Scientists Are Growing an Edible Cholera Vaccine in Rice
The world's attention has been focused on the coronavirus crisis but Yemen, Bangladesh and many others countries in Asia and Africa are also in the grips of another pandemic: cholera. The current cholera pandemic first emerged in the 1970s and has devastated many communities in low-income countries. Each year, cholera is responsible for an estimated 1.3 million to 4 million cases and 21,000 to 143,000 deaths worldwide.
Immunologist Hiroshi Kiyono and his team at the University of Tokyo hope they can be part of the solution: They're making a cholera vaccine out of rice.
"It is much less expensive than a traditional vaccine, by a long shot."
Cholera is caused by eating food or drinking water that's contaminated by the feces of a person infected with the cholera bacteria, Vibrio cholerae. The bacteria produces the cholera toxin in the intestines, leading to vomiting, diarrhea and severe dehydration. Cholera can kill within hours of infection if it if's not treated quickly.
Current cholera vaccines are mainly oral. The most common oral are given in two doses and are made out of animal or insect cells that are infected with killed or weakened cholera bacteria. Dukoral also includes cells infected with CTB, a non-harmful part of the cholera toxin. Scientists grow cells containing the cholera bacteria and the CTB in bioreactors, large tanks in which conditions can be carefully controlled.
These cholera vaccines offer moderate protection but it wears off relatively quickly. Cold storage can also be an issue. The most common oral vaccines can be stored at room temperature but only for 14 days.
"Current vaccines confer around 60% efficacy over five years post-vaccination," says Lucy Breakwell, who leads the U.S. Centers for Disease Control and Prevention's cholera work within Global Immunization Division. Given the limited protection, refrigeration issue, and the fact that current oral vaccines require two disease, delivery of cholera vaccines in a campaign or emergency setting can be challenging. "There is a need to develop and test new vaccines to improve public health response to cholera outbreaks."
A New Kind of Vaccine
Kiyono and scientists at Tokyo University are creating a new, plant-based cholera vaccine dubbed MucoRice-CTB. The researchers genetically modify rice so that it contains CTB, a non-harmful part of the cholera toxin. The rice is crushed into a powder, mixed with saline solution and then drunk. The digestive tract is lined with mucosal membranes which contain the mucosal immune system. The mucosal immune system gets trained to recognize the cholera toxin as the rice passes through the intestines.
The cholera toxin has two main parts: the A subunit, which is harmful, and the B subunit, also known as CTB, which is nontoxic but allows the cholera bacteria to attach to gut cells. By inducing CTB-specific antibodies, "we might be able to block the binding of the vaccine toxin to gut cells, leading to the prevention of the toxin causing diarrhea," Kiyono says.
Kiyono studies the immune responses that occur at mucosal membranes across the body. He chose to focus on cholera because he wanted to replicate the way traditional vaccines work to get mucosal membranes in the digestive tract to produce an immune response. The difference is that his team is creating a food-based vaccine to induce this immune response. They are also solely focusing on getting the vaccine to induce antibodies for the cholera toxin. Since the cholera toxin is responsible for bacteria sticking to gut cells, the hope is that they can stop this process by producing antibodies for the cholera toxin. Current cholera vaccines target the cholera bacteria or both the bacteria and the toxin.
David Pascual, an expert in infectious diseases and immunology at the University of Florida, thinks that the MucoRice vaccine has huge promise. "I truly believe that the development of a food-based vaccine can be effective. CTB has a natural affinity for sampling cells in the gut to adhere, be processed, and then stimulate our immune system, he says. "In addition to vaccinating the gut, MucoRice has the potential to touch other mucosal surfaces in the mouth, which can help generate an immune response locally in the mouth and distally in the gut."
Cost Effectiveness
Kiyono says the MucoRice vaccine is much cheaper to produce than a traditional vaccine. Current vaccines need expensive bioreactors to grow cell cultures under very controlled, sterile conditions. This makes them expensive to manufacture, as different types of cell cultures need to be grown in separate buildings to avoid any chance of contamination. MucoRice doesn't require such an expensive manufacturing process because the rice plants themselves act as bioreactors.
The MucoRice vaccine also doesn't require the high cost of cold storage. It can be stored at room temperature for up to three years unlike traditional vaccines. "Plant-based vaccine development platforms present an exciting tool to reduce vaccine manufacturing costs, expand vaccine shelf life, and remove refrigeration requirements, all of which are factors that can limit vaccine supply and accessibility," Breakwell says.
Kathleen Hefferon, a microbiologist at Cornell University agrees. "It is much less expensive than a traditional vaccine, by a long shot," she says. "The fact that it is made in rice means the vaccine can be stored for long periods on the shelf, without losing its activity."
A plant-based vaccine may even be able to address vaccine hesitancy, which has become a growing problem in recent years. Hefferon suggests that "using well-known food plants may serve to reduce the anxiety of some vaccine hesitant people."
Challenges of Plant Vaccines
Despite their advantages, no plant-based vaccines have been commercialized for human use. There are a number of reasons for this, ranging from the potential for too much variation in plants to the lack of facilities large enough to grow crops that comply with good manufacturing practices. Several plant vaccines for diseases like HIV and COVID-19 are in development, but they're still in early stages.
In developing the MucoRice vaccine, scientists at the University of Tokyo have tried to overcome some of the problems with plant vaccines. They've created a closed facility where they can grow rice plants directly in nutrient-rich water rather than soil. This ensures they can grow crops all year round in a space that satisfies regulations. There's also less chance for variation since the environment is tightly controlled.
Clinical Trials and Beyond
After successfully growing rice plants containing the vaccine, the team carried out their first clinical trial. It was completed early this year. Thirty participants received a placebo and 30 received the vaccine. They were all Japanese men between the ages of 20 and 40 years old. 60 percent produced antibodies against the cholera toxin with no side effects. It was a promising result. However, there are still some issues Kiyono's team need to address.
The vaccine may not provide enough protection on its own. The antigen in any vaccine is the substance it contains to induce an immune response. For the MucoRice vaccine, the antigen is not the cholera bacteria itself but the cholera toxin the bacteria produces.
"The development of the antigen in rice is innovative," says David Sack, a professor at John Hopkins University and expert in cholera vaccine development. "But antibodies against only the toxin have not been very protective. The major protective antigen is thought to be the LPS." LPS, or lipopolysaccharide, is a component of the outer wall of the cholera bacteria that plays an important role in eliciting an immune response.
The Japanese team is considering getting the rice to also express the O antigen, a core part of the LPS. Further investigation and clinical trials will look into improving the vaccine's efficacy.
Beyond cholera, Kiyono hopes that the vaccine platform could one day be used to make cost-effective vaccines for other pathogens, such as norovirus or coronavirus.
"We believe the MucoRice system may become a new generation of vaccine production, storage, and delivery system."
A new video game exposes players to the deceptive tactics that are used to spread misinformation online, in an attempt to reduce people's susceptibility to fake news.
There's no shortage of fake news going around the internet these days, but how do we become more aware as consumers of what's real and what's not?
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood."
Researchers at the University of Cambridge may have answered just that by developing an online game designed to expose and educate participants to the tactics used by those spreading false information.
"We wanted to see if we could preemptively debunk, or 'pre-bunk', fake news by exposing people to a weak dose of the methods used to create and spread disinformation, so they have a better understanding of how they might be deceived," Dr Sander van der Linden, Director of the Cambridge Social Decision-Making Lab, said in a statement.
"This is a version of what psychologists call 'inoculation theory', with our game working like a psychological vaccination."
In February 2018, van der Linden and his coauthor, Jon Roozenbeek, helped launch the browser game, "Bad News," where players take on the role of "Disinformation and Fake News Tycoon."
They can manipulate news and social media within the game by several different methods, including deploying twitter-bots, photo-shopping evidence, creating fake accounts, and inciting conspiracy theories with the goal of attracting followers and maintaining a "credibility score" for persuasiveness.
In order to gauge the game's effectiveness, players were asked to rate the reliability of a number of real and fake news headlines and tweets both before and after playing. The data from 15,000 players was evaluated, with the results published June 25 in the journal Palgrave Communications.
The results concluded that "the perceived reliability of fake news before playing the game had reduced by an average of 21% after completing it. Yet the game made no difference to how users ranked real news."
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale.
Additionally, participants who "registered as most susceptible to fake news headlines at the outset benefited most from the 'inoculation,'" according to the study.
Just 15 minutes of playing the game can have a moderate effect on people, which could play a major role on a larger scale when it comes to "building a societal resistance to fake news," according to Dr. van der Linden.
"Research suggests that fake news spreads faster and deeper than the truth, so combating disinformation after-the-fact can be like fighting a losing battle," he said.
"We are hoping to create what you might call a general 'vaccine' against fake news, rather than trying to counter each specific conspiracy or falsehood," Roozenbeek added.
Van der Linden and Roozenbeek's work is an early example of the potential methods to protect people against deception by training them to be more attuned to the methods used to distribute fake news.
"I hope that the positive results give further credence to the new science of prebunking rather than only thinking about traditional debunking. On a larger level, I also hope the game and results inspire a new kind of behavioral science research where we actively engage with people and apply insights from psychological science in the public interest," van der Linden told leapsmag.
"I like the idea that the end result of a scientific theory is a real-world partnership and practical tool that organizations and people can use to guard themselves against online manipulation techniques in a novel and hopefully fun and engaging manner."
Ready to be "inoculated" against fake news? Then play the game for yourself.
An astronaut peers through a portal in outer space.
What if people could just survive on sunlight like plants?
The admittedly outlandish question occurred to me after reading about how climate change will exacerbate drought, flooding, and worldwide food shortages. Many of these problems could be eliminated if human photosynthesis were possible. Had anyone ever tried it?
Extreme space travel exists at an ethically unique spot that makes human experimentation much more palatable.
I emailed Sidney Pierce, professor emeritus in the Department of Integrative Biology at the University of South Florida, who studies a type of sea slug, Elysia chlorotica, that eats photosynthetic algae, incorporating the algae's key cell structure into itself. It's still a mystery how exactly a slug can operate the part of the cell that converts sunlight into energy, which requires proteins made by genes to function, but the upshot is that the slugs can (and do) live on sunlight in-between feedings.
Pierce says he gets questions about human photosynthesis a couple of times a year, but it almost certainly wouldn't be worth it to try to develop the process in a human. "A high-metabolic rate, large animal like a human could probably not survive on photosynthesis," he wrote to me in an email. "The main reason is a lack of surface area. They would either have to grow leaves or pull a trailer covered with them."
In short: Plants have already exploited the best tricks for subsisting on photosynthesis, and unless we want to look and act like plants, we won't have much success ourselves. Not that it stopped Pierce from trying to develop human photosynthesis technology anyway: "I even tried to sell it to the Navy back in the day," he told me. "Imagine photosynthetic SEALS."
It turns out, however, that while no one is actively trying to create photosynthetic humans, scientists are considering the ways humans might need to change to adapt to future environments, either here on the rapidly changing Earth or on another planet. Rice University biologist Scott Solomon has written an entire book, Future Humans, in which he explores the environmental pressures that are likely to influence human evolution from this point forward. On Earth, Solomon says, infectious disease will remain a major driver of change. As for Mars, the big two are lower gravity and radiation, the latter of which bombards the Martian surface constantly because the planet has no magnetosphere.
Although he considers this example "pretty out there," Solomon says one possible solution to Mars' magnetic assault could leave humans not photosynthetic green, but orange, thanks to pigments called carotenoids that are responsible for the bright hues of pumpkins and carrots.
"Carotenoids protect against radiation," he says. "Usually only plants and microbes can produce carotenoids, but there's at least one kind of insect, a particular type of aphid, that somehow acquired the gene for making carotenoids from a fungus. We don't exactly know how that happened, but now they're orange... I view that as an example of, hey, maybe humans on Mars will evolve new kinds of pigmentation that will protect us from the radiation there."
We could wait for an orange human-producing genetic variation to occur naturally, or with new gene editing techniques such as CRISPR-Cas9, we could just directly give astronauts genetic advantages such as carotenoid-producing skin. This may not be as far-off as it sounds: Extreme space travel exists at an ethically unique spot that makes human experimentation much more palatable. If an astronaut already plans to subject herself to the enormous experiment of traveling to, and maybe living out her days on, a dangerous and faraway planet, do we have any obligation to provide all the protection we can?
Probably the most vocal person trying to figure out what genetic protections might help astronauts is Cornell geneticist Chris Mason. His lab has outlined a 10-phase, 500-year plan for human survival, starting with the comparatively modest goal of establishing which human genes are not amenable to change and should be marked with a "Do not disturb" sign.
To be clear, Mason is not actually modifying human beings. Instead, his lab has studied genes in radiation-resistant bacteria, such as the Deinococcus genus. They've expressed proteins called DSUP from tardigrades, tiny water bears that can survive in space, in human cells. They've looked into p53, a gene that is overexpressed in elephants and seems to protect them from cancer. They also developed a protocol to work on the NASA twin study comparing astronauts Scott Kelly, who spent a year aboard the International Space Station, and his brother Mark, who did not, to find out what effects space tends to have on genes in the first place.
In a talk he gave in December, Mason reported that 8.7 percent of Scott Kelly's genes—mostly those associated with immune function, DNA repair, and bone formation—did not return to normal after the astronaut had been home for six months. "Some of these space genes, we could engineer them, activate them, have them be hyperactive when you go to space," he said in that same talk. "When we think about having the hubris to go to a faraway planet...it seems like an almost impossible idea….but I really like people and I want us to survive for a long time, and this is the first step on the stairwell to survive out of the solar system."
What is the most important ability we could give our future selves through science?
There are others performing studies to figure out what capabilities we might bestow on the future-proof superhuman, but none of them are quite as extreme as photosynthesis (although all of them are useful). At Harvard, geneticist George Church wants to engineer cells to be resistant to viruses, such as the common cold and HIV. At Columbia, synthetic biologist Harris Wang is addressing self-sufficient humans more directly—trying to spur kidney cells to produce amino acids that are normally only available from diet.
But perhaps Future Humans author Scott Solomon has the most radical idea. I asked him a version of the classic What would be your superhero power? question: What does he see as the most important ability we could give our future selves through science?
"The empathy gene," he said. "The ability to put yourself in someone else's shoes and see the world as they see it. I think it would solve a lot of our problems."