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."
Would you leave your small child in the care of a robot for several hours a day? It may sound laughable at first, but think carefully.
"Given the huge amounts of money we pay for childcare, a [robot caregiver] is a very attractive proposition."
Robots that can care for children would be a godsend to many parents, especially the financially strapped. In the U.S., 62 percent of women who gave birth in 2016 worked outside the home, and day care costs are often exorbitant. In California, for instance, the annual cost for day care for a single child averages over $22,000. The price is lower in some states, but it still accounts for a hefty chunk of the typical family's budget.
"We're talking about the Holy Grail of parenting," says Zoltan Istvan, a technology consultant and futurist. "Imagine a robot that could assume 70 percent to 80 percent of the caregiver's role for your child. Given the huge amounts of money we pay for childcare, that's a very attractive proposition."
Both China and Japan are on the leading edge of employing specially designed social robots for the care of children. Due to long work schedules, shifting demographics and China's long-term (but now defunct) one-child policy, both countries have a severe shortage of family caregivers. Enter the iPal, a child-sized humanoid robot with a round head, expressive face and articulated fingers, which can keep children engaged and entertained for hours on end. According to its manufacturer, AvatarMind Robot Technology, iPal is already selling like hotcakes in Asia and is expected to be available in the U.S. within the next year. The standard version of iPal sells for $2,499, and it's not the only robot claimed to be suitable for childcare. Other robots being fine-tuned are Softbank's humanoid models Pepper and NAO, which are also considered to be child-friendly social robots.
iPal talks, dances, plays games, reads stories and plugs into social media and the internet. According to AvatarMind, over time iPal learns your child's likes and dislikes, and can independently learn more about subjects your child is interested in to boost learning. In addition, it will wake your child up in the morning and tell him when it's time to get dressed, brush his teeth or wash his hands. If your child is a diabetic, it will remind her when it's time to check her blood sugar. But iPal isn't just a fancy appliance that mechanically performs these functions; it does so with "personality."
iPal robot interacting with a boy.
The robot has an "emotion management system" that detects your child's emotions and mirrors them (unless your child is sad, and then it tries to cheer him up). But it's not exactly like iPal has the kind of emotion chip long sought by Star Trek's android Data. What it does is emotional simulation--what some would call emotional dishonesty--considering that it doesn't actually feel anything. But research has shown that the lack of authenticity doesn't really matter when it comes to the human response to feigned emotion.
Children, and even adults, tend to respond to "emotional" robots as though they're alive and sentient even when we've seen all the wires and circuit boards that underlie their wizardry. In fact, we're hardwired to respond to them as though they are human beings in a real relationship with us.
The question is whether the relationships we develop with robots causes social maladaptation, especially among the most vulnerable among us—young children just learning how to connect and interact with others. Could a robot in fact come close to providing the authentic back-and-forth that helps children develop empathy, reciprocity, and self-esteem? Also, could steady engagement with a robot nanny diminish precious time needed for real family bonding?
It depends on whom you ask.
Because iPal is voice-activated, it frees children to learn by interacting in a way that's more natural than interacting with traditional toys, says Dr. Daniel Xiong, Co-founder and Chief Technology Officer at AvatarMind. "iPal is like a "real" family member with you whenever you need it," he says.
Xiong doesn't put a time limit on how long a child should interact with iPal on a daily basis. He sees the relationship between the child and the robot as healthy, though he admits that the technology needs to advance substantially before iPal could take the place of a human babysitter.
It's no coincidence that many toymakers and manufacturers are designing cute robots that look and behave like real children or animals, says Sherry Turkle, a Professor of Social Studies and Science at MIT. "When they make eye contact and gesture toward us, they predispose us to view them as thinking and caring," she has written in The Washington Post. "They are designed to be cute, to provide a nurturing response" from the child. "And when it comes to sociable AI, nurturance is the killer app: We nurture what we love, and we love what we nurture."
What are we saying to children about their importance to us when we're willing to outsource their care to a robot?
The problem is that we get lulled into thinking that we're in an actual relationship, when a robot can't possibly love us back. If adults have these vulnerabilities, what might such lopsided relationships do to the emotional development of a small child? Turkle notes that while we tend to ascribe a mind and emotions to a socially interactive robot, "Simulated thinking may be thinking, but simulated feeling is never feeling, and simulated love is never love."
Still, is active, playful engagement with a robot for a few hours a day any more harmful than several hours in front of a TV or with an iPad? Some, like Xiong, regard interacting with a robot as better than mere passive entertainment. iPal's manufacturers say that their robot can't replace parents or teachers and is best used by three- to eight-year-olds after school, while they wait for their parents to get off of work. But as robots become ever more sophisticated, they're expected to become more and more captivating, and to perform more of the tasks of day-to-day care.
Some studies, performed by Turkle and fellow MIT colleague Cynthia Breazeal, have revealed a darker side to child-robot interaction. Turkle has reported extensively on these studies in The Washington Post and in her 2011 book, Alone Together: Why We Expect More from Technology and Less from Each Other. Most children love robots, but some act out their inner bully on the hapless machines, hitting and kicking them and otherwise trying to hurt them. The trouble is that the robot can't fight back, teaching children that they can bully and abuse without consequences. Such harmful behavior could carry over into the child's human relationships.
And it turns out that communicative machines don't actually teach kids good communication skills. It's well known that parent-child communication in the first three years of life sets the stage for a child's intellectual and academic success. Verbal back-and-forth with parents and caregivers is like food for a child's growing brain. One article published in JAMA Pediatrics showed that babies who played with electronic toys—like the popular robot dog AIBO—show a decrease in both the quantity and quality of their language skills.
Anna V. Sosa of the Child Speech and Language Lab at Northern Arizona University studied 26 ten- to 16-month-old infants to compare the growth of their language skills after they played with three types of toys: Electronic toys like a baby laptop and talking farm; traditional toys like wooden puzzles and building blocks; and books read aloud by their parents.
The play that produced the most growth in verbal ability was having books read to them, followed by play with traditional toys. Language gains after playing with electronic toys came dead last. This form of play involved the least use of adult words, the least conversational turn-taking with parents, and the least verbalizations from the children. While the study sample was small, it's not hard to extrapolate that no electronic toy or even more abled robot could supply the intimate responsiveness of a parent reading stories to a child, explaining new words, answering the child's questions, and modeling the kind of back-and-forth interaction that promotes empathy and reciprocity in human relationships.
Most experts acknowledge that robots can be valuable educational tools, but they can't make a child feel truly loved, validated, and valued.
Research suggests that the main problem of leaving children in the care of robots on a regular basis is the risk of their stunted, unhealthy emotional development. In Alone Together, Turkle asks: What are we saying to children about their importance to us when we're willing to outsource their care to a robot? A child might be superficially entertained by the robot while her self-esteem is systematically undermined.
Two of the most vocal critics of robot nannies are researchers at the University of Sheffield in the U.K., Noel and Amanda Sharkey. In an article published in the journal Interaction Studies, they claim that the overuse of childcare robots could have serious consequences for the psychological and emotional wellbeing of children.
They acknowledge that limited use of robots can have positive effects like keeping a child safe from physical harm, allowing remote monitoring and supervision by parents, keeping a child entertained, and stimulating an interest in science and engineering. But the Sharkeys see the overuse of robots as a source of emotional alienation between parents and children. Just regularly plopping a child down with a robot for hours of interaction could be a form of neglect that panders to busy parents at the cost of a child's emotional development.
Robots, the Sharkeys argue, prey upon a child's natural tendency to anthropomorphize, which sucks them into a pseudo-relationship with a machine that can never return their affection. This can be seen as a form of emotional exploitation—a machine that promises connection but can never truly deliver. Furthermore, as robots develop more intimate skills such as bathing, feeding and changing diapers, children will lose out on some of the most fundamental and precious bonding activities with their parents.
Critics say that children's natural ability to bond is prime territory for exploitation by toy and robot manufacturers, who ultimately have a commercial agenda. The Sharkeys noted one study in which a state-of-the-art robot was employed in a daycare center. The ten- to 20-month-old children bonded more deeply with the robot than with a teddy bear. It's not hard to see that starting the robot-bonding process early in life is good for robot business, as babies and toddlers graduate to increasingly sophisticated machines.
"It is possible that exclusive or near exclusive care of a child by a robot could result in cognitive and linguistic impairments," say the Sharkeys. They cite the danger of a child developing what is called in psychology a pathological attachment disorder. Attachment disorders occur when parents are unpredictable or neglectful in their emotional responsiveness. The resulting shaky bond interferes with a child's ability to feel trust, pleasure, safety, and comfort in the presence of the parent. Unhealthy patterns of attachment include "insecure attachment," a form of anxiety that arises when a child cannot trust his caregiver with meeting his emotional needs. Children with attachment disorders may anxiously avoid attachments and may not be able to experience empathy, the cornerstone of relationships. Such patterns can follow a child throughout life and infect every other relationship they have.
An example of the inadequacy of robot nannies rests on the pre-programmed emotional responses they have in their repertoires. They're designed to detect and mirror a child's emotions and do things like play a child's favorite song when he's crying or in distress. But such a response could be the height of insensitivity. It discounts and belittles what may be a child's authentic response to an upsetting turn of events, like a scraped knee from a fall. A robot playing a catchy jingle is a far cry from having Mom clean and dress the wound, and perhaps more importantly, kiss it and make it better.
Most experts acknowledge that robots can be valuable educational tools. But they can't make a child feel truly loved, validated, and valued. That's the job of parents, and when parents abdicate this responsibility, it's not only the child that misses out on one of life's most profound experiences.
So consider buying a robot to entertain and educate your little one—just make sure you're close by for the true bonding opportunities that arrive so fast and last so fleetingly in the life of a child.
The Top 8 Things to Know About Anti-Aging Research Right Now
Dr. Michael West has a storied legacy in the world of aging research. Twenty years ago, the company he started, Geron, hit upon a major breakthrough when his scientists isolated the active component for the gene that confers immortality to cells, called telomerase.
In the twenty years since, a new field has emerged: the science of extending the human "healthspan."
He was in the lab when scientists for the first time artificially turned on the gene in some skin cells donated by Dr. Leonard Hayflick, the man who had discovered back in 1965 that human cells age over time. Sure enough, with Geron's intervention, Hayflick's skin cells became immortal in the dish, and the landmark paper was published in Science in 1998.
In the twenty years since, a new field has emerged: the science of extending the human "healthspan" – the length of time people can live free of diseases related to aging. A substantial amount of preclinical and some clinical research is now underway, backed by heavy investments from some of the world's largest companies.
Today, Dr. West is the CEO of AgeX Therapeutics, a biotech company that is developing novel therapeutics to target human aging and age-related degenerative diseases using pluripotent stem cells. Dr. West recently shared some key insights with Editor-in-Chief Kira Peikoff about what's happening in this exciting space.
1) Pluripotent stem cells have opened the door for the first time in human history to manufacturing young cells and young tissue of any kind.
These are the body's master cells: They are self-replicating, and they can potentially give rise to any cell or tissue the body needs to repair itself. This year marks the 20th anniversary since their isolation for the first time in a lab.
"People in biotech say that the time from lab to discovery in products is about 20 years," West says. "But the good news is we're at that 20-year mark now, so you're seeing an explosive growth of applications. We can now make all cell types of the human body in a scalable manner."
2) Early human development could hold the key to unlocking the mystery of aging.
West believes that two things occur when the body forms in utero: telomerase, the immortalizing gene, gets turned off very early in development in the body cells like skin, liver, and nerves. Additionally, he thinks that a second genetic switch gets turned off that holds the potential for regeneration after injury.
"These insights open the door to intervention by the transfer of telomerase into the cells of the body."
"Very early when the body is first forming, if you cut the skin, it will not respond by scarring, but will regenerate scarlessly," he says. "But that potential gets turned off once the body is formed, about 8 weeks after fertilization. Then, you accumulate damage over a lifetime. Not only do cells have a finite capacity to replicate, but you have tissue damage."
However, there are animals in nature whose telomerase is never turned off, or whose regenerative ability is never turned off. The flatworm, for example, can regenerate its own head if it gets cut off, and it also shows no detectable aging. Lobsters are believed to be similar. (That's not to say it can't get caught and eaten for dinner.)
"These insights open the door to intervention by the transfer of telomerase into the cells of the body, or understanding how regeneration gets turned off, and then turning it back on," West says. "That's well within the power of modern medical research to understand."
3) Companies are investing tremendous resources into the anti-aging gold rush.
Devising interventions is the mission of AgeX, a subsidiary of BioTime, as well as a number of other companies.
"We're seeing a mad rush," West says. There's Google's Calico, which recently announced, with AbbVie Inc., another $1 billion into research for age-related diseases, on top of the previous $1.5 billion investment.
Other notable players include Unity Biotechnology, Samumed, Human Longevity Inc., RestorBio, Rejuvenate Bio,and Juvenescence (which is also an investor in AgeX).
"These are products in development by our company and others that the baby boomers can reasonably anticipate being available within their lifetimes."
4) The majority of clinical applications are still years away.
"What we've learned about turning back on this regenerative state, called induced tissue regeneration, is that the majority of the clinical implications are years away and will require years of clinical trials before potential FDA approval and marketing to the public," West says. "But we have found some potential near-term applications that we think may have a much faster track to commercialization. As you can imagine, we are all over those."
BioTime, Inc., AgeX's parent, has a regenerative medicine product in clinical trials for age-related macular degeneration, the leading cause of blindness in an aging population. While not yet approved by the FDA, BioTime has reported continued progress in the clinical development of the product now in Phase II trials.
Dr. Michael West, CEO of AgeX
Citi recently issued a major report, Disruptive Innovations VI, that included "Anti-Aging Medicines" as the number two innovation for investors to keep an eye on, and predicted that the first anti-aging therapies could receive regulatory approval by 2023.
5) Few, if any, medical interventions are available today that are proven to markedly slow aging - yet. But the Baby Boomers are not necessarily out of luck.
Buyer beware of any claims in the marketplace that a given skin cream or stem cell product will extend your life. More than likely, they won't.
"There are a lot of people trying to cash in on the aging baby boom population," West warns.
"When you hear claims of stem cell products that you can get now, it's important to understand that they are likely not based on pluripotent stem cell technology. Also, they are usually not products approved by the FDA, having gone through clinical trials to demonstrate safety and efficacy."
However, an array of young pluripotent stem cell-derived therapies are on a development track for future approvals.
One example is another program at AgeX: the manufacture of brown fat cells; these cells burn calories rather than store them. They burn circulating fat like triglycerides and sugar in the blood and generate heat.
"You lose brown fat in aging, and animal models suggest that if you restore that tissue, you can restore a metabolic balance to be more like what you had when you were young," says West. "When I was 18, I could drink milkshakes all day long and not gain an ounce. But at 50 or 60, most of us would rapidly put on weight. Why? We believe that one important factor is that with age, you lose this brown fat tissue. The loss throws your metabolism off balance. So the solution is conceptually simple, we plan to make young brown fat cells for transplantation to reset the balance, potentially to treat Type II diabetes or even obesity.
"These are products in development by our company and others that the baby boomers can reasonably anticipate being available within their lifetimes."
6) There is an ethical debate about how far to apply this new science.
Some people are speculating about whether genetic engineering might one day be used to program longer lifespans into humans at the earliest stages of development. (Note: it is against the law across the Western world to edit human embryos intended for reproduction, although just last week, Chinese scientists used CRISPR to repair a disease-causing mutation in viable human embryos.)
West sounds a cautionary note about such interventions meant to lengthen life. "For people who think not just about the science, but the ethics, safety is a major concern. It's entirely possible to genetically engineer babies, but when you make such modifications, it's an experiment, not just in human cells in a dish, but in a human being. I have a great reticence to put any human at risk unless it's a case where the person is suffering with a life-threatening disease, and the potential therapy is their last best hope."
"I have no doubt, zero doubt, that in the foreseeable future, we'll hear of a person who has lived to about 150."
7) The biggest challenge of intervening in human aging is cultural denial.
"The prospect of intervening in a profound way in human aging is still not seen as credible by the vast majority of thoughtful people around the world," West laments.
"Aging is a universal phenomenon, it's mankind's greatest enemy, but as a species we've adapted to the realities of finite lifespans and death. We have a whole infrastructure of belief systems around this, and many people see it as inevitable."
8) The lifespan for healthy children born today could surpass anything humanity has ever seen.
"It is at least 150 years of age," West predicts. "I have no doubt, zero doubt, that in the foreseeable future, we'll hear of a person who has lived to about 150. We know now it's possible. I've never said that publicly before, but I am comfortable now with the prediction. And, of course, if some people now living could live to 150 years of age, we have the prospect of them living to see even more powerful therapies. So, the question now is, what kind of a world are we going to make for future generations?"
[Editor's Note: Check out our latest video, which was inspired by Dr. West's exclusive prediction to leapsmag.]
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.