With Lab-Grown Chicken Nuggets, Dumplings, and Burgers, Futuristic Foods Aim to Seem Familiar
Sandhya Sriram is at the forefront of the expanding lab-grown meat industry in more ways than one.
"[Lab-grown meat] is kind of a brave new world for a lot of people, and food isn't something people like being brave about."
She's the CEO and co-founder of one of fewer than 30 companies that is even in this game in the first place. Her Singapore-based company, Shiok Meats, is the only one to pop up in Southeast Asia. And it's the only company in the world that's attempting to grow crustaceans in a lab, starting with shrimp. This spring, the company debuted a prototype of its shrimp, and completed a seed funding round of $4.6 million.
Yet despite all of these wins, Sriram's own mother won't try the company's shrimp. She's a staunch, lifelong vegetarian, adhering to a strict definition of what that means.
"[Lab-grown meat] is kind of a brave new world for a lot of people, and food isn't something people like being brave about. It's really a rather hard-wired thing," says Kate Krueger, the research director at New Harvest, a non-profit accelerator for cellular agriculture (the umbrella field that studies how to grow animal products in the lab, including meat, dairy, and eggs).
It's so hard-wired, in fact, that trends in food inform our species' origin story. In 2017, a group of paleoanthropologists caused an upset when they unearthed fossils in present day Morocco showing that our earliest human ancestors lived much further north and 100,000 years earlier than expected -- the remains date back 300,000 years. But the excavation not only included bones and tools, it also painted a clear picture of the prevailing menu at the time: The oldest humans were apparently chomping on tons of gazelle, as well as wildebeest and zebra when they could find them, plus the occasional seasonal ostrich egg.
These were people with a diet shaped by available resources, but also by the ability to cook in the first place. In his book Catching Fire: How Cooking Made Us Human, Harvard primatologist Richard Wrangam writes that the very thing that allowed for the evolution of Homo sapiens was the ability to transform raw ingredients into edible nutrients through cooking.
Today, our behavior and feelings around food are the product of local climate, crops, animal populations, and tools, but also religion, tradition, and superstition. So what happens when you add science to the mix? Turns out, we still trend toward the familiar. The innovations in lab-grown meat that are picking up the most steam are foods like burgers, not meat chips, and salmon, not salmon-cod-tilapia hybrids. It's not for lack of imagination, it's because the industry's practitioners know that a lifetime of food memories is a hard thing to contend with. So far, the nascent lab-grown meat industry is not so much disrupting as being shaped by the oldest culture we have.
Not a single piece of lab-grown meat is commercially available to consumers yet, and already so much ink has been spilled debating if it's really meat, if it's kosher, if it's vegetarian, if it's ethical, if it's sustainable. But whether or not the industry succeeds and sticks around is almost moot -- watching these conversations and innovations unfold serves as a mirror reflecting back who we are, what concerns us, and what we aspire to.
The More Things Change, the More They Stay the Same
The building blocks for making lab-grown meat right now are remarkably similar, no matter what type of animal protein a company is aiming to produce.
First, a small biopsy, about the size of a sesame seed, is taken from a single animal. Then, the muscle cells are isolated and added to a nutrient-dense culture in a bioreactor -- the same tool used to make beer -- where the cells can multiply, grow, and form muscle tissue. This tissue can then be mixed with additives like nutrients, seasonings, binders, and sometimes colors to form a food product. Whether a company is attempting to make chicken, fish, beef, shrimp, or any other animal protein in a lab, the basic steps remain similar. Cells from various animals do behave differently, though, and each company has its own proprietary techniques and tools. Some, for example, use fetal calf serum as their cell culture, while others, aiming for a more vegan approach, eschew it.
"New gadgets feel safest when they remind us of other objects that we already know."
According to Mark Post, who made the first lab-grown hamburger at Maastricht University in the Netherlands in 2013, the cells of just one cow can give way to 175 million four-ounce burgers. By today's available burger-making methods, you'd need to slaughter 440,000 cows for the same result. The projected difference in the purely material efficiency between the two systems is staggering. The environmental impact is hard to predict, though. Some companies claim that their lab-grown meat requires 99 percent less land and 96 percent less water than traditional farming methods -- and that rearing fewer cows, specifically, would reduce methane emissions -- but the energy cost of running a lab-grown-meat production facility at an industrial scale, especially as compared to small-scale, pasture-raised farming, could be problematic. It's difficult to truly measure any of this in a burgeoning industry.
At this point, growing something like an intact shrimp tail or a marbled steak in a lab is still a Holy Grail. It would require reproducing the complex musculo-skeletal and vascular structure of meat, not just the cellular basis, and no one's successfully done it yet. Until then, many companies working on lab-grown meat are perfecting mince. Each new company's demo of a prototype food feels distinctly regional, though: At the Disruption in Food and Sustainability Summit in March, Shiok (which is pronounced "shook," and is Singaporean slang for "very tasty and delicious") first shared a prototype of its shrimp as an ingredient in siu-mai, a dumpling of Chinese origin and a fixture at dim sum. JUST, a company based in the U.S., produced a demo chicken nugget.
As Jean Anthelme Brillat-Savarin, the 17th century founder of the gastronomic essay, famously said, "Show me what you eat, and I'll tell you who you are."
For many of these companies, the baseline animal protein they are trying to innovate also feels tied to place and culture: When meat comes from a bioreactor, not a farm, the world's largest exporter of seafood could be a landlocked region, and beef could be "reared" in a bayou, yet the handful of lab-grown fish companies, like Finless Foods and BlueNalu, hug the American coasts; VOW, based in Australia, started making lab-grown kangaroo meat in August; and of course the world's first lab-grown shrimp is in Singapore.
"In the U.S., shrimps are either seen in shrimp cocktail, shrimp sushi, and so on, but [in Singapore] we have everything from shrimp paste to shrimp oil," Sriram says. "It's used in noodles and rice, as flavoring in cup noodles, and in biscuits and crackers as well. It's seen in every form, shape, and size. It just made sense for us to go after a protein that was widely used."
It's tempting to assume that innovating on pillars of cultural significance might be easier if the focus were on a whole new kind of food to begin with, not your popular dim sum items or fast food offerings. But it's proving to be quite the opposite.
"That could have been one direction where [researchers] just said, 'Look, it's really hard to reproduce raw ground beef. Why don't we just make something completely new, like meat chips?'" says Mike Lee, co-founder and co-CEO of Alpha Food Labs, which works on food innovation more broadly. "While that strategy's interesting, I think we've got so many new things to explain to people that I don't know if you want to also explain this new format of food that you've never, ever seen before."
We've seen this same cautious approach to change before in other ways that relate to cooking. Perhaps the most obvious example is the kitchen range. As Bee Wilson writes in her book Consider the Fork: A History of How We Cook and Eat, in the 1880s, convincing ardent coal-range users to switch to newfangled gas was a hard sell. To win them over, inventor William Sugg designed a range that used gas, but aesthetically looked like the coal ones already in fashion at the time -- and which in some visual ways harkened even further back to the days of open-hearth cooking. Over time, gas range designs moved further away from those of the past, but the initial jump was only made possible through familiarity. There's a cleverness to meeting people where they are.
"New gadgets feel safest when they remind us of other objects that we already know," writes Wilson. "It is far harder to accept a technology that is entirely new."
Maybe someday we won't want anything other than meat chips, but not today.
Measuring Success
A 2018 Gallup poll shows that in the U.S., rates of true vegetarianism and veganism have been stagnant for as long as they've been measured. When the poll began in 1999, six percent of Americans were vegetarian, a number that remained steady until 2012, when the number dropped one point. As of 2018, it remained at five percent.
In 2012, when Gallup first measured the percentage of vegans, the rate was two percent. By 2018 it had gone up just one point, to three percent. Increasing awareness of animal welfare, health, and environmental concerns don't seem to be incentive enough to convince Americans, en masse, to completely slam the door on a food culture characterized in many ways by its emphasis on traditional meat consumption.
"A lot of consumers get over the ick factor when you tell them that most of the food that you're eating right now has entered the lab at some point."
Wilson writes that "experimenting with new foods has always been a dangerous business. In the wild, trying out some tempting new berries might lead to death. A lingering sense of this danger may make us risk-averse in the kitchen."
That might be one psychologically deep-seated reason that Americans are so resistant to ditch meat altogether. But a middle ground is emerging with a rise in flexitarianism, which aims to reduce reliance on traditional animal products. "Americans are eager to include alternatives to animal products in their diets, but are not willing to give up animal products completely," the same 2018 Gallup poll reported. This may represent the best opportunity for lab-grown meat to wedge itself into the culture.
Quantitatively predicting a population's willingness to try a lab-grown version of its favorite protein is proving a hard thing to measure, however, because it's still science fiction to a regular consumer. Measuring popular opinion of something that doesn't really exist yet is a dubious pastime.
In 2015, University of Wisconsin School of Public Health researchers Linnea Laestadius and Mark Caldwell conducted a study using online comments on articles about lab-grown meat to suss out public response to the food. The results showed a mostly negative attitude, but that was only two years into a field that is six years old today. Already public opinion may have shifted.
Shiok Meat's Sriram and her co-founder Ka Yi Ling have used online surveys to get a sense of the landscape, but they also take a more direct approach sometimes. Every time they give a public talk about their company and their shrimp, they poll their audience before and after the talk, using the question, "How many of you are willing to try, and pay, to eat lab-grown meat?"
They consistently find that the percentage of people willing to try goes up from 50 to 90 percent after hearing their talk, which includes information about the downsides of traditional shrimp farming (for one thing, many shrimp are raised in sewage, and peeled and deveined by slaves) and a bit of information about how lab-grown animal protein is being made now. I saw this pan out myself when Ling spoke at a New Harvest conference in Cambridge, Massachusetts in July.
"A lot of consumers get over the ick factor when you tell them that most of the food that you're eating right now has entered the lab at some point," Sriram says. "We're not going to grow our meat in the lab always. It's in the lab right now, because we're in R&D. Once we go into manufacturing ... it's going to be a food manufacturing facility, where a lot of food comes from."
The downside of the University of Wisconsin's and Shiok Meat's approach to capturing public opinion is that they each look at self-selecting groups: Online commenters are often fueled by a need to complain, and it's likely that anyone attending a talk by the co-founders of a lab-grown meat company already has some level of open-mindedness.
So Sriram says that she and Ling are also using another method to assess the landscape, and it's somewhere in the middle. They've been watching public responses to the closest available product to lab-grown meat that's on the market: Impossible Burger. As a 100 percent plant-based burger, it's not quite the same, but this bleedable, searable patty is still very much the product of science and laboratory work. Its remarkable similarity to beef is courtesy of yeast that have been genetically engineered to contain DNA from soy plant roots, which produce a protein called heme as they multiply. This heme is a plant-derived protein that can look and act like the heme found in animal muscle.
So far, the sciencey underpinnings of the burger don't seem to be turning people off. In just four years, it's already found its place within other American food icons. It's readily available everywhere from nationwide Burger Kings to Boston's Warren Tavern, which has been in operation since 1780, is one of the oldest pubs in America, and is even named after the man who sent Paul Revere on his midnight ride. Some people have already grown so attached to the Impossible Burger that they will actually walk out of a restaurant that's out of stock. Demand for the burger is outpacing production.
"Even though [Impossible] doesn't consider their product cellular agriculture, it's part of a spectrum of innovation," Krueger says. "There are novel proteins that you're not going to find in your average food, and there's some cool tech there. So to me, that does show a lot of willingness on people's part to think about trying something new."
The message for those working on animal-based lab-grown meat is clear: People will accept innovation on their favorite food if it tastes good enough and evokes the same emotional connection as the real deal.
"How people talk about lab-grown meat now, it's still a conversation about science, not about culture and emotion," Lee says. But he's confident that the conversation will start to shift in that direction if the companies doing this work can nail the flavor memory, above all.
And then proving how much power flavor lords over us, we quickly derail into a conversation about Doritos, which he calls "maniacally delicious." The chips carry no health value whatsoever and are a native product of food engineering and manufacturing — just watch how hard it is for Bon Appetit associate food editor Claire Saffitz to try and recreate them in the magazine's test kitchen — yet devotees remain unfazed and crunch on.
"It's funny because it shows you that people don't ask questions about how [some foods] are made, so why are they asking so many questions about how lab-grown meat is made?" Lee asks.
For all the hype around Impossible Burger, there are still controversies and hand-wringing around lab-grown meat. Some people are grossed out by the idea, some people are confused, and if you're the U.S. Cattlemen's Association (USCA), you're territorial. Last year, the group sent a petition to the USDA to "exclude products not derived directly from animals raised and slaughtered from the definition of 'beef' and meat.'"
"I think we are probably three or four big food safety scares away from everyone, especially younger generations, embracing lab-grown meat as like, 'Science is good; nature is dirty, and can kill you.'"
"I have this working hypothesis that if you look at the nation in 50-year spurts, we revolve back and forth between artisanal, all-natural food that's unadulterated and pure, and food that's empowered by science," Lee says. "Maybe we've only had one lap around the track on that, but I think we are probably three or four big food safety scares away from everyone, especially younger generations, embracing lab-grown meat as like, 'Science is good; nature is dirty, and can kill you.'"
Food culture goes beyond just the ingredients we know and love — it's also about how we interact with them, produce them, and expect them to taste and feel when we bite down. We accept a margin of difference among a fast food burger, a backyard burger from the grill, and a gourmet burger. Maybe someday we'll accept the difference between a burger created by killing a cow and a burger created by biopsying one.
Looking to the Future
Every time we engage with food, "we are enacting a ritual that binds us to the place we live and to those in our family, both living and dead," Wilson writes in Consider the Fork. "Such things are not easily shrugged off. Every time a new cooking technology has been introduced, however useful … it has been greeted in some quarters with hostility and protestations that the old ways were better and safer."
This is why it might be hard for a vegetarian mother to try her daughter's lab-grown shrimp, no matter how ethically it was produced or how awe-inspiring the invention is. Yet food cultures can and do change. "They're not these static things," says Benjamin Wurgaft, a historian whose book Meat Planet: Artificial Flesh and the Future of Food comes out this month. "The real tension seems to be between slow change and fast change."
In fact, the very definition of the word "meat" has never exclusively meant what the USCA wants it to mean. Before the 12th century, when it first appeared in Old English as "mete," it wasn't very specific at all and could be used to describe anything from "nourishment," to "food item," to "fodder," to "sustenance." By the 13th century it had been narrowed down to mean "flesh of warm-blooded animals killed and used as food." And yet the British mincemeat pie lives on as a sweet Christmas treat full of -- to the surprise of many non-Brits -- spiced, dried fruit. Since 1901, we've also used this word with ease as a general term for anything that's substantive -- as in, "the meat of the matter." There is room for yet more definitions to pile on.
"The conversation [about lab-ground meat] has changed remarkably in the last six years," Wurgaft says. "It has become a conversation about whether or not specific companies will bring a product to market, and that's a really different conversation than asking, 'Should we produce meat in the lab?'"
As part of the field research for his book, Wurgaft visited the Rijksmuseum Boerhaave, a Dutch museum that specializes in the history of science and medicine. It was 2015, and he was there to see an exhibit on the future of food. Just two years earlier, Mark Post had made that first lab-grown hamburger about a two-and-a-half hour drive south of the museum. When Wurgaft arrived, he found the novel invention, which Post had donated to the museum, already preserved and served up on a dinner plate, the whole outfit protected by plexiglass.
"They put this in the exhibit as if it were already part of the historical records, which to a historian looked really weird," Wurgaft says. "It looked like somebody taking the most recent supercomputer and putting it in a museum exhibit saying, 'This is the supercomputer that changed everything,' as if you were already 100 years in the future, looking back."
It seemed to symbolize an effort to codify a lab-grown hamburger as a matter of Dutch pride, perhaps someday occupying a place in people's hearts right next to the stroopwafel.
"Who's to say that we couldn't get a whole school of how to cook with lab-grown meat?"
Lee likes to imagine that part of the legacy of lab-grown meat, if it succeeds, will be to inspire entirely new fads in cooking -- a step beyond ones like the crab-filled avocado of the 1960s or the pesto of the 1980s in the U.S.
"[Lab-grown meat] is inherently going to be a different quality than anything we've done with an animal," he says. "Look at every cut [of meat] on the sphere today -- each requires a slightly different cooking method to optimize the flavor of that cut. Who's to say that we couldn't get a whole school of how to cook with lab-grown meat?"
At this point, most of us have no way of trying lab-grown meat. It remains exclusively available through sometimes gimmicky demos reserved for investors and the media. But Wurgaft says the stories we tell about this innovation, the articles we write, the films we make, and yes, even the museum exhibits we curate, all hold as much cultural significance as the product itself might someday.
Air pollution can lead to lung cancer. The connection suggests new ways to stop cancer in its tracks.
Forget taking a deep breath. Around the world, 99 percent of people breathe air polluted to unsafe levels, according to data from the World Health Organization. Activities such as burning fossil fuels release greenhouse gases that contribute to air pollution, which could lead to heart disease, stroke, asthma, emphysema, and some types of cancer.
“The burden of disease attributable to air pollution is now estimated to be on a par with other major global health risks such as unhealthy diet and tobacco smoking, and air pollution is now recognized as the single biggest environmental threat to human health,” wrote the authors of a 2021 WHO report.
The majority of lung cancer is attributed to smoking. But as pollution levels have increased, and anti-smoking campaigns have discouraged smoking, the proportion of lung cancers diagnosed in non-smokers has grown. The CDC estimates that 10 to 20 percent of lung cancers in the U.S. currently occur in non-smokers.
The mechanism between air pollution and the development of lung cancer has been unclear, but researchers at London’s Francis Crick Institute recently made an important breakthrough in understanding the connection. Lead investigator Charles Swanton presented this research last month at a conference in Paris.
Pollution awakens mutations
The Crick Institute scientists were able to identify a new link between common air pollutants and non-small cell lung cancer (NSCLC). They focused on pollutants called particulate matter, or PM, that are 2.5 microns wide, narrower than human cells.
Most cancer diagnosed in non-smoking people is NSCLC, but this type of cancer hasn’t received the same research attention as more common lung cancers found in smokers, according to Clare Weeden, a cancer researcher at the Crick Institute and a co-author of the study.
“This is a really underserved and under-researched population that we really need to tackle, as well as lung cancers that occur in smokers,” she says. “Lung cancer is the number one cancer killer worldwide.”
In the past, some researchers believed air pollution caused mutations that led to cancer. Others believed these mutations could remain dormant without any detriment to health until pollutants or other stressors triggered them to become cancerous. Reviving the latter hypothesis that carcinogens may activate pre-existing mutations, instead of directly causing them, the Crick researchers analyzed samples from 463,679 people in the UK and parts of Asia, noting mutations and comparing changes in gene expression in mice and human cells.
“The mutation can exist in a nascent clone without causing cancer,” says Emilia Lim, a bioinformatics expert and a co-first author of the Crick study. “It is the carcinogen that promotes a conducive environment for this one little clone to grow and expand into cancer. Through our work, we were able to revive excitement for this hypothesis and bring it to light.”
The study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
Other researchers had previously identified a link between mutations in certain genes that control epidermal growth factor receptors, or EGFR mutations, and the development of NSCLC. In a 2019 study of 250 people with this type of cancer, about 32 percent had the mutation. Women are more likely to have EGFR mutations than men.
Not everyone who has the EGFR mutation will develop lung cancer. Respirologist Stephen Lam studies lung cancer at the BC Cancer Research Centre in Vancouver, Canada, but was not involved in the Crick Institute research. He says the study explains a confusing pattern of lung cancer developing, particularly in women, despite a lack of environmental risk factors like smoking, secondhand smoke, or radon exposure. The culprit in these cases may have been too much PM 2.5 exposure.
More exposure leads to inflammation and lesions
The Crick researchers found that an excess of PM 2.5 in the air sparked an inflammatory process in cells within the lung. This inflammation set the stage for NSCLC to develop in people and mice with existing EGFR mutations.
The researchers also exposed mice without EGFR mutations to PM 2.5 pollution—an experiment that couldn’t be ethically conducted in humans—to link pollution exposure to NSCLC. The mice experiments also showed that NSCLC is dose-dependent; higher levels of exposure were associated with higher number of cancerous lesions forming.
Ultimately, the study “fundamentally changed how we view lung cancer in people who have never smoked,” said Swanton in a Crick Institute press release. “Cells with cancer-causing mutations accumulate naturally as we age, but they are normally inactive. We’ve demonstrated that air pollution wakes these cells up in the lungs, encouraging them to grow and potentially form tumors.”
Preventing cancer before it begins
Targeted therapies already exist for people with EGFR mutations who’ve developed NSCLC, but they have many side effects, according to Weeden. Researchers hope that making more definitive links between pollutants and cancer could help prevent people with EGFR or other mutations from developing lung cancer in the first place.
Along those lines, as an additional component of their study presented last month, the Crick researchers were able to prevent cancer in mice that had the EGFR mutations by blocking inflammation. They used an antibody to inhibit a protein called interleukin 1 beta, which plays a key role in inflammation. Scientists could eventually use such antibodies or other therapies to make a drug treatment that people can take to stop cancer in its tracks, even if they live in highly polluted areas.
Such potential could reach beyond lung cancer; in the past, Crick and other researchers have also found associations between exposure to air pollution and mesothelioma, as well as cancers of the small intestine, lip, mouth, and throat. These links could be meaningful to a growing number of people as climate change intensifies, and with increases in air pollution from fossil fuel combustion and natural disasters like forest fires.
Plus, air pollution is just one external condition that can flip the switch of these inflammatory pathways. Identifying a link between pollution and cancer “has wide ramifications for many other environmental factors that may [play] similar roles,” Weedon says. She hopes that the Crick study and future research in this area will offer some hope for non-smokers frustrated by cancer diagnoses.
Naked Mole Rats Defy Aging. One Scientist Has Dedicated Her Career to Finding Out How.
Rochelle "Shelley" Buffenstein has one of the world's largest, if not the largest, lab-dwelling colonies of the naked mole rat. (No one has done a worldwide tabulation, but she has 4,500 of them.) Buffenstein has spent decades studying the little subterranean-dwelling rodents. Over the years, she and her colleagues have uncovered one surprising discovery after another, which has led them to re-orient the whole field of anti-aging research.
Naked mole rats defy everything we thought we knew about aging. These strange little rodents from arid regions of Africa, such as Kenya, Ethiopia and Somalia, live up to ten times longer than their size would suggest. And unlike virtually every other animal, they don't lose physical or cognitive abilities with age, and even retain their fertility up until the end of life. They appear to have active defenses against the ravages of time, suggesting that aging may not be inevitable. Could these unusual creatures teach humans how to extend life and ameliorate aging?
Buffenstein, who is senior principle investigator at Calico Life Sciences, has dedicated her life to finding out. Her early interest in the animals of what is now Zimbabwe led to her current position as a cutting-edge anti-aging researcher at Calico, the Google-funded health venture launched in 2013. The notoriously secretive company is focused on untangling the mysteries of why animals and people age, and whether there are ways to slow or temporarily arrest the process.
The small, wrinkly animal, which lives in underground burrows in the hot, arid regions of Africa, is hardly the beauty queen of the mammalian kingdom. Furless, buck-toothed and tiny-eyed, the creatures look like they could use a good orthodontist, a protective suit of clothes and possibly, some spectacles to enhance their eyesight. But these rats more than make up for their unimpressive looks with their superlative ability to adapt to some of the most inhospitable conditions on earth.
Based on the usual rule that body size predicts lifespan, naked mole rats shouldn't live that long. After all, similarly-sized rodents like mice have a life expectancy of two years or less. But Buffenstein was one of the first scientists to recognize that naked mole rats live an extraordinarily long time, with her oldest animal approaching 39 years of age. In addition, they never become geriatric in the human sense, defying the common signs of aging — age-related diseases, cognitive decline and even menopause. In fact, the queens, or females that do all the breeding in a bee-like underground colony, remain fertile and give birth to healthy pups up until what would be considered very old age in humans. And the naked mole rat has other curious abilities, such as the ability to endure extreme low-oxygen, or hypoxic, conditions like those they encounter in their underground nests.
"One thing we've learned from these animals is that they stay healthy until the very end."
It's not that the naked mole rat isn't subject to the vicissitudes of life, or the normal wear and tear of biological processes. Over the years, Buffenstein and her colleagues have discovered that, while the process of oxidative stress — thought for 50 years to be the main cause of aging — occurs in the naked mole rat just as in any other animal, its damage does not accumulate with age. Oxidative stress occurs during normal cell metabolism when oxygen "free radicals" with one or more unpaired electrons wreak havoc on large cellular molecules, leaving microscopic debris in their wake that clogs up the gears of healthy cell function. Somehow, naked mole rats have an enhanced ability to clear out the damaged cells and molecules before they can set off the usual chain reaction of cell dysfunction and death, according to a 2013 paper in which Buffenstein is the lead author.
Oxidative stress is not the only factor known to be problematic in aging. Slowly accumulating damage to DNA typically leads to protein malfunction and improper folding. In humans and most other animals, these protein fragments can accumulate in cells and gum up the works. Only not so much in naked mole rats, which are able to maintain normal protein folding throughout their long life. After years of discoveries like these, Buffenstein has gradually reframed her focus from "what goes wrong to produce aging?" to "what goes right in the naked mole rat to help it defy the normal wear and tear of life?" Buffenstein's research suggests that the tiny mammals have a unique ability to somehow clear out damaged protein fragments and other toxic debris before they can cause disease and aging.
How She Got Here
Buffenstein ascribes her initial acquaintance with the naked mole rat to serendipity. Back in 1979, her postgraduate mentor Jenny Jarvis at the University of Cape Town in South Africa kept a small colony of rats in her office while studying the mechanisms that lead to the animals' unusual adaptive capabilities. It was Buffenstein's job to take care of them. Working with Jarvis, Buffenstein focused on understanding their unique adaptations to the extreme conditions of their natural habitat.
They studied the unusual behaviors regulating the rat colonies. For instance, they observed that designated "workers" dig the entire colony's underground tunnels and a single reproducing female breeds with only a small number of males. Buffenstein also examined how these animals are able to survive without the "sunshine hormone" — vitamin D — and their unusual modes of regulating their internal temperatures and converting food into energy. Though classified as mammals, the rodents simply don't conform to the mammalian handbook, having found ingenuous ways to alter their bodies and behavior that is fine-tuned to the scorching heat and aridity of their environment.
To escape the heat, they simply burrow underground and live in elaborate tunnels. To cope with the low-oxygen conditions underground, they slowed their metabolism and learned to live for extended periods of time in such hypoxic conditions that an ordinary animal would quickly suffocate. But it was slowly dawning on Buffenstein that the small creatures were exceptional in additional ways.
When Buffenstein got her first academic position at the University of Witwatersrand in Johannesburg, Jarvis said she could take some of the naked mole rats with her. When she did, Buffenstein noticed that the animals were living far longer than similarly sized rodents. "At that stage, they were about ten years old. Little did I know how long they would eventually show us they could live," she says.
In 1997, after accepting a position at the City College of New York, Buffenstein moved to the U.S. and took her rat colony with her. There she was able to pursue an evolving narrative about the humble naked mole rat that continued to defy expectations. As the years passed, it was becoming more and more evident that her observations could have major implications for aging research. Eventually, she took a position at the Barshop Institute for Aging and Longevity Studies in San Antonio, Texas.
One early observation of Buffenstein's suggested that the species most often used in aging research—mice, roundworms, fruit flies and yeast—have short lifespans and poor defenses against aging. These animals provide important insights into how aging works, and have revealed possible targets for intervention. But they don't show what goes right in apparently non-aging animals like the naked mole rat.
Buffenstein's years of studying the rats has laid the foundation for a whole new perspective in aging research.
"My hypothesis," she says, "is that naked mole rats are very good at removing damaged macromolecules and cells, thereby maintaining homeostasis and cell and tissue function. All the repair pathways examined by us and others in the field point to more efficient repair and more rapid responses to damaging agents." These include things like free radicals and radiation.
Buffenstein’s Legacy
Some researchers today are building on Buffenstein's foundational discoveries to home in on possible anti-aging mechanisms that lead to the extraordinary resilience of naked mole rats. University of Cambridge researcher and co-founder of the institution's Naked Mole-Rat Initiative, Ewan St. John Smith, is studying the animal's resistance to cancer.
In a 2020 paper published in Nature, Smith and his colleagues established that naked mole rats harbor cancer-causing genes, and these genes occasionally create cancer cells. But something in the rats shuts the multiplication process down before the cells can grow out of control and form tumors. Now, scientists want to know what mechanisms, exactly, are at play in preventing the cells from invading healthy tissues. Smith has hypothesized that the answer is somehow embedded in interactions in the cells' microenvironment.
He also thinks the animal's immune system could just be very effective at seeking out and destroying cancer cells. Several current cancer therapies work by boosting the body's immune system so it can attack and eliminate the toxic cells. It's possible that the naked mole rat's immune system naturally goes into hyper-drive when cancer cells appear, enabling it to nip the disease in the bud before tumors can form. A pharmacologist by training, Smith thinks that if there is some chemical mediator in the naked mole rat that supercharges its immune cells, perhaps that mediator can be synthesized in a drug to treat humans for cancer.
The naked mole rat's extreme tolerance to hypoxia could also play a role. "Interestingly," he says, "when cells become cancerous, they also become hypoxic, and naked mole rats are known to be very resistant to hypoxia.
He notes that a form of low-level hypoxia is also present in the bodies and brains of both aged mice and older humans. It's commonly seen in the brains of humans with Alzheimer's disease and other forms of age-related dementia. This suggests that hypoxia in humans — and in other mammals — may have a role to play in Alzheimer's and the aging process itself. Resistance to hypoxia could be why the naked mole rat, in Smith's words, "chugs along quite happily" in conditions that in humans are associated with disease and decline.
Smith cheerfully acknowledges his debt to Buffenstein for laying so much of the groundwork in a field rife with possible implications for anti-aging. "Shelley is amazing," he says. "Naked mole rats have a queen and I always refer to her as the queen of the naked mole rat world." In fact, Buffenstein gave Smith his first colony of rats, which he's since grown to about 150. "Some of them will still be around when I retire," he jokes.
Vera Gorbunova, a professor of biology and oncology at the University of Rochester who studies both longevity and cancer in naked mole rats, credits Buffenstein with getting others to study the animals for anti-aging purposes. Gorbunova believes that "cancer and aging go hand-in-hand" and that longer-lived animals have better, more accurate DNA repair.
Gorbunova is especially interested in the naked mole rat's ability to secrete a superabundance of a "super-sugar" molecule called hyaluronan, a ubiquitous additive to skin creams for its moisturizing effect. Gorbunova and others have observed that the presence of high concentrations of hyaluronan in the naked mole rat's extracellular matrix — the chemical-rich solution between cells — prevents the overcrowding of cells. This, perhaps, could be the key to the animal's ability to stop tumors from forming.
Hyaluronan is also present in the extracellular matrix of humans, but the naked mole rat molecule is more than five times larger than the versions found in humans or mice, and is thought to play a significant part in the animal's DNA repair. But just rubbing a cream containing hyaluronan over your skin won't stop cancer or aging. High concentrations of the substance in the extracellular matrix throughout your body would likely be needed.
Gorbunova notes that the naked mole rat offers a multitude of possibilities that could eventually lead to drugs to slow human aging. "I'm optimistic that there are many different strategies, because the naked mole rat likely has many processes going on that fight aging," she says. "I think that in a relatively short time, there will be bonafide treatments to test in animals. One thing we've learned from these animals is that they stay healthy until the very end."
So if naked mole rats don't become frail with age or develop age-related diseases, what does kill them? The answer, unfortunately, is usually other naked mole rats. Buffenstein has long noted that even though they live in highly cooperative colonies, they can be quite cantankerous when there's a disruption in the hierarchy, a sentiment echoed by Gorbunova. "Sometimes there are periods of peace and quiet, but if something happens to the queen, all hell breaks loose," she says. "If the queen is strong, everybody knows their place," but if the queen dies, the new queen is inevitably decided by violent competition.
To the casual observer, a strange, wrinkly rodent like the naked mole rat might seem to have little to teach us about ourselves, but Buffenstein is confident that her discoveries could have major implications for human longevity research. Today, at Calico's labs in San Francisco, she's focused entirely on the determining how anti-aging defense mechanisms in the rats could lead to similar defenses being stimulated or introduced in humans.
"The million-dollar question is, what are the mechanisms protecting against aging, and can these be translated into therapies to delay or abrogate human aging, too?"
Buffenstein fired up a new generation of scientists with multiple discoveries, especially the fundamental one that naked mole rats are subject to the same wear and tear over time as the rest of us, but somehow manage to reverse it. These days, the trailblazer is at work on untangling the molecular mechanisms involved in the animal's resistance to cardiac aging. On top of everything else, the small creature has a unique ability to fight off the scourge of heart disease, which is the leading cause of death in the industrialized world.
After all, the point is not to extend old age, but to slow down aging itself so that frailty and disability are compressed into a brief period after a long-extended period of vitality. By switching the focus from what goes wrong to mechanisms that defend against aging in the first place, the discoveries of Buffenstein and a new generation of researchers who are building on her groundbreaking research promise to be a driving force in the quest to extend not only life, but healthy, vigorous life in humans.
This article was first published by Leaps.org on June 23, 2021.