Scientists Are Devising Clever Solutions to Feed Astronauts on Mars Space Flights
Astronaut and Expedition 64 Flight Engineer Soichi Noguchi of the Japan Aerospace Exploration Agency displays Extra Dwarf Pak Choi plants growing aboard the International Space Station. The plants were grown for the Veggie study which is exploring space agriculture as a way to sustain astronauts on future missions to the Moon or Mars.
Astronauts at the International Space Station today depend on pre-packaged, freeze-dried food, plus some fresh produce thanks to regular resupply missions. This supply chain, however, will not be available on trips further out, such as the moon or Mars. So what are astronauts on long missions going to eat?
Going by the options available now, says Christel Paille, an engineer at the European Space Agency, a lunar expedition is likely to have only dehydrated foods. “So no more fresh product, and a limited amount of already hydrated product in cans.”
For the Mars mission, the situation is a bit more complex, she says. Prepackaged food could still constitute most of their food, “but combined with [on site] production of certain food products…to get them fresh.” A Mars mission isn’t right around the corner, but scientists are currently working on solutions for how to feed those astronauts. A number of boundary-pushing efforts are now underway.
The logistics of growing plants in space, of course, are very different from Earth. There is no gravity, sunlight, or atmosphere. High levels of ionizing radiation stunt plant growth. Plus, plants take up a lot of space, something that is, ironically, at a premium up there. These and special nutritional requirements of spacefarers have given scientists some specific and challenging problems.
To study fresh food production systems, NASA runs the Vegetable Production System (Veggie) on the ISS. Deployed in 2014, Veggie has been growing salad-type plants on “plant pillows” filled with growth media, including a special clay and controlled-release fertilizer, and a passive wicking watering system. They have had some success growing leafy greens and even flowers.
"Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources."
A larger farming facility run by NASA on the ISS is the Advanced Plant Habitat to study how plants grow in space. This fully-automated, closed-loop system has an environmentally controlled growth chamber and is equipped with sensors that relay real-time information about temperature, oxygen content, and moisture levels back to the ground team at Kennedy Space Center in Florida. In December 2020, the ISS crew feasted on radishes grown in the APH.
“But salad doesn’t give you any calories,” says Erik Seedhouse, a researcher at the Applied Aviation Sciences Department at Embry-Riddle Aeronautical University in Florida. “It gives you some minerals, but it doesn’t give you a lot of carbohydrates.” Seedhouse also noted in his 2020 book Life Support Systems for Humans in Space: “Integrating the growing of plants into a life support system is a fiendishly difficult enterprise.” As a case point, he referred to the ESA’s Micro-Ecological Life Support System Alternative (MELiSSA) program that has been running since 1989 to integrate growing of plants in a closed life support system such as a spacecraft.
Paille, one of the scientists running MELiSSA, says that the system aims to recycle the metabolic waste produced by crew members back into the metabolic resources required by them: “The aim is…to come [up with] a closed, sustainable system which does not [need] any logistics resupply.” MELiSSA uses microorganisms to process human excretions in order to harvest carbon dioxide and nitrate to grow plants. “Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources,” Paille adds.
Microorganisms play a big role as “fuel” in food production in extreme places, including in space. Last year, researchers discovered Methylobacterium strains on the ISS, including some never-seen-before species. Kasthuri Venkateswaran of NASA’s Jet Propulsion Laboratory, one of the researchers involved in the study, says, “[The] isolation of novel microbes that help to promote the plant growth under stressful conditions is very essential… Certain bacteria can decompose complex matter into a simple nutrient [that] the plants can absorb.” These microbes, which have already adapted to space conditions—such as the absence of gravity and increased radiation—boost various plant growth processes and help withstand the harsh physical environment.
MELiSSA, says Paille, has demonstrated that it is possible to grow plants in space. “This is important information because…we didn’t know whether the space environment was affecting the biological cycle of the plant…[and of] cyanobacteria.” With the scientific and engineering aspects of a closed, self-sustaining life support system becoming clearer, she says, the next stage is to find out if it works in space. They plan to run tests recycling human urine into useful components, including those that promote plant growth.
The MELiSSA pilot plant uses rats currently, and needs to be translated for human subjects for further studies. “Demonstrating the process and well-being of a rat in terms of providing water, sufficient oxygen, and recycling sufficient carbon dioxide, in a non-stressful manner, is one thing,” Paille says, “but then, having a human in the loop [means] you also need to integrate user interfaces from the operational point of view.”
Growing food in space comes with an additional caveat that underscores its high stakes. Barbara Demmig-Adams from the Department of Ecology and Evolutionary Biology at the University of Colorado Boulder explains, “There are conditions that actually will hurt your health more than just living here on earth. And so the need for nutritious food and micronutrients is even greater for an astronaut than for [you and] me.”
Demmig-Adams, who has worked on increasing the nutritional quality of plants for long-duration spaceflight missions, also adds that there is no need to reinvent the wheel. Her work has focused on duckweed, a rather unappealingly named aquatic plant. “It is 100 percent edible, grows very fast, it’s very small, and like some other floating aquatic plants, also produces a lot of protein,” she says. “And here on Earth, studies have shown that the amount of protein you get from the same area of these floating aquatic plants is 20 times higher compared to soybeans.”
Aquatic plants also tend to grow well in microgravity: “Plants that float on water, they don’t respond to gravity, they just hug the water film… They don’t need to know what’s up and what’s down.” On top of that, she adds, “They also produce higher concentrations of really important micronutrients, antioxidants that humans need, especially under space radiation.” In fact, duckweed, when subjected to high amounts of radiation, makes nutrients called carotenoids that are crucial for fighting radiation damage. “We’ve looked at dozens and dozens of plants, and the duckweed makes more of this radiation fighter…than anything I’ve seen before.”
Despite all the scientific advances and promising leads, no one really knows what the conditions so far out in space will be and what new challenges they will bring. As Paille says, “There are known unknowns and unknown unknowns.”
One definite “known” for astronauts is that growing their food is the ideal scenario for space travel in the long term since “[taking] all your food along with you, for best part of two years, that’s a lot of space and a lot of weight,” as Seedhouse says. That said, once they land on Mars, they’d have to think about what to eat all over again. “Then you probably want to start building a greenhouse and growing food there [as well],” he adds.
And that is a whole different challenge altogether.
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."
An Investigational Drug Offers Hope to Patients with a Disabling Neuromuscular Disease
Robert Thomas was a devoted runner, gym goer, and crew member on a sailing team in San Diego when, in his 40s, he noticed that his range of movement was becoming more limited.
He thought he was just getting older, but when he was hiking an uphill trail in Lake Tahoe, he kept tripping over rocks. "I'd never had this happen before," Robert says. "I knew something was wrong but didn't know what it was."
It wasn't until age 50 when he was diagnosed with Charcot-Marie-Tooth disease. The genetic disorder damages the peripheral nerves, which connect the brain and spinal cord to the rest of the body. This network of nerves is responsible for relaying information and signals about sensation, movement, and motor coordination. Over time, the disease causes debilitating muscle weakness and the loss of limb control.
Charcot-Marie-Tooth usually presents itself in childhood or in a person's teens, but in some patients, like Robert, onset can be later in life. Symptoms may include muscle cramping, tingling, or burning. Many patients also have high foot arches or hammer toes — toes that curl from the middle joint instead of pointing forward. Those affected often have difficulty walking and may lose sensation in their lower legs, feet, hands, or forearms. One of the most common rare diseases, it affects around 130,000 people in the United States and 2.8 million worldwide.
Like many people with Charcot-Marie-Tooth, or CMT, Robert wears corrective braces on his legs to help with walking. Now 61, he can't run or sail anymore because of the disease, but he still works out regularly and can hike occasionally. CMT also affects his grip, so he has to use special straps while doing some exercises.
For the past few years, Robert has been participating in a clinical trial for an investigational CMT drug. He takes the liquid formulation every morning and evening using an oral syringe. Scientists are following patients like Robert to learn if their symptoms stabilize or improve while on the drug. Dubbed PXT300, the drug was designed by French biopharmaceutical company Pharnext and is the farthest along in development for CMT. If approved, it would be the first drug for the disease.
Currently, there's no cure for CMT, only supportive treatments like pain medication. Some individuals receive physical and occupational therapy. A drug for CMT could be a game-changer for patients whose quality of life is severely affected by the disease.
Genetic Underpinnings
CMT arises from mutations in genes that are responsible for creating and maintaining the myelin sheath — the insulating layer around nerves. Pharnext's drug is meant to treat patients with CMT1A, the most common form of the disease, which represents about half of CMT cases. Around 5% of those with CMT1A become severely disabled and end up in wheelchairs. People with CMT1A have an extra copy of the gene PMP22, which makes a protein that's needed to maintain the myelin sheath around peripheral nerves.
Typically, an individual inherits one copy of PMP22 from each parent. But a person with CMT1A receives a copy of PMP22 from one parent and two copies from a parent with the disease. This extra copy of the gene results in excess protein production, which damages the cells responsible for preserving and regenerating the myelin sheath, called Schwann cells.
The myelin sheath helps ensure that a signal from the brain gets carried to nerves in the muscles so that a part of the body can carry out a particular action or movement. This sheath is like the insulation on an electrical cord and the action is like a light bulb. If the insulation is fine, the light bulb turns on. But if the insulation is frayed, the light will flicker.
"The same happens to these patients," says David Horn Solomon, CEO of Pharnext. "The signal to their muscle is weak and flickers." Over time, their muscles become weaker and thinner.
The PMP22 gene has proven difficult to target with a drug because it's located in a protected space — the Schwann cells that make up the insulation around nerves. "There's not an easy way to tamp it down," Solomon says.
Another company, Acceleron Pharma of Cambridge, Massachusetts, was developing an injectable CMT drug meant to increase the strength of leg muscles. But the company halted development last year after the experimental drug failed in a mid-stage trial. While the drug led to a statistically significant increase in muscle volume, it didn't translate to improvements in muscle function or quality of life for trial participants.
Made by Design
Pharnext's drug, PXT3003, is a combination of three existing drugs — baclofen, a muscle relaxant; naltrexone, a drug that decreases the desire for alcohol and opioids; and sorbitol, a type of sugar alcohol.
The company designed the drug using its artificial intelligence platform, which screened 20,000 existing drugs to predict combinations that could inhibit the PMP22 gene and thereby lower protein production. The AI system narrowed the search to several hundreds of combinations and Pharnext tested around 75 of them in the lab before landing on baclofen, naltrexone, and sorbitol. Individually, the drugs don't have much effect on the PMP22 gene. But combined, they work to lower how much protein the gene makes.
"How the drug inside the cell reduces expression isn't quite clear yet," says Florian Thomas, director of the Hereditary Neuropathy Center, and founding chair and professor in the department of neurology at Hackensack University Medical Center and Hackensack Meridian School of Medicine in New Jersey (no relation to Robert Thomas, the CMT patient). "By reducing the amount of protein being produced, we hopefully can stabilize the nerves."
In rodents genetically engineered to have the PMP22 gene, the drug reduced protein levels and delayed onset of muscle weakness when given to rats. In another animal study, the drug increased the size of the myelin sheath around nerves in rats.
"Like humans with CMT, one of the problems the animals have is they can't grip things, their grip strength is poor," Solomon says. But when treated with Pharnext's drug, "the grip strength of these animals improves dramatically even over 12 weeks."
Human trials look encouraging, too. But the company ran into a manufacturing issue during a late-stage trial. The drug requires refrigeration, and as a result of temperature changes, crystals formed inside vials containing the high dose of the drug. The study was a double-blind trial, meaning neither the trial participants nor investigators were supposed to know who received the high dose of the drug, who received the low dose, and who received a placebo. In these types of studies, the placebo and experimental drug should look the same so that investigators can't tell them apart. But because only the high dose contained crystals, not the low dose or placebo, regulators said the trial data could be biased.
Pharnext is now conducting a new randomized, double-blind trial to prove that its drug works. The study is recruiting individuals aged 16 through 65 years old with mild to moderate CMT. The company hopes to show that the drug can stop patients' symptoms from worsening, or in the best case scenario, possibly even improve them. The company doesn't think the drug will be able to help people with severe forms of the disease.
"In neurologic disease, you're looking for plasticity, where there's still the possibility of stabilization or reversal," Solomon says. Plasticity refers to the ability of the nervous system to change and adapt in response to stimuli.
Preventing Disability
Allison Moore, a CMT patient and founder and CEO of the Hereditary Neuropathy Foundation, has been following drug development for CMT since she founded the organization in 2001. She says many investigational drugs haven't moved forward because they've shown little success in animals. The fact that Pharnext's drug has made it to a late-stage human trial is promising, she says.
"It's really exciting," Moore says. "There's a chance that if you take the drug early before you're very severe, you'll end up not developing the disease to a level that's super disabling."
CMT has damaged Moore's peroneal nerve, a main nerve in the foot. As a result, she has foot drop, the inability to lift the front part of her foot, and needs to wear leg braces to help her walk. "The idea that you could take this early on and that it could stop progression, that's the hope that we have."
Thomas, the neurologist, says a drug doesn't have to be a cure to have a significant impact on patients. "If I have a CMT patient who's 50 years old, that patient will be more disabled by age 60," he says. "If I can treat that person with a drug, and that person is just as disabled at age 60 as they were at age 50, that's transformative in my mind."
While Robert Thomas says he hasn't noticed a dramatic improvement since he's been on the drug, he does think it's helping. Robert is now in an open-label study, which means he and his health provider are aware that he's receiving the drug.
When the COVID-19 pandemic hit, manufacturing and supply chain disruptions meant that Robert was without the trial drug for two months. When his medication ran out, his legs felt unstable again and walking was harder. "There was a clear distinction between being on and off that medication," he says.
Pharnext's current trial will take about a year and a half to complete. After that, the FDA will decide on whether to approve the drug for CMT patients.
As scientists learn more about the PMP22 gene and the more than 100 other genes that when mutated cause CMT, more precise treatments could be possible. For instance, scientists have used the gene-editing tool CRISPR to correct a CMT-causing mutation in human cells in the lab. The results were published August 16 in the journal Frontiers in Cell and Developmental Biology.
Pharnext is also interested in pursuing genetic treatments for CMT, but in the meantime, repurposed drugs may be the best shot at helping patients until more advanced treatments are available.