An assay using mass spectrometry could go to clinical trial within two years
Dark Daily has regularly observed that humans generate a variety of volatile substances—particularly in breath—which can be used for diagnostic purposes. But what if people, like certain trained animals, could smell the presence of disease before the onset of symptoms? What types of clinical laboratory testing biomarkers could be developed based on human-generated volatile organic compounds?
Researchers at the University of Manchester (UM) in the United Kingdom (UK) say their “breakthrough” test to diagnose Parkinson’s disease “can diagnose disease from skin swabs in three minutes,” according to a university press release.
Perdita Barran, PhD (right), head of the University of Manchester research team that developed the mass spectrometry Parkinson’s test, is shown above with Joy Milne (left), the retired nurse from Scotland who inspired Barran’s team to develop a new Parkinson’s biomarker and method for identifying it. “We are tremendously excited by these results which take us closer to making a diagnostic test for Parkinson’s Disease that could be used in clinic,” she said in a press release. A viable clinical laboratory test for Parkinson’s disease is greatly needed, as more than 10 million people worldwide currently live with the neurodegenerative disorder. (Photo copyright: University of Manchester.)
Using Mass Spectrometry to Analyze Sebum
The UM scientists hypothesized that the smell could be due to sebum, a light oily substance on skin that was going through a chemical change due to the Parkinson’s disease, Hull Daily Mail explained.
Increased sebum, which is produced by the sebaceous glands, is a hallmark of Parkinson’s, the researchers noted.
Their new method involves analysis of sebum using mass spectrometry, according to the JACS AU paper. The method, the researchers claim, makes it possible to diagnose Parkinson’s disease from skin swabs in three minutes.
“There are no cures for Parkinson’s, but a confirmatory diagnosis would allow [Parkinson’s patients] to get the right treatment and get the drugs that will help to alleviate their symptoms,” Perdita Barran, PhD, told the Hull Daily Mail. Barran is Chair of Mass Spectrometry in the Department of Chemistry and Director of the Michael Barber Centre for Collaborative Mass Spectrometry at UM’s Manchester Institute of Biotechnology. “What we are now doing is seeing if (hospital laboratories) can do what we’ve done in a research lab in a hospital lab,” she added.
Sebum Analyzed with Mass Spectrometry
Parkinson’s disease—the world’s fastest growing neurodegenerative disorder—needs “robust biomarkers” that could advance detection and head off onset of motor symptoms such as tremor, rigidity, and postural instability, the researchers note in their paper.
Their recent study builds on earlier 2019 findings they published in ACS Central Science about volatile compounds in sebum possibly being used as Parkinson’s biomarkers.
“Sebum is an underexplored biofluid, which is readily obtained from non-invasive skin swabs, which primarily consists of a mixture of triglycerides, cholesterol, free fatty acids, waxy esters, and squalene,” the researchers explained in their JACS AU paper.
The scientists sought, “to develop a method to analyze sebum in its native state to facilitate rapid assessment of the Parkinson’s disease status. Paper spray ionization mass spectrometry, which allows the direct analysis of compounds from paper, has previously been demonstrated to detect small molecules from unprocessed biofluids, such as blood and urine, but not to date with sebum,” they wrote.
The UM researchers used mass spectrometry to analyze sebum collected on cotton swabs from the backs of 79 people with Parkinson’s and 71 healthy individuals, BBC Scotland News reported.
Depanjan Sarkar, PhD, Research Associate, University of Manchester, further explained the technique in the UM news release:
Sebum is taken from the swab to filter paper cut in a triangle.
Using a solvent and voltage, sebum compounds transfer into the mass spectrometer.
“When we did this, we found more than 4,000 unique compounds of which 500 are different between people with Parkinson’s compared to the control participants,” Sarkar said.
Fatty Acids Make Assay Possible
Could fatty acids pave the way to an assay? The UM researchers believe so.
“We have identified two classes of lipids, namely [triglycerides] and diglycerides, as components of human sebum that are significantly differentially expressed in PD,” the researchers wrote in JACS AU. “Non-invasive sampling followed by PS-IM-MS [paper spray-ion mobility–mass spectrometry] analysis targeting these compounds could provide an inexpensive assay to support clinical phenotyping for the confirmatory diagnosis of Parkinson’s disease.”
A clinical trial for their test, which costs about $20, may be done within two years in Manchester area, the Daily Mail reported.
When Dark Daily reported in 2020 on Joy Milne’s unique ability to smell her husband’s Parkinson’s disease before it was formally diagnosed, we predicted a diagnostic test for Parkinson’s may be years away. And here it is, albeit with regulatory clearance needed following clinical trials.
It may in fact be possible to leverage sebum analysis to detect other diseases, the UM researchers noted.
For diagnostics developers, this story of Joy Milne and her husband Les Milne is a useful example of how, in tracking the life of a specific patient with a specific disease and close family members, researchers were able to identify a new class of biomarkers that could be used in a diagnostic assay.
It will be interesting to follow the University of Manchester researchers in their quest for a diagnostic mass spectrometry clinical laboratory test for Parkinson’s disease. According to Parkinson’s Foundation statistics, about 10 million people worldwide live with the neurodegenerative disorder. Such a new diagnostic test could be vitally important to medical laboratory care, and to patients and their families.
Will health monitoring with finger rings become more popular than wrist worn devices? One company hopes the answer is yes!
Personal health monitoring devices continue to grow smaller. Now there is a company selling a smart ring that fits on an individual’s finger. Clinical laboratory managers and pathologists may find this an interesting development, particularly because it shows progress in miniaturizing diagnostic capabilities and putting them into ever-smaller devices.
At the same time, health monitoring devices are becoming increasingly popular with consumers who want to track their overall health and certain medical conditions. However, devices currently on the market generally attach at the wrist like the Apple Watch and Fitbit.
Introduced by Movano, Inc. of Pleasanton, Calif., at the 2022 CES (Consumer Electronic Show) in Las Vegas, the Movano Ring tracks “sleep, heart rate variability, body temperature, and more,” according to the company’s website. Whether clinical laboratories will be involved with this data remains to be seen.
Primarily targeted at women, the Movano Ring offers “superior health-tracking technology and the convenient form,” according to Digital Trends.
The new smart ring device is expected to be released in beta form later this year. It is similar to the Oura Ring, which was launched in 2017 by OURA, located in Oulu, Finland (US office in San Francisco).
The Movano Ring (above) will come in four styles and be available later this year. The monitoring device “measures a user’s heart rate, temperature, SpO2, calories consumed, and steps taken, among other parameters generally tracked by smart wear. However, Movano’s app is the killer feature, as it can give actionable insights to users into their health so that they can make short-term, as well as long-term, changes,” Digital Trends reported. Clinical laboratories may one day be processing data streamed from these devices if the FDA grants class II medical device designation. (Photo copyright: Movano.)
Movano Seeks FDA Clearance
In an interview with MedTech Intelligence, Movano’s CEO John Mastrototaro, PhD, said the company saw a gap in the wearables market. “There was a real lack of solutions designed specifically for women and some of the unique health challenges women face as they age.”
Cuffless blood pressure testing and blood glucose monitoring are “holy grails for wearable tech,” and Movano plans to add them over time and testing of its radio frequency, The Verge reported.
“We’re taking the regulatory side of things very seriously,” Mastrototaro told The Verge.
In a news release, Movano announced completion of a study it conducted with University of California San Francisco “to assess the accuracy of the Movano Ring’s blood oxygen saturation (SpO2) and heart rate data.
“With results that exceeded the requirements of the industry standard used by FDA for evaluating SpO2 devices, this successful study is a promising step toward the company’s goal to provide medically-validated data to consumers and healthcare professionals,” the news release stated.
Seven participants wearing Movano Ring prototypes participated in the study to test the device’s accuracy during mild, moderate, and severe hypoxia, as well as heart rate changes while they were deprived of oxygen.
Comparing data to other reference devices, the researchers found the Movano Ring resulted in a 2% margin of error, which was well below the FDA’s 4% margin of error requirement for blood oxygen saturation, the news release stated.
Ring Works with Sensors, App
Sensors embedded in the Movano Ring collect data which is available to wearers through a smartphone application.
“Data from sensors that are embedded within the ring revolve around heart rate, heart rate variability, sleep respiration rate, temperature, blood oxygen, steps, calories, and other women-centric features. We want to have the app experience where all that sensor data is going to the app,” Mastrototaro explained in an interview with Medical Device and Diagnostic Industry.
“One of our goals is to translate those measures into what it means about your overall health. We don’t want to bombard people with data … we want to distill it all down to insights for people that help them understand how activities of daily living and their lifestyle affect their overall health,” he said.
Another Smart Ring
Meanwhile, wearable health device developer OURA recently released a third-generation ring model of its Oura Ring, which Engadget called a “technical marvel.”
“Taking the sensors from a smartwatch or fitness tracker and shrinking them into a ring is worthy of enormous praise … There’s much more tech crammed in this time around … including continuous heart rate tracking, temperature monitoring, blood oxygenation, and (menstrual) period prediction,” Engadget said.
OURA developed a new SpO2 feature to help ring wearers uncover problems in breathing while sleeping. In a blog post, scientists explained: “Typically, SpO2 is measured by placing a pulse oximeter on the tip of the finger … the Oura Ring measures light reflected back from the tissue. Fingertips provide good optical characteristics for this noninvasive measurement as blood vessels have thinner walls and are more diffused.”
The Oura Ring Generation 3 costs $299 and comes in silver, black, stealth, and gold finishes. There is a $5.99 monthly membership fee, and the app is compatible with Android and Apple iOS operating systems.
Wearable Health Monitoring Device Trend on the Rise
Over the years, Dark Daily and our sister publication The Dark Report have regularly covered the growing trend of consumers using wearable technologies to monitor their own health and the health of loved ones.
It should be clear to clinical laboratory leaders that popularity of wearable monitoring devices and digital healthcare is expanding among consumers. The data collected may soon find its way into new treatments for chronic illnesses and early warnings for diagnosticians.
Viral reservoir could be behind persistence, says study, which also suggests a blood biomarker could be found for clinical laboratory testing
Microbiologists and virologists working closely with physicians treating long COVID-19 patients will gain new insights in a study that found coronavirus spike protein in COVID-19 patients’ blood up to 12 months after diagnosis. The researchers believe their findings could be used to develop a clinical laboratory biomarker for long COVID-19.
Researchers at Brigham and Women’s Hospital and Massachusetts General Hospital said medical experts are not sure why some people have unwelcome symptoms weeks and months after a positive COVID-19 diagnosis, while others clear the infection without lingering effects.
The scientists believe if this work is validated, clinical laboratories might gain an assay to use in the diagnosis of long COVID-19.
“The half-life of spike protein in the body is pretty short, so its presence indicates that there must be some kind of active viral reservoir,” said David Walt, PhD (above), Professor of Pathology, Brigham and Women’s Hospital, and lead author of the study that found coronavirus spike protein in long COVID patients. The study findings indicate a potential clinical laboratory biomarker for long COVID-19. (Photo copyright: Brigham and Women’s Hospital.)
Viral Reservoir Possibly Behind Long COVID-19
The study suggests that SARS-CoV-2 finds a home in the body, particularly the gastrointestinal tract, “through viral reservoirs, where it continues to release spike protein and trigger inflammation,” Medical News Today reported.
Lead author of the study David Walt, PhD, Professor of Pathology, Brigham and Women’s Hospital and the Hansjörg Wyss Professor Biologically Inspired Engineering at Harvard Medical School, told The Guardian he “was motivated to carry out the study after earlier research by his colleagues detected genetic material from the COVID virus (viral RNA) in stool samples from children with multisystem inflammatory syndrome (a rare but serious condition that often strikes around four weeks after catching COVID) as well as spike protein and a marker of gut leakiness in their blood.”
Long COVID—also known as long-haul COVID, post-COVID-19, or its technical name, post-acute sequelae of COVID-19 or PASC—can involve health problems continuing weeks, months, or even years after a positive diagnosis, according to the federal Centers for Disease Control and Prevention (CDC).
Symptoms of long COVID, according to the researchers, include:
fatigue,
loss of smell,
memory loss,
gastrointestinal distress, and
shortness of breath.
“If someone could somehow get to that viral load and eliminate it, it might lead to resolution of symptoms,” Walt told the Boston Globe, which noted that the researchers may explore a clinical trial involving antiviral drugs for treatment of long COVID-19.
Clues from Earlier Studies on Long COVID-19
Medical conditions that persisted following a COVID-19 infection have been studied for some time. In fact, in an earlier study, Walt and others found children who developed a multisystem inflammation syndrome weeks after being infected by SARS-CoV-2, according to their 2021 paper published in The Journal of Clinical Investigation, titled, “Multisystem Inflammatory Syndrome in Children Is Driven by Zonulin-Dependent Loss of Gut Mucosal Barrier.”
Although these earlier studies provided clues, the cause of PASC remains unclear, the researchers noted. They planned to take a more precise look at PASC biology by using appropriate sampling and patient recruitment.
“Disentangling the complex biology of PASC will rely on the identification of biomarkers that enable classification of patient phenotypes. Here, we analyze plasma samples collected from PASC and COVID-19 patients to determine the levels of SARS-CoV-2 antigens and cytokines and identify a blood biomarker that appears in the majority of PASC patients,” the researchers wrote.
Finding a Marker of a Persistent Infection
The researchers used plasma samples from 63 people with a previous SARS-CoV-2 diagnosis (37 also had PASC), Medical News Today reported. Over a 12-month period, the researchers’ findings included:
Detection in 65% of PASC samples of full-length spike, S1 spike, and nucleocapsid throughout the year of testing.
Spike detected in 60% of PASC patient samples, and not found in the COVID-19 samples.
In an interview with Scientific American, bioengineer Zoe Swank PhD, post-doctoral researcher, Brigham and Women’s Hospital, and co-author of the study, said, “Our main hypothesis is that the spike protein is not causing the symptoms, but it’s just a marker that is released because you still have infection of some cells with SARS-CoV-2.”
In that article, Swank shared the scientists’ intent to do more research involving hundreds of samples over the course of the COVID-19 pandemic from many hospitals and people.
COVID-19 Not the Only Virus That Hangs On
Having a long-haul COVID-19 marker is a “game-changer,” according to an infectious disease expert who was not involved in the study.
“There has not so far been a clear, objective marker that is measurable in the blood of people experiencing long COVID-19,” Michael Peluso, MD, Assistant Professor, Medicine, University of California San Francisco, told Scientific American. “I hope their findings will hold up. It really would make a difference for a lot of people if a marker like this could be validated,” he added.
However, COVID-19 is not the only virus that could persist. Ebola also may linger in areas that skirt the immune system, such as the eye interior and central nervous system, according to a World Health Organization fact sheet.
Thus, medical laboratory leaders may want to follow the Brigham and Women’s Hospital research to see if the scientists validate their finding, discover a biomarker for long-haul COVID-19, and pursue a clinical trial for antiviral drugs. Such discoveries could have implications for how diagnostic professionals work with physicians to care for long COVID patients.
Study conducted on International Space Station found crew’s red blood cells were destroyed 54% faster in space than while on Earth
Hemolysis in blood specimens is something that clinical laboratories deal with every day. Now researchers in Canada have determined that, while astronauts are in space, hemolysis is a causative factor in the condition known as “space anemia.”
Hematologists whose clinical laboratories process a steady volume of complete blood count (CBC) tests to diagnosis anemia will want to take note of this research study, which was conducted at the University of Ottawa and on the International Space Station. Dubbed the “MARROW” study, it may have uncovered not only why astronauts suffer from anemia even a year after returning to Earth, but also how those insights can be applied to treatments for anemia and other blood diseases for Earthbound patients as well.
Anemia is caused by a marked decrease in the number of red blood cells and can lead to weakness, persistent fatigue, and slower brain function, which on Earth is concerning, but in space can be life threatening.
“Space anemia has consistently been reported when astronauts returned to Earth since the first space missions, but we didn’t know why,” said the study’s lead author Guy Trudel, MD, in a University of Ottawa news release.
Trudel is Director of the Bone and Joint Research Laboratory at the Ottawa Hospital Rehabilitation Centre in Canada. He is also a Rehabilitation Physician and Researcher at the Ottawa Hospital and Professor of Medicine at the University of Ottawa, and the principal investigator of the MARROW study, which is investigating the effects of microgravity on bone marrow, according to NASA.
“Our study shows that upon arriving in space, more red blood cells are destroyed, and this continues for the entire duration of the astronaut’s mission,” he added.
Although these scientific findings may not immediately lead to new methodologies for testing human blood for use in clinical laboratories, the insights gleaned from the study could inform future studies designed to learn how to get the body to produce more red blood cells in ways that benefit patients diagnosed with anemia or other blood disorders.
Guy Trudel, MD (above), Rehabilitation Physician and Researcher at the Ottawa Hospital and Professor at the University of Ottawa, is lead author of a Canadian study explaining why astronauts develop “space anemia.” In space, astronauts’ red blood cells are destroyed 54% faster than while on Earth, a finding that could have implications for space tourists and astronauts on longer missions to the moon and Mars, the researchers noted. (Photo copyright: University of Ottawa.)
Effects of Anemia Continue One Year after Returning to Earth
The MARROW research project, which was funded by the Canadian Space Agency (CSA), required the participation of 14 astronauts on the International Space Station.
The researchers began collecting data in October 2015 and completed their final tests in June 2020. They found that astronauts’ bodies destroyed 54% more red blood cells in space than would be normal on Earth, according to the study published in Nature Medicine.
“Thankfully, having fewer red blood cells in space isn’t a problem when your body is weightless,” Trudel said in the news release. “But when landing on Earth, and potentially on other planets or moons, anemia affecting your energy, endurance, and strength can threaten mission objectives. The effects of anemia are felt once you land and must deal with gravity again.”
The MARROW experiment detected the following changes:
During a six-month mission, astronauts’ bodies were destroying 54% more red blood cells than typical preflight rates.
Five of the 13 astronauts who had their blood drawn shortly after landing back on Earth were anemic. Red blood cell levels gradually improved three to four months post-flight.
The rate of red blood cell destruction remained 30% higher one year after landing than before missions to the International Space Station.
“Increased hemolysis as a primary effect of exposure to space constitutes a paradigm shift in our understanding of space anemia … Persistent hemolysis during space missions suggests that the longer the exposure, the worse the anemia,” the study’s authors wrote.
Measurements were made by testing the astronauts’ blood for iron levels and using breath tests to measure exhaled carbon monoxide. One molecule of carbon monoxide is produced every time one molecule of heme, the deep-red pigment in blood cells, is destroyed.
According to the researchers, the discovery that space travel increases red blood cell destruction:
highlights the need to screen astronauts and space tourists for existing blood or health conditions that are affected by anemia;
impacts longer missions to the moon and Mars, which would likely worsen an astronaut’s anemia;
suggests astronauts require an adapted diet; and
shows it is unclear how long the body can maintain this higher rate of destruction and production of red blood cells.
Space Study Could Lead to Better Healthcare on Earth
A 2007 NASA study published in Microgravity Science and Technology blamed space anemia on water loss during space flight decreasing the amount of hemoglobin in red blood cells. The study labeled space anemia a “15-day ailment” because those researchers believed issues resolved within 15 days of crew members returning to Earth.
The MARROW study, however, found much longer-lasting implications for astronauts in space, which could lead to new insights for patients on Earth. The Canadian Space Agency believes the study’s findings could lead to better understanding and monitoring of the effects of physical inactivity on seniors, bedridden patients, and those with reduced mobility or undergoing rehabilitation.
“The findings have implications for understanding the physiological consequences of space flight and anemia in patients on the ground,” Sulekha Anand, PhD, a professor in the Department of Biological Sciences at San Jose State University, told Reuters.
This latest study shows how discoveries in space continue to lead to advancements in scientists’ understanding of how the human body functions. That knowledge may one day provide the foundation for developing new or improved clinical laboratory tests for astronauts as well as everyday earthlings.
These findings hint at the role of pre-existing conditions in raising the risk of an individual having a severe case of COVID-19 once infected
At the University of Michigan, a team of pathologists have been researching the factors that might cause some patients infected by SARS-CoV-2 to suffer persistent respiratory problems, often described as “long COVID.” They have identified factors that place some individuals at higher risk for these problems.
Little is known about how the SARS-CoV-2 coronavirus affects the body long-term. Millions of people who have survived COVID-19 infections are living with chronic symptoms, including persistent respiratory problems such as shortness of breath. However, until now, it was not clear what may be causing these symptoms in some people but not others, even after the coronavirus has completely cleared their bodies.
Now, anatomic pathologists at Michigan Medicine, formerly the University of Michigan Health, believe they may have discovered what is causing ongoing respiratory problems in some patients who have recovered from the COVID-19 infection—pre-existing conditions.
The researchers examined lung biopsies from COVID-19 patients who continued to experience lingering symptoms. They discovered in some individuals lung damage that was present prior to contracting the virus.
“Some of the early publications and popular press around long COVID has implied or assumed that once you had COVID, everything that happens next is COVID-related,” said anatomic pathologist and senior author of the study Jeffrey Myers, MD (above), Vice Chair for Clinical Affairs and Quality at Michigan Medicine, in a news release. “Of course, that might or might not be true,” he added. (Photo copyright: University of Michigan.)
The research team analyzed lung biopsies from 18 COVID-19 survivors who were still experiencing respiratory symptoms or had abnormal computed tomography (CT) scans after the virus was no longer present in their bodies. The researchers found ground glass opacities on the radiological scans of 14 of those patients.
According to the news release, this finding indicates there were “areas of the lungs that appear as a cloudy gray color as opposed to the dark color of normal air-filled lungs, on a chest X-ray or CT scan.”
The biopsies exhibited evidence of pre-existing lung scarring and proof of diffuse alveolar damage, which is typically seen in patients with acute respiratory illnesses. Only five of the patients examined in the study were known to have lung disease prior to their COVID-19 diagnoses.
The researchers found that the most common condition present in these 18 patients was usual interstitial pneumonia (UIP). This condition, also known clinically as idiopathic pulmonary fibrosis (IPF), is a common form of pulmonary fibrosis that is characterized by progressive scarring and stiffening of both lungs.
“We were seeing a lot of UIP, which isn’t the pattern we tend to associate with acute lung injury,” said Kristine Konopka, MD, Clinical Associate Professor at Michigan Medicine and lead author of the study, in the news release. “So, we think these are patients who had lung disease prior to COVID and maybe they just weren’t being followed by primary care physicians. They then had COVID, are still sick, and their UIP is finally being picked up.”
Could Patients Have Lung Disease and Not Know it?
“The notion,” Myers noted in the news release, “that a person could have chronic lung damage and not know it was unheard of until relatively recently.” He also explained that UIP/IPF is a progressive disease that gets worse with time and that an infection like COVID-19 can accelerate the illness to a more serious condition known as an acute exacerbation of IPF, which can lead to death.
“SARS-CoV-2 comes along and does to the lung, from a pathology perspective, exactly what happens with an acute exacerbation,” Myers said.
The researchers also stated that it’s impossible to determine for certain whether the SARS-CoV-2 virus caused the UIP/IPF without the existence of full clinical histories of the patients prior to their COVID-19 diagnoses. They hope their research will motivate clinicians to be cautious before automatically attributing respiratory symptoms to long COVID in survivors of the virus. It is possible that the lung damage was present prior to the coronavirus.
“You shouldn’t make assumptions but [instead] ask the right questions, the first of which would be ‘I wonder if this is really COVID?’ What you do after that depends on the answer to that question,” he added.
This research is an example of how pathologists can add insight and value into the deeper understanding of the processes involved in specific diseases. Dark Daily invites any of our readers who are aware of other pathologist-authored studies or published papers about COVID-19 to alert us to the availability of those works.
