Sweet-Tasting Proteins Could Be the Cure for Your Diet Soda Habit

But consumers are haunted by the ghosts of zero-calorie sweeteners past.

Most of us know that sodas, while delicious, are unhealthy. People who drink one or more sugary drinks per day tend to gain weight and are also 26 percent more likely to develop type 2 diabetes than those who don’t. And that’s one of the reasons why food companies sold more than $11 billion worth of diet soft drinks to Americans in 2020 alone, in spite of growing alarm of how unhealthy the stuff actually is

The skepticism over sugar-free sodas is getting louder. In May, the World Health Organization (WHO) warned against consuming artificial sweeteners to lose weight. Even worse, the agency also found long-term consumption of non-sugar sweeteners could actually contribute to type 2 diabetes, cardiovascular disease, and early death. The WHO recommended that people instead strive to reduce their intake of sugar generally.

But when a colorful can of cold bubbly yum is staring you in the face, that’s easier said than done. With all due respect to those who subsist on water, quinoa, and oranges—what’s someone with a bona fide sweet tooth to do?

In Davis, California, a startup called Oobli is one of several companies pitching sweet protein substitutes as an alternative to sugary and non-sugar sweeteners, slipping a sweet protein called brazzein into iced tea blends. Originally found in the bright red or mottled gray berries of the oubli fruit tree, a unique species of shrub that grows in Central and West Africa, brazzein is between 500 and 5,000 times sweeter than sugar. It contains no carbohydrates, so it doesn’t have the metabolic complications of non-sugar sweeteners, like insulin spikes. 

But for an iced tea sold at a fairly steep price of $15 per 6-pack to take off, the company will have to convince dietitians and consumers alike that brazzein won’t turn out to be another fad sweetener that disappoints. The company will have to get consumers to accept that, for both economic and ecological reasons, the brazzein was grown in a lab via fermentation, courtesy of genetically edited yeast. And then there’s the problem of getting confirmation from the U.S. Food and Drug Administration (FDA) that it’s safe. (The company worked with third party labs to publish a peer-reviewed study that the sweet protein is safe, a finding affirmed by an external panel of experts, allowing the product to be sold in the United States. But some retailers won’t carry the product until the FDA issues a letter agreeing with these conclusions.)

The typical American consumes about 60 pounds of added sugar a year, almost half of it from beverages.

“Today, 75 percent of consumers in the U.S. are actively trying to reduce sugar,” says Ali Wing, the CEO of Oobli, which rebranded late last year from its former moniker Joywell Foods when it began marketing its first product, a brazzein-sweetened chocolate bar. “There’s 50 different forms of sugar, and they’ve been trying for the last 20 years, and it’s not going very well. They see an update every six weeks, on another sugar alternative that may actually be worse for you than we thought. Consumers are skeptical.”

But chocolate is only the start of the company’s ambitions. Oobli sees sugary beverages as the really promising niche market to go after. The typical American consumes about 60 pounds of added sugar a year, almost half of it from beverages. “It’s our sugar-delivery mechanism of choice,” says Jason Ryder, the company CTO and adjunct professor of chemical and biomolecular engineering at the University of California, Berkeley. 

“Beverages are the 800-pound gorilla of the problem,” Wing says. And that’s precisely why so many people turned to diet soda or sugar-free tea in the first place. 

More to a sweetener than meets the tongue

Decades of marketing has led us to believe that these zero-calorie drinks are inert—the equivalent of flavored water. 

Not so, says Ryder, as artificial sweeteners fool the body into thinking they are sugar. A recent study suggests that diet soda is unhealthy because it could stimulate food cravings or otherwise confuse the body—women and people who are obese ate more as a response to a sucralose-sweetened drink, as compared with a control group who drank regular sugar-sweetened soda.

Ali Wing, CEO of Oobli.

“Sugar and alternative sweeteners as a class, they are all small molecules, and they all do fundamentally the same thing,” he says. “They bombard your T1R2 and T1R3 taste receptors.” These molecules essentially overstimulate our systems, alerting them about the presence of sweet substances that used to be scarcely consumed, but are now ubiquitous.

Not only do the taste receptors on our tongue and in our gastrointestinal tract detect sweetness, they perform an important signaling function, Ryder says. “They tell your brain, ‘Hey, we’ve got sugar coming! It’s time to make insulin—we need to bring that sugar into our bloodstream, so we can send it to the cells that need it.’”

This sensitivity to the presence of sugar evolved, Ryder says, because of its relative scarcity tens of thousands of years ago. Apart from fruit in the summer, our Paleolithic ancestors only derived sugar from tubers, other starches, and complex carbohydrates. 

In contrast, the modern food system is awash in simple sugars and sweeteners, which effectively overload the taste receptors on our tongue and in our gut. And non-sugar sweeteners, like the aspartame in Diet Coke, play a trickster role, sparking an insulin response, even though these molecules don’t actually consist of any real sugar to be collected.

“Something like aspartame, you can’t metabolize it right, so it keeps hitting your insulin response,” Ryder says. “But there’s no sugar to bring in.”

And so this repeated tripping of our insulin can lead to type 2 diabetes and a host of other likely problems. Those include a potential association between long-term non-sugar sweetener consumption and cardiovascular disease, and disruption of the gut microbiome, the colony of helpful bacteria and other organisms in our gastrointestinal tract. 

Brazzein avoids this metabolic confusion because our bodies process proteins differently. It tastes sweet on the tongue, but breaks down in our gut without triggering an insulin response.

“They start to break down into peptides and amino acids,” says Ryder. “So whereas sugar and sucralose and aspartame will continue to trip your insulin response to all those taste receptors in your gut, the protein is already done.”

Nutritionists intrigued, though more data needed

Nutrition experts who spoke to offered qualified support for Oobli’s brazzein as a way to reduce the calories Americans get from sugary drinks, though each expressed a desire to see additional studies before fully endorsing any products.

“Is there a health advantage to brazzein-sweetened beverages? Yes, fewer calories than regular sugar, and thus less glycemic load,” says William Li, author of the book Eat to Beat Your Diet. He also adds that preliminary studies show the protein has antioxidant and anti-inflammatory properties, but no studies have been done to know what dose is required in humans. “So it is premature to speculate on the benefits or potential long-term side effects,” he says.

Christina Fasulo, a senior gastrointestinal dietitian at UCLA, finds brazzein promising as an alternative to the excessive amounts of sugar in the American diet. She also notes the compelling lab and animal results showing brazzein’s antioxidant and anti-inflammatory effects, but she says she would want to see studies in humans before recommending the substance to patients. 

Fasulo is also not wholly down on diet soda, noting the evidence against it is inconsistent. A recent meta-analysis of 20 randomized, controlled trials found that non-sugar sweeteners did in fact help lead to loss of weight and of fat. 

Danica Cowan, a dietitian at the University of California, San Francisco, agrees that sugar-sweetened beverages are a particular concern. That’s because our bodies more quickly process liquid calories, and you can drink sugary beverages much more quickly. “Most people are not going to eat five pieces of cake in a day,” she says. “But people may have five cans of Pepsi in a day.”

Cowan counsels patients to strive to reduce the sweetness of their diet generally, rather than finding sugar substitutes. That way, they become accustomed to a lower level of sweetness in foods. If they can’t totally cut out added sugars, she recommends naturally occurring sweeteners like stevia or monkfruit—but with a long-term goal of cutting even those substitutes out entirely. She advises patients to try to get accustomed to the natural sweetness of foods, rather than using the distorted hyper-sweetness of our current food system as the default setting. And part of William Li’s advice in Eat to Beat Your Diet is to give willpower a chance—drink mostly water, along with coffee, tea, and the occasional small serving of juice from a select list of fruit juices.

A sweetener of the future?

For those of us who can’t quite cut back on our afternoon sugary drinks, however, Oobli is one of several companies around the world trying to make sweet proteins into the next alternative sweetener. 

“The last thing we would want is to say, ‘You should feel bad for having a sweet tooth,’” says Oobli CEO Ali Wing.  

In addition to Oobli, there is a passel of other competitors. Irvine, California-based Sweegen recently received “generally recognized as safe” (GRAS) certification to sell brazzein as an industrial additive. With a marketing department working on overdrive, Sweegen has branded a portfolio of protein sweeteners as “Sweetensify” and touts the “sweet synergies” of brazzein and another sweet protein called thaumatin, along with a stevia product. 

“Every time we’ve tried to find the silver bullet of the perfect low-calorie, no-effect sweetener, we’ve come up short.”

An Israeli company based in Rehovot called Amai Proteins has created a “designer” version of a naturally occurring sweet protein called monellin, and it launched a trial run with Ocean Spray cranberry juice in 2020. A startup in Santa Monica called Nature’s Wild Berry recently won an $80,000 investment from Mark Cuban and Lori Grenier on Shark Tank, the startup pitch meeting game show. The winning product was a freeze-dried “miracle berry” that the company grows in Florida. The key component is a glycoprotein called miraculin that coats the tongue, causing even tart food to taste unusually sweet. In what one judge on the show called a “parlor trick,” even lemons, plain cranberry juice, and cider vinegar tasted sweet—in spite of no extra calories.

The hyper-sweetness of these seemingly guilt-free proteins is precisely what worries the nutritionist Danica Cowan. The sweet taste of non-sugar sweeteners that don’t actually deliver sugar is what causes more cravings, she says. “Every time we’ve tried to find the silver bullet of the perfect low-calorie, no-effect sweetener, we’ve come up short.”

But Ryder says that just tasting sweetness will not cause cravings, because the body metabolizes the brazzein as protein. “To the best of my knowledge, there is no conclusive evidence that there are long-term negative side effects, like more cravings, simply from tasting sweet things. The known negative side effects come from the metabolism of too much of the things themselves.”

This certainly sounds plausible. But as the nutrition experts say, we can’t know for sure how consuming a can of brazzein-sweetened drink regularly will affect complicated metabolic systems over time without additional studies.

Miracle berry (Synsepalum dulcificum). Oubli

The ecological justification

Ryder and Wing also make an environmental pitch for sweet proteins over sugar or non-sugar sweeteners. Brazzein only occurs in small amounts in the oubli berries on Pentadiplandra brazzeana trees found on the banks of rivers and at the edges of forests throughout the tropical sub-Saharan African belt that stretches from northern Angola to eastern Nigeria. The low abundance of these trees makes farming prohibitively expensive. And even if oubli fruit trees could be grown on an orchard, farming on a large scale would cause the same deforestation problems as palm oil production has in Indonesia or Madagascar—or for that matter that our excessive love of sugar has. Ryder points out that farmers have planted 65 million acres of sugar around the world, much of it in sensitive, tropical areas.

“With every 1 percent reduction in sugar, that’s 650,000 acres of sugar cane land that can either go to replace those rainforests that we’ve lost or grow more nutritive crops.”

So Oobli has turned to biotechnology and genetically modified yeast to produce a brazzein that is identical to the naturally grown protein from the tree. According to Ryder, the company has developed a fermentation process that is scalable, “which we have demonstrated in the manufacturing of our sweet proteins at commercial scale in three different countries.” This allows the company an economical source of sweet protein that also doesn’t result in razing forest to grow crops.

And to this reporter’s palate, the taste of Oobli’s tea is unobtrusively sweet, without the strange “off” tastes that stevia and synthetic sweeteners can have. I bought a six pack and only had two before my dessert-oriented sons drank the rest. Whereas Snapple or Arizona iced tea wallop the palate with sweetness, Oobli is smoothly balanced and lets the various lemon or peach tea flavors come through.

That said, brazzein behaves in the mouth differently than sugar. There is a slight delay from when it hits your tongue to when you perceive the sweetness. Therefore Oobli uses a small amount of sugar derived from agave in its tea, to avoid confusing the tongue. But the amount of added sugar is slight. A can of Oobli iced tea has only 7 grams of sugar, whereas a bottle of sweetened Snapple contains some 46 grams.

Creating a protein in a lab that’s hard to find in nature may feel like the opposite of the drive toward all things “natural” that’s behind the organic foods movement. Why can’t people just show some restraint, cut back on their diet Coke? Why can’t they just embrace fig-sweetened cookies or savory pies instead—or zero-calorie beverage standbys like coffee, tea, and water?

But in a country where 40 percent of adults are obese, such appeals to personal responsibility and dietary moralism feel glib and inadequate. Many of us Americans lack the restraint to cut back—or we simply don’t care. We suck down sodas like there’s no tomorrow—and let’s face it, that’s millions of us. Synthetic biology may well offer a way out. Making hyper-sweet proteins in a lab may be the best way to help us kick our caloric drinking problem.

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