June 23 | 2021
Naked Mole Rats Defy Aging. One Scientist Has Dedicated Her Career to Finding Out How.
Eve Herold is an award-winning science writer and consultant in the scientific and medical nonprofit space. A longtime communications and policy executive for scientific organizations, she currently serves as Director of Policy Research and Education for the Healthspan Action
Coalition. She has written extensively about issues at the crossroads of science and society, including regenerative medicine, aging and longevity, medical implants, transhumanism, robotics and AI, and bioethical issues in leading-edge medicine. Her books include Stem Cell Wars and
Beyond Human, and her latest book, Robots and the People Who Love Them, will be released in January 2024. Her work has appeared in Vice, Medium, The Washington Post and the Boston Globe, among others. She’s a frequent contributor to Leaps.org and is the recipient of the 2019
Arlene Eisenberg Award from the American Society of Journalists and Authors.
Naked mole rats have extraordinarily long lifespans and are extremely resistant to cancer.
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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.
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.
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Eve Herold is an award-winning science writer and consultant in the scientific and medical nonprofit space. A longtime communications and policy executive for scientific organizations, she currently serves as Director of Policy Research and Education for the Healthspan Action
Coalition. She has written extensively about issues at the crossroads of science and society, including regenerative medicine, aging and longevity, medical implants, transhumanism, robotics and AI, and bioethical issues in leading-edge medicine. Her books include Stem Cell Wars and
Beyond Human, and her latest book, Robots and the People Who Love Them, will be released in January 2024. Her work has appeared in Vice, Medium, The Washington Post and the Boston Globe, among others. She’s a frequent contributor to Leaps.org and is the recipient of the 2019
Arlene Eisenberg Award from the American Society of Journalists and Authors.
May 02 | 2023
Regenerative medicine has come a long way, baby
After a cloned baby sheep, what started as one of the most controversial areas in medicine is now promising to transform it.
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The field of regenerative medicine had a shaky start. In 2002, when news spread about the first cloned animal, Dolly the sheep, a raucous debate ensued. Scary headlines and organized opposition groups put pressure on government leaders, who responded by tightening restrictions on this type of research.
Fast forward to today, and regenerative medicine, which focuses on making unhealthy tissues and organs healthy again, is rewriting the code to healing many disorders, though it’s still young enough to be considered nascent. What started as one of the most controversial areas in medicine is now promising to transform it.
Progress in the lab has addressed previous concerns. Back in the early 2000s, some of the most fervent controversy centered around somatic cell nuclear transfer (SCNT), the process used by scientists to produce Dolly. There was fear that this technique could be used in humans, with possibly adverse effects, considering the many medical problems of the animals who had been cloned.
But today, scientists have discovered better approaches with fewer risks. Pioneers in the field are embracing new possibilities for cellular reprogramming, 3D organ printing, AI collaboration, and even growing organs in space. It could bring a new era of personalized medicine for longer, healthier lives - while potentially sparking new controversies.
Engineering tissues from amniotic fluids
Work in regenerative medicine seeks to reverse damage to organs and tissues by culling, modifying and replacing cells in the human body. Scientists in this field reach deep into the mechanisms of diseases and the breakdowns of cells, the little workhorses that perform all life-giving processes. If cells can’t do their jobs, they take whole organs and systems down with them. Regenerative medicine seeks to harness the power of healthy cells derived from stem cells to do the work that can literally restore patients to a state of health—by giving them healthy, functioning tissues and organs.
Modern-day regenerative medicine takes its origin from the 1998 isolation of human embryonic stem cells, first achieved by John Gearhart at Johns Hopkins University. Gearhart isolated the pluripotent cells that can differentiate into virtually every kind of cell in the human body. There was a raging controversy about the use of these cells in research because at that time they came exclusively from early-stage embryos or fetal tissue.
Back then, the highly controversial SCNT cells were the only way to produce genetically matched stem cells to treat patients. Since then, the picture has changed radically because other sources of highly versatile stem cells have been developed. Today, scientists can derive stem cells from amniotic fluid or reprogram patients’ skin cells back to an immature state, so they can differentiate into whatever types of cells the patient needs.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
The ethical debate has been dialed back and, in the last few decades, the field has produced important innovations, spurring the development of whole new FDA processes and categories, says Anthony Atala, a bioengineer and director of the Wake Forest Institute for Regenerative Medicine. Atala and a large team of researchers have pioneered many of the first applications of 3D printed tissues and organs using cells developed from patients or those obtained from amniotic fluid or placentas.
His lab, considered to be the largest devoted to translational regenerative medicine, is currently working with 40 different engineered human tissues. Sixteen of them have been transplanted into patients. That includes skin, bladders, urethras, muscles, kidneys and vaginal organs, to name just a few.
These achievements are made possible by converging disciplines and technologies, such as cell therapies, bioengineering, gene editing, nanotechnology and 3D printing, to create living tissues and organs for human transplants. Atala is currently overseeing clinical trials to test the safety of tissues and organs engineered in the Wake Forest lab, a significant step toward FDA approval.
In the context of medical history, the field of regenerative medicine is progressing at a dizzying speed. But for those living with aggressive or chronic illnesses, it can seem that the wheels of medical progress grind slowly.
“It’s never fast enough,” Atala says. “We want to get new treatments into the clinic faster, but the reality is that you have to dot all your i’s and cross all your t’s—and rightly so, for the sake of patient safety. People want predictions, but you can never predict how much work it will take to go from conceptualization to utilization.”
As a surgeon, he also treats patients and is able to follow transplant recipients. “At the end of the day, the goal is to get these technologies into patients, and working with the patients is a very rewarding experience,” he says. Will the 3D printed organs ever outrun the shortage of donated organs? “That’s the hope,” Atala says, “but this technology won’t eliminate the need for them in our lifetime.”
New methods are out of this world
Jeanne Loring, another pioneer in the field and director of the Center for Regenerative Medicine at Scripps Research Institute in San Diego, says that investment in regenerative medicine is not only paying off, but is leading to truly personalized medicine, one of the holy grails of modern science.
This is because a patient’s own skin cells can be reprogrammed to become replacements for various malfunctioning cells causing incurable diseases, such as diabetes, heart disease, macular degeneration and Parkinson’s. If the cells are obtained from a source other than the patient, they can be rejected by the immune system. This means that patients need lifelong immunosuppression, which isn’t ideal. “With Covid,” says Loring, “I became acutely aware of the dangers of immunosuppression.” Using the patient’s own cells eliminates that problem.
Microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, Loring's own cells have been sent to the ISS for study.
Loring has a special interest in neurons, or brain cells that can be developed by manipulating cells found in the skin. She is looking to eventually treat Parkinson’s disease using them. The manipulated cells produce dopamine, the critical hormone or neurotransmitter lacking in the brains of patients. A company she founded plans to start a Phase I clinical trial using cell therapies for Parkinson’s soon, she says.
This is the culmination of many years of basic research on her part, some of it on her own cells. In 2007, Loring had her own cells reprogrammed, so there’s a cell line that carries her DNA. “They’re just like embryonic stem cells, but personal,” she said.
Loring has another special interest—sending immature cells into space to be studied at the International Space Station. There, microgravity conditions make it easier for the cells to form three-dimensional structures, which could more easily lead to the growing of whole organs. In fact, her own cells have been sent to the ISS for study. “My colleagues and I have completed four missions at the space station,” she says. “The last cells came down last August. They were my own cells reprogrammed into pluripotent cells in 2009. No one else can say that,” she adds.
Future controversies and tipping points
Although the original SCNT debate has calmed down, more controversies may arise, Loring thinks.
One of them could concern growing synthetic embryos. The embryos are ultimately derived from embryonic stem cells, and it’s not clear to what stage these embryos can or will be grown in an artificial uterus—another recent invention. The science, so far done only in animals, is still new and has not been widely publicized but, eventually, “People will notice the production of synthetic embryos and growing them in an artificial uterus,” Loring says. It’s likely to incite many of the same reactions as the use of embryonic stem cells.
Bernard Siegel, the founder and director of the Regenerative Medicine Foundation and executive director of the newly formed Healthspan Action Coalition (HSAC), believes that stem cell science is rapidly approaching tipping point and changing all of medical science. (For disclosure, I do consulting work for HSAC). Siegel says that regenerative medicine has become a new pillar of medicine that has recently been fast-tracked by new technology.
Artificial intelligence is speeding up discoveries and the convergence of key disciplines, as demonstrated in Atala’s lab, which is creating complex new medical products that replace the body’s natural parts. Just as importantly, those parts are genetically matched and pose no risk of rejection.
These new technologies must be regulated, which can be a challenge, Siegel notes. “Cell therapies represent a challenge to the existing regulatory structure, including payment, reimbursement and infrastructure issues that 20 years ago, didn’t exist.” Now the FDA and other agencies are faced with this revolution, and they’re just beginning to adapt.
Siegel cited the 2021 FDA Modernization Act as a major step. The Act allows drug developers to use alternatives to animal testing in investigating the safety and efficacy of new compounds, loosening the agency’s requirement for extensive animal testing before a new drug can move into clinical trials. The Act is a recognition of the profound effect that cultured human cells are having on research. Being able to test drugs using actual human cells promises to be far safer and more accurate in predicting how they will act in the human body, and could accelerate drug development.
Siegel, a longtime veteran and founding father of several health advocacy organizations, believes this work helped bring cell therapies to people sooner rather than later. His new focus, through the HSAC, is to leverage regenerative medicine into extending not just the lifespan but the worldwide human healthspan, the period of life lived with health and vigor. “When you look at the HSAC as a tree,” asks Siegel, “what are the roots of that tree? Stem cell science and the huge ecosystem it has created.” The study of human aging is another root to the tree that has potential to lengthen healthspans.
The revolutionary science underlying the extension of the healthspan needs to be available to the whole world, Siegel says. “We need to take all these roots and come up with a way to improve the life of all mankind,” he says. “Everyone should be able to take advantage of this promising new world.”
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Eve Herold is an award-winning science writer and consultant in the scientific and medical nonprofit space. A longtime communications and policy executive for scientific organizations, she currently serves as Director of Policy Research and Education for the Healthspan Action
Coalition. She has written extensively about issues at the crossroads of science and society, including regenerative medicine, aging and longevity, medical implants, transhumanism, robotics and AI, and bioethical issues in leading-edge medicine. Her books include Stem Cell Wars and
Beyond Human, and her latest book, Robots and the People Who Love Them, will be released in January 2024. Her work has appeared in Vice, Medium, The Washington Post and the Boston Globe, among others. She’s a frequent contributor to Leaps.org and is the recipient of the 2019
Arlene Eisenberg Award from the American Society of Journalists and Authors.
Joy Milne's unusual sense of smell led Dr. Tilo Kunath, a neurobiologist at the Centre for Regenerative Medicine at the University of Edinburgh, and a host of other scientists, to develop a new diagnostic test for Parkinson's.
Forty years ago, Joy Milne, a nurse from Perth, Scotland, noticed a musky odor coming from her husband, Les. At first, Milne thought the smell was a result of bad hygiene and badgered her husband to take longer showers. But when the smell persisted, Milne learned to live with it, not wanting to hurt her husband's feelings.
Twelve years after she first noticed the "woodsy" smell, Les was diagnosed at the age of 44 with Parkinson's Disease, a neurodegenerative condition characterized by lack of dopamine production and loss of movement. Parkinson's Disease currently affects more than 10 million people worldwide.
Milne spent the next several years believing the strange smell was exclusive to her husband. But to her surprise, at a local support group meeting in 2012, she caught the familiar scent once again, hanging over the group like a cloud. Stunned, Milne started to wonder if the smell was the result of Parkinson's Disease itself.
Milne's discovery led her to Dr. Tilo Kunath, a neurobiologist at the Centre for Regenerative Medicine at the University of Edinburgh. Together, Milne, Kunath, and a host of other scientists would use Milne's unusual sense of smell to develop a new diagnostic test, now in development and poised to revolutionize the treatment of Parkinson's Disease.
"Joy was in the audience during a talk I was giving on my work, which has to do with Parkinson's and stem cell biology," Kunath says. "During the patient engagement portion of the talk, she asked me if Parkinson's had a smell to it." Confused, Kunath said he had never heard of this – but for months after his talk he continued to turn the question over in his mind.
Kunath knew from his research that the skin's microbiome changes during different disease processes, releasing metabolites that can give off odors. In the medical literature, diseases like melanoma and Type 2 diabetes have been known to carry a specific scent – but no such connection had been made with Parkinson's. If people could smell Parkinson's, he thought, then it stood to reason that those metabolites could be isolated, identified, and used to potentially diagnose Parkinson's by their presence alone.
First, Kunath and his colleagues decided to test Milne's sense of smell. "I got in touch with Joy again and we designed a protocol to test her sense of smell without her having to be around patients," says Kunath, which could have affected the validity of the test. In his spare time, Kunath collected t-shirt samples from people diagnosed with Parkinson's and from others without the diagnosis and gave them to Milne to smell. In 100 percent of the samples, Milne was able to detect whether a person had Parkinson's based on smell alone. Amazingly, Milne was even able to detect the "Parkinson's scent" in a shirt from the control group – someone who did not have a Parkinson's diagnosis, but would go on to be diagnosed nine months later.
From the initial study, the team discovered that Parkinson's did have a smell, that Milne – inexplicably – could detect it, and that she could detect it long before diagnosis like she had with her husband, Les. But the experiments revealed other things that the team hadn't been expecting.
"One surprising thing we learned from that experiment was that the odor was always located in the back of the shirt – never in the armpit, where we expected the smell to be," Kunath says. "I had a chance meeting with a dermatologist and he said the smell was due to the patient's sebum, which are greasy secretions that are really dense on your upper back. We have sweat glands, instead of sebum, in our armpits." Patients with Parkinson's are also known to have increased sebum production.
With the knowledge that a patient's sebum was the source of the unusual smell, researchers could go on to investigate exactly what metabolites were in the sebum and in what amounts. Kunath, along with his associate, Dr. Perdita Barran, collected and analyzed sebum samples from 64 participants across the United Kingdom. Once the samples were collected, Barran and others analyzed it using a method called gas chromatography mass spectrometry, or GS-MC, which separated, weighed and helped identify the individual compounds present in each sebum sample.
Barran's team can now correctly identify Parkinson's in nine out of 10 patients – a much quicker and more accurate way to diagnose than what clinicians do now.
"The compounds we've identified in the sebum are not unique to people with Parkinson's, but they are differently expressed," says Barran, a professor of mass spectrometry at the University of Manchester. "So this test we're developing now is not a black-and-white, do-you-have-something kind of test, but rather how much of these compounds do you have compared to other people and other compounds." The team identified over a dozen compounds that were present in the sebum of Parkinson's patients in much larger amounts than the control group.
Using only the GC-MS and a sebum swab test, Barran's team can now correctly identify Parkinson's in nine out of 10 patients – a much quicker and more accurate way to diagnose than what clinicians do now.
"At the moment, a clinical diagnosis is based on the patient's physical symptoms," Barran says, and determining whether a patient has Parkinson's is often a long and drawn-out process of elimination. "Doctors might say that a group of symptoms looks like Parkinson's, but there are other reasons people might have those symptoms, and it might take another year before they're certain," Barran says. "Some of those symptoms are just signs of aging, and other symptoms like tremor are present in recovering alcoholics or people with other kinds of dementia." People under the age of 40 with Parkinson's symptoms, who present with stiff arms, are often misdiagnosed with carpal tunnel syndrome, she adds.
Additionally, by the time physical symptoms are present, Parkinson's patients have already lost a substantial amount of dopamine receptors – about sixty percent -- in the brain's basal ganglia. Getting a diagnosis before physical symptoms appear would mean earlier interventions that could prevent dopamine loss and preserve regular movement, Barran says.
"Early diagnosis is good if it means there's a chance of early intervention," says Barran. "It stops the process of dopamine loss, which means that motor symptoms potentially will not happen, or the onset of symptoms will be substantially delayed." Barran's team is in the processing of streamlining the sebum test so that definitive results will be ready in just two minutes.
"What we're doing right now will be a very inexpensive test, a rapid-screen test, and that will encourage people to self-sample and test at home," says Barran. In addition to diagnosing Parkinson's, she says, this test could also be potentially useful to determine if medications were at a therapeutic dose in people who have the disease, since the odor is strongest in people whose symptoms are least controlled by medication.
"When symptoms are under control, the odor is lower," Barran says. "Potentially this would allow patients and clinicians to see whether their symptoms are being managed properly with medication, or perhaps if they're being overmedicated." Hypothetically, patients could also use the test to determine if interventions like diet and exercise are effective at keeping Parkinson's controlled.
"We hope within the next two to five years we will have a test available."
Barran is now running another clinical trial – one that determines whether they can diagnose at an earlier stage and whether they can identify a difference in sebum samples between different forms of Parkinson's or diseases that have Parkinson's-like symptoms, such as Lewy Body Dementia.
"Within the next one to two years, we hope to be running a trial in the Manchester area for those people who do not have motor symptoms but are at risk for developing dementia due to symptoms like loss of smell and sleep difficulty," Barran had said in 2019. "If we can establish that, we can roll out a test that determines if you have Parkinson's or not with those first pre-motor symptoms, and then at what stage. We hope within the next two to five years we will have a test available."
In a 2022 study, published in the American Chemical Society, researchers used mass spectrometry to analyze sebum from skin swabs for the presence of the specific molecules. They found that some specific molecules are present only in people who have Parkinson’s. Now they hope that the same method can be used in regular diagnostic labs. The test, many years in the making, is inching its way to the clinic.
"We would likely first give this test to people who are at risk due to a genetic predisposition, or who are at risk based on prodomal symptoms, like people who suffer from a REM sleep disorder who have a 50 to 70 percent chance of developing Parkinson's within a ten year period," Barran says. "Those would be people who would benefit from early therapeutic intervention. For the normal population, it isn't beneficial at the moment to know until we have therapeutic interventions that can be useful."
Milne's husband, Les, passed away from complications of Parkinson's Disease in 2015. But thanks to him and the dedication of his wife, Joy, science may have found a way to someday prolong the lives of others with this devastating disease. Sometimes she can smell people who have Parkinson’s while in the supermarket or walking down the street but has been told by medical ethicists she cannot tell them, Milne said in an interview with the Guardian. But once the test becomes available in the clinics, it will do the job for her.
[Ed. Note: A older version of this hit article originally ran on September 3, 2019.]
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