Kentucky Is a Natural for Molecular Farming
By Randy Weckman
Cast a glance out the window toward your backyard. Just look at all the biorefineries out there, making tens of thousands of compounds. Grasses, pansies—maybe, roses, and even bacteria—are all little, but very sophisticated, chemical factories working all day, every day, manufacturing all manner of chemicals.
Once you realize that, you can understand why scientists of the world are becoming enamored with the prospects of using these little chemical factories to create substances for use in medicines, insecticides, and plastics, to name just a few products.
In Kentucky, molecular farming—the growing of plants, animals, and microbes for their constituent biochemicals—already has begun. Four farmers around Owensboro already are producing molecules in about 45 acres of a plant that is a member of the Nicotiana family, which means it is closely related to tobacco. These plants aren’t treasured for the quality of golden leaf, but for the quantity of pricey molecules they produce.
And while a relative of tobacco is the first plant species grown in Kentucky for its molecules, other plant species likely will be used as chemical factories—producing extracts that could be used to manufacture molecules for a variety of purposes.
“We believe that growing tobacco— and other plants—for production of pharmaceuticals and other useful substances has a strong potential for supplementing many farmers’ incomes,” said Maelor Davies, a biochemist who is director of the Kentucky Tobacco Research Development Center (KTRDC) at the University of Kentucky College of Agriculture.
The KTRDC’s program for fine-tuning the use of tobacco cultivars to biomanufacture new materials is only one facet of a larger initiative in the College of Agriculture that seeks new crops and new uses for traditional crops for molecular farming. A $600,000 National Science Foundation grant for what’s called the Natural Products Alliance seeks to encourage molecular farming and biomanufacturing throughout the commonwealth by organizing an aggressive research and development program that involves researchers, farmers, and manufacturers.
“The Natural Products Alliance encourages both industry and academia to develop novel products—including animal, microbial, and plant-derived products—that will be produced in Kentucky and enhance the state’s economy,” said Nancy Cox, associate dean for research.
And while researchers seek to expand the domain of molecular farming to well beyond tobacco, it is believed that in Kentucky the quickest returns for molecular farming will be with tobacco, in some measure because of the University of Kentucky’s strong knowledge base in research. In addition, Kentucky farmers possess keen skills in producing the crop.
What’s needed for molecular farming?
It takes more than a snap of the fingers to turn a plant into a factory for making new materials. That's where bench scientists as well as production scientists and their due diligence come into focus.
"The University of Kentucky's world-renowned expertise with tobacco, coupled with its access to a great number of tobacco cultivar lines that have been used, is being marshaled into manipulating plants that will be ideally suited for manufacturing desired protein products in desired quantities," Davies said.
More than weeds
It‘s not just tobacco and other domesticated plants that can be transformed into chemical factories. Two pharmaceutical scientists at UK are working with College of Agriculture scientists to enhance the chemical-producing properties of a common Kentucky weed. College of Pharmacy researchers Peter Crooks and Linda Dwoskin, through their newly formed company, Yaupon Therapeutics Inc., are applying for an investigational new drug license from the Federal Drug Administration to begin the clinical development of a chemical derived from the Lobelia inflata plant.
Lobelia produces the alkaloid lobeline, which has been demonstrated to help people overcome dependencies on psychostimulant drugs such as methamphetamine, speed, and ecstasy.
Photo - Linda Dwoskin and Peter Crooks
“While Crooks and Dwoskin investigate the pharmaceutical aspect of this plant, other College of Agriculture researchers are providing expertise in domesticating the plant for commercial production,” Davies said.
Domesticating Lobelia inflata involves a two-faceted process: breeding a line that expresses the most of the desired chemical possible and learning what cultural practices are optimal for the efficient production of the plant, Davies said.
What about the economics?
“Pharmaceuticals produced in tobacco plants are moving through the regulatory system and will be on the market in the near future,” said Orlando Chambers, KTRDC's biotechnology relations director and an agricultural economist by training.
Rich Mundell (left)
and Orlando Chambers
“Profit levels for farmers will depend on the molecule produced and likely will be dictated by contracts between the farmer and the pharmaceutical company manufacturing the product,” he said.
Chambers noted that molecular farming provides a new diversification opportunity for Kentucky farmers, one for which they have the ability to be a leader in the industry.
Plants from which molecules are extracted must be grown close to the processing site, which means that jobs for Kentuckians will be created in processing as well as in production. And that should be a real boost to Kentucky's rural economies.
Mike Mullican:
Growing Molecules in Owensboro
As a UK agricultural engineering graduate, Mike Mullican '93 believed that he would have to move far away from his native Daviess County to work as an agricultural engineer, but that wasn't to be the case in the long run. First, working with Miles Enterprises, he was dispatched to the high plains of Nebraska, where he was an agricultural advisor for precision agriculture. Then, in 1998, he moved back to Daviess County as agronomic manager for Large Scale Biology, a California firm involved in biomanufacturing protein molecules using tobacco-related plants. He has served with that firm since, overseeing greenhouse and field production in Daviess County and in Homestead, Fla., where the company also maintains field production of plants.
At Large Scale Biology, Mullican manages several greenhouses on the outskirts of Owensboro that produce plants containing medically valuable molecules of aprotinin, which is administered to cardiopulmonary bypass surgical patients because it controls or minimizes the degradation of proteins, reducing the amount of blood needed by patients after surgery. (Currently, Large Scale Biology is working to gain FDA approval for its product for surgical uses; the standard product used now is extracted mainly from bovine lung tissue.)
 Large Scale Biology's manufacturing process starts with plants produced in greenhouses as well as on 45 acres of contract farmers' fields. Following harvest, the resulting mass is ground and the aprotinin extracted at its Owensboro facility. It takes several tons of tobacco tissue to extract a gallon of the product. All plants are coaxed to produce aprotinin by first being inoculated with a common tobacco virus that has been genetically modified with a gene to produce aprotinin. The virus infects the plants and then replicates throughout the plant tissues, accumulating aprotinin.
Mullican admits he has had to learn a lot of biology since he took the job with Large Scale Biology, but says that the agricultural engineering faculty's insistence on learning problem-solving skills has made that task relatively easy.
"At Large Scale Biology, we're doing science before it is in the textbooks. And problem-solving is the way we do that," he said.
Large Scale Biology recently began working on developing a technique to produce alpha galactosidase A, a therapeutic enzyme, using biomanufacturing in plants. Alpha galactosidase A is used to treat Fabry's disease, a rare but deadly genetic disease that causes the accumulation of fat in various organs of the body, including the eyes, heart, liver, and kidneys of those who inherit it. Untreated, most of those with the disease die by the time they reach middle age. The firm will seek FDA approval for clinical trials in humans soon.
(Mullican serves as president of the Green River chapter of the College of Agriculture Alumni Association.)
Natural Products Alliance
Kentucky is positioned for leadership in the new economy for biosciences that experts believe will account for 15 to 18 percent of the U.S. gross domestic product in two decades. A Natural Sciences Foundation grant of $600,000 to the University of Kentucky College of Agriculture created the Natural Products Alliance, which seeks to enhance the infrastructure necessary for Kentucky to distinguish itself as the global natural products leader. Other grants totaling $310,000 from the Kentucky Economic Development Finance Authority and the Kentucky Office for the New Economy also support the Natural Products Alliance.
The Natural Products Alliance is providing the substructure to move Kentucky's nascent bioscience industry forward by linking entrepreneurs with researchers and also by providing real-life experiences for students through internships.
Already, the Natural Products Alliance has “seeded” three Kentucky-based, start-up companies in the biosciences arena with small grants. Oraceuticals Inc. is developing a plant-extract based treatment for chronic infections of the mouth; Yaupon Therapeutics is refining production of a new treatment for drug addictions; and Allyix Inc. is transforming yeast to create valuable flavorings and fragrances.
Eight students from the University of Kentucky and other universities in Kentucky have been funded for internships with bioscience companies. The students, whose majors range from business and economics to chemical engineering to agricultural biotechnology, developed their entrepreneurial skills while working on new projects. These projects included researching ways to optimize fermentation for industrial-scale productions of biopharmaceuticals, performing financial analyses of companies potentially locating in Kentucky, and designing research to improve a natural products-based animal nutrition supplement.
(Left to right)
Dr. George Wagner, grad student Ryan Shepard, and Gabriel Wilmoth
“These internships allow students to develop not only their abilities particular to their field of study, but also their experience with all aspects of the entrepreneurial process,” said Nancy Cox, associate dean for research.
Kentucky currently has more than 30 companies with more than 1,200 employees in the natural products sector, said Gabriel Wilmoth, coordinator of the Natural Products Alliance.
“We expect those numbers to double within the next five years," he said.
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