One of the World’s Most Hated Plants Is Becoming a Public Health Rock Star
A plant in a growth chamber.
The recent Ebola virus outbreak in the Democratic Republic of Congo has refocused attention on the vaccine and treatment prospects for the highly contagious and deadly disease. As of late May, more than 7,500 doses of an experimental vaccine made by Merck Pharmaceuticals had been shipped to the beleaguered African nation, according to a World Health Organization press release.
Research was focused on the production of antibodies and vaccines in a novel manufacturing system: the tobacco plant.
Meanwhile, Ebola treatments were also sent. One of these, ZMapp, was successfully used to treat two American missionaries in Liberia in 2014. Charles Arntzen, who helped develop the treatment, calls that moment the highlight of his career: "It started in a lab as a fanciful idea that needed to be validated. In ten years, it was being used and people went from almost dead to almost recovered."
His initial research was focused on the production of antibodies and vaccines in a novel manufacturing system. That system was the tobacco plant—not the smoking variety, or nicotiana tabacum. But rather, a distant cousin called nicotiana benthamiana, which is native to Australia, where it grows abundantly.
ZMapp is made from the plant, as are other therapeutics and vaccines. Indeed, the once-maligned plant family has turned its image upside down in the public health world, now holding promise to prevent and treat many conditions.
Cheap, easy and plentiful
Research on the tobacco plant's medicinal potential goes back a few decades. In the early 1990s, research on plants as vaccine production platforms was just beginning. "We wanted to make a lower-cost vaccine manufacturing system to be used in developing countries to broaden our manufacturing base in the developing world," said Arntzen, who is the founding director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy at Arizona State University. "There was and still is a shortage of vaccines in the poorest countries."
"I've got a list of about fifty vaccines that should be made in tobacco."
Initially, research focused on food plants: bananas, tomatoes, and potatoes. While these efforts were successful, they were stymied by the "anti-GMO food establishment," Arntzen said. "I didn't want to spend my time fighting." So, they switched to the tobacco plant.
"I've got a list of about fifty vaccines that should be made in tobacco," said Denis Murphy, professor of biotechnology at the University of South Wales. "We know a lot about how to express genes in tobacco and get it made."
Unlike egg-based vaccines, which require a clean, sterile laboratory to make, and can therefore be an expensive process, Murphy said, tobacco-based vaccines are relatively cheap to make. The process is simple: Three weeks after being planted, the plants are dipped into a liquid containing proteins from the given virus. The plants grow the proteins for another week and then are harvested and chopped up. The green liquid that results is the vaccine, which is purified and then bottled up in precise doses.
"The tobacco plant doesn't seem to mind making all this foreign protein," Murphy added. "The plants will stay alive and look okay, and they will be full of vaccine protein. If you did this with an animal, you'd probably kill it."
Still, there are certain challenges to producing tobacco-based vaccines, particularly in the developing world, said Murphy, who is also a biotech consultant for the Food and Agricultural Organization of the United Nations.
"The purification process of the vaccine protein from leaves is still something for which you need a specialized lab. You couldn't have that in the Congo," he said. Security is another concern. "Someone could steal the plant and grow it themselves as a pirate version."
Even birds could be the culprit for tobacco plant theft. "What if a bird came and started eating the leaves? You might want netting or greenhouse growing. That can be much more problematic in a developing country."
While the ZMapp treatment for Ebola is produced from tobacco, efforts to develop a vaccine this way have not proved fruitful so far. (Merck's Ebola vaccine is made from livestock.) "Our tobacco-based vaccine would require three doses for a full effect, while the vaccine made by Merck may only require a single dose," Arntzen said. "Having to give three doses, over about a month, makes the tobacco-made vaccine much more cumbersome and expensive to deliver." Yet a tobacco-derived vaccine for another newsworthy illness is in the works.
On the frontier of a flu vaccine
Quebec City-based biopharmaceutical company Medicago is using a novel technique to make a flu vaccine with tobacco. This offers several advantages over the current method of developing the vaccine from eggs.
First of all, the production is quicker: five to six weeks, versus four to six months, which means that researchers can wait to identify the circulating flu strain for the upcoming season, rather than guess and risk being wrong.
Also, with tobacco, developers can use something called virus-like particles, instead of the actual flu virus.
"We hope to be on the market by the 2020/21 flu season."
"They have the structure of the flu virus, but not its full genetic code, so the virus doesn't replicate," said Anne Shiraishi, Medicago's communications manager. That's a big deal because the flu is a rapidly mutating virus, and traditional egg-based vaccines encourage those mutations – which wind up making the vaccines less effective.
This problem happens because the flu virus mutates a key protein to better attach to receptors in bird cells, but in humans, this mutation won't trigger an effective immune response, according to a Medicago fact sheet. That's why some people who have been vaccinated still get the flu. Indeed, the 2017 flu season had the lowest vaccine effectiveness record ever for H3N2 at 10 percent in the Southern Hemisphere, and 0 percent effective in the EU and UK in people over age 65. At least theoretically, their tobacco-derived flu vaccine could be far more successful, since no such mutations occur with the virus-like particles.
Last year, Medicago, which is 40 percent owned by cigarette company Philip Morris, began a phase 3 trial of the flu vaccine with 10,000 subjects in five countries: half are getting the vaccine, and half are getting a placebo. "We hope to announce really good results this fall," Shiraishi said. "We hope to be on the market by the 2020/21 flu season."
They're also preparing phase I trials for vaccines for the rotavirus and norovirus, two intractable gastro-intestinal viruses. They hope to roll those trials out in the next year or two.
Meanwhile, other research on antibodies is in their pipeline—all of it using tobacco, Shiraishi said. "We've taken something bad for public health and made it our mini factories."
Patients voice hope and relief as FDA gives third-ever drug approval for ALS
On Sept. 29, the FDA approved Relyvrio, a new drug for ALS, even though a study of 137 ALS patients did not result in “substantial evidence” that Relyvrio was effective.
At age 52, Glen Rouse suffered from arm weakness and a lot of muscle twitches. “I first thought something was wrong when I could not throw a 50-pound bag of dog food over the tailgate of my truck—something I use to do effortlessly,” said the 54-year-old resident of Anderson, California, about three hours north of San Francisco.
In August, Rouse retired as a forester for a private timber company, a job he had held for 31 years. The impetus: amyotrophic lateral sclerosis, or ALS, a progressive neuromuscular disease that is commonly known as Lou Gehrig’s disease, named after the New York Yankees’ first baseman who succumbed to it less than a month shy of his 38th birthday in 1941. ALS eventually robs an individual of the ability to talk, walk, chew, swallow and breathe.
Rouse is now dependent on ventilation through a nasal mask and uses a powerchair to get around. “I can no longer walk or use my arms very well,” he said. “I can still move my wrists and fingers. I can also transfer from my chair to the toilet if I have two of my friends help me.”
It’s “shocking” that modern medicine has very little to offer to people with this devastating condition, Rouse said. But there is hope on the horizon. Yesterday, the U.S. Food and Drug Administration approved Relyvrio, a drug made up of two parts, sodium phenylbutyrate and taurursodiol, to treat patients with ALS.
“This approval provides another important treatment option for ALS, a life-threatening disease that currently has no cure,” said Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in a statement. “The FDA remains committed to facilitating the development of additional ALS treatments.”
Until this point, the FDA had approved only two other medications—Riluzole (rilutek) in 1995 and Radicava (edaravone) in 2017—to extend life in patients with ALS, which typically kills within two to five years after diagnosis. That’s why earlier this week, Rouse was optimistic about the FDA’s likely approval of a controversial new drug for ALS.
When Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months, said Richard Bedlak, director of the Duke ALS Clinic. “It is not a cure, but it is definitely a step forward.”
“The whole ALS community is extremely excited about it,” he said the day before Relyvrio’s expected approval. “We are very hopeful. We’re on pins and needles.”
A study of 137 ALS patients did not result in “substantial evidence” that Relyvrio was effective, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee concluded in March. However, after some persuasion from FDA officials, patients and their families, the committee met again and decided to recommend approving the drug.
In January 2019, following an ALS diagnosis at age 58 in October the previous year, Jeff Sarnacki, of Chester, Maryland, was accepted into a trial for Relyvrio. “Because of the trial, we did experience hope and a greater sense of help than had we not had that opportunity,” said Juliet Taylor, his wife and caregiver. They both believed the drug “worked for him in giving him more time.”
In June 2019, Sarnacki chose an open-label extension, offered to patients by drug researchers after a study ends, and took the active drug until he died peacefully at home under hospice care in May 2020, five days after his 60th birthday. A retired agent with the federal Bureau of Alcohol, Tobacco, Firearms and Explosives who later worked as a security consultant, Sarnacki lived about 19 months after diagnosis, which is shorter than the typical prognosis.
His symptoms began with leg cramps in fall 2017 and foot drop in early 2018. A feeding tube was placed in 2019, as it became necessary early in his illness, Taylor said. He also took Radicava and Riluzole, the two previously approved drugs, for his ALS. “We were both incredulous that, so many years after Lou Gehrig’s own diagnosis, there were so few treatments available,” she said.
The dearth of successful treatments for ALS is “certainly not for lack of trying,” said Karen Raley Steffens, a registered nurse and ALS support services coordinator at the Les Turner ALS Foundation in Skokie, Ill. “There are thousands of researchers and scientists all over the world working tirelessly to try to develop treatments for ALS.”
Unfortunately, she added, research takes time and exorbitant amounts of funding, while bureaucratic challenges persist. The rare disease also manifests and progresses in many different ways, so many treatments are needed.
As of 2017, the Centers for Disease Control and Prevention estimated that more than 31,000 people in the U.S. live with ALS, and an average of 5,000 people are newly diagnosed every year. It is slightly more common in men than women. Most people are diagnosed between the ages of 55 and 75.
Most cases of ALS are sporadic, meaning that doctors don’t know the cause. There is about a one-year interval between symptom onset and an ALS diagnosis for most patients, so many motor neurons are lost by the time individuals can enroll in a clinical trial, said Richard Bedlack, professor of neurology and director of the Duke ALS Clinic in Durham, North Carolina.
Bedlack found the new drug, Relyvrio, to be “very promising,” which is why he testified to the FDA in favor of approval. (He’s a consultant and disease state speaker for multiple companies including Amylyx, manufacturer of Relyvrio.)
The “drug has different mechanisms of action than the currently approved treatments,” Bedlack said. He added that, when Relyvrio is taken in addition to Riluzole, it appears to slow functional decline by an additional 25 percent and extend life by another 6 to 10 months. “It is not a cure, but it is definitely a step forward.”
T. Scott Diesing, a neurohospitalist and director of general neurology at the University of Nebraska Medical Center in Omaha, said he hopes the drug is “as good as people anticipated it should be, because there are not too many options for these patients.”
"FDA went out on a limb in approving Relyvrio based on limited results from a small trial while a larger study remains in progress," said Florian P. Thomas, co-director of the ALS Center at Hackensack University Medical Center and the Meridian School of Medicine. "While it is definitely promising, clearly, the last word on this drug has not been spoken."
So far, Rouse's voice is holding up, but he knows the day will come when ALS will steal that and much more from him.
ALS is 100 percent fatal, with some patients dying as soon as a year after diagnosis. A few have lasted as long as 15 years, but those are the exceptions, Diesing said.
“If this drug can provide even months of additional life, or would maintain quality of life, that’s a big deal,” he noted, adding that “the patients are saying, ‘I know it’s not proven conclusively, but what do we have to lose?’ So, they would like to try it while additional studies are ongoing.” The drug has already been conditionally approved in Canada.
As his disease progresses, Rouse hopes to get a speech-to-text voice-generating computer that he can control with his eyes. So far, his voice is holding up, but he knows the day will come when ALS will steal that and much more from him. He works at I AM ALS, a patient-led community, and six of his friends have already died of the disease.
“Every time I lose a friend to ALS, I grieve and am sad but I resolve myself to keep working harder for them, myself and others,” Rouse said. “People living with ALS find great purpose in life advocating and trying to make a difference.”
Friday Five Podcast: New drug may slow the rate of Alzheimer's disease
On September 27, pharmaceuticals Biogen and Eisai announced that their drug, lecanemab, can slow the rate of Alzheimer's disease, according to a clinical trial. Today's Friday Five episode covers this story and other health research over the month of September.
The Friday Five covers important stories in health and science research that you may have missed - usually over the previous week, but today's episode is a lookback on important studies over the month of September.
Most recently, on September 27, pharmaceuticals Biogen and Eisai announced that a clinical trial showed their drug, lecanemab, can slow the rate of Alzheimer's disease. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend and the new month.
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This Friday Five episode covers the following studies published and announced over the past month:
- A new drug is shown to slow the rate of Alzheimer's disease
- The need for speed if you want to reduce your risk of dementia
- How to refreeze the north and south poles
- Ancient wisdom about Neti pots could pay off for Covid
- Two women, one man and a baby
Matt Fuchs is the editor-in-chief of Leaps.org. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him on Twitter @fuchswriter.