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Protein Therapy Could Heal Agbio Stephan Herrera If only agbio scientists had tried to develop therapeutic drugs first. Instead, agricultural biotechnology's first act was to cross a tomato with a flounder, to help the vegetable withstand frost. For a second act, the fledgling industry produced genetically modified corn and soybeans; that proved a boon to farmers and seed companies but won the scorn of environmental groups. Given the perfectly rational response of consumers to be wary of any potential danger in the food supply, the ensuing fear and loathing of these developments was to be expected. Now, however, agbio has a third act: medicine. "There is no doubt in my mind that agbio would be the crown jewel of biotechnology if it had pushed human therapeutics first, instead of frost-resistant tomatoes and super seeds," says Mich Hein, president and founder of Epicyte http://www.epicyte.com, which makes therapeutic antibodies from plants to treat human diseases. "I can assure you, Greenpeace has no objection to a cornfield that produces medicines." Now, thanks to the efforts of companies like Epicyte, there's a push to produce monoclonal antibodies (MAbs) -- the building blocks of therapeutic drugs that fight illnesses like AIDS and cancer -- from corn and other plants. And the companies are doing it on an industrial scale using a technique called molecular farming, which promises to be cheaper and faster than existing MAb-production techniques. If this gambit works, agbio just might shake its demon-seed image. According to Dain Rauscher Wessels, the market for MAb production is expected to grow to $8 billion by 2004, up from about $3 billion this year. Using molecular farming, Epicyte says it can produce commercial-scale quantities of MAbs in two and a half years, compared to the industry norm of four years, at less than half the typical $100 million to $500 million cost. Naturally, Epicyte isn't the only outfit vying for this promising market. Akkadix http://www.akkadix.com, CropTech http://www.croptech.com, Genzyme Transgenics, IPT, Medicago http://www.medicago.com/indexeng.html, MPB Cologne http://www.mpb-cologne.com, ProdiGene http://www.prodigene.com, SemBioSys Genetics http://www.sembiosys.ca, and other startups are also entering the field. Most of the bigger companies, like Dow AgroSciences http://www.dowagro.com and Syngenta, are getting involved, too. And MAbs aren't the only market; practically any protein can be produced in a plant. Genetically, molecular farming is straightforward, if a bit surreal. By inserting human genes into corn, for example, the kernels produce human proteins instead of natural plant proteins. This technique is similar to the genetic engineering being done with cows and mice, but with considerable cost and yield advantages. Think of a plant as simply a new host for the production of a protein. Certainly there are hurdles for molecular farmers. Convincing "big pharma" and biotech customers to buy these farm-raised molecules will be a slow process. But a pair of deals that ProdiGene recently struck with Eli Lilly and Avant are attracting attention. Competition from existing technologies will be fierce, too. Fermentation techniques using Chinese hamster ovary (CHO) cells, for example, have been in place for 25 years, and most drug companies have already spent billions building their protein-production lines around this platform. Moreover, it won't be easy to convince a general public skeptical of anything genetically modified that this new agbio bounty, which could appear in numerous drug compounds, is not also suspect. But proponents say the facts are on their side. "Producing a therapeutic protein from plants, instead of standard means like Chinese hamster ovaries, eliminates the risk of the mutant strains of genetically modified organisms people seem to be so worried about," says Robert Dose, vice president of business development at ProdiGene. Still, while plants cannot harbor mammalian viral or prion pathogens, like those that cause bovine spongiform encephalopathy (mad cow disease), there are some legitimate concerns. For example, the U.S. Food and Drug Administration and the generally centrist Union of Concerned Scientists want to know more about the environmental impacts and the risk to the food supply should a corn kernel packed with human proteins somehow get misplaced somewhere along the distribution chain. Fair enough. Despite these hurdles, the case for using plants to grow proteins is powerful. Plants are already the most efficient bioreactors on the planet: they relentlessly transform light energy into protein energy. In the lab, harvesting and extracting industrial quantities of proteins has been done mainly with fermentation methods that employ CHO-cell technologies. Another protein-production technique involves proteins commonly produced in cow's milk. But proteins from seeds are easier to purify than those obtained from hamsters or cows, because, from a molecular perspective, the ingredients are less complicated. Therefore, the purification process requires fewer steps and less-expensive equipment. SMALL-SCALE FARMING Enter molecular farming. Its development could help address the worldwide shortage of raw materials and manufacturing capacity to make the therapeutic proteins needed for MAbs. Companies like Immunex, Genentech, MedImmune, and many others are scrambling to finish building new facilities to keep up with demand for their popular MAb-based products. Before these new production facilities are completed, though, it's likely that demand for MAbs will outstrip supply, making the need for molecular farming more urgent. Meanwhile, companies like Medarex and Abgenix that produce MAbs from transgenic mice are betting they'll need help keeping up with demand, too. In anticipation of this, Medarex recently signed an antibody discovery and development deal with Epicyte. But not every company is rushing to embrace plant-produced MAbs. Many are concerned about glycosylation -- the possibility of diminished half-lives of antibodies produced by gene alterations in plants. "Transgenic plants look particularly good from an economic standpoint," says Jim Thomas, vice president of process sciences at Immunex. "The big issue is glycosylation." In other words, drug companies like their antibodies' half-lives boring and predictable. There are already 96 traditionally produced antibodies (primarily from hamsters or cows) in late-stage clinical trials and awaiting FDA approval, and nearly 500 or so in early stages. Typically, 70 to 80 percent of these won't make it to market. Those that do, particularly those designed for chronic illnesses like psoriasis, allergic asthma, and rheumatoid arthritis, will require thousands of kilograms of purified proteins to meet demand. Scarcely a fermentation facility in existence can produce more than 100 kg per year. A 200-acre cornfield, however, could produce enough raw materials -- the therapeutic proteins in corn plants -- to manufacture nearly any drug on the market today. Even with enormous cost savings, economies of scale, and ease of purification from molecular farming, calming fears about these agbio products won't be easy. "What scares people about agbio is the transgenics, the perceived risk to the environment, and public health," says Klaus Düring, president and CEO of MPB Cologne. "But what's to fear from a potato that just happens to produce a lot of proteins?" Consider last year's taco-shell fiasco. Some taco shells were found to contain the now-withdrawn StarLink brand of cornmeal, which wasn't approved for human consumption and was thought by some to possess an allergen. Millions of people ate products with StarLink and not one of them suffered so much as a bellyache. But the furor triggered dozens of product recalls, cost billions of dollars, and proved the last straw for Wall Street and venture capitalists. "Despite all the bad news," says C.S. Prakash, who runs the Center for Plant Biotechnology Research at Tuskegee University in Alabama, "agbio is really quite healthy, and if anything, the market potential is just increasing." He's right. Developing countries are sorely in need of the benefits that agbio has to offer. In those nations, agbio won't receive the kind of resistance it does in the developed world. Consider this: the global population is expected to swell by 73 million people a year through 2020, and most of this growth will occur in developing nations, where need outweighs the ethical issues surrounding genetically modified plants for food and medicine. People in nations like China, with 1.4 billion people, and India, with 1 billion, have no qualms about genetically modified food. Nor do people in most sub-Saharan African nations, where malnutrition, HIV, and tuberculosis among children are pandemic. Still, with so much potential, it remains to be seen whether the public can overcome its overblown fears. Nicholas Kalaitzandonakes, associate professor of agribusiness at the University of Missouri at Columbia and editor of the newsletter AgBioForum, remains hopeful. "You're looking at a technology with a life cycle of 100-plus years that's just beginning," he says. "It is not going away." Mr. Kalaitzandonakes believes that life could be difficult for agbio entrepreneurs at least until the backlash subsides, probably another few years. Or until the public understands that agbio is safer than traditional animal and plant breeding. "When you breed animals and plants you change hundreds of genes," he said. "With transgenics, you're changing one. It's a far safer, far more restricted approach," says Jay Short, president and chief technology officer of the biotech firm Diversa. HARD SELL Aside from quelling safety concerns, the immediate challenge for agbio is the skepticism of investors. Many public and private investors still see agbio companies as riskier than genomics firms, which often possess little more than a nifty algorithm to cull massive amounts of data, or than pharmaceutical startups, many of which have developed experimental drugs that have only a one-in-ten chance of reaching the market. The reason: the word agbio conjures images of sickly stock prices, lost write-offs for hasty spin-offs, and protesters wearing corncob costumes. Only a handful of VC firms are moved by molecular farming. The three most visible are Burrill http://www.burrillandco.com, Bay City Capital http://www.baycitycapital.com, and the ATP Group. Startups that are pursuing molecular farming also have to contend with nay-saying consultants hired by VC firms. Most of them argue that the agbio market is so dominated by Monsanto, Aventis Crop Science http://www.aventis.com, Syngenta, Dow, and DuPont that opportunities don't exist for startups in this sector. Since most of these consultants are employed by these big transgenic seed companies, the prophecy becomes self-fulfilling. "Agbio is not of interest to us, as there are only a few companies, and they all appear to be doing the same thing," says a VC who requested anonymity. "We looked at several plays, talked to Monsanto, and developed an unambiguous opinion." Indeed, biotech's old guard still dominates agbio through its control of the global seed business. But that technology has led to new technologies -- like molecular farming. The question is whether big pharma will further realize its inventions for drug development. Dow, for one, is an investor in Epicyte and others. But if the past is any indication, many of the big chemical companies that control the enabling patents on technologies like molecular farming will prefer to compete for markets by going to court. Epicyte's Mr. Hein knows well that Monsanto could squash his company or at least keep it from advancing in the market for years. "No doubt about it," he says. "The legal haggle over anything pertaining to genetically modified seeds has held back progress significantly. But up until now, there wasn't a shortage of antibodies, so I see the logjam breaking up one way or another." "The pendulum had swung perhaps too far [in agbio] to the
benefit of big grain producers and farmers," says Roger Wyse, managing
director at Burrill. "Now it's coming back to the middle around the health
benefits using genomic technologies." The big challenge for this sector
is to convince consumers that they need not fear the gene in the bottle.
Only then will molecular farming go from being a fringe, 100-year science
to a billion-dollar opportunity for therapeutic purposes.
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