The Next Biotech Harvest

At first glance, an aging industrial section of Cambridge, Mass., seems an odd place to look for the future of agriculture. The only plants are weeds along the railroad tracks and well-tended shrubs and trees dotting the entrances to the high-tech businesses that are rejuvenating the area. The agricultural heartland of the United States is a thousand miles away.

And you won’t find any greenhouses or pots of experimental plants inside Cereon Genomics. It looks like any other molecular genetics lab. Technicians prepare bar-coded samples; nearby, rows of sophisticated instruments that were originally developed for sequencing human genes form a high-speed manufacturing line. The difference is that the raw materials for this gene factory are often snippets of plants, and the product is information on the plant’s DNA-their genetic blueprints.

From his corner office, Roger Wiegand raises his eyebrows toward the automated equipment in back of him. Wiegand is Cereon’s director of genomics technology-the science of identifying genes and their functions. There may not be any greenery around, but for a longtime molecular biologist, Wiegand says, running Cereon’s lab is “like being a kid in a candy factory.”

The excitement is based on the conviction that the gene information being harvested at Cereon-and at other plant genomics labs sprouting up around the world-will help seed a biotech transformation of agriculture. Monsanto, the St. Louis-based agricultural and pharmaceutical giant, late last year committed to spend over $200 million to create Cereon, a wholly owned subsidiary it formed in an alliance with gene hunter Millennium Pharmaceuticals. The deal is one of the boldest moves in Monsanto’s makeover into a “life sciences” company. (In June, Monsanto announced plans to merge with American Home Products.) And it reflects the former chemical company’s deep-pockets belief that it can leverage the growing knowledge of genes into big business-and in so doing change how farmers and consumers think about plants.

Other companies share this vision. Several other chemical and drug giants, notably DuPont and Novartis (the Swiss company resulting from the 1996 merger of Ciba and Sandoz), have plowed billions into the dream. If these companies are right, within five years farmers will be planting cotton that is naturally colored to reduce the need for dyeing, as well as crops that harbor plastic. Growers will be armed with higher-yielding, bug-resistant crops. Consumers will pick up from supermarket shelves healthier and more nutritious foods that come from genetically modified plants. Further in the future, children will get vaccines through bananas or other foods, avoiding the terror of needles (see “Making Needles Needless,”).

Factories in the fields

the first transgenic crops were planted on a large scale in the United States two years ago and have quickly taken root in the economy. This year, genetically altered plants will make up about 15 percent of the U.S. corn harvest, about 30 percent of the soybean crop and more than half of the production of cotton. This first generation was begotten through the relatively simple trick of inserting a gene from a bacterium into a plant to produce a single trait; the results of such work include corn and cotton resistant to specific pests, as well as crops that tolerate several types of herbicides.

While this modest genetic tinkering may seem something short of a biotech revolution, bioengineered crops have taken farmers by storm. “People are surprised at how important the first couple of genes have been,” says Anthony Cavalieri, vice president at Des Moines-based Pioneer Hi-Bred International, a leading seller of seeds and a business partner with DuPont. “And this is just the front edge. It could be fundamental to how the whole agricultural sector works.”

Indeed, the real payoff is expected to come over the next several years as plant biologists begin not only to insert more genes into plants but also to redraw the genetic blueprints-and redirect the metabolic pathways-of many common crops. The vision is to rewire plants into cheap production units that can grow everything from modified foods to human vaccines to commodity chemicals. The reward for engineering these “output” traits in plants? According to John Pierce, DuPont’s head of discovery research in agriculture, it could mean getting a piece of industrial and food markets worth $500 billion per year.

Even for giant corporations, these are not small potatoes. Monsanto, for one, is working on a high-solids potato, as well as canola and soybeans with modified oil content. One strain of canola, for instance, is rich in beta-carotene to combat vitamin A deficiency, which is still a problem in many developing countries.

During the next several years, DuPont expects to begin marketing seeds for modified-oil soybeans as well as high-sucrose soybeans. Working with its partner Pioneer, DuPont has a half-dozen biotech crops nearing commercialization and expects to introduce plants with several traits “stacked” together. The company is also working on high-protein and high-oil crops for animal feeds (about 80 percent of U.S. corn is fed to animals).

Food for humans and farm animals is big business. But an even more lucrative bounty could eventually come from growing biotech crops that make highly prized materials and industrial products right in the plant. Why make synthetic dyes for cotton using highly toxic chemicals, the thinking goes, when the plants themselves could be genetically engineered to produce colored fiber? Why not turn plants into chemical factories?

Plant biologists at Monsanto and a Cambridge, Mass., start-up named Metabolix are separately working on a plastic grown in plants that could be ready for farmers as early as 2002. Prodigene, a two-year-old College Station, Tex., spin-off from Pioneer, is already selling industrial enzymes grown in transgenic corn and is developing other protein-based industrial products. Other labs are attempting to create plants that produce specialty oils that could serve as novel industrial ingredients for coatings and lubricants. Also on the drawing board are plant-based edible vaccines for diseases such as hepatitis and diarrhea.

“By tinkering with the control and activity of genes, you can make just about everything in plants,” says David Wheat, a longtime plant biotech consultant and president of the Boston-based Bowditch Group. “By understanding how an organism works at a molecular level, you can design new kinds of products-maybe even make products you’ve never seen before.”

Simple Arithmetic

The prospects in agricultural biotech are tantalizing enough that they are helping to drive a massive restructuring of the agricultural and chemical industries that is, in some cases, blurring the lines between the two (see “Seeding a New Industry,” sidebar). Monsanto and DuPont, in particular, have dug deeply into the new opportunities, gobbling up seed suppliers and plant biotech start-ups. Driven largely by the potential of biotech, Monsanto last year unceremoniously dumped its chemicals business, embracing biology as the wave of the future. In turn, this spring DuPont reorganized, forming a life sciences group (which includes its agricultural, drugs and biotech activities) and declaring that its future growth lies in the integration of chemistry and biotechnology.

Even staid Dow Chemical, the huge chemicals maker, has professed its desire to be a leading biotech player, targeting the development of plastics and industrial chemicals. “It’s a technology whose time has come,” says Fernand Kaufmann, Dow’s vice president of new businesses and strategic development. Kaufmann cautions, however, that it will take time for plant-grown chemicals to make a dent in the huge commodity markets, which are dominated by products made from petroleum.

DNA Databases

for the next few years, large-scale production of plastic will remain in the factory, not the field. Even in DuPont’s most advanced research projects for plant-based materials, Ireland concedes, scientists are still “unraveling the enzymatic pathways while simultaneously developing all the polymer chemistry. No one really understands how to control and regulate plant gene expression.”

But if plant genomics continues to accelerate at its current rate, it may become far easier to reach that goal. Most common crops have a large amount of DNA and about 50,000 genes-roughly half the number in humans. But using fast, automated machines honed for unraveling the human genome, plant geneticists are identifying genes more quickly than botanists know how to cultivate them.

Scott Tingey, director of DuPont’s genomics program, says technology has had a profound impact on the field. “A few years ago, it took two man-years to clone a plant gene,” Tingey says. “About half the time you were successful, the other half you fell on your face. Today, life is very different.” Over the last two years, DuPont has created a database of DNA sequences for corn, soybeans, wheat and rice. “It eliminates the tedious gene discovery process. That’s no longer the rate-limiting step in a project,” explains Tingey.

Biologists anticipate completing the sequencing of Arabidopsis (a weed that is the primary genetic model for plant genetics) by 2000, as a result of an international collaboration that began in 1989. That could be crucial because all flowering plants have essentially the same set of genes. “Within the next five years, we’ll know the function of all plant genes at some level,” predicts Stanford’s Somerville. “It’s a major change. We’ll be in a lot better position to make rational improvements in plants.”

Back at newly formed Cereon, one goal is to turn the sequencing of interesting genetic material into a routine, high-throughput production line. In particular, the company wants to accelerate the process of finding a DNA sequence responsible for a specific phenotype, or physical trait. “We are setting up systems that will allow molecular geneticists to go from a phenotype of interest to having a cloned gene, and knowing the sequence for that trait, in a very short time,” says Cereon president William Timberlake. “It now takes years to get at some of these genes,” Timberlake explains. “We would like to reduce that to weeks or months.”

But gathering all that gene information is only the first step. Oliver Peoples, co-founder of Metabolix, explains: “What do you do with all the gene information from genomics? You begin to engineer pathways to optimize the flow of carbon. It’s the end use of genomics-it’s the ultimate jigsaw puzzle.” In other words, the dream is to control the entire metabolism of a plant.

Companies intent on turning crop plants into factories are working on some preliminary steps. DuPont intends to sharpen its biology skills by making a plastic intermediate from sugar using genetically engineered microbes in a fermentation process. The intermediate is the key ingredient in a novel polymer that could compete with nylon, and the company plans to have a small-scale production facility up and running by late 2000. It will be DuPont’s first attempt at a biologically based production process, and, says Dorsch, it will guide the company’s plans for using biology to make materials.

Against one wall of Dorsch’s office is a diagram mapping the metabolic pathways in a bacterium. It resembles a chemical engineering flow diagram-the kind you see everywhere at DuPont-only it’s far more complex. The idea, Dorsch says, is to take advantage of the natural flows of carbon in the organism and to engineer subtle changes that allow you to siphon off a desired product. “Organisms are already tuned up to work very well. If you try to move a significant fraction of the carbon through a different pathway, you are getting toward having to completely re-engineer the beast. I don’t think we’re so audacious as to believe that that is something that will happen any time soon.” He quickly adds, “But we might get there.”

The DuPont research labs on the outskirts of Wilmington, Del., are sacred ground for polymer scientists and chemists. They are ground zero for modern American industrial chemistry, the place where nylon was invented. And petroleum-based chemistry has long reigned here. Now, says Ireland, biology is “revitalizing” the research. “The polymer chemists are excited about it because they see the possibilities inherent in the science. The biologists are excited because they see the opportunity to use their talents to make a lot of money for the company.”

Towering distillation columns are still more common than cornfields in Wilmington. But if DuPont and its rivals are successful, the gap between the agricultural markets and the chemical industry could soon be about to close. Indeed, the gap between industrial chemistry and biology already has.