Her Incredible Sense of Smell Helped Scientists Develop the First Parkinson's Test
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.]
As Our AI Systems Get Better, So Must We
As the power and capability of our AI systems increase by the day, the essential question we now face is what constitutes peak human. If we stay where we are while the AI systems we are unleashing continually get better, they will meet and then exceed our capabilities in an ever-growing number of domains. But while some technology visionaries like Elon Musk call for us to slow down the development of AI systems to buy time, this approach alone will simply not work in our hyper-competitive world, particularly when the potential benefits of AI are so great and our frameworks for global governance are so weak. In order to build the future we want, we must also become ever better humans.
The list of activities we once saw as uniquely human where AIs have now surpassed us is long and growing. First, AI systems could beat our best chess players, then our best Go players, then our best champions of multi-player poker. They can see patterns far better than we can, generate medical and other hypotheses most human specialists miss, predict and map out new cellular structures, and even generate beautiful, and, yes, creative, art.
A recent paper by Microsoft researchers analyzing the significant leap in capabilities in OpenAI’s latest AI bot, ChatGPT-4, asserted that the algorithm can “solve novel and difficult tasks that span mathematics, coding, vision, medicine, law, psychology and more, without needing any special prompting.” Calling this functionality “strikingly close to human-level performance,” the authors conclude it “could reasonably be viewed as an early (yet still incomplete) version of an artificial general intelligence (AGI) system.”
The concept of AGI has been around for decades. In its common use, the term suggests a time when individual machines can do many different things at a human level, not just one thing like playing Go or analyzing radiological images. Debating when AGI might arrive, a favorite pastime of computer scientists for years, now has become outdated.
We already have AI algorithms and chatbots that can do lots of different things. Based on the generalist definition, in other words, AGI is essentially already here.
Unfettered by the evolved capacity and storage constraints of our brains, AI algorithms can access nearly all of the digitized cultural inheritance of humanity since the dawn of recorded history and have increasing access to growing pools of digitized biological data from across the spectrum of life.
Once we recognize that both AI systems and humans have unique superpowers, the essential question becomes what each of us can do better than the other and what humans and AIs can best do in active collaboration. The future of our species will depend upon our ability to safely, dynamically, and continually figure that out.
With these ever-larger datasets, rapidly increasing computing and memory power, and new and better algorithms, our AI systems will keep getting better faster than most of us can today imagine. These capabilities have the potential to help us radically improve our healthcare, agriculture, and manufacturing, make our economies more productive and our development more sustainable, and do many important things better.
Soon, they will learn how to write their own code. Like human children, in other words, AI systems will grow up. But even that doesn’t mean our human goose is cooked.
Just like dolphins and dogs, these alternate forms of intelligence will be uniquely theirs, not a lesser or greater version of ours. There are lots of things AI systems can't do and will never be able to do because our AI algorithms, for better and for worse, will never be human. Our embodied human intelligence is its own thing.
Our human intelligence is uniquely ours based on the capacities we have developed in our 3.8-billion-year journey from single cell organisms to us. Our brains and bodies represent continuous adaptations on earlier models, which is why our skeletal systems look like those of lizards and our brains like most other mammals with some extra cerebral cortex mixed in. Human intelligence isn’t just some type of disembodied function but the inextricable manifestation of our evolved physical reality. It includes our sensory analytical skills and all of our animal instincts, intuitions, drives, and perceptions. Disembodied machine intelligence is something different than what we have evolved and possess.
Because of this, some linguists including Noam Chomsky have recently argued that AI systems will never be intelligent as long as they are just manipulating symbols and mathematical tokens without any inherent understanding. Nothing could be further from the truth. Anyone interacting with even first-generation AI chatbots quickly realizes that while these systems are far from perfect or omniscient and can sometimes be stupendously oblivious, they are surprisingly smart and versatile and will get more so… forever. We have little idea even how our own minds work, so judging AI systems based on their output is relatively close to how we evaluate ourselves.
Anyone not awed by the potential of these AI systems is missing the point. AI’s newfound capacities demand that we work urgently to establish norms, standards, and regulations at all levels from local to global to manage the very real risks. Pausing our development of AI systems now doesn’t make sense, however, even if it were possible, because we have no sufficient ways of uniformly enacting such a pause, no plan for how we would use the time, and no common framework for addressing global collective challenges like this.
But if all we feel is a passive awe for these new capabilities, we will also be missing the point.
Human evolution, biology, and cultural history are not just some kind of accidental legacy, disability, or parlor trick, but our inherent superpower. Our ancestors outcompeted rivals for billions of years to make us so well suited to the world we inhabit and helped build. Our social organization at scale has made it possible for us to forge civilizations of immense complexity, engineer biology and novel intelligence, and extend our reach to the stars. Our messy, embodied, intuitive, social human intelligence is roughly mimicable by AI systems but, by definition, never fully replicable by them.
Once we recognize that both AI systems and humans have unique superpowers, the essential question becomes what each of us can do better than the other and what humans and AIs can best do in active collaboration. We still don't know. The future of our species will depend upon our ability to safely, dynamically, and continually figure that out.
As we do, we'll learn that many of our ideas and actions are made up of parts, some of which will prove essentially human and some of which can be better achieved by AI systems. Those in every walk of work and life who most successfully identify the optimal contributions of humans, AIs, and the two together, and who build systems and workflows empowering humans to do human things, machines to do machine things, and humans and machines to work together in ways maximizing the respective strengths of each, will be the champions of the 21st century across all fields.
The dawn of the age of machine intelligence is upon us. It’s a quantum leap equivalent to the domestication of plants and animals, industrialization, electrification, and computing. Each of these revolutions forced us to rethink what it means to be human, how we live, and how we organize ourselves. The AI revolution will happen more suddenly than these earlier transformations but will follow the same general trajectory. Now is the time to aggressively prepare for what is fast heading our way, including by active public engagement, governance, and regulation.
AI systems will not replace us, but, like these earlier technology-driven revolutions, they will force us to become different humans as we co-evolve with our technology. We will never reach peak human in our ongoing evolutionary journey, but we’ve got to manage this transition wisely to build the type of future we’d like to inhabit.
Alongside our ascending AIs, we humans still have a lot of climbing to do.
Story by Big Think
Our gut microbiome plays a substantial role in our health and well-being. Most research, however, focuses on bacteria, rather than the viruses that hide within them. Now, research from the University of Copenhagen, newly published in Nature Microbiology, found that people who live past age 100 have a greater diversity of bacteria-infecting viruses in their intestines than younger people. Furthermore, they found that the viruses are linked to changes in bacterial metabolism that may support mucosal integrity and resistance to pathogens.
The microbiota and aging
In the early 1970s, scientists discovered that the composition of our gut microbiota changes as we age. Recent studies have found that the changes are remarkably predictable and follow a pattern: The microbiota undergoes rapid, dramatic changes as toddlers transition to solid foods; further changes become less dramatic during childhood as the microbiota strikes a balance between the host and the environment; and as that balance is achieved, the microbiota remains mostly stable during our adult years (ages 18-60). However, that stability is lost as we enter our elderly years, and the microbiome undergoes dramatic reorganization. This discovery led scientists to question what causes this change and what effect it has on health.
Centenarians have a distinct gut community enriched in microorganisms that synthesize potent antimicrobial molecules that can kill multidrug-resistant pathogens.
“We are always eager to find out why some people live extremely long lives. Previous research has shown that the intestinal bacteria of old Japanese citizens produce brand-new molecules that make them resistant to pathogenic — that is, disease-promoting — microorganisms. And if their intestines are better protected against infection, well, then that is probably one of the things that cause them to live longer than others,” said Joachim Johansen, a researcher at the University of Copenhagen.
In 2021, a team of Japanese scientists set out to characterize the effect of this change on older people’s health. They specifically wanted to determine if people who lived to be over 100 years old — that is, centenarians — underwent changes that provided them with unique benefits. They discovered centenarians have a distinct gut community enriched in microorganisms that synthesize potent antimicrobial molecules that can kill multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. In other words, the late-life shift in microbiota reduces an older person’s susceptibility to common gut pathogens.
Viruses can change alter the genes of bacteria
Although the late-in-life microbiota change could be beneficial to health, it remained unclear what facilitated this shift. To solve this mystery, Johansen and his colleagues turned their attention to an often overlooked member of the microbiome: viruses. “Our intestines contain billions of viruses living inside bacteria, and they could not care less about human cells; instead, they infect the bacterial cells. And seeing as there are hundreds of different types of bacteria in our intestines, there are also lots of bacterial viruses,” said Simon Rasmussen, Johansen’s research advisor.
Centenarians had a more diverse virome, including previously undescribed viral genera.
For decades, scientists have explored the possibility of phage therapy — that is, using viruses that infect bacteria (called bacteriophages or simply phages) to kill pathogens. However, bacteriophages can also enhance the bacteria they infect. For example, they can provide genes that help their bacterial host attack other bacteria or provide new metabolic capabilities. Both of these can change which bacteria colonize the gut and, in turn, protect against certain disease states.
Intestinal viruses give bacteria new abilities
Johansen and his colleagues were interested in what types of viruses centenarians had in their gut and whether those viruses carried genes that altered metabolism. They compared fecal samples of healthy centenarians (100+ year-olds) with samples from younger patients (18-100 year-olds). They found that the centenarians had a more diverse virome, including previously undescribed viral genera.
They also revealed an enrichment of genes supporting key steps in the sulfate metabolic pathway. The authors speculate that this translates to increased levels of microbially derived sulfide, which may lead to health-promoting outcomes, such as supporting mucosal integrity and resistance to potential pathogens.
“We have learned that if a virus pays a bacterium a visit, it may actually strengthen the bacterium. The viruses we found in the healthy Japanese centenarians contained extra genes that could boost the bacteria,” said Johansen.
Simon Rasmussen added, “If you discover bacteria and viruses that have a positive effect on the human intestinal flora, the obvious next step is to find out whether only some or all of us have them. If we are able to get these bacteria and their viruses to move in with the people who do not have them, more people could benefit from them.”
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.
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