San Diego County now has the third largest concentration of public bioscience companies, behind the Bay Area and New England. A decade ago, the region ranked fifth, just one indication of how much progress the biotech industry has made here.

With a market capitalization of about $17 billion and more than 5,000 employees, San Diego’s public biotech companies have become a powerhouse in their own right, with blockbuster products such as Idec’s Rituxan for non-Hodgkin’s lymphoma, and groundbreaking research from genomics companies such as Sequenom. Inevitably, big pharmaceutical companies such as Novartis have decided to plant their banner here; Novartis alone is investing $850 million in the region.

Steve Mayfield, associate professor at Scripps Research Institute and a member
of the San Diego Center for Molecular Agriculture, says San Diego now is one
of the premier plant biology centers in the world. (photo/Alan Decker)

But quietly, San Diego’s biotech industry also has become a giant in the emerging field of agricultural biotechnology. Growing better crops doesn’t have the pizzazz of curing AIDS or Alzheimer’s disease, but as the Green Revolution’s logical extension, it could save millions of lives, virtually eliminate malnutrition, make plants salt- and drought-tolerant, clean up toxic waste sites and even serve as living factories to produce less expensive pharmaceuticals.

A decade ago, Mycogen Corp. was pretty much the only major player in San Diego agbiotech. Then pharmaceutical giant Novartis set up a research center called the Novartis Agricultural Discovery Institute (Novartis and fellow pharmaceutical company AstraZenea later spun off their agbiotech holdings under the name Syngenta, and renamed the research center the Torrey Mesa Research Institute).

Other local agbiotech companies include Akkadix and Dow AgroSciences. The efforts of these companies are complemented by a substantial research presence at UCSD, Scripps and the Salk Institute.

In late August, the Encinitas City Council approved plans to build a $27 million agbiotech research center at the Paul Ecke Ranch. Famous for its poinsettias and other ornamentals, the Paul Ecke Ranch intends to collaborate with local scientists to improve its offerings.

The San Diego Center for Molecular Agriculture is the newest player on the local agbiotech scene. It was founded last year by UCSD, Scripps and Salk researchers as a focal point for agbiotech research. Two of its founders, Salk researchers Joanne Chory and Detlef Weigel, have joined an ambitious project to create a “virtual plant” by characterizing all the genes and proteins of the model plant Arabidopsis thaliana by 2010. By creating a computer-generated “clickable plant,” scientists could greatly speed up agbiotech research.

People tend to think of California agricultural biotech research as being concentrated at UC Davis or UC Riverside, says Maarten Chrispeels, a UCSD biology professor and San Diego Center for Molecular Agriculture member. “People know that basic biology research institutes do research that is relevant to medicine, but they’re generally ignorant of the fact that the same institutes do research that is relevant to agriculture,” Chrispeels says. “One of our purposes by choosing this name was to focus people’s attention on this.”

Seconding this view is Steve Mayfield, an associate professor in the department of cell biology at the Scripps Research Institute.

“Certainly San Diego now is, in everyone’s estimation, one of the premier plant biology centers in the world, along with the Bay Area and Boston,” says Mayfield, who also is a member of the San Diego Center for Molecular Agriculture. “In terms of biotech impact on a community, I would say plant biology and agbiotech is more important for San Diego than it is for any of those other places. Agricultural biotech in the Bay Area could come or go and it wouldn’t make one lick of difference to those guys because what’s driving their economy are computers and the rest of high-tech.”

What follows is the story of the new science arising from San Diego’s burgeoning biotech industry — and what it means to humanity.

From The Sea To Labs
San Diego’s role in agbiotech began, appropriately enough, with the sea. Kelco, formed in the 1920s, processed seaweed to get food thickeners and other products, and later added bacterial fermentation to expand its product line. The company lost its independence long ago. It was bought by drug maker Merck in 1972, by agrichemical giant Monsanto in 1995, and sold last year for $685 million to Hercules Inc. of Wilmington, Del.

Kelco, now known as CP Kelco, still has about 450 employees in San Diego, but most of its workforce is located elsewhere. The local plant was hit hard by recent increases in natural gas prices, causing the company to consider shuttering its operations.

Most of local agbiotech developed the same way as with biomedicine, with research. Scripps, Salk and UCSD all hired prominent plant biologists such as the Salk’s Chory. In 1997, Chory and other collaborators discovered a receptor in Arabidopsis for steroids, similar to those for steroids in animals, hinting at previously unknown growth mechanisms in plants. Two years later, Chory’s team found a gene that controls the level of a steroid that regulates plant stem length. This could lead to things like hedges that never need trimming.

At the level of molecular biology, there’s a strong link between agricultural biology and animal biology research, says Akkadix CEO Jerry Caulder, a local biotech veteran and former CEO of Mycogen.

“If you look at it from a Darwinian standpoint, there has to be, because the animal and plant kingdoms branched off from each other a few hundred million years ago, but at one time they were pretty much the same. If you consider that the human genome overlaps about 50 percent with the banana genome, it doesn’t surprise you that you’re going to find a lot of these common receptors and genes ... DNA is DNA, and the basic stuff we’re doing is the same.”

Epicyte, an agbiotech company seeking to use plants as pharmaceutical factories, was founded in 1996 by Scripps Research Institute researchers Andrew Hiatt and Mich Hein. Other local agbiotech companies look to San Diego area researchers for new discoveries as well as the skilled lab technicians and scientists they need to find new products.

“Syngenta came here specifically because Scripps was here and they wanted to be associated with us, but also because Salk and UCSD have very good biologists there,” says Mayfield, who collaborates with Epicyte. “When you’re a company, what you’d like to have around you is an academic environment your scientists can interact with.”

Epicyte’s goal is to produce therapeutic human monoclonal antibodies in plants, using a technology called “Plantibodies.” Monoclonal antibodies are now produced in animals such as mice, a process that can be quite costly. Manufacturing monoclonals in plants could not only be less expensive, but scaling up production would be much easier.

While Epicyte is developing antibody production in plants such as corn, Mayfield concentrates his research on algae. These simpler plants have much the same biochemistry at the molecular level as do higher plants, Mayfield says, but without the complex developmental factors that guide the growth of multicellular organisms.

“Higher plants are complex, sophisticated organisms, and to engineer those takes quite a bit of time and work. We work on a single-celled algae that is a eukaryotic cell (containing a nucleus) and acts just like a plant in many things it does, but has an advantage that we can grow on petri dishes. We can grow transgenic algae in a few weeks instead of six to eight months. Ultimately, a lot of the things we do in algae, whether they’re expressing antibodies, or making modified lipids or carotinoids, may be done in higher plants. This is just a test system for those.”

Late last month, the Torrey Mesa Research Institute completed the rice genome map in collaboration with Myriad Genetics Inc. of Salt Lake City, Utah. Because rice’s genetic structure is very similar to that of other cereals, this feat has great implications for enhancing food crops.

With no research budget, the San Diego Center for Molecular Agriculture isn’t trying to duplicate what Salk, Scripps, UCSD and Syngenta are doing. Rather, its goal is to give scientists from those organizations and other local plant scientists a place to converse with each other, hold seminars and in general to rub elbows, Mayfield says. So the center asks for small amounts of money, about $5,000 to $10,000, to publish papers and perform other special tasks.

“Promoting that physical interaction of people is often how you get collaborations and new ideas and projects going forward,” Mayfield says. “Every time we have a lunch or meeting, I’ll see either a new postdoc or faculty member, or just talk to an old one I haven’t seen in a few years. I’ll either get some latest technical tool they may have that could help me or just some idea from telling them what I’m working on.”

The center holds monthly meetings, Chrispeels says. An event tentatively planned for next year will be a symposium sponsored with UCSD Connect, with agricultural biotech speakers invited from around the country. Corporate sponsors include Akkadix, Digital Gene Technologies, Dow AgroSciences, Dupont and Syngenta.

Setbacks And A Comeback
Agbiotech has had some nasty public relations setbacks in recent years, due to protests by some environmental groups about genetically modified food organisms. Some of the concerns relate to possible harm GMOs can have on consumers; others relate to potential harm to the environment if GMOs were to escape into the wild. Last August, self-proclaimed anti-agbiotech vandals destroyed thousands of plants at a UCSD field station; however, most of the plants were produced through traditional breeding and technically not GMOs.

But these concerns will eventually fade away, predicts Mayfield and Caulder.

Caulder says research also is moving away from transplanting genes from one species to another to finding genes within a species that can be selectively promoted or modified to produce desirable results, such as making plants salt-tolerant or drought-resistant. That would eliminate one major criticism of anti-agbiotech activists, that transgenic plants, by crossing the species boundary, could produce organisms with unknown and possibly dangerous characteristics.

Chrispeels says agbiotech companies are learning from the controversy and will bring onto the market biotech foods that directly benefit consumers. The current controversy is fueled by a lack of benefits consumers can see at the table, he says, such as foods that prevent disease or have other desirable qualities.

“Things like putting Bt toxin into corn (to repel insect pests) were of limited obvious benefit to the consumer,” Mayfield says. “It’s an advantage to the farmer and an advantage to the guy selling the corn, so I perfectly understand why people have complaints about that. But that’s the first generation of stuff. Certainly in the very near future what’ll come out are things that are of direct benefit to the consumer.” Such products will either be foods that are nutritionally better or, as with Epicyte, pharmaceuticals for human diseases.

Bt, Bacillus thuringiensis, is a bacterium that makes toxins harmful to insects and other related pests, but not humans. The gene for the toxin is transplanted into corn to make it resistant to insect pests.

In September, 2000, Epicyte and The Dow Chemical Co. signed a multimillion-dollar research and development program for making monoclonals in plants. One of the goals is to ensure that monoclonals made in plants would be stable enough to store, along with developing a process to purify the monoclonals from the rest of the plant.

In October, Epicyte announced it had received $2.3 million in Small Business Innovation Research grants to develop sexual health products, including anti-HIV antibodies. Such products inexpensively made would be especially useful in AIDS-ravaged and poverty-stricken southern Africa.

“As soon as that stuff starts to show up, I think people will have a completely different realization of what agbiotech and the potential for it really is,” Mayfield says of the new generation of agbiotech products. “I don’t think anybody will have a complaint about those kinds of GMOs.”

Epicyte’s Chief Executive, Christopher G. Clement, says that if the required regulatory approvals are received without complications, antibody therapeutics made from plants could be on the market in five years. When this happens, Clement says, the reduced cost and greater availability of antibody therapeutics will make possible prevention of diseases in ways not thought of today.

“If you could make more antibodies, you could radically change the way this market is constructed,” Clement says. “A lot of the limitations are simply due to the fact that there is not the capacity to increase production. We’re not talking (an increase of) 25, 30 or 50 percent — we’re talking about orders of magnitude increase in production. If the markets develop the way we see them, and particularly if antibodies are used prophylactically, then I think alternatives to (bacterial) fermentation will become the market standard.”

The Poinsettia Alliance
The planned 10-acre biotech center at the Paul Ecke Ranch has yet to break ground because the company is looking for partners to defray the multimillion-dollar cost of construction. The idea is that researchers in food-based agriculture can use the greenhouses along with conveniently located research labs, and research on ornamental plants can piggyback on that.

That’s a smart strategy, says Akkadix CEO Caulder. “The markets for ornamentals are just so small that you can’t afford to do much with them as a primary research target,” he says. “But they are very good secondary and tertiary research targets. For example, one of the genes that we (at Akkadix) are looking at controls flowering. Obviously, this could be very important in the production of ornamentals, but the market is so small that you would not develop that for those in the beginning. You’re going to look at agronomic crops, where you have 80 million acres of corn, and maybe 2,500 acres of carnations.

“Where that might change is with the production of novel fragrances,” Caulder continues. “Then you would start looking at the metabolic pathways in roses and carnations. When you move over to using plants as biofactories, then the ornamentals become much more important. The complexity of the smell of a flower is huge. Or to try to duplicate the aroma of coffee for instance, you’re talking probably 500 chemicals. So if you could enhance those, and get all kinds of flavorings from plants, then that is certainly a very viable area, and an area we’re interested in.”

Caulder and the others laboring in the vineyards of San Diego County’s agbiotech industry have waited a long time to see their subspecialty gain recognition, overshadowed by the spectacular success of biomedicine. But as local agbiotech researchers and companies ally to focus their efforts, they point the way to future growth. Biotechnology already is converging with information technology. As agricultural biotech converges with medical biotechnology, San Diego’s biotech companies will have even more fertile fields to sow.