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."
Clever Firm Predicts Patients Most at Risk, Then Tries to Intervene Before They Get Sicker
Health firm Populytics tracks and analyzes patient data, and makes care suggestions based on that data.
The diabetic patient hit the danger zone.
Ideally, blood sugar, measured by an A1C test, rests at 5.9 or less. A 7 is elevated, according to the Diabetes Council. Over 10, and you're into the extreme danger zone, at risk of every diabetic crisis from kidney failure to blindness.
In three months of working with a case manager, Jen's blood sugar had dropped to 7.2, a much safer range.
This patient's A1C was 10. Let's call her Jen for the sake of this story. (Although the facts of her case are real, the patient's actual name wasn't released due to privacy laws.).
Jen happens to live in Pennsylvania's Lehigh Valley, home of the nonprofit Lehigh Valley Health Network, which has eight hospital campuses and various clinics and other services. This network has invested more than $1 billion in IT infrastructure and founded Populytics, a spin-off firm that tracks and analyzes patient data, and makes care suggestions based on that data.
When Jen left the doctor's office, the Populytics data machine started churning, analyzing her data compared to a wealth of information about future likely hospital visits if she did not comply with recommendations, as well as the potential positive impacts of outreach and early intervention.
About a month after Jen received the dangerous blood test results, a community outreach specialist with psychological training called her. She was on a list generated by Populytics of follow-up patients to contact.
"It's a very gentle conversation," says Cathryn Kelly, who manages a care coordination team at Populytics. "The case manager provides them understanding and support and coaching." The goal, in this case, was small behavioral changes that would actually stick, like dietary ones.
In three months of working with a case manager, Jen's blood sugar had dropped to 7.2, a much safer range. The odds of her cycling back to the hospital ER or veering into kidney failure, or worse, had dropped significantly.
While the health network is extremely localized to one area of one state, using data to inform precise medical decision-making appears to be the wave of the future, says Ann Mongovern, the associate director of Health Care Ethics at the Markkula Center for Applied Ethics at Santa Clara University in California.
"Many hospitals and hospital systems don't yet try to do this at all, which is striking given where we're at in terms of our general technical ability in this society," Mongovern says.
How It Happened
While many hospitals make money by filling beds, the Lehigh Valley Health Network, as a nonprofit, accepts many patients on Medicaid and other government insurances that don't cover some of the costs of a hospitalization. The area's population is both poorer and older than national averages, according to the U.S. Census data, meaning more people with higher medical needs that may not have the support to care for themselves. They end up in the ER, or worse, again and again.
In the early 2000s, LVHN CEO Dr. Brian Nester started wondering if his health network could develop a way to predict who is most likely to land themselves a pricey ICU stay -- and offer support before those people end up needing serious care.
Embracing data use in such specific ways also brings up issues of data security and patient safety.
"There was an early understanding, even if you go back to the (federal) balanced budget act of 1997, that we were just kicking the can down the road to having a functional financial model to deliver healthcare to everyone with a reasonable price," Nester says. "We've got a lot of people living longer without more of an investment in the healthcare trust."
Popultyics, founded in 2013, was the result of years of planning and agonizing over those population numbers and cost concerns.
"We looked at our own health plan," Nester says. Out of all the employees and dependants on the LVHN's own insurance network, "roughly 1.5 percent of our 25,000 people — under 400 people — drove $30 million of our $130 million on insurance costs -- about 25 percent."
"You don't have to boil the ocean to take cost out of the system," he says. "You just have to focus on that 1.5%."
Take Jen, the diabetic patient. High blood sugar can lead to kidney failure, which can mean weekly expensive dialysis for 20 years. Investing in the data and staff to reach patients, he says, is "pennies compared to $100 bills."
For most doctors, "there's no awareness for providers to know who they should be seeing vs. who they are seeing. There's no incentive, because the incentive is to see as many patients as you can," he says.
To change that, first the LVHN invested in the popular medical management system, Epic. Then, they negotiated with the top 18 insurance companies that cover patients in the region to allow access to their patient care data, which means they have reams of patient history to feed the analytics machine in order to make predictions about outcomes. Nester admits not every hospital could do that -- with 52 percent of the market share, LVHN had a very strong negotiating position.
Third party services take that data and churn out analytics that feeds models and care management plans. All identifying information is stripped from the data.
"We can do predictive modeling in patients," says Populytics President and CEO Gregory Kile. "We can identify care gaps. Those care gaps are noted as alerts when the patient presents at the office."
Kile uses himself as a hypothetical patient.
"I pull up Gregory Kile, and boom, I see a flag or an alert. I see he hasn't been in for his last blood test. There is a care gap there we need to complete."
"There's just so much more you can do with that information," he says, envisioning a future where follow-up for, say, knee replacement surgery and outcomes could be tracked, and either validated or changed.
Ethical Issues at the Forefront
Of course, embracing data use in such specific ways also brings up issues of security and patient safety. For example, says medical ethicist Mongovern, there are many touchpoints where breaches could occur. The public has a growing awareness of how data used to personalize their experiences, such as social media analytics, can also be monetized and sold in ways that benefit a company, but not the user. That's not to say data supporting medical decisions is a bad thing, she says, just one with potential for public distrust if not handled thoughtfully.
"You're going to need to do this to stay competitive," she says. "But there's obviously big challenges, not the least of which is patient trust."
So far, a majority of the patients targeted – 62 percent -- appear to embrace the effort.
Among the ways the LVHN uses the data is monthly reports they call registries, which include patients who have just come in contact with the health network, either through the hospital or a doctor that works with them. The community outreach team members at Populytics take the names from the list, pull their records, and start calling. So far, a majority of the patients targeted – 62 percent -- appear to embrace the effort.
Says Nester: "Most of these are vulnerable people who are thrilled to have someone care about them. So they engage, and when a person engages in their care, they take their insulin shots. It's not rocket science. The rocket science is in identifying who the people are — the delivery of care is easy."
In The Fake News Era, Are We Too Gullible? No, Says Cognitive Scientist
Cognitive scientist Hugo Mercier says the real challenge is not fighting fake news, but figuring out "how to make it easier for people who say correct things to convince people."
One of the oddest political hoaxes of recent times was Pizzagate, in which conspiracy theorists claimed that Hillary Clinton and her 2016 campaign chief ran a child sex ring from the basement of a Washington, DC, pizzeria.
To fight disinformation more effectively, he suggests, humans need to stop believing in one thing above all: our own gullibility.
Millions of believers spread the rumor on social media, abetted by Russian bots; one outraged netizen stormed the restaurant with an assault rifle and shot open what he took to be the dungeon door. (It actually led to a computer closet.) Pundits cited the imbroglio as evidence that Americans had lost the ability to tell fake news from the real thing, putting our democracy in peril.
Such fears, however, are nothing new. "For most of history, the concept of widespread credulity has been fundamental to our understanding of society," observes Hugo Mercier in Not Born Yesterday: The Science of Who We Trust and What We Believe (Princeton University Press, 2020). In the fourth century BCE, he points out, the historian Thucydides blamed Athens' defeat by Sparta on a demagogue who hoodwinked the public into supporting idiotic military strategies; Plato extended that argument to condemn democracy itself. Today, atheists and fundamentalists decry one another's gullibility, as do climate-change accepters and deniers. Leftists bemoan the masses' blind acceptance of the "dominant ideology," while conservatives accuse those who do revolt of being duped by cunning agitators.
What's changed, all sides agree, is the speed at which bamboozlement can propagate. In the digital age, it seems, a sucker is born every nanosecond.
The Case Against Credulity
Yet Mercier, a cognitive scientist at the Jean Nicod Institute in Paris, thinks we've got the problem backward. To fight disinformation more effectively, he suggests, humans need to stop believing in one thing above all: our own gullibility. "We don't credulously accept whatever we're told—even when those views are supported by the majority of the population, or by prestigious, charismatic individuals," he writes. "On the contrary, we are skilled at figuring out who to trust and what to believe, and, if anything, we're too hard rather than too easy to influence."
He bases those contentions on a growing body of research in neuropsychiatry, evolutionary psychology, and other fields. Humans, Mercier argues, are hardwired to balance openness with vigilance when assessing communicated information. To gauge a statement's accuracy, we instinctively test it from many angles, including: Does it jibe with what I already believe? Does the speaker share my interests? Has she demonstrated competence in this area? What's her reputation for trustworthiness? And, with more complex assertions: Does the argument make sense?
This process, Mercier says, enables us to learn much more from one another than do other animals, and to communicate in a far more complex way—key to our unparalleled adaptability. But it doesn't always save us from trusting liars or embracing demonstrably false beliefs. To better understand why, leapsmag spoke with the author.
How did you come to write Not Born Yesterday?
In 2010, I collaborated with the cognitive scientist Dan Sperber and some other colleagues on a paper called "Epistemic Vigilance," which laid out the argument that evolutionarily, it would make no sense for humans to be gullible. If you can be easily manipulated and influenced, you're going to be in major trouble. But as I talked to people, I kept encountering resistance. They'd tell me, "No, no, people are influenced by advertising, by political campaigns, by religious leaders." I started doing more research to see if I was wrong, and eventually I had enough to write a book.
With all the talk about "fake news" these days, the topic has gotten a lot more timely.
Yes. But on the whole, I'm skeptical that fake news matters very much. And all the energy we spend fighting it is energy not spent on other pursuits that may be better ways of improving our informational environment. The real challenge, I think, is not how to shut up people who say stupid things on the internet, but how to make it easier for people who say correct things to convince people.
"History shows that the audience's state of mind and material conditions matter more than the leader's powers of persuasion."
You start the book with an anecdote about your encounter with a con artist several years ago, who scammed you out of 20 euros. Why did you choose that anecdote?
Although I'm arguing that people aren't generally gullible, I'm not saying we're completely impervious to attempts at tricking us. It's just that we're much better than we think at resisting manipulation. And while there's a risk of trusting someone who doesn't deserve to be trusted, there's also a risk of not trusting someone who could have been trusted. You miss out on someone who could help you, or from whom you might have learned something—including figuring out who to trust.
You argue that in humans, vigilance and open-mindedness evolved hand-in-hand, leading to a set of cognitive mechanisms you call "open vigilance."
There's a common view that people start from a state of being gullible and easy to influence, and get better at rejecting information as they become smarter and more sophisticated. But that's not what really happens. It's much harder to get apes than humans to do anything they don't want to do, for example. And research suggests that over evolutionary time, the better our species became at telling what we should and shouldn't listen to, the more open to influence we became. Even small children have ways to evaluate what people tell them.
The most basic is what I call "plausibility checking": if you tell them you're 200 years old, they're going to find that highly suspicious. Kids pay attention to competence; if someone is an expert in the relevant field, they'll trust her more. They're likelier to trust someone who's nice to them. My colleagues and I have found that by age 2 ½, children can distinguish between very strong and very weak arguments. Obviously, these skills keep developing throughout your life.
But you've found that even the most forceful leaders—and their propaganda machines—have a hard time changing people's minds.
Throughout history, there's been this fear of demagogues leading whole countries into terrible decisions. In reality, these leaders are mostly good at feeling the crowd and figuring out what people want to hear. They're not really influencing [the masses]; they're surfing on pre-existing public opinion. We know from a recent study, for instance, that if you match cities in which Hitler gave campaign speeches in the late '20s through early '30s with similar cities in which he didn't give campaign speeches, there was no difference in vote share for the Nazis. Nazi propaganda managed to make Germans who were already anti-Semitic more likely to express their anti-Semitism or act on it. But Germans who were not already anti-Semitic were completely inured to the propaganda.
So why, in totalitarian regimes, do people seem so devoted to the ruler?
It's not a very complex psychology. In these regimes, the slightest show of discontent can be punished by death, or by you and your whole family being sent to a labor camp. That doesn't mean propaganda has no effect, but you can explain people's obedience without it.
What about cult leaders and religious extremists? Their followers seem willing to believe anything.
Prophets and preachers can inspire the kind of fervor that leads people to suicidal acts or doomed crusades. But history shows that the audience's state of mind and material conditions matter more than the leader's powers of persuasion. Only when people are ready for extreme actions can a charismatic figure provide the spark that lights the fire.
Once a religion becomes ubiquitous, the limits of its persuasive powers become clear. Every anthropologist knows that in societies that are nominally dominated by orthodox belief systems—whether Christian or Muslim or anything else—most people share a view of God, or the spirit, that's closer to what you find in societies that lack such religions. In the Middle Ages, for instance, you have records of priests complaining of how unruly the people are—how they spend the whole Mass chatting or gossiping, or go on pilgrimages mostly because of all the prostitutes and wine-drinking. They continue pagan practices. They resist attempts to make them pay tithes. It's very far from our image of how much people really bought the dominant religion.
"The mainstream media is extremely reliable. The scientific consensus is extremely reliable."
And what about all those wild rumors and conspiracy theories on social media? Don't those demonstrate widespread gullibility?
I think not, for two reasons. One is that most of these false beliefs tend to be held in a way that's not very deep. People may say Pizzagate is true, yet that belief doesn't really interact with the rest of their cognition or their behavior. If you really believe that children are being abused, then trying to free them is the moral and rational thing to do. But the only person who did that was the guy who took his assault weapon to the pizzeria. Most people just left one-star reviews of the restaurant.
The other reason is that most of these beliefs actually play some useful role for people. Before any ethnic massacre, for example, rumors circulate about atrocities having been committed by the targeted minority. But those beliefs aren't what's really driving the phenomenon. In the horrendous pogrom of Kishinev, Moldova, 100 years ago, you had these stories of blood libel—a child disappeared, typical stuff. And then what did the Christian inhabitants do? They raped the [Jewish] women, they pillaged the wine stores, they stole everything they could. They clearly wanted to get that stuff, and they made up something to justify it.
Where do skeptics like climate-change deniers and anti-vaxxers fit into the picture?
Most people in most countries accept that vaccination is good and that climate change is real and man-made. These ideas are deeply counter-intuitive, so the fact that scientists were able to get them across is quite fascinating. But the environment in which we live is vastly different from the one in which we evolved. There's a lot more information, which makes it harder to figure out who we can trust. The main effect is that we don't trust enough; we don't accept enough information. We also rely on shortcuts and heuristics—coarse cues of trustworthiness. There are people who abuse these cues. They may have a PhD or an MD, and they use those credentials to help them spread messages that are not true and not good. Mostly, they're affirming what people want to believe, but they may also be changing minds at the margins.
How can we improve people's ability to resist that kind of exploitation?
I wish I could tell you! That's literally my next project. Generally speaking, though, my advice is very vanilla. The mainstream media is extremely reliable. The scientific consensus is extremely reliable. If you trust those sources, you'll go wrong in a very few cases, but on the whole, they'll probably give you good results. Yet a lot of the problems that we attribute to people being stupid and irrational are not entirely their fault. If governments were less corrupt, if the pharmaceutical companies were irreproachable, these problems might not go away—but they would certainly be minimized.