Is Drought Over for Pharming Science2007.Pdf
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In the bag. These cultured carrot cells are engineered to make a human drug. MANY A CHILD HAS BEEN TOLD “CARROTS eign protein much as if it were one of the might be simpler to process because they are good for you.” That advice could soon take plant’s own genes. would be free of animal pathogens. on new meaning for people with Gaucher dis- However, technological hurdles and a Other discoveries followed. In 1995, for ease, an inherited metabolic disorder that leads lack of interest from drug companies have instance, Arntzen’s group reported in Science to liver and bone problems. Patients must now hamstrung “pharming,” as have worries that that potatoes engineered to make a cholera on April 12, 2009 be injected every 2 weeks with a manufactured pharma crops will escape from their experi- protein worked as a vaccine when the spuds enzyme that costs on average $200,000 a year, mental plots and taint the food supply. As a were fed to mice. Such “edible vaccines” could making it one of the most expensive drugs ever. result, many companies have abandoned this offer developing countries cheap oral vaccines If ongoing clinical trials go well, the 5000 Gaucher research or gone under. And no plant- that didn’t require refrigeration, Arntzen sug- patients on the therapy could soon have a made drugs for humans have made it to gested (Science, 5 May 1995, p. 658). second option—a cheaper version of the the pharmacy. A company called Large Scale Biology enzyme that stays in the bloodstream longer But academic scientists and some compa- Corp. in Vacaville, California, came up with a and can be injected less often. nies have persisted, improving yields of shortcut. It didn’t bother to create a new If the U.S. Food and Drug Administration plant-made drugs and developing innovative tobacco strain when it wanted to produce an www.sciencemag.org (FDA) approves recombinant glucocerebrosi- ways to keep pharming inside the lab, or the antigen for a lymphoma vaccine. It simply dase, it will be good news not only for medicine greenhouse. Several plant-made pharmaceu- sprayed tobacco plants with a tobacco mosaic but also for a community far removed from the ticals (PMPs) are now in patient trials (see virus carrying the appropriate gene. The clinic: plant scientists. Protalix Biotherapeutics chart, p. 474). Moreover, the European leaves produced useful amounts of the vaccine in Karmiel, Israel, produces this new version of Union, the Bill and Melinda Gates Founda- protein within 14 days. The drug worked in the protein in giant plastic bags, not in steel vats tion, and the U.S. Department of Defense are mice, suggesting that vaccines tailored to lym- of mammalian cells like most biologics are. fertilizing the field with new funding. “We’re phoma patients’ tumors could be made in Downloaded from The bags are filled with transgenic carrot cells actually not doing too bad,” says Julian Ma, plants in just weeks. And because the plants that are cultured and then processed to extract an immunologist at St. George’s University carried the foreign gene only until they shed the drug. “If Protalix gets regulatory approval, of London in the U.K. “It’s just that everyone their leaves, they were potentially more that would [make it] the first plant-made phar- is in a hurry.” acceptable than permanently modified crops. maceutical,” says plant scientist Charles Arntzen of Arizona State University in Tempe. Fields of dreams “For people who work in this field, it will be a The excitement over plant-made very exciting step forward.” pharmaceuticals began with a Arntzen is chasing an elusive dream: using 1989 paper in Nature showing whole plants as factories to make drugs. that monoclonal antibodies could Nearly 20 years ago, when researchers first be produced in tobacco. The paper showed that a tobacco plant could be engi- “really captured the imagination,” neered to crank out an antibody, they envi- says Ma. Monoclonal antibodies sioned harvesting cheap supplies of therapeu- were being used to treat a growing tic proteins, antibodies, and vaccines from vast number of diseases, from arthritis fields of crops. For this approach, researchers to cancer, but were expensive to isolate the target gene and usually insert it into make in mammalian cells. So- a bacterium called Agrobacterium that readily called plantibodies appeared to Temporary transgenic. Fluorescing protein shows infects the plants and passes on the gene. The offer a cheaper production tobacco leaf’s pharming gene becomes part of the plant and is passed method—a kilogram might cost potential. CREDITS (TOP TO BOTTOM): PROTALIX; BAYER AG BAYER CREDITS (TOP TO BOTTOM): PROTALIX; from one generation to the next, producing for- $100 rather than $3 million—and www.sciencemag.org SCIENCE VOL 320 25 APRIL 2008 473 Published by AAAS Plant Genomes Safety in Washington, D.C., says Selected Plant-Made Pharmaceuticals enforcement is “horrendous.” As a result, “we don’t think [drugs] should Company Plant Grown in Drug or product Disease Status be in any food crops, indoors or out- doors,” he adds. Many ecologists and Human drugs some plant scientists are also leery of Protalix Biotherapeutics carrot cell culture glucocerebrosidase Gaucher disease Phase III trial* using food crops for pharma. “It’s too Biolex Therapeutics duckweed indoor chambers alpha interferon hepatitis C Phase II trial* dangerous,” says Kenneth Palmer, SemBioSys Genetics safflower field insulin diabetes Phase I/II trial † former director of the vaccine pro- Meristem Therapeutics corn field lipase cystic fibrosis Phase III trial † gram at Large Scale Biology. These concerns drove many com- Other products panies away from using food crops Ventria Bioscience rice field lactoferrin, lysozyme diarrhea Efficacy trial § such as corn for pharmaceuticals. A Cobento Arabidopsis greenhouse human intrinsic factor Vitamin B-12 deficiency Approved †† few big companies, such as Monsanto, dropped PMP research altogether. Planet Biotechnology tobacco field secretory antibody vaccine tooth decay E.U. approved Stung by bad press and lack of interest Dow AgroSciences tobacco cell culture poultry vaccine Newcastle disease USDA approved from drug companies, many leading CIGB, Cuba tobacco greenhouse vaccine purification antibody hepatitis B On market plant pharma companies have folded, * Ongoing; † Projected late 2008; § Completed; †† In Ukraine. including ProdiGene and Large Scale Steps along the way. No plant-made human drug has made it through final clinical trials, but several “pharmed” Biology. As Palmer puts it, “the proteins are close to or on the market as supplements, a vaccine reagent, and a medical device. field imploded.” on April 12, 2009 Scores of biotech companies sprang up to make a pig vaccine sprouted in a soybean field Close to the clinic commercialize these discoveries, and some in Nebraska. For this and an Iowa mishap, the Despite the setbacks, a handful of companies in big agbiotech companies got involved as U.S. Department of Agriculture (USDA) the United States and Europe haven’t given up. well. By the mid-1990s, more than 180 com- fined the company $250,000 and made it pay A few have plowed ahead with food crops, panies and organizations were working on $3 million to buy and destroy tainted soy- grown outdoors, for their pharma products; pharming, according to the Biotechnology beans. The incident stoked opposition from others have focused on other plants or on Industry Organization. farmers and activists worried about “drugs in unconventional growing schemes. The companies soon ran into technological your cornflakes.” Meristem Therapeutics in Clermont- snags, however. Biotechnologists couldn’t Other companies underestimated the pub- Ferrand, France, plans to start final clinical www.sciencemag.org always get plants to express enough protein and lic’s concerns. A company called Ventria Bio- trials for a corn-grown gastric lipase for cystic had trouble purifying the protein product. science that wanted to conduct field trials of fibrosis patients by the end of the year. And the Efforts to make edible vaccines stalled after rice containing two breast-milk proteins useful Canadian company SemBioSys Genetics Inc. researchers realized that the amount of antigen in combating diarrhea drew the ire of rice uses transgenic safflower—“much less of a fluctuated widely from plant to plant. Arntzen growers in California, then Missouri. It wound lightning rod than some other crops,” says CEO thinks that oral vaccines made from dried plant up in Kansas, where no other rice is grown. Andrew Baum—to produce insulin, which material could work for developing countries, USDA tightened its rules for field trials of should be in clinical trials this year. Companies Downloaded from but a vaccine without a strictly controlled dose pharma plants in 2003 to prevent mistakes like such as Protalix and Biolex Therapeutics side- “would never be approved” in the United the ProdiGene episode. But skeptics were not step the growing of crops altogether: the former States, he says. assuaged. Bill Freese of the Center for Food with its carrot-cell culture to make a Gaucher Another reality check: lukewarm interest disease enzyme, and the latter by producing from the big drug companies. They didn’t interferon using duckweed, tiny clonal plants much care that plant-made drugs would be grown as a layer in clear plastic bags. “We are (SOURCE) INDIVIDUAL COMPANIES AND MOLECULARFARMING.COM; SEMBIOSYS AND MOLECULARFARMING.COM; (SOURCE) INDIVIDUAL COMPANIES cheaper to make because production is a careful not to be associated with whole-plant small chunk of the cost of drug development; transgenic technology,” says Protalix CEO the big-ticket item is clinical trials. The com- David Aviezer. SCIENCE panies were also leery of the regulatory hur- New technologies are attracting attention. dles, because both the drug and the new pro- To boost expression, the German biotech Icon duction process would have to clear FDA.