lulosic biomass (Fig. 2). In ten years, experts say, the entire industry will be based on such feedstock. IB will help governments and industries meet new environmental mandates. With new pollution regulations pegged to Kyoto Protocol targets scheduled for phase-in around the world (but rather infamously not in the United States), some sound reasons exist for governments and industries to invest in technologies that will help the industrial complex pollute a lot less. At a time when public opinion of the biotechnology industry and genetically modified (GM) crops remains divided, and the price and volatility of crude oil remains high, the political appeal of IB is seductive. What’s more, although no major environmental group has publicly endorsed IB, none have dismissed it either. 671 © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology F E AT U R E Brussels touts “There is no question that from a scientific standpoint, industrial biotech has a great story to tell,” IDC Life Sciences (Framingham, MA, USA) vice president Jim Golden says. “But the commercial issues are the killers. The world’s industrial complex wants to change, needs to change, but sees change as very expensive and risky. I don’t see industry investing in [IB] until government regulations force them to.” Just as it was forced to do with recycled products, the US government must now also give purchasing preference to environmentally friendly biobased products, too, ranging from lubricants to fibers, plastics and paints. But if history and recent movements are any guide, the European Union (EU, Brussels) will probably be the globe’s real change agent. Indeed, even though American biotech and chemical companies are said to be investing in IB on a far grander scale than their counterparts in Europe—and although public opinion of GMOs and biotechnology in the EU remains mixed at best—the EU has in the past demonstrated more willingness than the US to mandate the costly adoption of industrial innovations designed to benefit the environment and public health. Whether its regulations are designed to boost industrial and consumer recycling or to reduce industrial pollution, Europe tends to issue regulations first and ask questions about cost and feasibility later. European environmentalists have far more political sway with industrial regulations and corporate behavior of these chemical companies than their American counterparts. Because they have been forced to endure years of ‘green’ regulations, some of the world’s most environmentally innovative chemical companies like Henkel (Düsseldorf, Germany), BASF (Ludwigshafen, Germany) and Degussa (Düsseldorf, Germany) are based in Europe. In an effort to nudge Brussels along, the Royal Belgian Academy Council of Applied Science (Brussels) recently published a report touting IB and warning of Europe’s failure to adopt it2. “Europe is not doing enough to develop this new technology and the European chemical sector may quickly lose the dominant position it still enjoys today,” the report says. It urges Europe to consider renewable resources like sugars and vegetable oils that could be converted into a variety of fine and bulk chemicals, pharmaceuticals, biocolorants, solvents, bioplastics, vitamins, food additives, biopesticides, enzymes and biofuels like ethanol and diesel. Is the EC listening? They ought to be. “Whereas the price for fossil resources such as petroleum will continue to go up, agricultural raw materials are becoming increasingly 672 cheaper,” co-author of the report Wim Soetaert of Ghent wrote. “Contrary to common belief, we have now reached the point where renewable raw materials are only half as expensive as their fossil counterparts. The only limitation is the technology to efficiently convert these renewable raw materials into useful products and industrial biotechnology is the key technology in that respect.” Europeans still care about the Kyoto Protocol, which obliges them to reduce greenhouse gas emissions by 2010. Belgium will need to cut its emissions over the next six years by roughly 14% to meet these targets. Renewable energy could fill the void. “Up to now renewable energy sources cover only 5.8% of the total energy consumption in the EU,” Soetaert wrote. “Car fuel accounts for the EU’s greatest dependence on fossil fuels.” The EC wants biofuels to make up 5.75% of total engine fuel consumption in Europe by 2010. Today that percentage is just 0.3%. Agricultural crops (biomass) could again replace fossil fuels and be converted in biorefineries into bioethanol, biogas or biodiesel. To meet EC targets for Kyoto, some 9.3 million tons of bioethanol will need to be produced annually in Europe by 2010. To meet this goal, 3.7 million hectares of wheat and sugar beets will be needed. At present, the EU pays farmers to keep 5.6 million hectares idle, so nobody can complain that there isn’t enough fertile land to indulge this IB experiment. Additionally, the recently published Directive (2003/30/EC) of the European Parliament and Council produced guidelines and production targets to expand the production and use of biofuels derived from agricultural, forestry and organic waste products3. The biofuels target for 2005 is 2% of transportation fuel and 5.75% by 2010. As a result of the directive, the 15 member states of the EU have until December 31, 2004 to develop a strategy for meeting these targets and turning that strategy into national law. As ever, the overall success of IB in Europe, and to some extent elsewhere around the world, will rely heavily upon government intervention, specifically government mandates that require industry to start the slow process of incorporating biotechnology into all manufacturing and waste disposal plans. Can the science keep up? Brent Erickson, head of the IB division of the Biotechnology Industry Organization (BIO; Washington, DC), says that compared to making medicines or GM crops, IB is straightforward and up to the task of assuming its place in history. IB, he says, is really nothing more than GM organisms or enhanced microbe technology with a twist. The old way of processing biomass was based on mashing the plant to bits, then subjecting this mash to high heat and acids in hopes of extracting sugars for further fermentation by existing natural yeasts or microbes. Today, a far more elegant, if not gentler solution is being developed that calls for pretreating the biomass using cellulase enzymes developed with metabolic engineering, gene shuffling and other technologies to selectively cleave the cellulose molecules into their con- Box 1 The downside of IB Not everybody views industrial biotechnology (IB) as the missing link in the evolution of the industrial complex. For every Dow, Cargill and DuPont, there are thousands of companies that don’t even know that IB exists. And for all the environmental promises, it remains to be seen how any industry could possibly be as clean and green as IB purports to be. Aside from the organic variety, farming requires the spreading of millions of liters of pesticides, herbicides and fertilizers, which are known to leach into groundwater and then find their way into nearby lakes, rivers and drinking water wells. Although motor fuels mixed with ethanol have been shown to cut hydrocarbon and carbon monoxide emissions, research shows they also produce increased levels of toxins called aldehydes and peroxyacyl nitrates (PANs). PANs are painful eye irritants and are toxic to plants. PANs can linger in the air for days and contribute mightily to the low-hanging brown haze known as smog, especially on cold winter days. Because PANs do not quickly dissipate in the atmosphere, they can be carried around the globe by trade winds. Plants that produce ethanol in the US have in the past run afoul of the Environmental Protection Agency (Washington, DC) for themselves emitting volatile organic compounds like formaldehyde and acetic acid, both of which are carcinogens, and methanol, which is classified as a hazardous pollutant. Techniques for efficiently refining and safely disposing of the massive volumes of petrochemicals produced by industry are well understood by industry and regulators. The same cannot be said for refining and disposing similar volumes of fermented plant matter, some of which has been genetically engineered. VOLUME 22 NUMBER 6 JUNE 2004 N ATURE BIOTECHNOLOGY F E AT U R E © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology Box 2 Lingering questions “Even though they are different, in a sense, I think biotech critics in Europe could draw parallels between [IB] and GMOs because of their very strong feelings about GMOs,” says Emmanuelle Schuler of Rice University, who has studied the power of public perceptions about GMOs and nanotech. “It’s impossible to say yet whether [IB] will produce the same negative feelings in the end. A lot depends upon how critics and the media frame the risks and rewards of [IB].” It’s just a matter of time until IB risks—real and perceived—will become a focal point. Those who think that IB won’t be controversial have not, for example, looked at J. Craig Venter’s research at his self-funded Institute for Biological Energy Alternatives (Rockville, MD, USA). Dr. Venter is making astonishing headway creating synthetic microorganisms that are capable of consuming heat-trapping greenhouse gases like CO2 and converting that CO2 into methane or hydrogen, which could be retrofitted into power plants as scrubbers. What Dr. Venter might view as rather prosaic genetic engineering that might one day be used in the battle against global warming, others will view only as Dr. Venter’s latest quest to play God, this time by creating a new life form whose unintended consequences are unknowable. “Yes, critics love to exploit the danger of the unknown. But they might not be so quick to do so if the biotech industry would stop promising panaceas and admit that there is no such thing as a risk-free technology. I know that sounds trite, but the public has mixed feelings about biotech in general because the industry totally dismissed some valid concerns about GM crops like the degree to which they could be kept separate from non-GM crops,” says Margaret Mellon, who tracks biotechnology issues for the Union of Concerned Scientists in Washington, DC. Cynics among the biotech industry emphasize that despite the best efforts of groups such as Greenpeace to scare away farmers and consumers around the world, global demand for GM crops continues to grow. According to a recent study by the International Service for the Acquisition of Agri-biotech Applications4, GM seeds are now being planted on nearly 20% of the world’s farm acreage. Just eight years ago, that figure was 0%. Cynics also raise another fair point when they argue that biotech companies—and their government promoters—can only do so much to alter public opinion about the disruption of globalism, the power of multinational corporations and the deep-seated fears about genetic engineering, which are all the indelible traits of the biotech industry today. stituent sugars.“Yes, [IB] has been around for a long time,” says Erickson. “But comparing the old with the new IB is a bit like comparing finger counting to a calculator in terms of power and efficiency.” Although it is still a mystery to most of the industrial complex, IB promoters have managed to convince a small but influential group of large industrial firms to pay tens of millions to either buy IB products or incorporate IB systems and processes into their supply chain and manufacturing lines. This group includes companies like Royal Dutch/Shell, British Petroleum (London), Ford (Detroit, MI, USA), Toyota (Tokyo), Mitsubishi (Tokyo), Dow (Midland, MI, USA), Degussa and BASF. “For years I have tried with little success to convince our clients that there is something to this [IB] prospect,” says Frankfurt-based Jens Riese of McKinsey & Co. “Now these companies are coming to me, looking for insights.” Some companies are already quite a ways down the path of IB adoption. The Dutchbased chemical company, DSM (Heerlen), in its recent annual report, reported that it had reached a milestone in 2003: some $2 billion in product sales, all made possible through IB. DuPont (Wilmington, DE, USA) recently reported that it has invested $500 million on a bioprocessing plant designed to produce Sorona polymer and adipic acid, both used to make fibers that are spun into textiles. Dow and grain giant, Cargill (Minneapolis, MN, USA), sank close to $800 million into a ‘biorefinery’ designed to turn Nebraska corn into polylactic acid (PLA). Last year the Bush administration pledged an unprecedented $400 million in grants to spur IB research and development. Governments in Europe have spent almost that amount. Much of this funding has gone to public laboratories, but a growing portion of government funding is going to private companies too, some of it to giants like Cargill Dow, DuPont and Archer Daniels Midland (Decatur, IL, USA). More typical are the $17 million grant awarded to biotech Genencor (Palo Alto, CA, USA) and the $15 million to Novozymes (Bagsvaerd, Denmark), to better understand how to tailor enzyme structure and tempera- NATURE BIOTECHNOLOGY VOLUME 22 NUMBER 6 JUNE 2004 ture response to boost efficiency (Table 1). Indeed, all of this attention on IB hasn’t hurt the fortunes of biotechs with IB bona fides. Little-noticed outfits from the US, Canada, Europe and Australia such as Genencor, ViroTec (Queensland, Australia), Iogen, Metabolix (Cambridge, MA, USA), Maxygen-Codexis (Redwood City, CA, USA), Diversa (San Diego, CA, USA) and Novozymes are finding that there is growing interest in their insights into using GM microbes to convert crops to industrial products. The VTT Technical Research Centre of Finland, for example, is attracting attention with its stronger, more specialized biodegradable plastics using flax fibers that can be run through the same injection-molding equipment used for standard plastic products. (Typically, industry relies upon the stubbornly resilient fiberglass to improve the mechanical qualities of plastics, which also resists recycling.) The Dutch company Hycail (Noordhorn) helped develop biocomposites. The firm has a pilot factory for lactic acid–based raw materials that is producing 400 tons of the stuff a year. Momentum for the masses Some have argued that big business cannot now afford not to invest in biomass and bioprocesses. Maybe so, but one should not confuse enthusiasm in polls and media stories with the rather more solid commitment needed for a company to divert capital and talent to IB operations. Companies won’t adopt IB simply out of concern for the environment. And the wise ones won’t try to use IB simply as a marketing gimmick. But, as the OECD states, they might adopt IB to cut costs. The development of indigo dye is a good example of how important it is for IB companies to choose their targets wisely. Several years ago, a few companies thought they could edge into the multimillion-dollar market for the indigo dye used in denim jeans and jackets. The traditional chemical process used to produce this dye was expensive and cumbersome. The working premise is that a generic plantbased dye could be produced for much less, and faster, than the petrochemical-based version. In theory, they were right. In practice, nothing could have been farther from the truth. As companies like Genencor quickly learned, manufacturers in Asia could make traditional indigo dye the old-fashioned way for a fraction of what the IB upstarts could do with plant dye. The Asian companies had access to cheap labor and didn’t have to worry about expensive, environmentally sensitive cleanup and disposal. On the flip side, there have been some spectacular successes in IB over the years such as 673 © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology F E AT U R E the manufacture of vitamin B2. Before the late 1980s, it was made entirely from chemicals like barbuturic acid and aniline. Today, 85% of it is made from glucose fermented from beets. IB is advantageous with regard to cost, but the market is small. “The global market for B2 is not even $200 million,” says the Basel-based life sciences consultant, Christian Suter, who was formerly with Hoffman LaRoche, which dominates the B2 market. “Vitamins and some nutraceuticals are about the biggest gamble pharmaceutical and biotech companies have made on [IB]. I don’t see them producing medicine from plants anytime soon.” But there is beginning to be overlap between IB and food and agricultural biotechnology. This is especially true in the production of industrial enzymes and pharmaceuticals in plants. With most of the $500 billion prescription medicines business built around high-margin, well-understood small molecules, it is understandable why drug companies have done little more than dabble in IB over the years. IB companies say that what keeps plant sciences from infiltrating the drug industry is more culture than cost or lack of scientific expertise. Proponents at companies like Epicyte (San Diego, CA, USA), Prodigene (College Station, TX, USA), CropDesign (Ghent, Belgium) and Akkadix (La Jolla, CA, USA) argue that the manufacture of antibodies, for example, could be done faster and cheaper than in traditional fermentation systems. Despite that cultural impediment and the conspicuous dearth of plant-based protein success stories, drug companies remain curious. Most drug companies have been dabbling in plant systems for decades with seemingly little to show for it, but somehow they cannot quite bring themselves to cut and run. And that is why investors continue to support startups chasing after the elusive planticeutical. Indeed, can produce lipase 14 times cheaper in corn. Quebec’s Medicago aims to spend $34 million developing alfalfa with novel genetic traits to produce recombinant proteins for pharmaceutical and nutraceutical markets. Figure 2 Iogen’s biofuels plant. (Image courtesy of Iogen, Ottawa, ON, Canada.) hope springs eternal in the medicines sector of IB. Projects like those underway at the French firm, Meristem (Clermont-Ferrand) are typical of this hope and investment. This spring, the company will spend millions of dollars planting a special variety of GM corn near Holyoke, CO. Meristem uses corn to produce lipase, an enzyme that our bodies produce naturally—at least those of us who do not have cystic fibrosis. At present, these patients get their lipase from an expensive process that harvests the enzyme from the glands of pigs. According to an interview with company officials in an article in the Rocky Mountain News (Denver, CO, USA), Meristem claims that it Table 1 Selected DOE projects Company (and partners) Amount of grant Project Cargill Dow (Iogen, Shell Global Solutions) $26 million Biorefining Cargill (Codexis, Redwood City, CA; Pacific Northwest National Laboratories (PNNL), Richland, WA, USA) $6 million New biorefinery platform Dupont (Diversa, Deere and Co.) $18.3 million Biorefinery for ethanol production Genencor $17 million Biomass conversion to ethanol National Corn Growers Association (St. Louis, MO) (Archer Daniels Midland; PNNL) $2.4 million Corn fiber use Novozymes $14.8 million High-efficiency enzyme systems Source: US DOE (http://www.greenUbiz.com/frame/1.cfm?targetsite=http://www.ott.doe.gov/biofuels) 674 Model organisms Boosters like to hold out the Cargill Dow example as proof that once company executives get their minds around IB, it’s an easy sell. It isn’t, and the story of how Cargill convinced Dow to sign on to the Blair project is a perfect example of the reason. With revenues of $80 billion, Cargill is the largest private company in the US. That heft and private ownership structure give the company flexibility that most firms do not possess. And it took Cargill chemist Pat Gruber the better part of a decade to find a partner and get his PLA project off the ground. Eventually, the Cargill group was able to convince Dow that it could produce commercial-grade PLA from corn with profit margins orders of magnitude greater than anything that can be found in the chemical industry. Those margins have yet to be seen on an income statement. Still, the textiles division of Cargill Dow, which uses PLA to make a product it sells under the brand name Ingeo, has close to 150 customers for Ingeo including Burlington Industries, Bed, Bath & Beyond, Faribault Woolen Mills and Pacific Coast Feather Co. But it was an uphill battle to convince customers to buy Ingeo materials that are considerably more expensive and almost entirely untested in the market relative to traditional materials.“Industrial biotech is a long, complicated value chain,” says Gruber—indeed, a value chain that is not well understood by most manufacturers. “Plants and biotechnology are still viewed in the [manufacturing industries] as a novelty that doesn’t pay for itself,” says Pol Bamelis, former head of R&D at Bayer AG (Leverkusen, Germany) and now chairman of CropDesign, which makes GM crop seed and animal feed. “Until the cost-benefit proposition of [IB] improves, most industrial companies will stick to what they know best—chemistry.” Mana from McKinsey Since McKinsey first published its bullish report on IB in late 2001, it has revised its projections only slightly (Table 2). These days, though, Riese is keen to point out that McKinsey’s IB predictions are really just scenarios. “Actually, they’re not really predictions as much as prospects,” he said. “What we’re saying is that if certain things like investments, customer acceptance and the like, fall in line VOLUME 22 NUMBER 6 JUNE 2004 N ATURE BIOTECHNOLOGY F E AT U R E Table 2 Decreasing the footprint Case studies Environmental impacta Economic impacta © 2004 Nature Publishing Group http://www.nature.com/naturebiotechnology Energy efficiency Vitamin B2 (BASF) Cephalexin (DSM) Scouring enzyme (Novozymes) NatureWorks (Cargill Dow) Sorona (DuPont) Ethylene from biomass (future scenario) Raw material consumption CO2 emissions Production costs + ++ + + + 0 ++ ++ + ++ ++ ++ + + 0 ++ + ++ + + + 0 + – aReduction for biotechnological processing: ++ more than 50% reduction, 0 for neutral (± 10%), and – for more than 50% increased. Source: http://www.Europabio.org. with expectations, then one can extrapolate certain conclusions about the impact that will have on output and sales.” According to one of McKinsey’s estimates, IB will contribute to 10–20% of the global chemical industry output, which would amount to some $160 billion worth of products. In specialty chemicals, McKinsey feels that 55% of what it calls IB’s “value-creation potential” will be the result of IB’s ability to help companies boost revenues and cut raw materials and waste disposal costs; in bulk chemicals, 75% of value-creation potential will be the result of cost reductions. (In the production of PVC, for example, a common plumbing material, waste disposal costs can amount to 40% of production costs.) McKinsey is particularly bullish on the role biotech will play in the future of the vitally important polymer market, which accounts for a quarter of total chemical market sales today. McKinsey consultants have been saying for the past few years that increased revenues in the IB polymer business will contribute up to 60% of “estimated value creation” and 40% of reduced costs. They believe that “biotechnology has significant advantages over conventional processes in delivering new functionality and improving time-to-market” in products like polyester, nylon, thermosets and thermoplastics. By 2010, they estimate that 10% of polymers could involve biotechnology in some form through biotech monomer production or biotech polymerizations. Mindful that biotech boosters have overpromised before, BIO’s Erickson cautions against reading too much into best-case scenarios. “I admit that $160 billion is a best-case estimate,” he says. “But even if it is off by 50% that is still a big market.” Erickson further cautions that in many cases, it will be difficult to draw a straight line from an IB process or raw material to a product’s sales revenues in the way that analysts can plot from a successful biotech drug. Likewise, companies that adopt IB should not expect the kind of reception from investors and analysts that often greets a public announcement related to a company’s intent to make medicines for, say, cancer. “Industrial biotech is not sexy,” says Erickson. “It is not addressing an unmet medical need,” but on the other hand, you don’t have to deal with clinical trials and FDA approval. Meeting the challenge Like any emerging technology, the path of IB development has been circuitous, complicated by technical, economic and political factors. Convincing skeptical companies entrenched in business models based on petrochemicals, or those that cannot afford to take costly gambles on technologies whose ability to produce costeffective results in a predictable time frame is unproven, is no small challenge, either. Like other tectonic forces that have come before it, IB’s progress will also be influenced by public opinion of biotechnology in general (Box 2). In the past, the public has greeted this industry’s medicines with enthusiasm and its plant innovations with mixed emotions, largely because the latter was seen as being potentially harmful to the environment. With environmental benefits placed squarely in the middle of IB’s benefits package, the risk-reward calculus changes—boosters hope, for the better. It boils down to this: without government prodding, unless IB can benefit these five things—products, prices, profits, people and the planet—this green dream won’t have a happy ending. What a shame that would be. 1. Riese, J. Surfing the Third Wave: New Value Chain Creation Opportunities in Industrial Biotechnology. (McKinsey & Company, Frankfurt, Germany, 2003). 2. Industrial Biotechnology and Sustainable Chemistry (Royal Belgian Academy Council of Applied Sciences, Brussels, January 2004). 3. Directive 2003/30/EC of the European Parliament and of the Council on the Promotion of the Use of Biofuels or Other Renewable Source for Transport, May 8, 2003. 4. James, C. Preview: Global Status of Commercialized Transgenic Crops 2003. ISAAA Briefs no. 30 (International Service for the Acquisition of AgriBiotech Applications, Ithaca, NY, USA, 2003). NATURE BIOTECHNOLOGY VOLUME 22 NUMBER 6 JUNE 2004 675 ...
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