New York Times
May 14, 2000
Joe Williams, a Virginia tobacco farmer, has been forced to cut his production nearly in half over the last three years as people have kicked the smoking habit. But he is hoping that a small experimental plot he just planted will hold the key to his staying on the farm. That tobacco has been genetically engineered to produce not cigarettes but pharmaceuticals.
Plants containing drugs could, indeed, represent a new high-priced crop. "If we can actually find a medical use for tobacco that saves lives, what a turnaround for the much-maligned tobacco plant," said Christopher Cook, chief executive of ToBio, a company recently formed by Virginia tobacco farmers like Mr. Williams to grow drugs in cooperation with the CropTech Corporation of Blacksburg, Va.
The production of drugs in genetically altered plants -- called molecular farming or biopharming -- seems poised to represent the next wave in agricultural biotechnology. Until now, efforts have mainly been directed at protecting crops from pests and improving the taste and nutrition of food.
But just as the production of bioengineered foods has been controversial, molecular farming is already raising some safety and environmental concerns. Chief among them is that drugs might end up in the general food supply, either because crops or seeds are misrouted during processing or because pollen from a drug-containing crop in an open field fertilizes a nearby food crop. What if insects eat the drug-containing plants or if the drug leaks into the soil from the roots?
About 20 companies worldwide are working on producing pharmaceuticals in plants, according to the Bowditch Group, a Boston consulting firm. A handful of such drugs are already being tested in human clinical trials, including vaccines for hepatitis B and an antibody to prevent tooth decay.
There have been dozens of field tests like the one on Mr. Williams's farm, aimed at seeing if products ranging from hemoglobin to urokinase, a clot-dissolving drug, can be grown in crops like corn, tobacco or rice. In a closely related effort, companies are also trying to use plants to produce industrial chemicals.
Proponents say that farming for pharmaceutical proteins would be far cheaper than the current practice of producing these drugs in genetically modified mammalian cells grown in vats. That could lower the price of drugs produced by biotechnology, some of which now cost tens or even hundreds of thousands of dollars a year per patient.
In some cases, the drugs would not even have to be extracted from the plant. Scientists are testing edible vaccines in which people would be protected from diseases by eating genetically engineered foods.
As these crops get closer to market, regulators are trying to figure out how to ensure their safety. Last month, the Food and Drug Administration and the Agriculture Department held a public meeting in Ames, Iowa, to discuss the issue.
The regulators say some safeguards are already in place. To minimize environmental risks, all field tests of drug-producing plants must receive government permits, while some field tests of other modified crops require only that the government be notified, said Michael Schechtman, biotechnology coordinator for the Agriculture Department. In addition, the distance by which the drug-bearing plants must be isolated from other plants to prevent cross-pollination is double the usual distance used by seed companies to assure purity of their seeds, he said. And although genetically modified food crops are often deregulated after the product becomes commercial, he added, the planting of drug-containing crops is likely to be regulated forever.
But Norman C. Ellstrand, a professor of genetics at the University of California at Riverside and an expert on pollen flow, said that long-distance pollen flow is poorly understood and that the appropriate isolation distance for drug-producing plants would depend on the particular crop and drug. "It's just not clear that setting a double distance is going to solve everything," he said.
Indeed, biopharming lies on the border of medical biotechnology, which has been largely free of controversy, and food biotechnology, which has been beset by protests.
Some executives in the fledgling industry say that because medicines clearly help people, their activity is not generating the same kind of resistance as the production of genetically modified food crops. In addition, they say, drugs are tested and regulated far more stringently than biofoods. "It's being received entirely differently," said William S. White, president of Integrated Protein Technologies, a unit of the Monsanto Company that is trying to grow drugs in corn.
But critics of agricultural biotechnology say that such companies, which underestimated the public reaction to bioengineered foods, are repeating the mistake. Michael Hansen of Consumers Union, for one, said the public had no idea about the work being done to produce drugs in plants. "Once they have an idea, the thought of putting drugs in plants is not going to go over well," he said.
Some companies producing drugs in plants are already being hit. Axis Genetics of Britain went out of business a few months ago, saying the protests over bioengineered food had scared off investors. Groupe Limagrain, a French seed company, says it has been conducting its field tests in the United States because the dispute over modified crops is greater in Europe. And Planet Biotechnology Inc. of Mountain View, Calif., keeps the location of its greenhouses secret to prevent vandalism by protesters, as has happened to companies growing modified food products.
Companies are considering various techniques to keep drug-producing crops from accidentally entering the food supply, including the implanting of a gene to turn drug-producing crops a different color from other crops.
Techniques are also being developed to prevent cross-pollination. CropTech, for instance, said its tobacco would be harvested before sexual maturity. Some drugs needed in small quantities might be grown only in greenhouses, rather than open fields.
Just as with food, biocrops should be able to produce large quantities of drugs at low cost, advocates say. The newest factories now used to produce pharmaceutical proteins in genetically modified mammalian cells can cost $100 million or more and can produce a few hundred kilograms a year at most. Drugs made in such factories can cost thousands of dollars per gram to produce.
For many biotechnology drugs already on the market, this is not a problem because prices are high and only minuscule amounts are needed. But some drugs under development, like an antibody-containing cream for herpes, are likely to require much larger quantities and not to be able to command high prices.
"They cannot make these drugs using the old technologies," said Mr. White of Monsanto's Integrated Protein Technologies. "It's just not going to be cost effective to do so." Mr. White said his company could produce 300 kilograms of a purified drug for a $10 million capital investment and a cost of $200 a gram.
Planet Biotechnology is in clinical trials of an antibody, produced in genetically altered tobacco, that blocks the bacteria that cause tooth decay. Elliott L. Fineman, the chief executive, said it would be impossible to use mammalian cells to produce the 600 kilograms a year that might be needed in a cost-effective way. But the entire supply could be affordably produced on a single large tobacco farm.
Still, the companies wanting to grow drugs have found the going somewhat rough. The Large Scale Biology Corporation, formerly Biosource Technologies, did the first field test of a drug produced by a plant in 1991 but still does not have a drug in clinical trials.
Drug companies are hesitant to depart from existing technology. And some industry experts are not convinced that plants would be cheaper when the cost of extracting the drug from the plant is considered. "With respect to purifying it and isolating it, a plant can pose challenges," said Norbert G. Riedel, president of the Baxter Healthcare Corporation's recombinant DNA business.
Moreover, the production of drugs in plants faces competition from production in the milk of genetically modified animals. This also offers potentially high volumes at low costs, and the animal milk companies are closer to bringing products to market. Some already have deals signed with major drug companies.
The plant-drug companies say their technique is safer because mammalian cells and animal milk can introduce harmful viruses into the drug, while plant viruses are not known to infect people.
There could be other problems, however, including contamination by pesticides and plant chemicals like nicotine. The F.D.A., which is preparing draft guidelines for production of such drugs, is considering such issues as assuring that the pharmaceutical protein does not change form during plant growth, harvesting and storage.
Yet another issue is that the sugars attached to proteins by plants are different from those attached by animals. This could prevent the plant-derived drug from working and could cause allergies, said Dr. Gary A. Bannon, professor of biochemistry and molecular biology at the University of Arkansas medical school.
Molecular farming might not prove to be the salvation of vast numbers of farmers since the acreage needed will probably be small. Mr. White of Monsanto said even a drug needed in large quantities could be produced on a few thousand acres of corn, a mere blip compared with the roughly 77 million acres of corn grown in the United States.
But Brandon J. Price, chief executive officer of CropTech, which is working with the Virginia farmers, said 45,000 acres would be needed to satisfy the entire worldwide demand for human serum albumin, a blood product that his company wants to produce in tobacco.
Said Mr. Williams, the Virginia farmer, "We're looking at thousands and thousands of acres if it takes off and goes."
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Last Updated on 5/15/00
By Karen Lutz