Fields of Gene Factories

Los Angeles Times

June 4, 2001

Fields of Gene Factories;



For the bioengineering revolution, the next big step may be plants that can make industrial chemicals and drugs. Why build expensive facilities when you can just grow what you need?

BY AARON ZITNER, TIMES STAFF WRITER

OMAHA - Stepping over the stubble of last year's cornstalks, Barry Wiggins used a measuring wheel to pace off an exact acre of farmland. He marked the plot with orange flags, then used a hand-held gizmo to take a satellite reading of its precise location on Earth. Only then did Wiggins rip open a bag of seed corn and pour it into the planting equipment that sat behind his tractor.

When the corn sprouts here, it will not look like anything special. But the federal government is requiring unusual measures to mark this field because this corn is not intended for anyone's dinner plate. Instead, it has been genetically engineered to produce a pharmaceutical: a protein being tested as a vaccine for hepatitis B.

For the gene revolution, this looks to be the next big step: turning plants into factories to make drugs and industrial chemicals. And for a world already sorting out its views on genetically modified foods, the coming wave of crops adds new and urgent questions about the practice of tinkering with genes.

Already, human trials have begun on "edible vaccines" grown in genetically engineered corn and potatoes. Building medicines into cornflakes or other foods could be especially helpful for developing countries, where syringes, refrigeration and trained medical workers often are scarce. "There's no doubt that this could be very important," said Jose Luis Di Fabio, an official with the Pan American Health Organization. About 1.6 million unvaccinated children die each year of diseases for which vaccines exist, he said.

U.S. farmers also could benefit, as companies promise to pay a premium for growing the new plants. In a bid to help ailing tobacco farmers, Congress and the state of Virginia have funded research on modifying tobacco to produce pharmaceuticals, which might lead to new, high-value crops.

For chemical makers, the new crops offer a tantalizing proposition: Why build expensive factories when you can simply grow chemicals? By moving a chicken gene into corn, one company already makes an industrial protein used in labs around the world. Other companies are betting that gene-altered plants will cut the costs of making chemicals used in plastics, detergents and construction materials.

"Think of all the things that could be grown this way," said Anthony Laos, president of ProdiGene Inc., the Texas company that employs Wiggins and created the hepatitis B corn, the result of adding a virus gene to the crop. "Nothing's going to happen overnight, but in 10 years I could see 10% of the country's corn acres devoted to this."

Known as "biopharming," the process of growing chemicals in modified plants marks a new direction for biotechnology. Scientists first added genes to plants in 1983, but so far the technology has mostly been used to make crops resistant to weedkillers and insects--which cuts the cost of farming.

Biopharming raises many questions familiar from the debate about genetically engineered foods. The main fears are that adding foreign genes to plants will prompt allergic reactions in people who eat them, and that the genes might cause unwanted changes in soil, in insect populations and in the broader environment. But in transforming plants to grow things that people do not normally consume, biopharming may raise additional concerns.

"Now we also have to worry about taking vaccines unexpectedly from these plants," said Joseph Mendelson, legal director for the Center for Food Safety, a critic of industrial agriculture. "When you talk about something like a vaccine or chemical that could spread to the environment, I would say that it raises the concerns to a higher level."

Some groups see genetic manipulation as an unacceptable exploitation of nature. One radical group, the Earth Liberation Front, even says it set fires recently at a Seattle genetics research laboratory and an Oregon tree nursery, doing more than million in damage.

Federal regulators say they are keeping a watchful eye on biopharming, requiring permits when new crops are grown in open fields. To prevent pollen from carrying modified genes to new plants, the U.S. Department of Agriculture requires farmers to separate gene-altered plants from conventional crops by several hundred feet. The agency sometimes asks growers to remove the pollen-bearing parts of the plant as well.

To clarify the permit requirements, the Agriculture Department and the Food and Drug Administration expect to publish a "guidance" document this summer that spells out what companies must do to grow, transport and contain biopharmed crops. "They're not going to process them anywhere near your food," said Kathryn Stein, an FDA official. "The facility would have to be dedicated to pharmaceuticals.

"Also, we have control over the disposal of all waste materials--what happens to the residue of the corn, for example--and we will restrict that so that it does not go into food or feed."

Still, a debacle last year involving one type of genetically engineered corn gave a black eye to regulators and to biotechnology companies and has sharpened scrutiny of their work. Sold under the name StarLink, the corn won approval as an animal feed but not for human consumption, as regulators wanted more evidence that it would not provoke allergies.

StarLink was grown on less than 0.4% of U.S. corn acreage in 1999. But thanks largely to poor controls after harvest, it turned up in 430 million bushels of corn and triggered a recall of more than 300 brands of taco shells, corn breads and other processed foods. Its creator, Aventis SA of France, is expected to pay 0 million to farmers in crop buyback programs and other costs. U.S. taxpayers will spend as much as million to buy contaminated seed stocks from seed distributors.

The episode prompted some critics to say that corn and other food crops should never be modified for nonfood purposes. "Promises were made about containment and segregation, and they weren't kept, and you might say they could never be kept," said Philip Regal, a University of Minnesota biologist.

Biopharming firms say comparisons to StarLink are unfair. StarLink and most other genetically engineered seeds are sold to farmers, who then market the crops. But ProdiGene does not sell its seeds. It pays farmers for the use of farmland and for certain growing chores. Laos said: "We basically do all the harvesting. What's valuable to us needs to be extracted from the corn, so we never let it get out of our hands."

Biopharming companies also say that, in some ways, their work is not novel.

The biotechnology industry already makes dozens of drugs by moving human or other genes into bacteria, yeast or hamster ovary cells, then encouraging those genes to make proteins. Many proteins can be used as drugs or as industrial chemicals.

The process, however, requires highly sterile factories, with fermentation tanks and sophisticated purification processes. By moving the same genes into plants, companies might save millions of dollars in construction and operating costs. If a protein drug is a big hit, its manufacturer would simply plant more of it. And if the market collapses, the company would just grow less.

One company, Epicyte Pharmaceutical Inc. of San Diego, says it will be able to make the same quantity of drugs with 200 acres of corn that a 0-million factory would produce in one year.

ProdiGene makes a similar claim. Since 1996, it has been selling a version of avidin, a marker protein that helps laboratory workers track what is going on in chemical reactions.

Avidin has traditionally come from chicken eggs, but ProdiGene scientists moved the avidin gene out of chickens and into corn. Today, the company says, a single .50 bushel of corn yields the same amount of avidin that comes from a ton of eggs, which costs about ,000.

The new wave of crops is aimed at sizable markets. The -billion market for antibody drugs, used to treat cancer, inflammation and other ailments, is expected to grow to billion by 2004. Epicyte is developing several "plantibodies," or human antibodies grown in plants.

One scientist, Guy Cardineau of Dow AgroSciences, told a conference last year that biopharmed chemicals and drugs could be a 0-billion market within 10 years. However, the cost of extracting proteins from plants could make some biopharmed products too costly. And like other drug-makers, biopharming companies must show the FDA that their products are safe and effective. Because of the way plants manipulate sugars, a protein made in plants is sometimes different than the same protein made in mammalian cells.

Plants also may cleave or fold the protein incorrectly, said Dr. William Haseltine, chief executive of Human Genome Sciences Inc., which has invested heavily in traditional methods of making gene-derived drugs. "We believe there are enough risks in the development of new drugs. To add another one--that is, the method of production--is unwise." Moreover, it is unclear whether edible vaccines from plants actually work. The body's digestive system is designed to break down proteins before they reach the bloodstream. Very few oral vaccines exist today; the oral polio vaccine is the most common.

But some scientists say that is only a function of cost. "What if you need 1,000 or 10,000 times the protein to make an oral vaccine work?" asked John Howard, chief scientific officer at ProdiGene. "The cost would be prohibitive--except if you grew it in plants."

Hugh Mason, a plant biologist at Cornell University, and colleagues last year showed that a hepatitis B vaccine grown in potatoes produced an immune response when fed to mice. Similar tests have been conducted on humans, but they have not yet been published. "I can say they were encouraging," Mason said. At the Nebraska cornfield that Wiggins planted recently, the focus was not on whether the hepatitis B corn would ever find a market. Instead, Wiggins and other ProdiGene workers were trying to make sure it would not find its way to any other field.

After measuring and mapping their test plot, they planted two rows of conventional corn around the edges. The conventional corn was intended to catch any pollen that might escape from the gene-altered crop. And next year, workers said, this plot would be planted with soy, another way to make sure that stray pollen does not move to new corn plants. "The only pollen flying around here will be non-transgenic," said Donna Delaney, a plant geneticist, as she supervised the planting. "Make sure that people know we're doing our best to keep this stuff out of their food."