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Botanical Biopharming

Green-thumbed biotechs say they can use plants to make drugs faster, cheaper, and better than top pharmaceutical companies.

By | September 1, 2010

Courtesy of Medicago

In 2001, ProdiGene was a poster child for the plant biotechnology industry. A privately owned biotech in College Station, Texas, ProdiGene was the first to successfully commercialize a product made from a transgenic plant—a protein called trypsin produced in corn kernels and sold to the pharmaceutical industry for mammalian cell culturing. They also had more than 18 other plant-made products in development, including vaccines for traveler’s diarrhea, hepatitis B, and AIDS. That spring, the MIT Technology Review voted ProdiGene’s oral vaccine patent one of the “five patents that will transform business and technology.”

But a year later, things began to spiral downhill. In September 2002, the US Department of Agriculture ordered ProdiGene to destroy 155 acres (63 hectares) of corn in Iowa that may have cross-pollinated with a nearby test site of ProdiGene’s transgenic corn. Then in October, the USDA seized 500,000 bushels of soybeans contaminated by ProdiGene’s corn in Nebraska. In the end, ProdiGene was slapped with over $2 million in fines and clean-up fees by the government. “That was the end of ProdiGene,” says Zivko Nikolov, former vice president of bioprocessing at the company.

It wasn’t the end for all plant biotechnology companies, however. Since the first human-like enzyme was produced from transgenic tobacco in 1992 at Virginia Polytechnic Institute, the biotech industry has seen a wave of companies try their hand at “biopharming”—plant-based pharmaceutical production. These companies challenge the status quo of biomanufacturing, purporting that plant-based technology has the potential to produce complex biomolecules cheaper, easier, and faster than traditional pharmaceutical facilities.

Rather than grow human or animal cells on expensive, nutrient-rich media, for example, biopharming derives its manufacturing energy from the sun. Genes can be inserted into the cells of plants such as corn, tobacco, and alfalfa, and the plant does the hard work transcribing and folding the protein, using only the Earth’s abundant raw materials—water, carbon dioxide, and soil. Plants can also be grown in large fields, offering a much greater volume of product than a constricted, multimillion dollar manufacturing plant.

But with major obstacles remaining—such as the introduction of the first plant-made human pharmaceutical product to the market—the handful of plant biotechs in existence today remain a bit uneasy. “Until we actually get one of these over the goal line, you can never say you are out of troubled waters,” says Joseph Boothe, VP of research and development at SemBioSys, a plant biotech based in Canada.

Still, these companies are convinced the model is a good one, and having learned from the failures of the 60 or so plant biotechs that have flourished, then floundered, they are working hard to push their products to the market. With new, alternative crops and techniques, and the first product on the cusp of FDA approval, it may be the beginning of a new era for plant biotech. “There are no major bottlenecks now. We have to just go and do it,” says Nikolov. “This is just about the time we’re going to see the first successes from plant biotech.”

Under the sun

The early, great hope of plant biotechnology was that transgenic corn and soybeans could be used to grow inexpensive biopharmaceuticals in vast quantities over thousands of acres. The crops had already been engineered for other purposes, such as pest and herbicide resistance, so the genetics of each plant were well known. Yet as ProdiGene’s early tribulations demonstrated, one of the biggest risks of field growing is the contamination of nearby food crops. But with virtually unlimited space and free energy, a few companies hold out hope to grow under the sun. “Growing on an agricultural scale, we can get high-capacity production and low-cost economics because we’re able to harness natural solar power to grow the material,” says Boothe.

Bioreactors manufacture plant cell-based protein drugs using disposable containers
Protalix Biotherapeutics

One solution to ProdiGene’s cross-contamination problem is to simply use different crops. Ventria Bioscience, based in Junction City, Kan., grows transgenic rice designed to produce recombinant human lactoferrin and lysozyme—proteins found in human breast milk that have a variety of applications in medicine—and currently sells the products to the pharmaceutical industry. Because rice is self-pollinating with pollen grains that lose their viability 5 minutes after shedding from the plant, plants grown far enough away from other agricultural fields are unlikely to contaminate other crops.

SemBioSys, based in Calgary, Canada, turned to a different self-pollinating plant—safflower, a thistle-like spiny plant with small, bright flowers. Sometimes cultivated for the vegetable oil in its seeds, safflower is not a popular food or industrial crop in the United States, so SemBioSys is able to tightly isolate their fields. The company genetically engineers the plants to produce medically relevant proteins on oilbodies within the seeds of the plant. The oilbodies, which are lighter than water, are then separated from the rest of the seed proteins by simple centrifugation, reducing the time and cost of downstream processing.

“This is just about the time we’re going to see the first successes from plant biotech.” —Zivko Nikolov, former vice president of bioprocessing at ProdiGene

With the high-volume potential of safflower—the company can produce over one kilogram of insulin per acre of safflower production, says Boothe—SemBioSys filled its pipeline with high-demand drugs whose availability is currently limited by the costs and capacity constraints of traditional manufacturing. The company has completed a Phase I/II trial on their lead product, insulin, one of the largest-volume pharmaceutical protein products on the market. They are also developing Apo AIMilano, a novel protein for the treatment of atherosclerosis. While needed by fewer patients than insulin, Apo AIMilano is required in very high doses, making its total demand “potentially even exceeding the volumes required for insulin,” says Boothe.

Quick and dirty

Most plant biotechs, however, have moved indoors, either to greenhouses or facilities with artificial light. Within confined spaces, without the promise of mass production over thousands of acres, these biotechs are instead carving themselves specialized niches in the pharmaceutical market. Medicago and Bayer Innovation GmbH, for example, are looking for speed, using the rapid-growth plants to develop products that are needed quickly and with short notice, such as vaccines.

Biolex Therapeutics genetically transforms the water-based plant Lemna to produce drug candidates
Biolex Therapeutics

Founded in 1999, Quebec, Canada-based Medicago is developing flu vaccines in the leaves of tobacco plants. During last year’s potential flu pandemic, the pharmaceutical industry “came along with vaccines that were too little and too late,” says Andy Sheldon, the company’s president and CEO. “Technology is now needed that can respond to these problems [quickly],” he adds. In the company’s facilities, 5-week-old tobacco plants are exposed to a vacuum process that forces bacteria containing genetic material from a pandemic virus into the plant cells. The plants are then placed back in a greenhouse, and 5 days later, there is a “massive expression” of viral proteins, says Sheldon, in the form of virus-like particles (VLPs)—the protein shells of the virus that lack the infectious genetic material. The VLPs are then harvested, purified, and made into a vaccine. The company is currently beginning a Phase II trial for an H5N1 pandemic flu vaccine, and also has a seasonal vaccine in development.

Biolex Therapeutics, a North Carolina State University spin-off founded in 1997, has defined their niche in hard-to-make proteins. This company’s workhorse is lemna, also known as duckweed—a tiny, aquatic clonal plant that doubles its biomass every 36 hours—and is skilled at making proteins that mammalian cells struggle, and often fail, to produce. In facilities that look remarkably like a traditional biomanufacturing site, the company grows duckweed under artificial light in 1-by-2–meter bags of growth media and has produced over 40 proteins, including cytokines, vaccines, antibodies, and biosimilars. “We have not found a protein we haven’t been able to make appropriately,” says the president and CEO of Biolex, Jan Turek. “But in the end, as a privately funded company, we want to make sure we’re focusing on making ones with value for the pipeline.”

Those valuable proteins, Biolex has determined, are controlled release interferon for the treatment of hepatitis C (currently preparing for a Phase III trial), an antibody for non-Hodgkins B-cell lymphoma, and a human recombinant plasmin to dissolve blood clots—an enzyme pharma companies have struggled to produce for over 20 years, says Turek. “Traditional expression systems are just not able to make it,” he says, but with the duckweed system, Biolex can produce it at commercial levels.

Waiting for approval

Despite the speed, diversity, and low cost of their systems, biopharming companies are still waiting to be invited to the pharma lunch table. “Even though the pharmaceutical and biotech industries are on the cutting edge of technology, at the same time they can be somewhat conservative in terms of adopting these [plant manufacturing] technologies themselves,” says Boothe. “It can be a bit of a challenge for us to communicate what we can do with our systems.” But even one example of a plant-made drug on the market will make all the difference, the biotech executives agree. “I’d be very pleased to see anything produced from plants on the market as soon as possible,” says Nikolov.

That first may soon come from Protalix, a biotech based in Israel that produces proteins from carrot cell cultures in disposable plastic bioreactors. The company’s lead product is recombinant glucocerebrosidase, a treatment for Gaucher disease—a rare genetic disorder caused by a deficiency of the enzyme that breaks down fatty substances. In June 2009, Genzyme temporarily halted production of their modified glucocerebrosidase, Cerezyme, produced in mammalian cell cultures, due to viral contamination. The drug is one of the most expensive biologics on the market, costing a reported $250,000 a year, and generally taken for life.

Fearing no other ready supply of the drug, the FDA granted orphan drug status and fast-tracked Protalix’s drug in August 2009. Three months later, Protalix granted Pfizer Inc. the rights to develop and commercialize the treatment in a $115 million deal and filed a New Drug Application with the FDA. Their decision is expected next month.

“It ought to move fast,” says Maurice Moloney, founder of SemBioSys and current director and CEO of Rothamsted Research in the United Kingdom. The Protalix-Pfizer partnership is a prime example of what needs to happen for plant biotechs to get their drugs on the market, he adds. “None of the plant-based companies are big enough to do it on their own.”

Comments

Avatar of: anonymous poster

anonymous poster

Posts: 107

September 9, 2010

This article raises some interesting questions. How does the trypsin not digest all the other proteins in the corn kernels? I can see how there may be issues with eating food that contains active trypsin, but what about vaccine proteins? Can you develop immunity just by eating the corn? And how do soybeans get cross-pollinated by corn?
Avatar of: anonymous poster

anonymous poster

Posts: 3

September 9, 2010

Dear Colleagues: This idea is not new. Some of the best medications that are still in use today came from plants: digoxin used for congestive heart came from Digitalis purpura, quinine for malaria from Cinchona bark, vincristine/vinlastine for cancer came from Vinca rosea, morphine as one of the most powerful analgesics, came from opium poppy (papaver somniferum), and many other plant alkaloids, and so on. Germany, India, and China have been producing medications from plants ('biopharming') for years. I am glad that we in the US are thinking along these lines with a lot of learning to do. \n
Avatar of: Ed Rybicki

Ed Rybicki

Posts: 82

September 10, 2010

Great article! Nice coverage; positives as well as negatives, and a decent depth. As one involved in the field, it is great to see something as well-rounded as this.\n\nI think the field is just hitting stride round about now: after the eat-a-vaccine-banana-a-day hype subsided, reality has set in - and products are starting to flow, and big pharma is moving in.

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