When two American aid workers came down with the deadly Ebola virus recently, an experimental treatment materialized seemingly out of nowhere. How did a possible miracle drug for one of the deadliest diseases in Africa come to be grown half a world away in a small town in Kentucky?
Because of chewing tobacco, malaria, Charles Darwin and Australia.
For decades, tobacco has been a solution in search of the right problem, and Ebola might be that problem.
In the 1990s, when smoking rates slipped below 30 percent, Kentucky tobacco farmers began to look for another way to make money. And a lot of eyes turned to Daviess County.
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There had always been a lot of tobacco grown in the Owensboro area, including acres of a variety known as "dark air-cured" for Pinkerton, a local chewing tobacco company.
But what was growing there now was different: it would never be smoked or dipped.
A California start-up called Biosource Technologies was paying Daviess County farmers to grow genetically altered tobacco that could produce pharmaceuticals.
One of the first was Rod Kuegel, then president of the Burley Tobacco Growers Cooperative Association, the "pool" buyer for unsold tobacco for cigarettes. At the time, burley was still Kentucky's top agricultural crop, worth more than $840 million.
But Kuegel was keen for a new opportunity.
"We grew a cat vaccine," Kuegel said last week. Biosource was happy with the results but didn't want to plant more.
"The man said, 'The good thing is we got 3 million doses of cat vaccine,'" Kuegel said. "'The downside is we've got 3 million doses of cat vaccine.'"
That was typical of the early stages of the business. Sure, you could do it, but would it make any money?
For decades, farmers around Owensboro had been growing tobacco for Red Man, made by Pinkerton. In 1985, as smokeless tobaccos were gaining market share, Swedish Match bought Pinkerton. In the early '90s, the company built a tobacco research and processing facility in Owensboro to explore the chemical potential of tobacco called the Reserca R&D Station.
Out in Vacaville, Calif., a tech startup company called Large Scale Biology was working on genetically engineering ways to make drugs with plants, including tobacco, which has long been the plant equivalent of the white lab rat.
Tobacco was the first plant to be successfully spliced with foreign genes. Tobacco mosaic virus, so named because of the mottled pattern it produces in tobacco leaves, was the first virus ever discovered and purified.
Large Scale Biology pioneered ways to use the tobacco mosaic virus to get foreign genes into plants, which would then reproduce the desired proteins.
By 1995, a company called Biosource was looking for a way to ramp up production of their experimental drugs, including a vaccine they hoped would fight malaria, so they came to Owensboro. (Biosource would acquire Large Scale Biology in 1999, choosing to keep that name.)
There was widespread interest in using tobacco to produce vaccines and treatments for everything from an antibody to fight tooth decay to an anti-inflammatory protein for use in cardiovascular surgery, along with treatments for orphan diseases — defined by the FDA as conditions that affect fewer than 200,000 people nationwide — cancer, AIDS and infectious threats.
While many companies were experimenting with genetically modified crops such as corn, tobacco — because it wasn't a food crop — seemed safer and easier.
The technology for pharmaceutical production worked well, but commercializing the process remained problematic. Large Scale Biology had no experience in the arduous and expensive process of getting a new drug through the FDA approval process.
By 2005, the company was in financial trouble. It filed for bankruptcy in January 2006.
"It might be fair to say Large Scale Biology was ahead of its time, and ran out of money before the technology was mature enough," said Kenneth Palmer, a University of Louisville researcher who worked at Large Scale Biology.
"They laid the groundwork — they had a very innovative group of plant virologists who developed the expression systems to induce plants to make proteins they don't normally make, like antibodies," Palmer said. "They developed a lot of the basic technologies currently used today."
Daviess County farmers are progressive, Kuegel said, and many hoped Large Scale Biology would give them another revenue stream from tobacco, a crop they knew how to grow very well.
They envisioned large fields of bioengineered tobacco that wouldn't require the same level of expensive manual labor as traditional tobacco.
But the use of a modified version of the tobacco mosaic virus sprayed on plants created new headaches: growers of conventional tobacco worried about gene transfers. And the federal Food and Drug Administration worried about consistency.
The answer was to go indoors to grow everything in a clean environment and keep the conditions tightly controlled. No thunderstorms or droughts, no hail or insect swarms.
But that also meant fewer big fields of tobacco and fewer farmers getting paid to grow it for pharmaceutical companies.
Instead, the company would build an indoor facility the size of a Wal-Mart supercenter with 32,000 square feet of growing space, filled with a totally different kind of tobacco, Nicotiana benthamiana, with its own interesting history.
Not your smoking tobacco
In December 1831, when HMS Beagle set sail on a five-year survey of South America, Charles Darwin was aboard as gentleman naturalist. Darwin was a social equal of Capt. John FitzRoy, and they got along. Ship's surgeon Robert McCormick, who had expected to be the naturalist discovering all the new and interest flora and fauna, became increasingly put out at the favoritism shown Darwin, who got the plum trips ashore while McCormick fumed.
By April, McCormick asked for and received permission to leave; he was replaced by his assistant, the Barbados-born Benjamin Bynoe. Darwin took Bynoe under his wing, teaching him useful collecting techniques. When they arrived at the Galapagos Islands, Bynoe and Darwin camped on Santiago for a week with their servants, gathering fish, snails, birds, reptiles and some insects. Bynoe was there when Darwin began to realize that the species of the various islands were all different; before this, he had not labeled them by island.
In 1836, the Beagle returned to England via Tahiti and Australia, and Darwin went off to study his finds and write the observations that lead to his famous treatise on natural selection, On the Origin of Species.
When the Beagle left the next year to survey Western Australia, which had become a British colony in 1829, Bynoe again went along and this time was both surgeon and naturalist. Somewhere along the northern coast, Bynoe picked up a species of wild tobacco, according to a paper on the history of the plant written in 2008 by UK tobacco genomics professor David Zaitlin, UK plant pathologist Michael Goodin and two other professors at Washington State University and North Carolina State University.
A specimen of this plant wound up in the records of the Royal Botanic Gardens in Kew, where it was eventually named in honor of botanist George Bentham, who described it in his Flora Australiensis in 1868.
Nicotiana benthamiana turns out to have unique characteristics that have made it a darling of modern science.
Because the species developed in isolation, benthamiana has no built-in resistance to much of anything, said Orlando Chambers, director of the Kentucky Tobacco Research and Development center. That makes it easy to infect with the altered tobacco mosaic virus and with agrobacterium, a gene-swapping bacteria that causes tumors in plants.
Modern science also discovered that N. benthamiana, unlike other common research plants, is terrific for a process called "agrofiltration," in which tissues are flooded with liquid that spreads quickly throughout the entire leaf.
Benthamiana is fast growing but could never survive outside, Chambers said. It is perfect for large-scale indoor growing in soil-free systems, where the plants can be completely controlled.
In Owensboro, the facility also uses automated systems that can infuse whole plants in agrobacterium-laced solutions, which the plants soak up. The agrobacterium carries the foreign genes into the plants, which are then reproduced in bulk. In just a week or two the desired compounds are extracted from the plants.
Since the 1970s at least, tobacco researchers had known the plant could produce copious amounts of chemicals. The problem was finding something worth the effort.
One of Large Scale Biology's last projects was an individualized "vaccine" for non-Hodgkin's lymphoma that would use each patient's own cancer to create the "cure" and grow it in bulk.
"Sixteen patients enrolled and were given 16 different vaccines, one each," Palmer said. The goal of the trial was to see if the vaccines were safe, he said. They were, and the outcome was promising. Other pharmaceutical companies are pursuing this avenue of research.
The success came too late for Large Scale Biology, but it proved a tobacco-grown pharmaceutical could be safe. And the speed and relatively cheap cost of the process made it a very attractive option to outside drug researchers, which became the saving grace for the facility.
Owensboro hospital to the rescue
As Large Scale Biology was on the verge of going out of business, Kentucky agricultural entrepreneur Billy Joe Miles came to the rescue.
Miles, who has a farm less a mile from the plant, had toured the Owensboro facility as well as Large Scale Biology's California labs with Gov. Paul Patton, University of Kentucky president Lee Todd and Jim Ramsey, future University of Louisville president.
"I got a call saying the company had gone bankrupt and they were going to close the plant in Owensboro," Miles remembered last week. He quickly arranged to cover employees' salaries and keep the doors open while he worked out a plan to save it.
As chairman of the University of Kentucky board of trustees, his first thought was UK, where the Kentucky Tobacco Research and Development Center is located.
But the deal didn't quite come together, so Miles turned to two other boards with which he was affiliated: the Owensboro hospital and the Kentucky Agricultural Financing Corp., a loan pool set up with money the state got from cigarette makers in the tobacco settlement.
The ag fund loaned the hospital $3.6 million, and Owenboro Medical Health Systems completed the $6.4 million purchase that spring.
Renamed Kentucky BioProcessing, the facility has become a leader worldwide in commercial-scale production of proteins in plants, often on a contract basis.
In July 2007, KBP began a collaboration with Mapp Biopharmaceutical and Arizona State University's Biodesign Institute to work on Ebola. With a grant from the Army, ASU's Charles Arntzen and Mapp developed the treatment that was used last week on American aid workers Dr. Kent Brantly and Nancy Writebol.
KBP also drew the interest of the Defense Advanced Research Projects Agency. In 2010, following the H1N1 flu scare, DARPA awarded a contract to the Owensboro plant to show that flu vaccine could be made quickly and safely in tobacco plants. Benthamiana could grow the vaccine much faster than other, egg-based vaccine production systems. KBP and similar facilities are primed to grow millions of doses of vaccine for the next pandemic.
"This system would represent a significant alternative in the nation's ability to protect itself from potential biological threats," KBP said in a new release last year. "This proof-of-concept program will be focused on influenza, but the system would be adaptable to producing recombinant proteins against other types of pathogens."
Kuegel, who recently toured the plant with a group of farmers, said the flu vaccine was a crucial hit.
"They created several million doses for the government," he said. "There's no facility in the U.S. that can replicate the speed and accuracy that Kentucky BioProcessing can deliver."
In January, the Owensboro hospital sold KBP to Reynolds American, which is continuing to operate it as a contract bioprocessing facility.
Philip Patterson, president and CEO of Owensboro Health, said the time had come to let KBP go.
"When the board rescued it, they understood the importance of the work going on, work that was still largely conceptual at the time. But the board saw there was promise and value economically for Owensboro," Patterson said.
"The reason we sold it was we wanted to find the right research partner, a company that could provide significant funding needed to take the next step. Obviously we found that in Reynolds American. They have the expertise at an international level to truly take the work being done at KBP and give it far reaching opportunities. ... It's exciting, and I think there's more to come."
The next phase
The University of Kentucky also maintains a connection to KBP. Scientists at the Tobacco Researcher center in Lexington are working on improving benthamiana, to "humanize" it so that the chemicals it reproduces are even more compatible.
Palmer now heads the Owensboro Cancer Research Center, a partnership between U of L and the hospital, and is still collaborating with KBP.
Last week, just as Ebola was making headlines worldwide, U of L and Palmer were announcing another major grant, $14.7 million from the National Institutes of Health to develop a gel that would block transmission of HIV, the virus that causes AIDS.
They will use the tobacco plants to "manufacture" a critical protein from red algae.
The U of L program also has received major grants to develop a cheaper second-generation HPV vaccine to fight cervical cancer and a vaccine for cholera that also could fight colon cancer. All will be grown in KBP's plants.
So far, only one plant-based pharmaceutical has made it onto the market anywhere in the world — a treatment for Gaucher disease, a rare genetic disorder of the liver — made by an Israeli company using carrot cells.
For Ebola, KBP was preparing for the first human drug trials later this year when the request came to ship doses to Atlanta's Emory University for the American aid workers. Now, with calls to make the serum more widely available, those efforts may speed up.
If treatment is proved to have helped Brantly and Writebol and if the results can be borne out with further testing, the drug, called ZMapp, may give biopharmaceuticals the big winner its has long needed to attract significant investment.