November 1, 2006 (Vol. 26, No. 19)

But Will Important Innovations Be Nipped in the Bud?

Fruits and flowers are not the only things blooming in the tropics. At the invitation of the U.S. State Department, I presented a series of lectures and briefings in the Philippines about an exciting advance in agricultural biotechnology: biopharming—the programming of plants to produce pharmaceuticals that can be purified or that might even be delivered by eating the plant material itself.

The early-stage R&D I saw during my travels was astonishing. University of the Philippines, Manila, Professor Nina Barzaga—The Illustrious Nina, as she is known locally—has introduced into banana plants the genes that express potential vaccine proteins for typhoid fever, rabies, and HIV. Dr. Barzaga and her collaborators intend to process the bananas sufficiently to be able to standardize the dose, by converting them to dried banana chips, for example, and then to carry out clinical testing.

As I met with scientists, regulators, agency heads, and senior politicians, I found that while much of the science is stunning, as in much of the rest of the world over-regulation is a significant obstruction to progress.

The concept of biopharming is not new. Many common medicines, such as codeine, morphine, bulk laxatives, and the anticancer drugs taxol and vincristine have long been purified from plants. But biopharming’s great promise lies in using gene-splicing or genetic modification, techniques to make old plants do radical new things. Gene-splicing has been applied to plants for decades in order to improve their nutritional value and agronomic traits (yield, pest- and drought-resistance, etc.). The production of high value-added substances is a logical, straightforward extension.

Biopharming offers tremendous advantages over traditional methods for producing pharmaceuticals. There is great potential for reducing the costs of production. The energy for product synthesis comes from the sun, and the primary raw materials are water and carbon dioxide. And if it becomes necessary to expand production, it is much easier to plant a few additional hectares than to build a new bricks-and-mortar manufacturing facility. (Think Tamiflu, the anti-influenza drug, which is in short supply.)

Finally, vaccines produced in this way will be designed to be heat-stable so that no refrigeration chain from manufacturer to patient will be required—a major advance for use in developing countries, especially in the tropics and throughout Africa.

Biopharmed Products

Approximately two dozen companies worldwide are involved in biopharming, about half have products in clinical trials, and at least one biopharmed medical diagnostic is being sold. The spectrum of products is broad, ranging from the prevention of tooth decay and the common cold to treatments for cancer and cystic fibrosis. In April, California-based Ventria Bioscience ( reported favorable clinical results with two human proteins biopharmed in rice and used to treat pediatric diarrhea.

There are major, interrelated obstacles to moving these projects through to commercialization, however. Excessive, unscientific regulation, the bleating of anti-biotech nongovernmental organizations (NGOs), and shortfalls in funding all conspire against the projects; worse still, these negative factors reinforce one another.

Over-regulation makes field trials difficult and hugely expensive to do, which makes it hard to attract big pharma collaborators or funders. In addition, the NGOs endlessly wring their hands about risks and point skeptically (and cynically) to the absence of medical breakthroughs.

Critics of the new technology have made dire predictions of contamination of the food supply, warning of “drugs in your corn flakes.” However, the sophistication of modern agriculture enables us to sequester different crop varieties when necessary and to cultivate safely the same species of crops for food and for new pharmaceuticals. Having said that, one must admit that human error is inevitable, so it is reasonable to ask, What is the likelihood of consumers’ sustaining injury if a few biopharmed plants find their way into the food supply?

In order for unwanted health effects to occur, several highly improbable events would have to occur. First, the active drug substance would have to be present in the final food product—say, corn chips or oil, if the drug were made in corn, for example —at sufficient levels to exert an adverse effect from either direct toxicity or allergy. But there is generally a huge dilutional effect, as small amounts of biopharmed material are pooled into a much larger harvest. With few exceptions (e.g., peanuts), even an allergic reaction requires the presence of more than a minuscule exposure. Second, the active agent would need to survive milling and other processing and cooking. Third, it would need to be orally active (usually, proteins are not because they are degraded in the gut).

The probability that all of these events would occur is extremely low.

To be sure, biopharming, conducted unwisely, could present valid safety concerns. It would be irresponsible, for example, to produce the antiwrinkle drug Botox in an edible plant, except under very high conditions of containment, probably in a greenhouse or screenhouse. The active ingredient in the drug is, after, all, the highly lethal botulinum toxin (which is safe when injected under the skin in tiny doses).

One constant around the world is the over-regulation of agricultural biotechnology, especially biopharming. For example, the regulations of the U.S. Department of Agriculture impose highly prescriptive standards that fail to take into account the actual risks of a given situation, but mindlessly dictate one-size-fits-all, draconian requirements. These include large buffer zones between biopharmed and other crops; restrictions on subsequent use of land used to grow biopharmed plants; and the setting aside of planting, storage, and harvesting equipment exclusively for biopharmed crops.

Moreover, the USDA has imposed a zero-tolerance for any biopharmed crop in food—which is unscientific, unrealistic, and unnecessary. (Regulators seem to have forgotten about the long-established tolerance levels in grains for unwanted substances such as insect parts, rodent droppings, and harmful fungal toxins.)

Countries such as the Philippines that lack large, sophisticated regulatory apparatuses often follow the lead of the U.S. or the United Nations, whose regulations are lethal to innovation in poorer countries. If you are running a small-scale but high-quality R&D operation that can’t test its biopharmed plants in the field because of regulatory obstacles, it is hard to convince potential commercial collaborators that you are for real.

Biopharming can bring us safe, affordable, innovative solutions to some of the world’s most vexing health problems, but to harvest its benefits we will need to inject science and common sense into public policy. If we fail to do so, biopharming’s development costs will continue to be hugely inflated, only very high-value-added products will become development candidates, and consumers worldwide ultimately will see few biopharmed drugs in the pharmacy. And in the process, the impressive work of people like The Illustrious Nina will be for naught.

Henry I. Miller, M.D., is a fellow at Stanford University’s Hoover Institution. From 1989 to 1993, he was director of the U.S. FDA’s Office of Biotechnology. E-mail: miller@

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