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COLUMN ONE : Vaccines in Your Vegetables : Genetic gardeners are trying to grow crops that could save millions of lives. Their discoveries might make immunizing a child against hepatitis as easy as eating a banana.

TIMES SCIENCE WRITER

Most farmers sow fields of alfalfa and reap acres of salad greens. Mitch Hein is cultivating alfalfa sprouts that could stem a cholera epidemic.

In a locked vault behind a chain-link fence in a corner of an underground parking garage, Hein, a scientist at the Scripps Research Institute, is tending a garden of unusually potent health food.

Each green plastic pot in the cell biologist’s growth chamber contains a scraggly alfalfa seedling that he has genetically engineered to contain just enough of the deadly cholera toxin that he believes will confer immunity on anyone who eats enough of it.

Each plant is an edible vaccine.

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No need for purified, refrigerated serum or hypodermic needles.

Just salad dressing.

While scientists at large biotechnology firms labor to improve supermarket tomatoes or create crops resistant to chemical sprays, a handful of researchers such as Hein are transforming ordinary fruits and vegetables into unconventional vaccines that promise to revolutionize public health.

If these genetic gardeners are successful--and human clinical trials bear out their preliminary laboratory findings--an apple one day actually may keep the doctor away. Vaccinations against common diseases that kill tens of millions of people every year could involve no more than a slice of bread or a piece of fruit.

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The researchers want to eradicate deadly diseases by simply giving people in developing countries the genetically engineered seeds that will sprout edible vaccines. They hope to reach the point where people who have no medical training, in villages far from hospitals or public health stations, would find tending to their health as easy as tilling a garden.

That day is years away, but scientists are making significant strides toward demonstrating that such plants are feasible. Last month, Hein harvested his first crop of the alfalfa vaccine from a small field in Ardmore, Okla. Now, 15 crates of sprouts are drying in a corner of his La Jolla lab.

Biologists like Hein are seeking ways to link agriculture and human medicine. They have coupled advanced theories of how the body’s immune system fights off disease with the latest in recombinant DNA technology.

They are trying to take advantage of the natural ability to build resistance against an illness through exposure to edible nontoxic compounds called antigens, which are isolated from a virulent virus or bacteria. The antigens provoke the antibodies that confer immunity without making you sick.

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Charles Arntzen at Texas A & M University is trying to develop a banana that can prevent hepatitis B, an illness that strikes up to 300 million people worldwide.

Arntzen, a molecular biologist, already has produced a potato that prevents gastroenteritis. At Washington University in St. Louis, biology professor Roy Curtis is engineering vaccines that use broccoli, turnips and Brussels sprouts.

Just to prove that it could be done, Curtis developed tobacco that curbs tooth decay by serving as a vaccine against the bacteria responsible for dental caries. He has no intention of allowing it to be sold.

“What we are doing is oddball stuff in terms of what people think of as traditional research,” Arntzen said.

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Plants have long played a major role in medicine. About one-fourth of prescription drugs used in the United States owe their origins to plant substances, according to Brian Bloom, vice president of research at the New York Botanical Gardens.

As scientists have become frustrated by their inability to synthesize new drugs from scratch, they are rummaging through the botanical medicine chest with increasing fervor.

Since 1991, researchers at the Missouri Botanical Garden have been collecting twigs, bark, flowers and fruit for the National Cancer Institute in tropical Africa and Madagascar. The material will be screened for potential anti-cancer and anti-HIV treatments. This fall, the New York Botanical Gardens began a $2-million prospecting project for Pfizer Inc. to scour the United States for plants that can serve as sources for new medicines.

With no natural remedy readily available for many diseases, some scientists are creating in the laboratory the plants that nature neglected to provide.

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The research into edible vaccines holds particular promise for the public health of many developing countries, where such diseases as cholera--which are easily preventable through sanitation--kill as many as 10 million uninoculated children every year, health experts said.

Until recently, cholera outbreaks could be readily controlled by antibiotics. But since 1980, cholera strains have appeared that are resistant to common antibiotics such as ampicillin, streptomycin, and tetracycline.

An injectable cholera vaccine exists, but even inexpensive vaccines are beyond the reach of countries in which the annual public health expenditure averages $10 per person. The newest recombinant DNA vaccines are very expensive. A new injectable hepatitis vaccine is safer and more effective than conventional treatments, but it can cost up to $100 per person. At the same time, AIDS and the potential for contaminated needles have turned inoculation into a significant health risk in some Third World countries.

The edible vaccines in development would probably be no more effective than most vaccines available today, but they would be cheaper and easier to distribute.

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Working independently of one another, Hein, Arntzen and Curtis hope to develop an affordable and safe way for even the most poverty-stricken parts of the world to protect themselves against disease.

“We are on an idealistic quest,” Arntzen said of his lab at the university’s Albert B. Alkek Institute of Biosciences and Technology. “We have to come up with a way to deliver genetically engineered vaccines to places like Bangladesh, India, China and Thailand, in a production system that is appropriate for the Third World.

“The simplest thing is to give them a seed. Let them plant it, grow it and harvest it,” he said.

That is why he thought of the banana.

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“We wanted something you could feed uncooked to children. We wanted something that is easy to transport, not something that would need refrigeration,” Arntzen said. “I challenge anyone to come up with something better than a banana.”

If he is successful, the cost of a hepatitis vaccination could drop to less than a penny per person. But there is more than one obstacle.

First, until recently, no one had been able to manipulate the fruit’s genetic structure by forcing new genes into the plant’s cells in the laboratory. Last month, during a conference on AIDS vaccines sponsored by the National Institutes of Health, Arntzen reported that his team had solved that part of the problem. Now they are testing to determine how much of the hepatitis antigen the bananas contain.

Hein’s work with alfalfa and the cholera antigen is typical of how the development of such vaccines is unfolding.

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It takes about six months to create plants that contain the foreign genes, Hein said. He used a natural genetic engineer, a plant disease called agrobacterium, to insinuate the new genes into the alfalfa cells. Then he cultivated seedlings from the altered cells.

Hein said he chose cholera as the basis for an experimental vaccine because he could be sure that an antigen from the lethal disease would survive the stomach’s corrosive acids long enough to generate antibodies.

Hein’s edible vaccine relies on the same basic idea as more conventional vaccines: When a sickness grips the body, it leaves an indelible imprint that allows the immune system to recognize the invading microbe quickly the next time it appears and to mobilize antibodies against it. That is why childhood diseases such as measles rarely recur.

To reduce the risk that they will cause the disease they are meant to prevent, conventional vaccines use injections of weakened or dead disease organisms to provoke production of antibodies. The measles vaccine contains pathogens that have been crippled or killed. The tuberculosis vaccine contains live bacteria. The diphtheria and tetanus vaccines contain purified antigens from killed bacteria.

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Using recombinant DNA technology, researchers can isolate the genes that trigger immunity, cut them free with enzymes and insert them into a harmless organism. Scientists have used the technique to create vaccine serums by genetically altering bacteria. Those products still require refrigeration and injections.

Until recently, no one thought to use plants instead.

Major hurdles remain. To perfect such edible vaccines, researchers must also learn how to make their plants produce the disease antigens reliably and in large enough quantities to be effective.

In a first step in creating his plant vaccine, Hein used a part of the cholera toxin, called the cholera b-chain, which is unusually adept at penetrating the moist mucosal cells that line the throat, stomach and intestines. The cholera a-chain, which is normally linked to the b-chain, causes the severe dehydration that is the most deadly symptom of the disease.

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But by itself, the b-chain can stimulate production of antibodies, without risk of causing the disease. Researchers still also must make sure the antigens do not backfire by causing a little-understood phenomenon called oral tolerance, which makes the immune system drop its guard against invading microbes.

“If you inhibit the ability of the animal to mount an immune response, it could make an infection even worse,” Curtis said.

Hein quickly demonstrated that laboratory animals fed the pure antigen mixed into their normal meals would develop immunity to cholera and not oral tolerance.

The recent field test, conducted with the Samuel Roberts Nobel Foundation, was necessary to demonstrate that the new alfalfa plants, growing in a more natural setting exposed to weather, insects and other environmental influences, would show measurable levels of the cholera toxin.

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“They definitely produce the antigen,” Hein said. “But they produce it in lower levels than they did when we had the plants in the laboratory. We are not yet sure of the reason.”

Now he is mulching the dried plants into “mouse chow” and feeding it to laboratory mice in order to calculate how much they need to digest to develop immunity. Then he hopes to learn how the plant is concentrating the cholera antigen in its tissue and how to control the amount.

“After that point, it is not science anymore, it is eating. That is culinary art,” Hein said. “Should we serve it up as oatmeal, or serve it up as bread, or as alfalfa sprouts?”

Edible Vaccines

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Conventional vaccines use injections of weakened or dead disease organisms to provoke production of antibodies.

Today, researchers can cut loose the genes that trigger immunity from a disease organism and insert them in a harmless organism such as an alfalfa plant to create an “edible vaccine.” The antigens in the new plant provoke the antibodies that confer immunity without actually making anyone sick.

Here is how researchers at the Scripps Research Institute created an alfalfa-based vaccine against cholera.

1. Antigen is isolated from cholera toxin.

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2. Antigen genetic sequence is cut out with restriction enzymes.

3. Antigen genes are inserted into cells of an organism that causes a plant disease called crown gall.

4. New genes are transferred into the alfalfa plant by infecting it with the transformed crown gall disease.

5. New plant cells are cultured, now containing the cholera antigen.

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6. Alfalfa is regenerated.

7. The plant appears to confer immunity to cholera in lab animals that eat the alfalfa.

Source: Scripps Research Institute


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