In your farming career, you have about 40 crops to get things right. Bill and Joe Horan were ahead of schedule in 2002 when they first grew pharmaceuticals in recombinant crops. The enterprise began with a shoebox-sized, triple-sealed container of corn representing one biotech company’s multi-million-dollar investment in genetic technology.
This family farm has grown modified corn, tobacco, rice and potatoes that produce medically valuable drugs and enzymes. The high-profit, highly regulated farm enterprise diversifies them from low-margin commodity crops. (They also grow commodity corn.) “So, three of us make a living from about 4,000 acres of corn,” Bill Horan says.
Their crops are a next-generation pharmaceutical production system. The Horans call it biomanufacturing. They biologically reproduce transgenic medical proteins, vaccines and therapeutic compounds.
It’s safer and less expensive to reproduce biomedicines in plants because plants don’t carry animal contaminants such as mad cow disease, HIV, circoviruses, etc., says Scott Deeter, CEO of Ventria Bioscience, which develops these products. And plants reproduce pharmaceuticals the same every time (or perfect fidelity, as they say in the industry).
The Horans once grew this seed reproduced in highly regulated, special transgenic corn. They have since begun growing specialized potatoes on their Rockwell City, Iowa, farm, making Hepatitis-B vaccine and virus antibodies. They’ve also produced nicotine-free tobacco.
How it began
About 14 years ago, the Horans began growing a recombinant human enzyme, lipase, in transgenic corn. Lipase is needed by cystic fibrosis patients. To these fourth-generation farmers, this is a promising way to attract agriculture’s best and brightest back to rural America. “South America cannot compete with us on this because they lack the regulatory system it requires,” Horan says.
The Horans invested countless hours of online research to identify this high-margin, new business that potentially allows farmers to generate some real dollars. Horan was exposed to nutraceuticals (food extracts known for their health-improving content, such as amino acids, essential fatty acids or high-vitamin content) as a NCGA board member, but learned that pharmaceuticals were more profitable.
Their search identified a French company, Meristem Therapeutics, which used corn as its plant platform of choice. It was interested in larger production. “We thought we knew something about growing corn, so we contacted and invited them to visit us here; and they invited us to visit them in France,” Horan says.
The Horans assembled a delegation to pitch Meristem on their ability to multiply their protein in a cornfield. The group included the Iowa Senate Majority Leader, a member of the Iowa banking community, a grain merchandiser, a French-speaking scientist from LG Seeds’ parent company, Limagrain, and a regional Extension specialist from Iowa State University. In fewer than six months, the Horans had a contract to multiply pharmaceutical proteins at their farm.
Meristem sought offshore growers, for fear of French GMO activists destroying genetically engineered crops, Horan says.
The Horans began growing modified corn as their crop host, to reproduce lipase (a fat-digesting enzyme needed by cystic fibrosis patients). The transgenic corn was isolated by time, biology and distance to prevent pollen drift.
They removed its transgenic tassels before they produced pollen, and isolated it with 1 square mile of soybeans. “We used commercial corn to pollinate the silks on the transgenic corn. You only get half as much protein, but you remove any risk of spreading the transgenic protein,” Horan says. They harvested the medicinal crop with a special combine and stored it in a locked barn, burning discarded material and plowing over the test plot to bury dropped kernels. They sprayed any volunteers the next spring with glyphosate.
Their biggest plot has been 40 acres; some are less than 1 acre.
The commercially valuable protein was spliced into the Horans’ recombinant corn to biologically reproduce medicinal proteins. The plant multiplies it along with the rest of its 2,000 proteins, Horan says. “The plant’s replication is perfect, so it’s less expensive than doing this in a stainless steel lab vat where it sometimes mutates and contaminates an entire batch.”
Plants can make large amounts of protein at relatively low cost compared to other methods, Deeter says.
The Horan brothers also collaborated with other biologic firms on six projects, including Ventria Bioscience, Symbiosis, Calgary, and with Iowa State University Plant Transformation Facility Director and geneticist Kan Wang to multiply her protein. (When Wang applied for a permit to reproduce proteins, the regulators suggest that she contact the Horan brothers, since they had a successful track record.)
Each crop has pluses and minuses, Horan says. Corn reproduces more protein per plant than any other crop, but its pollen can stray for miles.
Potatoes and tobacco
“Potatoes are much safer to grow, and they poison mammals, so we don’t worry about wildlife eating them,” Horan says. “We fence our plots anyway to keep wildlife and people out. We also hand weed nightshade, which can distribute potatoes’ transgenic material. Potatoes’ disadvantage is that they’re almost all starch, and its much lower protein content lowers its protein reproduction.
“PhD researchers know how to insert genes into plants,” Horan says, ”but we know more about ‘outdoor manufacturing.’ When I graduated from college, I knew everything there was to know about growing corn and soybeans. But now after my 40th crop, I know how little I know about growing corn and soybeans. Every year I’ve learned a whole new chapter. And people wearing lab coats don’t know what we do or how to do it. They readily admit that they need to work with successful farmers in order to scale successful production.”
For a time, the Horans grew a nicotine-free form of tobacco, but the market demand for it was weaker than expected. “The consumer did not want to quit as much as researchers thought,” Horan says. “Tobacco was one of the first plants to have its genome mapped, but it releases a protein-destroying enzyme as soon as you cut (harvest) a leaf, so harvesting it without losing proteins is a problem. They devised a work-around (refrigerated trucks in the field at harvest), but low consumer demand killed the project.”
The Horans also grow human RNA (messenger DNA) in potatoes for a German company. “It’s very competitive and very new,” Horan says. “That could develop into a lot of acres.” They produce a protein that will be applied topically (on the skin), and the potential market is much larger than it was for lipase.”
Besides potatoes, the Horans also grow dryland rice. It’s a host plant to reproduce two immune-system-boosting compounds found in breast milk to help chemotherapy and immuno-compromised patients.
Horan Brothers Ag Enterprises is the only U.S. farm with a USDA-APHIS permit to grow unapproved biologics, so medical biotech companies now approach them. (This is the same category that Roundup Ready soybeans and Bt corn once were before being approved for final farm use. They eventually evolved into a less regulated category, but the medical proteins the Horans produce will always remain unapproved biologics. However, APHIS, the regulatory agency for these crops, has evolved from a policing agency to much more supportive role than when they first began, Horan says.)
“We systematize things so that anyone can do what we do. For example, we’ve standardized potato tuber storage, and a fertilizer application system. We make one person responsible for each operation. It’s not rocket science, but things have to be done exactly right.”
Horan adds, “For the present three-year USDA-APHIS permit on our potato operation, we need to scout the plot weekly and document anything unusual, such as a lack of insects or birds, or volunteer tubers.”
Edible E. coli vaccine
Another Horan collaboration was working with Kan Wang to develop an oral E. coli vaccine. Wang is Director of Iowa State University Plant Transformation Facility.
When consumed by a sow in transgenic corn, the E. coli resistance passes through her milk to piglets, vaccinating them against scours. The Horans’ enterprise has been multiplying an oral vaccine of E. coli in corn to prove that the vaccine is effective for all mammals, including soldiers in theatre, Horan says. The product requires about $300 million to commercialize.
When other farmers ask how to do this, Horan tells them to research pharmaceutical companies and find one with press releases on this, and contact them. “Most of them won’t respond, but perhaps one out of 20 will,” he says. “Then you convince the company that you’re a trustworthy professional who gets along with people, use the latest farming technology and are environmentally sensitive.
Ventria Bioscience’s CEO sees this enterprise as a natural for farmers. “Most farmers are entrepreneurs,” Deeter says. “Most have to be to survive and thrive. They wake up every morning and show why America is unique: because they don’t fear innovation.”
Biology behind what Horans grow
Ventria Bioscience, Junction City, Ill., uses transgenic rice plants as biological factories to make medicinal and research products, and to manufacture pharmaceuticals and vaccines. Its customers include the top 20 U.S. pharmaceutical companies. One of its products is a protein found in mothers’ milk that potentially reduces chronic inflammation, common among HIV patients. It undergoes massive USDA-APHIS and FDA tests, spanning a decade or more. The 10% of products that pass regulatory testing and certification is “spliced” into rice seed genes. “Our technology is ideal for products needed in large amounts,”Ventria’s Deeter says.
The company’s moving forward with an edible, rice-based Lyme vaccine for animal Lyme vectors like mice who carry the disease.
“Several products have been developed in plants that are on the market today, and we expect this to continue to expand.
“The cost to develop a pharmaceutical product is generally $1.2 billion. This includes the cost of failures (the 99% that do not make it to market),” Deeter says. “We’re going back to the origins: humans have lived on plants, animals have lived on plants; they are the base source of the planet’s nutrition.”
$100 million market
As clever as the Horans’ pharmaceutical enterprise is, it represents “a very small niche market,” says Pam Johnson, Floyd, Iowa, farmer and former chair of NCGA and of Iowa Corn, a group that ferrets out new corn-based income opportunities.
Twenty biotech companies applied for USDA-APHIS permits to grow new medical-protein products in corn, rice, tobacco, potatoes and rice in America in 2015, but none of them have been planted yet, observes Karen Batra, director, Food and Agriculture Communications, Biotechnology Industry Organization (BIO.org).
“Typically, it takes 100 pre-clinical product candidates to have 10 successful products enter human clinical studies,” says Ventria Bioscience’s Deeter, who develops these biologic products duplicated in crops. “Then, of those 10 in human clinical studies, one will make it to market as a pharmaceutical. This is why medicines are so expensive to develop.
“We need more farmers like the Horans. Today, the market is fairly small relative to the potential. I’d guess the current plant-made pharmaceutical market (recombinants only) is about $100 million,” Deeter says.