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."
[Editor's Note: To learn more about this exciting field, check out: The Top 8 Things to Know About Anti-Aging Research Right Now.]
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.
After You Die, Your Digital Self Could Live on as a Chatbot
My wife and I visited a will-and-trust lawyer after our first son was born. Everything seemed simple and clear until the lawyer asked, without missing a beat, "So, what about your social media management?" My wife looked at me and, even though I'm more tech savvy, I felt as confused as a Luddite.
One can imagine chatbots becoming the next generation of care management alongside funeral services, and will and testaments.
"Social media management?" I laughed, making a joke about my wife spending more time on Facebook than I do. But the lawyer's question was serious, as were the legal documents asking for our profile page links, passwords, and related information.
What do you want to happen to your Facebook, Twitter, and other social media platforms after you die? Your grandfather may have wanted his cremated ashes poured into the Ganges, or a burial in a prepaid plot. But unlike earlier generations, whose personas ended with their last breath, your bits and bytes could live on across multiple servers, holding a space for you online like a digital obelisk. Or, if you desire, your relatives can do the equivalent of a DNR: Delete account.
"It is the future of 'Get your affairs in order,'" says John Havens, Executive Director of the IEEE Global Initiative on Ethics of Autonomous and Intelligent Systems. He remembers being pulled aside when his father was being put into the ICU and realizing that his dad wasn't going to come back.
Havens says if we are lucky enough to know that we are wrapping up our time, then we have the opportunity not just to bow out of the digital world gracefully, but to have our digital persona carry on beyond us. This persona could go beyond today's static memorial pages on Facebook and Instagram; it could be an interactive computer program designed from your specific speech patterns, memories, and personality – a chatbot.
"I could have an algorithm trained to hear what I say and how I say it," Havens told me. "You can say, 'I'm Damon and I'm going to pass in the next few months, but, you know, over the past six months, I've created a chatbot to continue our conversations. In the upcoming months, my partner or loved ones will let you know when the chatbot will take over and be involved.'"
The chatbot could become an extension of you on platforms like Messenger or WhatsApp, for example. One can imagine this becoming the next generation of care management alongside funeral services, and will and testaments. You can see the future in Eugenia Kuyda, an entrepreneur who successfully created an interactive chatbot of her late friend, Roman Mazurenko, just based on his text messages. Her new program, Replika, may eventually give us the same technology so we, too, can all potentially do the same with our loved ones. Expect other tech companies to follow suit.
There is now no real separation between IRL and online – just as there may be an increasingly blurred line between our personas before and after death.
Chatbots offer us an irresistible decision: They are artificial intelligence programs built to have conversations with people, usually within a service capacity like canceling a shipping order or getting to the right help desk. You can view it as a modern-day helpline and, no doubt, you've interacted with chatbots when you've made purchases online. Chatbots are now becoming verbal, too, managing phone calls you make to your credit card company, local utilities, and other daily operations.
We witnessed our future this spring when Google showed off Google Duplex. It is a voice-driven system that will call people on your behalf with the intention, Google says, to manage your life. At the Google I/O conference, Google CEO Sundar Pichai showed Duplex calling a hair salon and interacting with the human receptionist – with nearly all the pauses, mmm-hmms, and colloquialisms as its female counterpart. "The amazing part is the assistant can actually understand the nuances of conversation," Pichai said to the rapt tech audience.
Recode's Kurt Wagner explained the immediate problem with the Google Duplex demo, which is the same problem technologists so often overlook: What if someone uses your technology in ways you didn't intend? "The major concern with that demo was that Google Assistant never said it was a robot or told the salon that the call was being recorded. When pressed by members of the media in the days after the demo, Google declined to comment, leading some to believe the company had simply overlooked this privacy element altogether."
"This is why disclosure will be so huge," Havens says. "When people call, they will begin with, 'Hello. I am a human.'"
This conflict between the physical and the digital is now coming to a head, though it isn't the clichéd man against machine Skynet conspiracy theories, but rather us against us. Today, it is as if we are split into two or, perhaps more accurately, two personas – our "real-life" persona and our online persona – and we're now experiencing fatigue trying to hold center.
It is a new phenomenon reflective of our social media: Media forerunners like MySpace and Friendster as well as classic websites like LiveJournal and Tumblr allowed us to explore the online world – and, in a sense, the physical world beyond our physical reach – using avatars as close to or as far from our real selves as we desired. On the Internet, nobody knows you're a dog.
Facebook truly eliminated the powerful choice of anonymity, as its extensive verification process required people to give up anonymity to participate in the biggest social network in the world. This was a willful, purposeful decision by Facebook: Founder Mark Zuckerberg has been an advocate of being yourself online, and the former Director of Market Development Randi Zuckerberg infamously said, "I think anonymity on the Internet has to go away… People behave a lot better when they have their real names down."
This was Facebook's intention and, whether or not its theory of people behaving better is true, especially in light of the 2016 U.S. Presidential election, the effects on us are real. Sex workers and other high-risk, anonymity-driven entrepreneurs are being outed via social media. The parallel rise in online addiction clinics isn't a coincidence, as the blur between the physical self and the digital self has never been hazier. There is now no real separation between IRL and online – just as there may be an increasingly blurred line between our personas before and after death.
Chatbots represent a tempting form of convenience: A way to remove our cognitive load to an assistant that will manage our relationships.
We have Carrie Fisher starring in the next Star Wars movie, potentially winning the first truly post-humous Oscar thanks to technology that can help transition older footage into live-recorded footage. Similar, more subtle turns occurred with Paul Walker in the Fast and the Furious 7, which used a combination of CGI and stand-ins. But a key difference is that we actually know they are dead before the movie is even released. As not-famous individuals, we have the ethical choice (duty?) to disclose that information to our social media followers after we die.
While we're still alive, though, chatbots represent a tempting form of convenience: A way to remove our cognitive load to an assistant that will manage our relationships. The rub is that our online relationships are our personal relationships, so we're not just potentially automating, say, our social media feed or our online postings, but our responsibilities in the real-life relationships that we've built. There is no line.
"It's naïve to think that the Google Duplex that was designed to make your hair appointments won't be used to do more difficult things like break up with a girlfriend," Havens says. "Record 50 words, use different inflections, and put in phrases like 'It's not you, it's me.' Why wouldn't people do that?"
Well, it really depends on the person. My wife and I ended up leaving the social media management section of our will blank for now. I even took a long social media sabbatical to connect with people more in person. If my online relationships and my in-person relationships are all becoming the same, then maybe it's OK to let them die – just like I will.