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."
This Startup Uses Dust to Fight Sweatshops
"Dust thou art, and unto dust shalt thou return." Whoever wrote that famous line probably didn't realize that dust actually contains a secret weapon.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain."
Far from being a collection of mere inanimate particles, dust is now recognized as a powerful tool filled with living sensors. Studying those sensors can reveal an object's location history, which can help brands fight unethical manufacturing.
"We have developed the capability to turn dust into data that can be used to trace problems in the supply chain," explains Jessica Green, the CEO of Phylagen, a San-Francisco-based company that she co-founded in 2014.
So how does the technology work?
Dust gathers everywhere—on our bodies, on objects—and that dust contains microbes like bacteria and viruses. Just as we humans have our own unique microbiomes, research has shown that physical locations have their own identifiable patterns of microbes as well. Visiting a place means you may pick up its microbial fingerprint in the dust that settles on you. The DNA of those microbes can later be sequenced in a lab and matched back to the place of origin.
"Your environment is constantly imprinted on you and vice versa," says Justin Gallivan, the director of the Biotechnology Office at DARPA, the research and defense arm of the Pentagon, which is funding Phylagen. "If we have a microbial map of the world," he posits, "can we infer an object's transit history?"
So far, Phylagen has shown that it's possible to identify where a ship came from based on the unique microbial populations it picked up at different naval ports. In another experiment, the sampling technology allowed researchers to determine where a person had walked within 1 kilometer in San Francisco, because of the microbes picked up by their shoes.
Data scientist Roxana Hickey, left, and CEO Jessica Green of Phylagen.
One application of this technology is to help companies that make products abroad. Such companies are very interested in determining exactly where their products are coming from, especially if foreign subcontractors are involved.
"In retail and apparel, often the facilities performing the subcontracting are not up to the same code that the brands require their suppliers to be, so there could be poor working conditions," says Roxana Hickey, a data scientist at Phylagen. "A supplier might use a subcontractor to save on the bottom line, but unethical practices are very damaging to the brand."
Before this technology was developed, brands sometimes faced a challenge figuring out what was going on in their supply chain. But now a product can be tested upon arrival in the States; its microbial signature can theoretically be analyzed and matched against a reference database to help determine if its DNA pattern matches that of the place where the product was purported to have been made.
Phylagen declined to elaborate further about how their process works, such as how they are building a database of reference samples, and how consistent a microbial population remains across a given location.
As the technology grows more robust, though, one could imagine numerous other applications, like in police work and forensics. But today, Phylagen is solely focused on helping commercial entities bring greater transparency to their operations so they can root out unauthorized subcontracting.
Then those unethical suppliers can – shall we say – bite the dust.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Surfing for Science: A Fin Sensor Is Making Waves
For David Walden, a Southern Californian, surfing is a lifestyle, not a hobby. The 38-year-old works nights at a seafood restaurant to leave his mornings free for surfing.
While the surfers are doing what they love, they are also collecting information that is helping scientists better understand the ocean.
"Once you fall in love with the ocean, you need it like a daily cleanse or refresher," he says. "The positive mental and physical effects of the ocean, the endorphins and dopamine, keep you addicted in a good way."
Given his dedication to surfing, Walden was delighted when he became one of more than 200 surfers last year to test Smartfin, a 5-1/2-inch surfboard fin that contains a circuit board, a rechargeable battery, a GPS device, a sensor that captures temperature to one-hundredth of a degree, and a motion sensor that tracks the movement of the waves. While Walden and his fellow surfers are doing what they love, they are also collecting information that is helping scientists better understand the health of the near-shore ocean and how its chemistry is shifting due to climate change.
"I'm excited to be a part of it," Walden says. "I like to tell people I surf for science."
Back on shore, the surfers download the Smartfin data via a smartphone app so they can be accessed by scientists and other interested parties. (You can see where Smartfin surfers go at this interactive map.)
By putting sensors directly onto surfboards, oceanographers can collect data to help them better understand the global-warming related changes occurring in coastal oceans in temperature, salinity, and pH, all properties that have huge implications for the species that live in near-shore ecosystems.
There is much unknown about coastal waters because it's so difficult to obtain meaningful measurements. Traditional methods to monitor the close shore, such as bottle samples and buoys, are time consuming and expensive and tend to get damaged by the surf.
The Smartfin is the brainchild of Dr. Andy Stern, a retired neurologist. He and his brother-in-law, sculptor and filmmaker Todd McGrain, run The Lost Bird Project, a nonprofit devoted to raising awareness about climate change and other environmental issues. Stern brought his super fin idea to engineer Benjamin Thompson, who spent several years creating a prototype in his garage workshop. Smartfin was further developed by scientists at the Scripps Institution of Oceanography at the University of California at San Diego.
"The big challenge was to make a sensor small enough to fit in the fin but still produce good measurements," says Andreas Andersson, an associate professor of geoscience research at Scripps.
The Surfrider Foundation, a surfer-led nonprofit environmental organization, came aboard two years ago to distribute the Smartfin to its San Diego members.
Smartfin has also made a splash with scientists at the University of the Sunshine Coast in Queensland on the eastern coast of Australia. They are using the fin's temperature sensor to better understand how climate change is affecting the movement and distribution of marine life. And at the Plymouth Marine Laboratory in Plymouth, United Kingdom, the Smartfin's precise temperature readings of the near-shore ocean's surface are being used to improve the accuracy of satellites that monitor the ocean from hundreds of miles away.
"It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin."
"The hope is that Smartfin will improve the satellite measurements, which could improve the retrieval of temperature data around the world," says Dr. Phil Bresnahan, Smartfin's lead engineer at Scripps. In the future, the fin will include sensors to measure pH, chlorophyll (algae), dissolved oxygen, and turbidity (water clarity).
Stern envisions a time when thousands of surfers, paddle boarders, and other water enthusiasts worldwide will have Smartfins and be downloading data for scientists and environmentalists. Right now, there are approximately 70 surfers in the San Diego area using Smartfin and an additional 30 globally.
Scientists have plenty of evidence that global warming is largely caused by humans. Now they are trying to figure out what the long-term effects of climate change may be. For example, scientists are trying to predict which sections of coral reef, which house 25 percent of marine species, are most vulnerable so interventions can be developed to save them. Because of its small size, Smartfin is ideal to measure temperature changes in coral reefs.
Smartfin was also intended to be an educational tool. "It's a great way to start a different conversation about climate change," says Stern. "It's hard to talk about climate change in a way that's not boring or gloomy, but there's nothing gloomy or depressing about surfers and Smartfin. People want to hear more."
Turning surfers into citizen scientists makes perfect sense, says David Pasquini, 35, a longtime surfer who works for the British Consulate General's office in Oceanside, Calif. "Anyone who spends a lot of time in the ocean is aware of the changes happening in the ecosystem, the climate," says Pasquini. "Everyone asks, 'What can I do?'" Surfing with Smartfin, Pasquini feels like he is giving back.
"I know the data will be analyzed and eventually used to make a policy that helps with climate change. That's a great feeling--just by surfing, doing something you love, you're contributing."