The experimental drug ZMapp, which doctors have recently started using to treat patients with Ebola, starts out a lot like a cigarette: It’s grown in tobacco plants. So far, it’s been given to seven people, with mixed results. (Two have subsequently died, though it's not clear whether the drug was just ineffective or made their conditions worse.)
ZMapp is not a typical pharmaceutical. It is a cocktail of proteins that mimics different parts of the human immune response, boosting the body’s natural defense against an intruder. It doesn’t fight the virus itself but gives your body a jump-start on fighting it on its own. These antibodies are often manufactured by injecting animals with pieces of a disease-causing agent and harvesting what the animals produce in responses. Such therapeutic antibodies have been developed for many diseases, including Crohn’s disease, Alzheimer’s, and a number of cancers.
Scientists have also developed a vegan technique that can be carried out on a large scale: Instead of making the drug in mice or rabbits, companies such as ZMapp producer Kentucky Bioprocessing, a subsidiary of tobacco company Reynolds American, grow antibodies in tobacco plants (though a different species from the kind you light up).
The company declined interview requests, but Keith Wycoff, vice president of research at Planet Biotechnology, which develops antibody-based drugs in tobacco, explained how it works at his company.
“We use a common soil bacteria that naturally introduces a portion of its own DNA into this plant, but it’s been engineered so it no longer causes plant disease,” he said. “Instead, it inserts whatever DNA we want and tells the plant cells, ‘Start making a different protein.’ ”
The technique is called agroinfiltration. In its simplest form, the process goes like this: Scientists force a plant-infecting bacteria, genetically modified to include a gene for the desired protein, into a leaf by pressing a syringe (no needle) against a tiny nick in the plant’s skin. The bacteria, a natural soil pathogen, can then wriggle its way into the surrounding cells and hijack their production systems, basically bossing them into churning out the medicine.
That process makes a leafy medicine factory the size of a coin, but there’s an even more efficient way of forcing the bacteria into cells and spreading the manufacturing throughout the plant. First, plants are flipped upside down and dipped into vats of bacteria-infused liquid. Then the plants are shoved into a vacuum, which sucks all the air out of the space between cells.
“Plant leaves are basically a bag with a lot of loose cells inside,” Wycoff said. “When we pull a vacuum, it takes all the air out of the bag. When we release the vacuum, the bacteria is sucked into the leaf and allowed to infiltrate the cells,” making a plant-size medicine factory.
Once the plants are “infected” with the genes, scientists give them around a week to marinate and pump out medicine. Then the plants are chopped up finely, and the proteins are extracted through both physical and chemical filtration.
Some medications are even produced in the kind of tobacco you smoke, using the more typical genetic engineering technique of growing a whole plant from a modified cell. Pharmaceuticals produced via agroinfiltration, such as ZMapp, are more commonly grown in Nicotiana benthamiana, a close relative of cigarette tobacco.
Still, much of the work is being done in states with historic ties to tobacco farming, including Kentucky, the second-largest producer. Together with North Carolina, the leading tobacco grower, the two states account for nearly three-quarters of the U.S. harvest. That may be good news to farmers, as the ag side of the cigarette industry has been in a steep decline since health concerns over nicotine first cropped up in the 1950s. Production has dropped from 2 billion pounds annually in the 1970s to 601 million pounds in 2011, according to the USDA. So it’s not surprising that cigarette companies have financial interests in many of the biotech firms working with tobacco plants—or that own them outright.
To some extent, the use of tobacco is a legacy: Tobacco was one of the first plants to be genetically engineered, so scientists know a great deal about it. N. benthamiana also is particularly amenable to agroinfiltration, eagerly taking up the bacteria and producing a high concentration of the proteins per kilogram of what scientists call “biomass,” or overall plant matter.
Planet Biotechnology has experimented with other tobacco species, but it doesn’t work with plants that people eat. “We avoid food plants to avoid any concerns that genetically modified proteins will be eaten unintentionally,” Wycoff said. (Some companies use food crops for agroinfiltration, though, including heads of lettuce and carrot cells.)
The no-contamination bonus works the other way too.
“The good thing about plants is they don't harbor any human diseases,” says Orlando Chambers, managing director of Kentucky Tobacco Research and Development at the University of Kentucky. That means scientists don’t have to worry about contaminants, such as viruses that could affect humans, as they would if they were filtering the antibodies out of mammal blood.
Besides Ebola, tobacco is also being used as a factory for antibodies against West Nile virus, which kills hundreds of people in the United States every year. Researchers at Arizona State University used antibodies grown in N. benthamiana (as well as in lettuce) to save 90 percent of mice that had been given a lethal dose of the virus.
Wycoff’s company is using tobacco to develop antibody treatments for dental cavities and the common cold. It is also looking beyond typical therapeutic antibodies to see what other kinds of biological drugs tobacco can produce.
Of Planet Biotechnology’s upcoming products, the farthest along is a treatment for anthrax that combines two types of protein in one biological medicine. It works as a decoy, luring anthrax toxin away from human cells and neutralizing it.
Another of the company’s prospective disease treatments is for Middle Eastern respiratory syndrome, or MERS, a deadly virus that everyone was freaking out about before Ebola came back to freak us out more. As of July, MERS had killed an estimated 291 people out of 837 confirmed infections. The Planet Biotechnology treatment is a decoy, similar to the anthrax treatment. It’s been effective at saving human cells from the virus in a dish, and the company is now applying for cash to start testing in live animals.
Tobacco agroinfiltration can also be used for preventive measures, including traditional vaccines. Medicago, a biotech company owned jointly by Mitsubishi and Philip Morris, is moving through clinical trials with its tobacco-produced flu vaccine, funded largely by the Defense Advanced Research Projects Agency. Current production of the flu vaccine relies on incubating chicken eggs for six months; agroinfiltration clocks in at around a week.
Despite tobacco’s bad rap, nonsmokers don’t have to worry: None of these medicines will give you a nicotine buzz. While N. benthamiana contains the chemical, “the nicotine is all gone when we purify the protein,” Wycoff said.