The "Making Sense of Science" podcast features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This monthly podcast is hosted by journalist Kira Peikoff, founding editor of the award-winning science outlet Leaps.org.
This month, our guest is notable genetics pioneer Dr. George Church of Harvard Medical School. Dr. Church has remarkably bold visions for how innovation in science can fundamentally transform the future of humanity and our planet. His current moonshot projects include: de-extincting some of the woolly mammoth's genes to create a hybrid Asian elephant with the cold-tolerance traits of the woolly mammoth, so that this animal can re-populate the Arctic and help stave off climate change; reversing chronic diseases of aging through gene therapy, which he and colleagues are now testing in dogs; and transplanting genetically engineered pig organs to humans to eliminate the tragically long waiting lists for organs. Hear Dr. Church discuss all this and more on our latest episode.
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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.
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.
In June 2012, Kirstie Ennis was six months into her second deployment to Afghanistan and recently promoted to sergeant. The helicopter gunner and seven others were three hours into a routine mission of combat resupplies and troop transport when their CH-53D helicopter went down hard.
Miraculously, all eight people onboard survived, but Ennis' injuries were many and severe. She had a torn rotator cuff, torn labrum, crushed cervical discs, facial fractures, deep lacerations and traumatic brain injury. Despite a severely fractured ankle, doctors managed to save her foot, for a while at least.
In November 2015, after three years of constant pain and too many surgeries to count, Ennis relented. She elected to undergo a lower leg amputation but only after she completed the 1,000-mile, 72-day Walking with the Wounded journey across the UK.
On Veteran's Day of that year, on the other side of the country, orthopedic surgeon Cato Laurencin announced a moonshot challenge he was setting out to achieve on behalf of wounded warriors like Ennis: the Hartford Engineering A Limb (HEAL) Project.
Laurencin, who is a University of Connecticut professor of chemical, materials and biomedical engineering, teamed up with experts in tissue bioengineering and regenerative medicine from Harvard, Columbia, UC Irvine and SASTRA University in India. Laurencin and his colleagues at the Connecticut Convergence Institute for Translation in Regenerative Engineering made a bold commitment to regenerate an entire limb within 15 years – by the year 2030.
Dr. Cato Laurencin pictured in his office at UConn.
Photo Credit: UConn
Regenerative Engineering -- A Whole New Field
Limb regeneration in humans has been a medical and scientific fascination for decades, with little to show for the effort. However, Laurencin believes that if we are to reach the next level of 21st century medical advances, this puzzle must be solved.
An estimated 185,000 people undergo upper or lower limb amputation every year. Despite the significant advances in electromechanical prosthetics, these individuals still lack the ability to perform complex functions such as sensation for tactile input, normal gait and movement feedback. As far as Laurencin is concerned, the only clinical answer that makes sense is to regenerate a whole functional limb.
Laurencin feels other regeneration efforts were hampered by their siloed research methods with chemists, surgeons, engineers all working separately. Success, he argues, requires a paradigm shift to a trans-disciplinary approach that brings together cutting-edge technologies from disparate fields such as biology, material sciences, physical, chemical and engineering sciences.
As the only surgeon ever inducted into the academies of Science, Medicine and Innovation, Laurencin is uniquely suited for the challenge. He is regarded as the founder of Regenerative Engineering, defined as the convergence of advanced materials sciences, stem cell sciences, physics, developmental biology and clinical translation for the regeneration of complex tissues and organ systems.
But none of this is achievable without early clinician participation across scientific fields to develop new technologies and a deeper understanding of how to harness the body's innate regenerative capabilities. "When I perform a surgical procedure or something is torn or needs to be repaired, I count on the body being involved in regenerating tissue," he says. "So, understanding how the body works to regenerate itself and harnessing that ability is an important factor for the regeneration process."
The Birth of the Vision
Laurencin's passion for regeneration began when he was a sports medicine fellow at Cornell University Medical Center in the early 1990s. There he saw a significant number of injuries to the anterior cruciate ligament (ACL), the major ligament that stabilizes the knee. He believed he could develop a better way to address those injuries using biomaterials to regenerate the ligament. He sketched out a preliminary drawing on a napkin one night over dinner. He has spent the next 30 years regenerating tissues, including the patented L-C ligament.
As chair of Orthopaedic Surgery at the University of Virginia during the peak of the wars in Iraq and Afghanistan, Laurencin treated military personnel who survived because of improved helmets, body armor and battlefield medicine but were left with more devastating injuries, including traumatic brain injuries and limb loss.
"I was so honored to care for them and I so admired their steadfast courage that I became determined to do something big for them," says Laurencin.
When he tells people about his plans to regrow a limb, he gets a lot of eye rolls, which he finds amusing but not discouraging. Growing bone cells was relatively new when he was first focused on regenerating bone in 1987 at MIT; in 2007 he was well on his way to regenerating ligaments at UVA when many still doubted that ligaments could even be reconstructed. He and his team have already regenerated torn rotator cuff tendons and ACL ligaments using a nano-textured fabric seeded with stem cells.
Even as a finalist for the $4 million NIH Pioneer Award for high-risk/high-reward research, he faced a skeptical scientific audience in 2014. "They said, 'Well what do you plan to do?' I said 'I plan to regenerate a whole limb in people.' There was a lot of incredulousness. They stared at me and asked a lot of questions. About three days later, I received probably the best score I've ever gotten on an NIH grant."
In the Thick of the Science
Humans are born with regenerative abilities--two-year-olds have regrown fingertips--but lose that ability with age. Salamanders are the only vertebrates that can regenerate lost body parts as adults; axolotl, the rare Mexican salamander, can grow extra limbs.
The axolotl is important as a model organism because it is a four-footed vertebrate with a similar body plan to humans. Mapping the axolotl genome in 2018 enhanced scientists' genetic understanding of their evolution, development, and regeneration. Being easy to breed in captivity allowed the HEAL team to closely study these amphibians and discover a new cell type they believe may shed light on how to mimic the process in humans.
"Whenever limb regeneration takes place in the salamander, there is a huge amount of something called heparan sulfate around that area," explains Laurencin. "We thought, 'What if this heparan sulfate is the key ingredient to allowing regeneration to take place?' We found these groups of cells that were interspersed in tissues during the time of regeneration that seemed to have connections to each other that expressed this heparan sulfate."
Called GRID (Groups that are Regenerative, Interspersed and Dendritic), these cells were also recently discovered in mice. While GRID cells don't regenerate as well in mice as in salamanders, finding them in mammals was significant.
"If they're found in mice. we might be able to find these in humans in some form," Laurencin says. "We think maybe it will help us figure out regeneration or we can create cells that mimic what grid cells do and create an artificial grid cell."
What Comes Next?
Laurencin and his team have individually engineered and made every single tissue in the lower limb, including bone, cartilage, ligament, skin, nerve, blood vessels. Regenerating joints and joint tissue is the next big mile marker, which Laurencin sees as essential to regenerating a limb that functions and performs in the way he envisions.
"Using stem cells and amnion tissue, we can regenerate joints that are damaged, and have severe arthritis," he says. "We're making progress on all fronts, and making discoveries we believe are going to be helping people along the way."
That focus and advancement is vital to Ennis. After laboring over the decision to have her leg amputated below the knee, she contracted MRSA two weeks post-surgery. In less than a month, she went from a below-the-knee-amputee to a through-the-knee amputee to an above-the-knee amputee.
"A below-the-knee amputation is night-and-day from above-the-knee," she said. "You have to relearn everything. You're basically a toddler."
Kirstie Ennis pictured in July 2020.
Photo Credit: Ennis' Instagram
The clock is ticking on the timeline Laurencin set for himself. Nine years might seem like forever if you're doing time but it might appear fleeting when you're trying to create something that's never been done before. But Laurencin isn't worried. He's convinced time is on his side.
"Every week, I receive an email or a call from someone, maybe a mother whose child has lost a finger or I'm in communication with a disabled American veteran who wants to know how the progress is going. That energizes me to continue to work hard to try to create these sorts of solutions because we're talking about people and their lives."
He devotes about 60 hours a week to the project and the roughly 100 students, faculty and staff who make up the HEAL team at the Convergence Institute seem acutely aware of what's at stake and appear equally dedicated.
"We're in the thick of the science in terms of making this happen," says Laurencin. "We've moved from making the impossible possible to making the possible a reality. That's what science is all about."