‘Pharming’ tobacco to beat Ebola
September 1976: In the remote village of Yambuku, in the north of Zaire (now the Democratic Republic of Congo), a mysterious disease outbreak ravages the community. The disease, a type of hemorrhagic fever, starts with a fever, severe headache, and joint and muscle pain. This is followed by vomiting and diarrhea. Later, the “hemorrhagic” part may set in, with internal and external bleeding. The agonizing disease is fatal in up to ninety percent of cases.
An international team dispatched to the region hunts down the culprit: a highly contagious, thread-like virus that has never been seen before. They name the new pathogen after a nearby river snaking through the region: Ebola. The word means “black river” in Lingala, the local language.
In the following decades, more than 20 similar outbreaks occur.
January 2014: The still-obscure disease strikes again, this time blazing across the country of Guinea before radiating to neighboring Liberia and Sierra Leone. Hospitals are overrun as desperate efforts to contain the spread of Ebola are outpaced by the virus’s implacable wave of destruction. The outbreak is the largest epidemic of the disease in history, claiming over 11,000 lives.
In the nearly 40 years since Ebola first struck the tiny village of Yambuku, no vaccine or treatment has been developed to prevent or cure the disease.
Charles Arntzen, a plant biologist, infectious disease specialist and founding director of Arizona State University’s Biodesign Institute, grimly recalls the moment in 2014 when Ebola reemerged from its refuge in the African bush.
“Hearing that the virus was once again causing disease and death was not surprising, but seeing the rapid spread as it entered densely populated cities was scary,” he says.
At the Biodesign Institute’s Center for Infectious Diseases and Vaccinology, Arntzen had been pursuing a way to develop low-cost vaccines and therapeutics to fight infectious diseases in the developing world by growing them in plants, or “pharming.” His plant of choice is tobacco, a fast-growing, large-leafed organism that Arntzen says is an ideal bio-factory for producing disease-fighting proteins.
“You need a living system to manufacture proteins, and we tried a number of plants,” Arntzen says. “But we settled on tobacco because it produces a lot of biomass quickly, and there is a lot known about viruses that infect it. We reengineer these plant-infecting viruses and design them to make the proteins we want. The tobacco plant becomes a Xerox machine producing a massive amount of the drugs, such as monoclonal antibodies.”
In addition to naturally occurring disease outbreaks, another threat plagued researchers and public health officials, coming into sharp focus in the aftermath of the September 11, 2001 terrorist attacks on the U.S. Publications by former Russian scientists described how pathogens like Ebola could potentially be weaponized and unleashed on populations in acts of bioterrorism.
In 2001, with funding from the U.S. Army, Arntzen set out to design a manufacturing system that could be rapidly mobilized, producing drugs that could be stockpiled and deployed in the event of a bioterror emergency. His ASU research team collaborated with Larry Zeitlin and Kevin Whaley of Mapp Biopharmaceutical, a small San Diego-based startup.
In 2011, Arntzen and his colleagues at Mapp published back-to-back papers in the Proceedings of the National Academy of Sciences. Recognizing the possibility of an Ebola disaster, they proposed a novel means of combating the virus, using plant-made vaccines and antibodies to bind with and neutralize it.
“It’s been a creative wonderland within the Biodesign Institute that has allowed us to chase ideas that maybe initially sounded a little crazy.” --Charles Arntzen
Experiments using a mouse model demonstrated that both a tobacco-derived vaccine as well as a potent cocktail of plant-derived monoclonal antibodies—“plantibodies”—could produce a robust, system-wide response to Ebola. The vaccine could inoculate the recipient against future exposure to the virus, while the antibodies could be used as a post-exposure therapeutic.
Subsequent research showed the protective potential of the new therapy, called ZMapp. In animal studies, ZMapp offered 100 percent protection from Ebola virus disease, even five days after the onset of infection.
The 2014 catastrophe in West Africa reinvigorated concerns about the threat of emergent pathogens. The lethality of the virus, combined with a crippled health infrastructure in the afflicted region, produced a deadly mix. Additionally, local burial customs that accelerated spread of disease and lack of adequate protection for medical personnel created a perfect storm.
In a remarkable turn of events, ZMapp would face its ultimate test. Under the provisions of compassionate use, intravenous doses of ZMapp were delivered to physician Kent Brantly and health care worker Nancy Writebol. The pair had been infected with Ebola while serving as volunteers in Africa.
The experimental drug was used in a desperate effort to save the two Ebola patients, even as their families were contemplating funeral arrangements. Both patients made a remarkable turnaround within hours of receiving treatment and were transported home to the U.S., where both made a full recovery.
“When I heard the details of the recovery of these two health care workers, it was an amazing moment,” Arntzen recalls. “It was possible to draw a straight line from a bench-top idea that many would have called zany, to a life-saving event.”
The U.S. government has awarded $25 million for a massive manufacturing scale-up of ZMapp.
Arntzen stresses that ZMapp’s startling results to date must still be experimentally and statistically replicated. Mapp has been granted approval to conduct human clinical trials to fully assess the drug’s effectiveness.
Meanwhile, Arntzen’s Biodesign colleagues, including Qiang “Shawn” Chen, Hugh Mason and Tsafrir Mor, continue to pursue plant-based vaccines and therapeutics to combat other health threats such as West Nile virus, dengue fever, nerve agents and even cancer.