IN THE WORLD OF MOLECULAR FARMING, PLANTS ARE LIVING FACTORIES THAT PRODUCE CHEAP DRUGS, PLASTICS, EVEN HUMAN BLOOD PROTEINS. RESEARCHERS HOPE - AND CRITICS FEAR - WE'LL REAP WHAT WE SOW.
GLOBE AND MAIL | November 4, 1999 | LEONARD ZEHR, Biotechnology Reporter
Ste-Foy, Que. In a nondescript greenhouse across the street from the Place Ste-Foy shopping centre, Medicago Inc. is, according to this story, zapping human DNA into alfalfa plants, transforming them into "living factories" capable of producing the building blocks of life-saving drugs.
In St. Louis, biochemical giant Monsanto Co. has produced genetically modified canola and cress plants that sprout polymers, the first step in making biodegradable plastic.
In Malaysia, scientists have spliced a human gene into the DNA of a rubber tree so that instead of producing latex, the tree also is a source of human serum albumin, a protein essential to the blood that is widely used by hospitals to treat shock.
Welcome to the world of molecular farming, a small but fast-growing segment of biotechnology that uses plants to manufacture a shopping list of protein molecules that can be turned into vaccines, industrial enzymes, cosmetics and vitamins.
Through a process called electroporation, Medicago zaps alfalfa pollen cells and a strand of human DNA with an electric charge, propelling particles of DNA into the cells. The pollen is returned to the alfalfa flower and seeds produced from natural fertilization are tested to determine whether they are transgenic - engineered with a foreign gene in addition to their own genetic makeup - and contain the human DNA. As the plant grows, it is cloned into hundreds of transgenic copies.
Louis-P. Vezina, the company's scientific director, was cited as saying even the experts didn't believe that molecular farming would come to fruition so quickly, adding, "When I presented this technology at a conference four years ago, people looked at me like I was crazy."
To be sure, plants have been used for medicinal purposes for thousands of years. A predecessor of aspirin dates back to Hippocrates, who treated pain with a concoction made from tree bark. North American Indians were renowned for turning roots into salves for wounds. More recently, taxol, a leading anticancer drug, was developed from the bark of the Pacific yew tree.
Drug companies have traditionally used one of three costly and time-consuming methods to make the active molecules for pharmaceuticals: fermentation systems, human cell cultures or insect cell cultures.
But advances in molecular genetics are fuelling an avalanche of leading-edge research around the world with transgenic plants, the engine for molecular farming.
The natural ability of plants to assemble genetic information into proteins makes them more efficient and economical than cell culture production systems.
Cheap drugs may spring upin field trials
And, unlike human cell cultures, there's virtually no risk of spreading viral infections from a plant system.
After transgenic plants are harvested, they are often shredded or ground up, a process that induces the plant to kick out protein molecules. A series of chemical treatments purifies the protein. In medicine, the process is designed to generate low-cost, high-volume and pure sources of the ingredients that go into many expensive pharmaceuticals.
Brian Morrissey, an assistant deputy minister of research with Agriculture Canada, was cited as telling a conference this summer that "biotechnology and in particular, molecular farming, may be as important to the future of agriculture as the computer has been to today's overall economy."
From a largely research focus today, molecular farming will create an industry with worldwide sales exceeding $50-billion (U.S.) between 2002 and 2008, predicts Francois Arcand, Medicago's general manager.
"Over the next few years, the public will be hearing a great deal about molecular farming," he promises. "Plants have the ability to produce tons of molecules ... at costs that will be three to 15 times lower than those obtained with current methods.
"That will free up billions of dollars from the health care system that could be used for new drug research."
Alfalfa sprouts as a drug
Industry heavyweights such as Dow Chemical Co. of Midland, Mich., Monsanto and E.I. du Pont de Nemours & Co. of Wilmington, Del., are taking leading roles in the fledgling science. Monsanto and DuPont already have dominant stakes in the field, including important patents for technologies to deliver foreign DNA into plants.
In a recent address at Boston College, Chad Holliday, DuPont's chief executive officer, said his company was studying the potential use of "green manufacturing plants to make useful chemicals."
He predicted that DuPont will derive 25 per cent of its revenue in 2010 from areas other than those requiring depletable raw materials. "Achieving this goal will involve growing our revenues from plant biotechnology feedstocks faster than from other parts of our company."
Dupont's bullish game plan is helping drive Canada's two front-runners in molecular farming, SemBioSys Genetics Inc. of Calgary and Medicago, which derives its name from the Latin word for alfalfa.
Last month, Medicago and Cleveland-based BioInFiNix Ltd. teamed up in a deal to make interferon-beta from alfalfa to treat respiratory syncytial virus (RSV) infections, a form of pneumonia that hits children and the elderly especially hard.
Elsebeth Baumgartner, BioInFiNix's general partner, says existing treatments with ribavirin and Respigam against RSV are largely inadequate.
The disease leads to over 100,000 pediatric hospitalizations and 10,000 deaths a year in the United States, she says.
But interferon-beta, widely viewed as a potential treatment for RSV, costs $30,000 a gram to manufacture in a fermentation vessel. Medicago figures it can produce interferon-beta at a cost that is "10 to 20 times lower than existing methods," says Mr. Vezina.
The joint venture between BioInFinix and Medicago expects to begin Phase I clinical trials, the first stage in human drug testing, using interferon-beta derived from alfalfa next year.
Medicago, which acquired exclusive rights for electroporation from the U.S. Department of Agriculture in 1998, has extracted insulin, glutenin, interleukin-2 and other antibodies from alfalfa.
In Calgary, SemBioSys Genetics has developed a transgenic technique that uses oleosin proteins in oilseed crops such as canola and flax. These proteins attach themselves to oils in seeds.
"By engineering the seed to produce a fusion between the oleosin and a commercially desirable protein, the system will allow for low-cost protein production," says Andrew Baum, president of SemBioSys.
The technology, which was discovered at the University of Calgary, has attracted Dow Chemical's agrosciences subsidiary, which has invested in SemBioSys. Mr. Baum says he is unable to discuss the product SemBioSys has developed or the identity of its second corporate partner - or even the industry the new product would target - because of a confidentiality agreement.
"We're in product development with our first product and hope to soon enter product development with our second," he says. "We've recovered [the protein from transgenic flax], purified it and it works."
SemBioSys hopes to market its product between 2001 and 2003, subject to regulatory review, the expansion of manufacturing capacity and marketing plans, he adds.
For many scientists, however, tobacco, corn and potatoes are the Big Three in transgenic research. At the top of the heap is tobacco, which has long been considered the easiest crop to genetically engineer, says Mr. Brandle of Agriculture Canada.
In a field trial with low-nicotine transgenic tobacco at Delhi, Ont., this past summer, Mr. Brandle's plants were treated to recover a human gene for a protein called interleukin-10 (IL-10), a potential treatment for inflammatory bowel syndrome and Crohn's disease.
The IL-10 that he and his team recovered is expected to enter pre-clinical animal studies at London Health Sciences Centre this fall. If it passes muster, it could replace existing IL-10, which now costs $78 a microgram, or $78-million a gram.
Despite potential savings, molecular farming has its critics. "I'm concerned with the very process of introducing genes into different genomes," says Ann Clark, a crop science professor at the University of Guelph.
For one thing, genes can enter unrelated organisms in soil, she says.
"Once this stuff gets loose, it's a completely uncontrollable thing. I don't think we've given near enough consideration to the impact of genetic engineering on nature."
At its annual conference last year, the International Federation of Organic Farming Movements declared that genetic engineering represents the biggest threat to organic agriculture.
"Because it is molecular and non-degradable, it pervades, and invades forever," the association said. As a result, it can affect microbial soil technologies, livestock feeds and supplements, raw and processed human foods, and vitamins.
As part of the Delhi field trial, the Canadian Food Inspection Agency determined that transgenic tobacco must be harvested prior to flowering and must be at least 10 metres away from other tobacco plants.
Whatever the risk of genetic contamination, supporters of molecular farming say the life-saving benefits of cheap pharmaceuticals more than compensate.
