What Science Says about Age-old Health Adages

Cara Rosenbloom wrote . . . . . . . . .

Questionable nutritional advice is easily amplified in our digital world, but older generations have always passed down health adages that younger generations found difficult to believe.

Did your parents ever encourage you to drink fish oil to boost brain power before an exam, or offer mustard when you had a muscle cramp? My folks believed ginger relieves nausea. I was curious whether these adages and folk remedies could withstand the scrutiny of science — or whether they’re bunk.

So I set out to research a few of them.

An apple a day keeps the doctor away

This well-known statement is based on an 1860s Welsh proverb that eating apples will diminish doctor visits. And it has actually been put to the test — in a 2015 April Fools’ Day issue of JAMA Internal Medicine (while the topics were zany, the studies were real).

Researchers investigated whether people who reported eating apples daily actually had fewer annual doctor visits or were in better overall health.

Of the 8,399 study participants, 753 ate at least one small apple daily. The results showed that 39 per cent of apple eaters avoided physician visits compared to 34 per cent of non-appleeaters, which was not a statistically significant difference. Researchers did find that apple eaters were a bit less likely to require prescription medications compared to non-apple-eaters, leading to the joke that “an apple a day keeps the pharmacist away.”

Of course, the doctor proverb shouldn’t be taken literally, but the overall sentiment is true: eating vegetables and fruits daily does have health benefits. That’s because the combination of fibre, vitamins, minerals and phytonutrients may help reduce inflammation and combat cardiovascular disease and some types of cancer.

Carrots are good for your eyes

This narrative traces back to the Second World War. In 1940, British Royal Air Force pilots began using radar to shoot down enemy planes in the dark. To keep this new technology a secret, the Ministry of Information’s propaganda was that the pilots had great visual accuracy because they ate carrots, which improved their night vision.

It seemed plausible, too, because carrots are rich in the antioxidant beta carotene, the precursor to vitamin A.

Once absorbed by the body, vitamin A helps make rhodopsin, a pigment that helps eyes work better in low light.

Carrots can help if you have vitamin A deficiency that causes poor night vision, but of course they can’t really help you (or fighter pilots) see in complete darkness. So, yes, carrots are good for eyesight, but other foods rich in beta carotene, such as sweet potatoes, squash and leafy green vegetables, have the same benefits.

Turkey makes you tired

We’ve all heard this one after Thanksgiving dinner: “The turkey made you fall asleep!” Turkey contains an amino acid (a building block of protein) known as tryptophan, which the body uses to generate serotonin, which helps promote sleep. So then there must be something to this whole turkey-sleep connection, right?

Not so fast. Turkey contains no more tryptophan than beef, eggs, fish or chicken, and tryptophan has a hard time getting past the blood-brain barrier, so it’s not an effective sleep inducer on its own. But the effect of tryptophan increases when insulin levels are high, as happens after you eat a carb-rich meal — such as a Thanksgiving dinner with stuffing, potatoes and apple pie. So it’s actually carbs that increase serotonin levels and help with the production of the hormone melatonin, which makes you sleepy. Eating a large meal can have a similar effect because there’s increased blood flow to the stomach for digestion, and decreased blood flow to the brain. So it’s definitely not just turkey that makes you sleepy.

Ginger relieves nausea

This remedy has strong roots. More than 5,000 years ago, people from India and China used ginger as a tonic to treat many ailments. The most common and well-established historical use is to alleviate nausea and vomiting. Today, many clinical studies support the use of ginger for exactly this purpose.

Research shows that ginger helps relieve nausea and vomiting caused by motion sickness, morning sickness in pregnancy, during chemotherapy treatments and post-surgically after anesthetic. It’s thought that the constituents in ginger — including gingerols and shogaols — help speed gastric emptying, which relieves nausea. Some people sip ginger tea for relief, while others prefer to take a ginger capsule, and studies show that both options can work. My mom used to open a can of ginger ale when I was queasy. While she was on the right track, it turns out many soda brands use artificial flavouring rather than real ginger, so those are of little benefit.

Fish is good for your brain

In his 1930 short-story collection Very Good Jeeves, British author and humorist P.G. Wodehouse wrote: “They say fish are good for the brain. Have a go at the sardines and come back and report.” Wodehouse was onto something!

In 2016, researchers found weekly consumption of fish was associated with high volume of grey matter, the dark tissue of the brain that’s in charge of processing information and controlling vision and memory. Many people have postulated that the value of fish comes largely from omega-3 fats, which play many important roles in brain health. Yet, interestingly, this study showed that any fish — not just those high in omega-3 fat — had this positive effect. Another review study found that fish intake may help delay cognitive impairment and Alzheimer’s disease, but cast doubt as to whether the omega-3 fats are the reason. That means taking omega-3 fish oil supplements (or drinking cod liver oil) for brain health may not cut it — there’s something about eating a whole fish fillet that’s more beneficial.

Mustard helps with leg cramps

Have you ever been jolted from sleep with a leg cramp, or felt your calf seize after a run? Maybe you were told to take a shot of pickle juice or a teaspoon of yellow mustard. For years, people assumed this worked because the pickles and mustard contain fluids and sodium, which may help ease leg cramps caused by dehydration or an electrolyte imbalance. But research doesn’t confirm this reasoning.

In one study, researchers induced leg cramps in male subjects, then gave them pickle juice or water. The pickle juice made the cramps go away faster, but the effect was not because of restoring body fluids, or the water would have worked just as well. Plus, the researchers found no changes in plasma electrolytes or volume in the five minutes after ingesting the pickle juice. They concluded that the benefit from pickle juice could not be explained by rapid restoration of body fluids or electrolytes.

Now researchers believe the problem is not actually with the muscle itself, but with the motor neurons that send signals to it, which become hyperactive. The researchers hypothesize that strong flavours (as in mustard or pickle juice) stimulate neurons in the mouth and upper GI tract, which in turn restores the normal activity of the motor neurons involved in muscle cramping — sort of like a distraction.

There are no rigorous studies to prove this interesting theory, so drinking pickle juice remains mostly unsubstantiated. But if it works for you, drink up.

Source: Winnipeg Free Press newspaper

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A New Theory of Obesity

Ellen Ruppel Shell wrote . . . . . . . . .

Nutrition researcher Kevin Hall strives to project a Zen-like state of equanimity. In his often contentious field, he says he is more bemused than frustrated by the tendency of other scientists to “cling to pet theories despite overwhelming evidence that they are mistaken.” Some of these experts, he tells me with a sly smile, “have a fascinating ability to rationalize away studies that don’t support their views.”

Among those views is the idea that particular nutrients such as fats, carbs or sugars are to blame for our alarming obesity pandemic. (Globally the prevalence of obesity nearly tripled between 1975 and 2016, according to the World Health Organization. The rise accompanies related health threats that include heart disease and diabetes.) But Hall, who works at the National Institute of Diabetes and Digestive and Kidney Diseases, where he runs the Integrative Physiology section, has run experiments that point fingers at a different culprit. His studies suggest that a dramatic shift in how we make the food we eat—pulling ingredients apart and then reconstituting them into things like frosted snack cakes and ready-to-eat meals from the supermarket freezer—bears the brunt of the blame. This “ultraprocessed” food, he and a growing number of other scientists think, disrupts gut-brain signals that normally tell us that we have had enough, and this failed signaling leads to overeating.

Hall has done two small but rigorous studies that contradict common wisdom that faults carbohydrates or fats by themselves. In both experiments, he kept participants in a hospital for several weeks, scrupulously controlling what they ate. His idea was to avoid the biases of typical diet studies that rely on people’s self-reports, which rarely match what they truly eat. The investigator, who has a physics doctorate, has that discipline’s penchant for precise measurements. His first study found that, contrary to many predictions, a diet that reduced carb consumption actually seemed to slow the rate of body fat loss. The second study, published this year, identified a new reason for weight gain. It found that people ate hundreds more calories of ultraprocessed than unprocessed foods when they were encouraged to eat as much or as little of each type as they desired. Participants chowing down on the ultraprocessed foods gained two pounds in just two weeks.

“Hall’s study is seminal—really as good a clinical trial as you can get,” says Barry M. Popkin, a professor of nutrition at the University of North Carolina at Chapel Hill, who focuses on diet and obesity. “His was the first to prove that ultraprocessed foods are not only highly seductive but that people tend to eat more of them.” The work has been well received, although it is possible that the carefully controlled experiment does not apply to the messy way people mix food types in the real world.

The man who designed the research says he is not on a messianic mission to improve America’s eating habits. Hall admits that his four-year-old son’s penchant for chicken nuggets and pizza remains unshakable and that his own diet could and probably should be improved. Still, he believes his study offers potent evidence that it is not any particular nutrient type but the way in which food is manipulated by manufacturers that plays the largest role in the world’s growing girth. He insists he has no dog in any diet wars fight but is simply following the evidence. “Once you’ve stepped into one camp and surrounded yourself by the selective biases of that camp, it becomes difficult to step out,” he says. Because his laboratory and research are paid for by the national institute whatever he finds, Hall notes that “I have the freedom to change my mind. Basically, I have the privilege to be persuaded by data.”

THE CARB TEST

Hall once had great sympathy for the theory that specific nutrients—in particular carbs—were at fault for our collective losing battle with body weight. “I knew that consumption of carbohydrates increases insulin levels in the blood and that insulin levels affect fat storage and fat cells,” he says. “So it was certainly plausible that consumption of carbohydrates versus other macronutrients could have a deleterious effect on body weight. But while plausible, it wasn’t certain, so I decided to test it.”

In Hall’s carb study, 10 men and nine women, all obese, were sequestered in a hospital ward at the National Institutes of Health and fed a high-carbohydrate/low-fat diet for two weeks. Then they left for a short time and returned to repeat another two-week stint. For the first five days of each stay, the balance was kept at 50 percent carbohydrate, 35 percent fat and 15 percent protein, with calorie intakes matched to their energy expenditure—measured in a specially constructed metabolic chamber—to ensure they neither gained nor lost weight. Over the next six days of each stay, they ate a diet with 30 percent fewer calories from the carb category.

“We were not surprised to find that when you manipulate the level of carbohydrates versus fats, you do see very different insulin levels,” Hall says. He had expected the low-carb diet would reduce insulin activity. “But what did surprise us was that we did not see a significant effect of the sharply lower insulin levels on the rate of calories burned over time or on body fat.” Typically lowered insulin affects the way fat cells burn calories. Yet, Halls says, “we found that the reduced-carbohydrate diet slightly slowed body fat loss.” It also slightly increased the loss of lean body mass. A year later Hall and his colleagues did a similar experiment over a longer, eight-week period. This time they cut carbohydrates to very low levels. In the end, they found no meaningful difference in body fat loss or calorie expenditure between the very low-carb diet and a baseline high-carb/high-sugar diet. The scientists published the first results in 2015 in the journal Cell Metabolism and the second set in 2016 in the American Journal of Clinical Nutrition.

If it’s not carbohydrates, what is to blame for our global obesity problem? Sure, meal portions today are larger, food more abundant, and many of us are eating more calories than people did decades ago. But with temptations so plentiful, almost all Americans could be overeating—yet a good number do not. That, Hall thinks, is the real nutrition mystery: What factors, for some people, might be acting to override the body’s inborn satiety mechanisms that otherwise keep our eating in check?

PROCESSED CALORIES

Hall likes to compare humans to automobiles, pointing out that both can operate on any number of energy sources. In the case of cars, it might be diesel, high-octane gasoline or electricity, depending on the make and model. Similarly, humans can and do thrive on any number of diets, depending on cultural norms and what is readily available. For example, a traditional high-fat/low-carb diet works well for the Inuit people of the Arctic, whereas a traditional low-fat/high-carb diet works well for the Japanese. But while humans have evolved to adapt to a wide variety of natural food environments, in recent decades the food supply has changed in ways to which our genes—and our brains—have had very little time to adapt. And it should come as no surprise that each of us reacts differently to that challenge.

At the end of the 19th century, most Americans lived in rural areas, and nearly half made their living on farms, where fresh or only lightly processed food was the norm. Today most Americans live in cities and buy rather than grow their food, increasingly in ready-to-eat form. An estimated 58 percent of the calories we consume and nearly 90 percent of all added sugars come from industrial food formulations made up mostly or entirely of ingredients—whether nutrients, fiber or chemical additives—that are not found in a similar form and combination in nature. These are the ultraprocessed foods, and they range from junk food such as chips, sugary breakfast cereals, candy, soda and mass-manufactured pastries to what might seem like benign or even healthful products such as commercial breads, processed meats, flavored yogurts and energy bars.

Ultraprocessed foods, which tend to be quite high in sugar, fat and salt, have contributed to an increase of more than 600 available calories per day for every American since 1970. Still, although the rise of these foods correlates with rising body weights, this correlation does not necessarily imply causation. There are plenty of delicious less processed foods—cheese, fatty meats, vegetable oil, cream—that could play an equal or even larger role. So Hall wanted to know whether it was something about ultraprocessing that led to weight gain. “Basically, we wondered whether people eat more calories when those calories come from ultraprocessed sources,” he says.

Tackling that question is not simple. The typical nutritional study, as noted earlier, relies on self-reports of individuals who keep food diaries or fill out questionnaires from memory. But Hall knew that in the case of ultraprocessed foods, that approach would fail to provide convincing evidence either way. For one thing, nutrition study participants are notorious for cheating on dietary surveys—claiming more broccoli and fewer Double Stuf Oreos than they actually eat or “forgetting” drinking that third beer with friends. For another, with such a large percentage of the American diet coming from ultraprocessed foods, it would be hard to find a group of people with a markedly different diet for comparison.

To avoid these and related problems, in 2018 Hall turned once again to the metabolic ward, where he randomly assigned 20 adult volunteers to receive either ultraprocessed or unprocessed diets for two weeks. Then people switched: if they had been on one diet, they went on the alternative one for two more weeks. (Clearly, 20 is not a large enough sample size from which to draw conclusions that apply to the public as a whole, but this pilot study was meant as a “proof of concept” on which to build future, larger studies. Subjecting more people to the strict study regimen at this preliminary stage, Hall says, “would be unethical.”) Dietitians scrupulously matched the ultraprocessed and processed meals for calories, energy density, fat, carbohydrate, protein, sugars, sodium and fiber. They also made sure that the research subjects had no taste preference for one category of food over the other. On both diets, participants were instructed to eat as much or as little of the meals and snacks as they liked.

This past spring, in his office, Hall showed me color photographs of each of the meals and snacks. The ultraprocessed meals included food such as canned ravioli, hot dogs, burgers topped with processed cheese, white bread, margarine and packaged cookies. Breakfast in this category had foods such as turkey bacon, sugared cereals, egg substitutes, Tater Tots, fruit-flavored drinks (most sweetened with artificial sweetener) and Spam. The unprocessed meals had dinners with roast beef, rice pilaf, couscous and pasta and breakfasts with nuts, vegetable omelets fried in oil, hash browns cooked with butter, and full-fat yogurt.

Roast beef, pasta and fried eggs are very appealing to many of us, and it would not have been shocking if people ate more of these than they ate, say, ultraprocessed Spam. But that’s not what happened. Hall’s results, published earlier this year in Cell Metabolism, showed that on the ultraprocessed diet people ate about 500 extra calories every day than they did when eating the unprocessed diet, an increase that caused them to gain about two pounds in two weeks. “What was amazing about Hall’s findings was how many extra calories people eat when they are faced with ultraprocessed foods,” says Carlos Augusto Monteiro, a physician and professor of nutrition and public health at the School of Public Health at the University of São Paulo in Brazil.

A GUT-BRAIN DISCONNECT

Why are more of us tempted to overindulge in egg substitutes and turkey bacon than in real eggs and hash brown potatoes fried in real butter? Dana Small, a neuroscientist and professor of psychiatry at Yale University, believes she has found some clues. Small studies the impact of the modern food environment on brain circuitry. Nerve cells in the gut send signals to our brains via a large conduit called the vagus nerve, she says. Those signals include information about the amount of energy (calories) coming into the stomach and intestines. If information is scrambled, the mixed signal can result in overeating. If “the brain does not get the proper metabolic signal from the gut,” Small says, “the brain doesn’t really know that the food is even there.”

Neuroimaging studies of the human brain, done by Small and others, indicate that sensory cues—smells and colors and texture—that accompany foods with high-calorie density activate the striatum, a part of the brain involved in decision-making. Those decisions include choices about food consumption.

And that is where ultraprocessed foods become a problem, Small says. The energy used by the body after consuming these foods does not match the perceived energy ingested. As a result, the brain gets confused in a manner that encourages overeating. For example, natural sweeteners—such as honey, maple syrup and table sugar—provide a certain number of calories, and the anticipation of sweet taste prompted by these foods signals the body to expect and prepare for that calorie load. But artificial sweeteners such as saccharin offer the anticipation and experience of sweet taste without the energy boost. The brain, which had anticipated the calories and now senses something is missing, encourages us to keep eating.

To further complicate matters, ultraprocessed foods often contain a combination of nutritive and nonnutritive sweeteners that, Small says, produces surprising metabolic effects that result in a particularly potent reinforcement effect. That is, eating them causes us to want more of these foods. “What is clear is that the energetic value of food and beverages that contain both nutritive and nonnutritive sweeteners is not being accurately communicated to the brain,” Small notes. “What is also clear is that Hall has found evidence that people eat more when they are given highly processed foods. My take on this is that when we eat ultraprocessed foods we are not getting the metabolic signal we would get from less processed foods and that the brain simply doesn’t register the total calorie load and therefore keeps demanding more.”

Small says that animal studies bear out the theory that ultraprocessed foods disrupt the gut-brain signals that influence food reinforcement and intake overall. “We’ve gone in with this cavalier attitude, that a calorie is a calorie, but a lot of foods have unintended consequences,” she says. “For example, in the natural world, carbohydrates almost always come packaged with fiber, whereas in ultraprocessed foods, fiber is either not there at all or included in a form not found in nature. And it is rare to find carbohydrates and fat in the same food in nature, but ultraprocessed foods tend to have both in one package. We’ve created all these hyperpalatable foods filled with fat, sugar, salt and additives, and we clearly prefer these foods. But these foods don’t necessarily provoke satiety. What they seem to provoke is cravings.”

Small and other scientists speculate that ultraprocessed foods in some sense resemble addictive drugs, in that consuming them leads not to satisfaction but to a yearning for more. Neuroscientist Ann Graybiel of the Massachusetts Institute of Technology, a recognized expert on habit formation, says that external cues—like the mere sight of a candy bar—can provoke a reflexive response that causes the brain to encourage a behavior almost automatically. “Part of what’s happening when habits form is ‘chunking,’” she says. “You learn the behavior pattern, and your brain packages the whole sequence, including the beginning and the end markers, so you don’t have to think about it further.” (Certain neurons in the striatum are responsible for grouping behaviors into a single, habitual routine.)

Eating large amounts of ultraprocessed foods may actually change brain circuitry in ways that increase sensitivity to food cues, adds Kent Berridge, a professor of psychology and neuroscience at the University of Michigan. He has shown this effect in rodents. “When you give rats junk-food diets, some gain weight, but others do not. In those that became obese, their dopamine systems changed, and they became hypersensitive to food cues—they became superfocused on that one reward. They showed no more pleasure, but they did show more wanting, and that wanting led to more actions—that is, more food-seeking behavior.”

But this is not a uniform reaction, Berridge emphasizes, and he does not think it will turn out to be the only cause of overeating. “It’s very plausible that altering foods (through ultraprocessing) could trigger this response in some of us, but my guess is that we aren’t going to find that it affects all of us in the same way. My guess is that in the case of obesity, we are going to find subgroups—that is, that there are different avenues to becoming obese depending on one’s genes.”

FOOD FIGHT

Not all researchers agree that Hall’s avenue—the ultraprocessed one—is the major road leading to obesity. Rick Mattes, a professor of nutrition science at Purdue University and the incoming head of the American Society of Nutrition, says that he is concerned that Hall is damning a whole food category without sufficient cause. “He’s saying that ultraprocessed foods result in overeating, but there is no [large] body of evidence to support that claim. My view is that how items are manipulated may not be the primary driver of our response to them but that it is the nutrient composition that is the more relevant factor.”

Hall points out that he did match the nutritional composition of the diets, but Mattes has several other objections. Perhaps the most serious is that the participants were offered only ultraprocessed or unprocessed foods in each leg of the study. “In the real world, people would mix” different food types, he wrote in an e-mail. “This is not a fault with the study, but it is a serious issue when attempting to extrapolate the findings to free-living people.”

Another possible factor driving overconsumption of ultraprocessed foods is that they are eaten quickly, so people could devour a lot before any satiation mechanisms kick in to slow them down. Ultraprocessed foods tend to be energy-dense and pack a relatively large number of calories into a relatively small package. This, too, might encourage rapid consumption that bypasses satiety mechanisms. Still, fast eating does not explain why people continued to eat more ultraprocessed food at their next meal, when, at least in theory, they should have been less hungry.

If ultraprocessed foods are indeed a big problem, the question is what, if anything, we can and should do about them. When I asked Hall, he was reluctant to call for stringent measures such as a tax on these foods. “I worry that because almost 60 percent of our calories come from ultraprocessed foods, taxing those foods might add to some people’s food insecurity,” he says. “We’ve found an association of ultraprocessed foods and overeating, and there are many hypotheses about the causal mechanism. But until you fully understand the mechanism, it’s too early to intervene. It could be that the additives and artificial flavoring are having an impact or that ultraprocessed foods have micronutrient deficiencies that the body senses and responds to by overeating. There are likely other factors as well. We just don’t know—yet.”

At the same time, he does think the available evidence on ultraprocessed foods is a reason to worry about them: “We can change our diet to minimize the damage. And for now I think that’s where we need to set our sights.” The food industry can help, perhaps by designing more foods with less processing, but people have to show they want such food by buying more of it. “I’m no evangelist,” Hall asserts, “but I do think that the public demand on the food system is more powerful than any government regulation.” His job in all this, he says, is to get the science right.

Source : Scientific American

Can mRNA Disrupt the Drug Industry?

Ryan Cross wrote . . . . . . . . .

On a brisk morning in April, dozens of investors filed into a Marriott hotel conference hall in Kendall Square, the biotech hub of Cambridge, Mass., for the first Moderna Therapeutics platform science day. They gathered hoping to get a rare, inside look at the science behind what the start-up had long claimed to be a disruptive drug platform: carefully designed molecules called messenger RNA that prompt the body to make its own medicine. The concept has attracted billions in funding, but the company had largely kept details of how the technique works under wraps.

“Why are we so passionate about messenger RNA?” Moderna President Stephen Hoge asked the attentive audience. “It starts with the question of life,” he explained. “And in fact, all life that we know flows through messenger RNA. … In our language, mRNA is the software of life.”

Cells use mRNA to translate the static genes of DNA into dynamic proteins, involved in every bodily function, Hoge explained. Biotech companies make some of these proteins as drugs in large vats of genetically engineered cells. It’s a time-consuming and costly process.

Moderna offered a different proposition: What if instead, mRNA was given therapeutically? In theory, it could prompt proteins to be made in your body. It would put the drug factory inside you.

The idea Hoge was selling is straightforward, but its implementation is not. When mRNA is injected into the body, it triggers virus-detecting immune sensors. That event causes cells to shut down protein production, thus foiling the therapy. And even if the molecule makes it into the cell—another challenge that has long vexed drug delivery experts—the mRNA might not make enough protein to actually be useful.

Moderna now employs more than 600 people, the majority of them scientists, and spends enormous sums—over $450 million in the past five years—learning how to make and improve its mRNA therapies. This year, the firm will invest another $100 million. It’s an astonishing sum for a company that is still years away from a marketed product or even a late-stage experimental drug. Hoge told investors at the R&D day that his firm has no intention of slowing the pace of its investment. “Over the next five years we will invest the next half billion dollars.”

Indeed, just a few months later, Moderna executives were making their next splashy move: opening the doors to their first drug manufacturing plant, in Norwood, Mass. The $110 million project gives Moderna full control over the mRNA used in its preclinical and clinical studies.

It’s all part of CEO Stéphane Bancel’s long-term vision to transform the drug industry the same way that the first biotech companies, like Amgen, Biogen, and Genentech, did when they began developing protein therapies called biologics in the eighties. Biologics are now the fastest-growing segment of the drug industry, and in theory, mRNA could replace them all. “This is a 20-year job,” Bancel told the R&D day crowd. “We believe we are just starting.”

Moderna’s slick storytelling has helped Bancel raise over $1.7 billion—all from private investors—to try to realize his ambitious plan. It has also invited skeptics, who would like to see those ambitions backed up by data.

But Moderna has catalyzed an excitement for therapeutic mRNA that is spilling into other start-ups and even big pharma companies. Collectively, they think they have overcome some of the fundamental challenges of translating mRNA from idea to product. Years of behind-the-scenes research have created a surprisingly deep, but early-stage, pipeline of mRNA therapeutics. Already, mRNA is being tested in a dizzying array of studies, including therapies for rare genetic diseases, cancer immunotherapies, and vaccines for infectious diseases.

“You could ultimately use mRNA to express any protein and perhaps treat almost any disease,” Hoge said in a recent interview with C&EN. “It is almost limitless what it can do.”

Although Moderna helped put mRNA therapeutics on the map, efforts to use it as a therapy predate the company by at least two decades. In 1990, University of Pennsylvania scientist Katalin Karikó proposed using mRNA as an alternative to DNA-based gene therapy. Both techniques can produce therapeutic proteins, but while DNA’s effect is permanent, mRNA offers a temporary fix. Karikó reasoned that would alleviate some of the long-term safety concerns surrounding gene therapy, “but nobody was interested,” she says.

At the time, mRNA was difficult to work with. Scientists could isolate only small amounts of the material, which was then easily destroyed by RNA-chopping enzymes found on skin and in the air. And immune reactions to mRNA injections in animals suggested the technique wasn’t as safe as Karikó had hoped.

She forged ahead anyway and, with her colleague Drew Weissman, made a simple but game-changing discovery in 2005. The researchers replaced one of mRNA’s four chemical building blocks, a nucleoside called uridine, with a slightly modified nucleoside called pseudouridine. Amazingly, the modified mRNA evaded immune sensors (Immunity 2005, DOI: 10.1016/j.immuni.2005.06.008). “We submitted that for a patent, and that was the birth of therapeutic RNA,” Weissman says.

In 2006, Karikó started her own mRNA therapy company. Her start-up quickly dissolved, but three German firms—CureVac, BioNTech, and Ethris—would soon have more success. Ingmar Hoerr, cofounder of CureVac, won the first major funding for the field that year. “mRNA is like a memory stick,” Hoerr recalls explaining to software billionaire Dietmar Hopp. “You can just plug the memory stick into the body, it reads the information, makes any protein you want, and the body cures itself.” Hopp led a $26 million investment in the company.

Although the field was still largely under the radar, other labs began copying Karikó and Weissman’s trick. In 2010 Harvard University scientist Derrick Rossi used modified mRNA to encode proteins that reprogrammed adult cells into embryonic-like stem cells. Harvard cardiovascular scientist Kenneth Chien, now at the Karolinska Institute, and Massachusetts Institute of Technology’s famed serial entrepreneur Robert Langer spotted mRNA’s therapeutic potential and joined Rossi in pitching a stem cell company to the venture capital firm Flagship Pioneering.

Flagship’s CEO, Noubar Afeyan, saw a much farther flung potential for mRNA. He asked the group to explore mRNA as a tool for making all kinds of protein therapies. The academics subsequently showed that modified mRNA injected into mice could produce proteins in the liver that were secreted and circulated in the blood. Afeyan was sold. The quartet founded Moderna in 2010, and Afeyan recruited Bancel as CEO the next year.

After spending two years in stealth mode, Moderna burst onto the biotech scene in 2012 with $40 million from Flagship and other investors. It wouldn’t take long for more money to pile up.

In their academic labs, Rossi and Chien injected mRNA encoding a protein called vascular endothelial growth factor (VEGF) directly into the hearts of mice. Scientists had long surmised that VEGF could heal heart tissue damaged during a heart attack, but VEGF proteins don’t stick around long enough, so simply injecting the proteins doesn’t work. The VEGF-encoding mRNA, however, lingered in cells, making enough of the protein to improve the animals’ survival and health after a heart attack (Nat. Biotechnol. 2013, DOI: 10.1038/nbt.2682).

That study formed the backbone of Moderna’s first big pharma partnership, a collaboration with AstraZeneca in 2013 that included a $240 million investment. After replicating the VEGF experiment in mice and pigs, AstraZeneca launched a study to test the therapy in people who recently had heart attacks. It’s now Moderna’s most advanced program, in a Phase II clinical trial.

Since then, Moderna has struck additional pharma partnerships and earned itself a reported valuation of more than $7 billion. “Moderna was so important because they brought attention to the field,” Hoerr says. Subsequent to Moderna’s AstraZeneca partnership, CureVac raised more than a $100 million and forged partnerships with Boehringer Ingelheim and Eli Lilly & Co. to develop mRNA therapies for cancer.

BioNTech, founded in 2008, has also undergone a recent growth spurt. In the past three years it has inked mRNA drug development deals with Sanofi, Genentech, and Pfizer, and earlier this year it raised $270 million in private funds. “It took a while for the pharmaceutical community to really get their head around the mRNA approach,” Sean Marett, BioNTech’s chief business officer, says. “Now all pharmaceutical companies are looking at mRNA.”

As investors lined up for mRNA companies, so did the critics. Moderna hasn’t released any data from the VEGF trial yet, and until 2017, Rossi and Chien’s study was the only scientific research publication that the company could point to as validation of its technology.

Moderna kept its science under the radar by continuing to raise funds from private investors rather than become a publicly traded company. That decision, coupled with its executives’ propensity to aggrandize its mission, has instilled a reputation of secrecy—and a skepticism around its technology—that has proved hard to shake. It doesn’t help that there are only a handful of academic scientists working in the largely industry-dominated mRNA therapy field. “I would much rather know what is going on in the field and be able to learn from everyone else,” Weissman says. “Right now they are all learning from us.”

And as cash continues to flow into the field, expectations continue to rise. “There is huge momentum now,” Hoerr says. “And since everybody is promising something, everybody has to deliver.”

MODERNA UNVEILED

For any of these firms to be successful, they need to prove themselves capable of solving a few key problems: avoiding an immune reaction, safely shuttling the therapy into the appropriate cells, and making sure the mRNA yields enough protein to have an effect. On that April morning in Kendall Square, Moderna began to pull back the curtain on its efforts to overcome these challenges.

Melissa Moore, who was brought on as chief scientific officer in late 2016, has been at the center of this movement toward transparency. Moore brings a distinguished pedigree to the start-up. She was a postdoc in geneticist Phillip Sharp’s lab at MIT when he won the Nobel Prize in Physiology or Medicine in 1993 for his work on RNA. Moore then went on to study RNA as a Howard Hughes Medical Institute investigator for nearly two decades and was a founding codirector of the RNA Therapeutics Institute at the University of Massachusetts Medical School.


ANATOMY OF AN mRNA

Scientists are learning how to modify and control mRNA to make it more druglike for predictable protein production.

5′ cap: The endcap offers a foothold to initiate the process of translating the mRNA into a protein. Decapping enzymes also bind here to break down mRNA. In humans, the cap is normally a molecule called 7-methylguanosine linked to the mRNA via a triphosphate bridge, but chemists are creating new caps to maximize protein translation and ward off decapping enzymes.

5′ UTR: This untranslated region is key for determining how efficiently the mRNA is translated into a protein. It can also affect the mRNA’s stability.

Coding region: The ribosome, the cell’s protein-making machinery, reads this sequence and translates it to produce a protein. Because there are many different ways to write an mRNA code that will lead to the creation of the same protein, scientists look for variants that produce their desired amount of protein.

3′ UTR: Modifying this untranslated region can increase or decrease the mRNA’s stability. Scientists can also add a code here called a microRNA target sequence that limits which cells use the mRNA.

Poly(A) tail: A long sequence of adenosines (A), usually more than 100 of them, protects this end of the mRNA from degradation.

Whole mRNA: Using modified nucleosides, such as pseudouridine in place of the normal uridine, helps the mRNA evade immune cell and intracellular sensors that detect foreign RNA. Changing the sequence also alters how the lengthy mRNA strand interacts with itself, a way of controlling the speed of protein production.


Under Moore’s watch, Moderna’s scientific shyness has begun to abate. The company published a dozen mRNA research studies in 2017, and several more are on the way. “We are discovering things that we hope will rewrite the textbooks,” she says.

Those discoveries involve deciphering the molecular rules for changing the potency and longevity of mRNA molecules. The doses of traditional drugs are carefully measured before they are used, but the amount of protein that a single mRNA makes can vary widely. Cells can reuse a single mRNA to make on the order of 1,000 to 10,000 proteins. Controlling that number will help mRNA work more like traditional therapies.

One way to tune the amount of protein an mRNA makes is called codon optimization. There are many ways to write an mRNA code to produce the exact same protein, and the possible number of variants is often too large to test experimentally. So Moderna data scientist Andrew Giessel is using machine learning to determine the rules for changing an mRNA sequence to produce more or less protein, as desired. Moore says a publication describing his methods is in the works.

Actually getting the mRNA into cells is another challenge. A common solution is to wrap the mRNA in fatty vessels called lipid nanoparticles. Scientists have labored for years to make these vessels safe and effective while developing another kind of therapy, called small interfering RNA (siRNA). Chemists eventually ironed the kinks out for delivering siRNA, but those molecules are only 20 or so nucleotides long. mRNAs, meanwhile, span hundreds to thousands of nucleotides and will thus require newly designed lipid nanoparticles.

The importance of delivery is not lost on Moderna. It’s the area with the most room for improvement and the biggest focus for the company’s chemists, Moore says. One proxy for success is how much mRNA escapes from endosomes, the cellular structures that ingest lipid nanoparticles. Moore says Moderna’s current favorite lipid nanoparticle, N1GL, breaks out of the endosome 25 times as much as standard lipid nanoparticles (Mol. Ther. 2018, DOI: 10.1016/j.ymthe.2018.03.010).

An even bigger long-term challenge will be getting mRNA into specific cells of the body. Lipid nanoparticles have a tendency to aggregate in the liver. That could make mRNA useful for producing therapeutic proteins and antibodies that are secreted from liver cells and circulated in the bloodstream. But getting mRNA therapies into other organs will require either direct injection into that tissue—as in AstraZeneca’s post-heart attack VEGF study—or fancy new control systems.

Moderna has revealed the blueprints for one such system used to ensure its mRNA is made only inside cancer cells. Moderna scientist Ruchi Jain designed an mRNA that causes cancer cells to self-destruct but is recognized by, and destroyed in, healthy cells (Nucleic Acid Ther. 2018, DOI: 10.1089/nat.2018.0734).

Moderna isn’t divulging all its secrets. But even these glimpses of its research engine suggest it has scientists devoted to nearly every conceivable aspect of turning mRNA into a therapy. “There is no reason to believe it can’t be done,” Hoge told the investor crowd in April. “There is every reason to believe it is going to be hard.”

mRNA’S MANY APPLICATIONS

If Moderna and others can work out all the technical challenges, mRNA’s killer application could be making protein therapies inside cells, a place that biologic drugs cannot go. Many rare genetic diseases are marked by dysfunctional or deficient proteins.

The most advanced program in the field got its start in 2008, when Shire Pharmaceuticals quietly began working on mRNA therapies for people with cystic fibrosis. The goal was to replace the broken CFTR proteins, found in the lungs of people with the disease, with fully functional CFTR copies.

Led by Michael Heartlein, in 2011 the Shire team began collaborating with a new German mRNA start-up called Ethris to develop a cystic fibrosis mRNA therapy with lipid nanoparticles that could hold up under the pressure of being aerosolized for inhalable delivery into the lungs. “It was not an easy task,” Heartlein says. “Lots of work, lots of trial and error, and lots of formulations that didn’t pan out or weren’t safe.”

Shire sold its mRNA programs to a start-up called RaNA Therapeutics in 2017, and Heartlein left to become CSO of the firm. RaNA later rebranded itself as Translate Bio, and this June it became the first publicly traded mRNA start-up, raising $122 million in its initial public offering.

Another company, Vertex Pharmaceuticals, has already received U.S. Food & Drug Administation approval for multiple small-molecule drugs that improve lung function in many people with cystic fibrosis. Still, the possibility of making a fully functional, correct version of CFTR with mRNA has allure. Vertex’s drugs are not effective across all the mutations that cause the disease, but a single mRNA therapy could treat everyone. Translate Bio’s cystic fibrosis mRNA therapy is now in a Phase I clinical study, making it the first company to test an mRNA therapy for a rare genetic disease in humans. Moderna and Vertex Pharmaceuticals are working on a similar treatment, still in preclinical stages.

Moderna, Translate Bio, Ethris, and other companies have earlier-stage programs aiming to treat genetic diseases that, like cystic fibrosis, can’t be addressed by existing protein therapies.

But most of the money in the mRNA field has gone to a different application of the technology: vaccines. Traditional vaccines use bits of injected proteins to train the immune system to take down future viruses displaying those same proteins. Manufacturing them takes months, a timescale too slow to combat emerging epidemics. mRNA vaccines, on the other hand, simply encode these protein fragments in a single mRNA strand. And as mRNA companies optimize and scale up their enzymatic production of mRNA, scientists anticipate these vaccines could be made in a matter of weeks.

It’s considered the easiest test case of the technology, since the mRNA needs to produce only a small amount of protein for the vaccine to work, and setting off the body’s RNA immune sensors a little won’t hurt. “It is low-hanging fruit,” Weissman says.

Its potential has still spurred several major mRNA vaccine collaborations: The U.S. government and the Bill & Melinda Gates Foundation invested in Moderna’s mRNA vaccine programs for diseases caused by viruses like Zika and HIV; Sanofi partnered with Translate Bio to develop infectious disease mRNA vaccines; and Pfizer last month teamed up with BioNTech to develop mRNA flu vaccines.

Many companies think mRNA vaccines can help the immune system tackle cancer too. There are many variations of the technique, but in general the mRNA encodes proteins made on cancer cells, which teaches the immune system to recognize and target tumors. CureVac is developing mRNA cancer vaccines alone and in partnerships with Boehringer Ingelheim and Eli Lilly & Co. BioNTech has multiple programs of its own too. And Merck & Co. made a splash into the field through a $200 million deal with Moderna in 2016 and another $125 million this year.

Moderna and Merck are taking the technology a step further to develop individualized cancer vaccines, in which a unique therapy is designed and manufactured for each patient. It starts with a tumor biopsy, genetic sequencing, and a proprietary algorithm that picks 20 tumor mutations that are most likely to help the immune system home in on the cancer. Those mutations are encoded into an mRNA, which is injected into the patient’s muscle and used to provide a molecular mug shot that sends the immune system seeking tumors. Genentech and BioNTech have a similar program, and results from the first 13 people stoked excitement for the technology (Nature 2017, DOI: 10.1038/nature23003), but larger studies will be required to prove its worth.

PLOWING AHEAD

Moderna, along with the mRNA field at large, still has a lot to prove. So far, it has published human data only from its early-stage flu vaccine study (Mol. Ther. 2017, DOI: 10.1016/j.ymthe.2017.03.035). Bigger studies lie ahead, and Moderna is wasting no time on its trek toward becoming the next major biotech.

In a forested pocket of Norwood, Mass., a 45-minute drive south of Kendall Square, Moderna’s glistening new drug factory is hard at work making mRNA. Upstairs, an army of machines and robotic handlers, accompanied by a few scattered employees, are each month creating up to 1,000 batches of new mRNA molecules for preclinical testing.

Downstairs, in a series of clean rooms, enzymes repetitively transcribe DNA templates into copious strands of mRNA, which are then formulated into lipid nanoparticles for the company’s expansive clinical pipeline.

Human tests are underway for 10 mRNA therapies, and with another 11 preclinical programs disclosed, Moderna shows no hesitation in exploring mRNA’s versatility. CEO Bancel has often said that Moderna’s total number of preclinical programs exceeds 100. “Our problem is trying to figure out what things to develop further,” CSO Moore explains. “We have an embarrassment of riches.”

Such bravado is one reason the company continues to garner scrutiny. But backing by pharma giants has helped legitimize Moderna and, more broadly, the field. “I know how Merck’s internal engine works. It is very science driven,” says Yusuf Erkul, a former cancer scientist at Merck & Co. “There is no way that Moderna would have got that funding without significant data to back it up.” After learning about the field, Erkul started his own mRNA therapy start-up, Kernal Biologics, in 2016, focused on cancer therapies.

Many scientists, including Nobel Prize winner Sharp, used to think mRNA therapy would be too technically difficult to make a reality. “They’ve totally convinced me it is possible to do,” he says of Moderna. Now it’s a matter of proving it works in humans and without side effects or complications that would encumber its practicality, Sharp adds. “That’s the litmus test.”

In the meantime, Moderna remains confident of its progress. “We already have things working,” Moore says. “There are no challenges that are limiting us in any way of getting stuff into the clinic.”

Moore is often asked how she feels about her jump from academia to industry. She doesn’t mince words about her decision. “It was a once-in-a-lifetime opportunity to use everything I’ve done in my career to develop an entirely new therapeutic modality that I think has the potential to completely disrupt the drug development and biologics space,” Moore says. “So, it is not industry. It is Moderna.”

Source: Chemical and Engineering News

Designing a Better Low-fat Potato Chip

Munching on low-fat potato chips might reduce the guilt compared with full-fat versions, but many people don’t find the texture as appealing. Now, researchers have developed a technique to analyze potato chips’ physical characteristics from simulated first bite to swallow, which they say could be used to help formulate a tastier low-fat snack. They report their results in the Journal of Agricultural and Food Chemistry.

Cutting fat in potato chips usually involves reducing the vegetable oil content. However, the oil helps give the product its characteristic crunch, taste and mouthfeel. When food scientists formulate a new low-fat chip, they often rely on trained sensory panelists to tell them how well the new snack simulates the full-fat version. This process can be expensive, time-consuming and often subjective, since perceptions can vary based on factors like a person’s saliva flow rate and composition. While at PepsiCo, Stefan Baier –– now at Motif Ingredients –– and Jason Stokes’ team at the University of Queensland wanted to develop a more objective method to analyze the physical characteristics of a potato chip at four stages of simulated eating: the first bite, when the chip is taken from the package and broken by the teeth; comminution, when the chip particles are broken down further and wet by saliva; bolus formation, when the small, softened particles begin to clump as enzymes in saliva digest the starches; and swallow, when the clumped mass moves to the rear of the mouth and is finally swallowed.

To develop their method, called in vitro oral processing, the researchers used different instruments to measure the physical characteristics of chips with various oil contents at each of the four stages. For example, for the “first bite” stage, they conducted mechanical testing to measure the force required to break the chips, and for bolus formation, they measured the hydration rate of particles in buffer as the fragments became a soft solid. The researchers used the results to design a lower-fat chip coated in a thin layer of seasoning oil, which contained a small amount of a food emulsifier. The seasoning oil made the low-fat chip more closely resemble the greasiness of a full-fat one in tests with sensory panelists, but it only added 0.5% more oil to the product. Food scientists could use the new technique to link physical measurements with sensory perceptions, the researchers say.

Source: American Chemical Society

Japanese Startup Will Sell Cultured Foie Gras by 2021

Catherine Lamb wrote . . . . . . . . .

At SKS Japan this week, lots of speakers have been predicting what the future of food might look like: it might be cooked by robotic articulating arms, it might be carbon neutral, or it might be personalized to individuals’ specific tastes.

But the most futuristic vision of all might have come from Yuki Hanyu, CEO and founder of DIY cultured meat community Shojinmeat. He sketched out a time in which we’re all living on Mars, growing steak in bioreactors in much the same way we brew beer right now.

That reality is still a long way off. However, right now Hanyu is still working on quite a few projects pushing us towards a future in which everyone — yes, even you — can grow their own meat, and cultured meat is available in your corner supermarket.

Shojinmeat was the original enterprise, but in 2015 Hanyu spun out Integriculture, a startup creating full-stack cellular agriculture solutions. After his session at SKS Japan, Hanyu described his company’s projected timeline to me:

2019

By the end of this year Integriculture will start selling Space Salt, a dried version of cell culture media. For those who don’t nerd out on cellular agriculture, media is the liquid “food” that allows animal cells to rapidly proliferate to form meat. Space Salt is Integriculture’s (secret) proprietary blend of salt and food safe amino acids, which, when mixed with water, forms a DIY cell culture media. Hanyu wants to sell it to home enthusiasts who can use it to grow their own meat using Shojinmeat guide.

2020

While its focus is cultured meat, in 2020 Integriculture is also planning to sell its media for use in cosmetic applications, specifically as an anti-aging skincare product.

2021

In 2021, Integriculture will launch its first cell-based meat product: foie gras. Hanyu said that they decided to tackle foie gras as its first product because of its creamy texture, which means that they don’t have to emulate the texture and chew of meat. Since foie gras is already quite expensive, starting with that product will also presumably give consumers less of a sticker shock when they see its high price. Accordingly they plan to launch first in high-end restaurants in Japan.

“We’re not aiming for massive revenue at first,” Hanyu told me during SKS Japan. Instead, he’s expecting that the foie gras launch will be more of a proof of concept to show that cell-based meat is feasible and delicious. He also wants it to help establish regulatory guidelines for cultured animal products in Japan.

Which brings us back to the Space Salt. Presumably, when Integriculture starts selling its cell-based foie gras, Japanese food regulatory bodies will ask the company what’s in it in order to approve it for public consumption. At that time Hanyu and his team plan to show that the only two inputs are duck liver cells and Space Salt (plus water), the latter of which contains ingredients that are already sold on the market. He’s hoping that if they prove that duck liver and Space Salt are both already available for purchase, then by the transitive property their cell-based foie gras shouldn’t pose a problem.

If the 2021 restaurant launch goes as planned, Integriculture will start selling foie gras in supermarkets in 2023.

An ambitious timeline, to be sure — and that’s just the tip of the iceberg. The JST (Japan Science and Technology) Agency, part of the Japanese government, is investing part of its $20 million funding in Integriculture’s research for large-scale cell-based meat. The company is also working with JAXA (the Japanese Aerospace Exploration Agency) on its Space Food X program, which is developing closed-loop food solutions for space travelers.

That’s a lot of balls to juggle for the startup, especially one with only 13 employees and ¥300 million (USD 2.7 million) in funding. There’s also relatively little local support: despite the fact that cultured meat will likely debut in Asia, Japan is still quite light on cellular agriculture startups.

Interestingly, there’s at least one other company openly working in the cell-based meat space — and it’s a big one. Nissin Foods, the instant ramen giant, is partnering with the University of Tokyo to develop their own small cultured meat cubes to include in their freeze-dried ramen packs.

However, as they’re a large company which would require billions of tiny cell-based meat cubes — and they need to make them cheaply to keep down the cost of their product — Hanyu said that they’re likely 10 years away from actually incorporating cultured pork or chicken into the ramen packs.

Maybe then highbrow consumers will be able to have instant noodles with lab-grown foie gras.

Source: The Spoon