Brave New Foods

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First, genetic scientists worked to save crops.

Now they are engineering plants to produce human vaccines.

But they get consumers to take the medicine? BY FRED GUTERL

Watching Plants grow was never Hugh Mason’s idea of a good time. He was always more interested in organic molecules – DNA, proteins, viruses – than in the organisms themselves. But these days he’s spending a lot of time fretting over tomatoes. They grow in pots – dozens of them – in a greenhouse at Cornell University’s Boyce Thompson Institute in upstate New York. At first glance they seem quite ordinary – bright red and a bit larger than a golf ball.

Upon closer inspection, however, there’s something odd about them. What is it, exactly? Mason pauses, allowing his visitor a few moments of puzzlement. His boyish face and calm demeanor are reassuring in a molecular biologist whose specialty is tampering with food. A few years ago he was inserting foreign genes into plants to make them better able to resist drought when a colleague suggested a more exciting possibility: why not find genes that would make common edible plants produce vaccines against human diseases.

That is precisely what Mason’s trying to do. The tomatoes he nurtures bear a synthetic gene that causes them to produce a protein identical to the one that serves as a protective shield for the Norwalk virus, which causes stomachache and diarrhea. Mice that eat the tomatoes (freeze-dried and powdered) develop immune responses to the virus. Later this year Mason hopes to serve his fruit to people, and then test its efficacy by exposing them to the live virus. This research, he hopes, will lead to radically cheaper ways of making and delivering vaccines.

If this technology is ever going to see the light of day, Mason and his colleagues will have to perform a similarly radical altering of public attitudes toward genetically modified (GM) foods. When the first GM food products were introduced a few years ago, they were targeted narrowly at farmers (and American farmers at that) protecting crops from insects and herbicides. Partly for this reason, their benefits have gone largely unappreciated by the public. The next generation, by contrast, is aimed squarely at consumers. Products being developed in laboratories throughout the world include not only vaccine-bearing plants like Mason’s tomatoes but food staples such as rice, corn, soy and other vegetables and vegetable by products with enhanced nutritional value.

To get there is going to require surmounting a lot of public distrust. In the past few years agro-biotechnology has joined nuclear physics as one of the world’s most reviled scientific endeavors. The food industry and its regulators are partly to blame: they are guilty of serious bungling, including grossly underestimating the degree to which people – and in particular Europeans – are sensitive to any tampering with what they eat. Dark, unconscious fears about what scientists do is one thing, but who wants to confront them each time you raise a fork?

Despite Mason’s benevolent nerdiness, there is definitely something odd – sinister, perhaps? – about those bright little tomatoes. “Have you figured out what it is?” he asks. “It’s the leaves. They’re crinkly. ” Sure enough. Unlike the smooth leaves of a normal tomato plant, Mason’s are wrinkled, as though they had been dried on the stem. It doesn’t affect the taste of the tomatoes or their safety, he explains. “It’s just an undesirable result of them being transgenic. I’m not entirely sure why it happens. Maybe because they have an excess number of chromosomes. It doesn’t happen in all of the plants. Most of them look pretty normal.”

What are crinkly leaves compared with the potential of tomato vaccines to prevent illness in thousands of children who die each year because they haven’t been vaccinated against such commonplace illnesses as diphtheria, diarrhea, whooping cough, polio, and measles? Unlike many conventional vaccines, food-borne ones wouldn’t need refrigeration. They could be distributed as seeds and grown locally, making them cheaper to deliver to remote Third World villages. It’s not hard to imagine how much easier and safer it would be to deliver, say, a tuberculosis vaccine contained in the genome of a tomato or banana than in a perishable serum that must be injected with a syringe.

When Mason’s mentor, biologist Charles Arntzen, first proposed engineering plants to make vaccines more than 10 years ago, Mason recalls being “stunned ”. “The plan sounded a bit crazy, but I couldn’t think of a reason why it wouldn’t work,” he says. They chose to start with a vaccine for hepatitis B that was derived from a gene found in yeast. They spliced the yeast gene onto some plant DNA and used an “agrobacterium” to deliver the genetic material to cells of a tobacco plant. From each cell they cultivated complete plants, extracted leaf cells and examined them with an electron microscope. At last they found what they were looking for: the hepatitis B antigen – a harmless protein that, once in a person’s bloodstream, would trigger an immune response to the disease. They knew they had engineered a plant that contained the desired yeast gene and that would manufacture the hepatitis B vaccine.

The experiment was encouraging, but when the two scientists began talking about their work at conferences, they realized how naïve their original idea of plant-borne vaccines had been. “The idea was, maybe we can produce the vaccine in plants, and then with common agricultural methods you could scale up. If you need a million more doses, you just plant a few more rows. But it turns out you have to worry about correct dosages and all sort of things like that. You have to treat these plants as pharmaceuticals, not food.”

Mason and Arntzen have since grown potatoes that express Norwalk virus and E. coli antigens. They’ve served the potatoes – raw, because cooking might damage the antigens – to human test subjects and succeeded in stimulating immune responses. The tests established not only that vaccines can be grown in plants but that they can survive the trip through the stomach to the bloodstream. But much remains to be done before the technology is ready for general use. Scientists don’t know how much vaccine a person would need to eat to ensure protection and how often, and how to avoid overdosing. Dosage levels of plant-borne vaccines are low, so researchers need to find a way to boost them. Eating vaccines might also lead to “ oral tolerance ”, suppressing the immune response and rendering the vaccine impotent. “There’s been some really excellent work,” says Roger Beachy, president of the Danforth Plant Science Center in St. Louis, Missouri. “But can we really protect people or animals with these vaccines? It’s still an open question.”

Academic research alone isn’t enough to answer this question. These research curiosities will first have to be developed into potential products, which will have to run the gantlet of approvals and trials for new medicines. The problem is that the current public distaste for GM foods has made it difficult to find the investment needed to develop these products in the first place.

Europe is the center of opposition. Europe’s antipathy over GM foods dates back to the late 1980s, when the German chemical giant Hoechst collided with environmentalists over its plants to use then leading-edge GM techniques to manufacture insulin at a plant in Frankfurt. Even though similar methods were already used in the United States, Germany’s influential Greens could not be convinced that the plant was safe. It was 10 years before it was finally allowed to open.

The insulin affair paled, however, next to the fiasco of St. Louis-based Monsanto Corp. It blundered int o the European market with GM corn and soy varieties tailored for the benefit of American farmers. French activist Josè Bovè led a group that stormed a Monsanto plant in the Brazilian town of Não Me Toque, trashing several hectares of transgenic soybeans. The police simply looked on as the experimental plots were turned into so much genetically modified mulch. The firm eventually launched a public-relations campaign explaining the merits of GM foods, but too late. ‘The message was never fully explained”, says David Hughes, professor of food marketing at Imperial College, London. “People just thought that the company was trying to pull the wool over their eyes. ” Monsanto’s perceived arrogance was all the more damaging because the mad-cow scandal had made Europeans leery of the food industry in general.

The Monsanto case was only one of the food industry’s screw-ups. The US Environmental protection Agency made the dubious decision to approve the Starlink variety of GM corn, made by agrosciences firm Aventis, for animals but not people. In 2000 the corn was found in the products of fast-food restaurant Taco Bell. The incident made regulators wary, slowing approvals for research trials. ProdiGene, a Texas-based biotech firm formed in 1996 to develop food-borne vaccines for livestock, saw its funding from venture capitalists virtually dry up overnight. “Venture capitalists got cold feet,” says chief scientist John Howard. “They started asking, “Are you ever going to be able to market this stuff?”

ProdiGene fared better than the Cambridge, England-based Axis Genetics, which developed edible vaccines for hepatitis B.

Edible Vaccines

The first step in making a food-borne vaccine is to find a gene that produces an antigen, a harmless protein that your body mistakes for a virus. Put gene into a plant, eat it and your immune system does the rest.

1). Viral genes that produce antigens for a specific disease are implanted into agrobacterium microbes, which can easily infiltrate plant cells; 2). Tissue from a potato plant is placed into a petri dish that contains the agrobacterium; 3). The agrobacterium transfers the anigen-producing gene into the potato’s genetic material; 4). Plant cells containing the gene regenerate into a complete plant; 5). In soil, modified plants grow and produce potatoes that make antigens; 6). When people eat the potatoes, antigens enter the digestive tract; 7) macrophages – components of the immune system – absorb the antigens and display pieces of them on their surfaces; 8). Other immune bodies called helper T cells bind to these antigens and “remember” what they look like so they can recognize a real infection later on; 9). The helper T’s produce additional cells, which cruise the bloodstream looking for virus-infected cells displaying antigens for the specific disease; 10). Upon finding an infected cell, the T cell attach to it, releasing toxic substances that eventually kill it.

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