Findings may lead to new clinical laboratory biomarkers for predicting risk of developing MS and other autoimmune diseases
Scientists continue to find new clinical laboratory biomarkers to detect—and even predict risk of developing—specific chronic diseases. Now, in a recent study conducted at the University of California San Francisco (UCSF), researchers identified antibodies that develop in about 10% of Multiple Sclerosis (MS) patients’ years before the onset of symptoms. The researchers reported that of those who have these antibodies, 100% develop MS. Thus, this discovery could lead to new blood tests for screening MS patients and new ways to treat it and other autoimmune diseases as well.
The UCSF researchers determined that, “in about 10% [of] cases of multiple sclerosis, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge,” Yahoo Life reported, adding that “when [the patients] are tested at the time of their first disease flare, the antibodies show up in both their blood and cerebrospinal fluid.”
That MS is so challenging to diagnose in the first place makes this discovery even more profound. And knowing that 100% of a subset of MS patients who have these antibodies will develop MS makes the UCSF study findings quite important.
“This could be a useful tool to help triage and diagnose patients with otherwise nonspecific neurological symptoms and prioritize them for closer surveillance and possible treatment,” Colin Zamecnik, PhD, scientist and research fellow at UCSF, told Yahoo Life.
“From the largest cohort of blood samples on Earth, we obtained blood samples from MS patients years before their symptoms began and profiled antibodies against self-autoantibodies that are associated with multiple sclerosis diagnosis,” Colin Zamecnik, PhD (above), scientist and research fellow at UCSF, told Yahoo Life. “We found the first molecular marker of MS that appears up to five years before diagnosis in their blood.” These findings could lead to new clinical laboratory tests that determine risk for developing MS and other autoimmune diseases. (Photo copyright: LinkedIn.)
UCSF Study Details
According to the MS International Foundation Atlas of MS, there are currently about 2.9 million people living with MS worldwide, with about one million of them in the US. The disease is typically diagnosed in individuals 20 to 50 years old, mostly targeting those of Northern European descent, Yahoo Life reported.
To complete their study, the UCSF scientists used the Department of Defense Serum Repository (DoDSR), which is comprised of more than 10 million individuals, the researchers noted in their Nature Medicine paper.
From that group, the scientists identified 250 individuals who developed MS, spanning a period of five years prior to showing symptoms through one year after their symptoms first appeared, Medical News Today reported. These people were compared to 250 other individuals in the DoDSR who have no MS diagnosis but who all had similar serum collection dates, ages, race and ethnicities, and sex.
“The researchers validated the serum results against serum and cerebrospinal fluid results from an incident MS cohort at the University of California, San Francisco (ORIGINS) that enrolled patients at clinical onset. They used data from 103 patients from the UCSF ORIGINS study,” according to Medical News Today. “They carried out molecular profiling of autoantibodies and neuronal damage in samples from the 500 participants, measuring serum neurofilament light chain measurement (sNfL) to detect damage to nerve cells.
“The researchers tested the antibody patterns of both MS and control participants using whole-human proteomeseroreactivity which can detect autoimmune reactions in the serum and CSF,” Medical News Today noted.
Many who developed MS had an immunogenicity cluster (IC) of antibodies that “remained stable over time” and was not found in the control samples. The higher levels of sNfL in those with MS were discovered years prior to the first flare up, “indicating that damage to nerve cells begins a long time before symptom onset,” Medical News Today added.
“This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes,” the UCSF scientists wrote in Nature Medicine.
“We believe it’s possible that these patients are exhibiting cross reactive response to a prior infection, which agrees with much current work in the literature around multiple sclerosis disease progression,” Zamecnik told Yahoo Life.
It “validates and adds to prior evidence of neuro-axonal injury occurring in patients during the MS preclinical phase,” the researchers told Medical News Today.
Implications of UCSF’s Study
UCSF’s discovery is a prime example of technology that could soon work its way into clinical use once additional studies and research are done to support the findings.
The researchers believe their research could lead to a simple blood test for detecting MS years in advance and discussed how this could “give birth to new treatments and disease management opportunities,” Neuroscience News reported.
Current MS diagnosis requires a battery of tests, such as lumbar punctures for testing cerebrospinal fluid, magnetic resonance imaging (MRI) scans of the spinal cord and brain, and “tests to measure speed and accuracy of nervous system responses,” Medical News Today noted.
“Given its specificity for MS both before and after diagnosis, an autoantibody serology test against the MS1c peptides could be implemented in a surveillance setting for patients with high probability of developing MS, or crucially at a first clinically isolated neurologic episode,” the UCSF researchers told Medical News Today.
The UCSF discovery is another example of nascent technology that could work its way into clinical use after more research and studies. Microbiologists, clinical laboratories, and physicians tasked with diagnosing MS and other autoimmune diseases should find the novel biomarkers the researchers identified most interesting, as well as what changed with science and technology that enabled researchers to identify these biomarkers for development.
Discovery highlights how ongoing microbiome research points to new opportunities that can lead to development of more effective cancer screening clinical laboratory tests
New research from the Fred Hutchinson Cancer Center in Seattle once again demonstrates that the human microbiome plays a sophisticated role in many biological processes. Microbiologists and anatomic pathologists who diagnose tissue/biopsies will find this study’s findings intriguing.
This breakthrough in colon cancer research came from the discovery that a “subspecies” of a common type of a bacteria that resides in the mouth and causes dental plaque also “shields tumor cells from cancer treatment,” according to NBC News.
The scientists inspected colorectal cancer (CRC) tumors and found that 50% of those examined featured a subspecies of Fusobacterium nucleatum (F. nucleatum or Fn) and that this anaerobic bacterium was “shielding tumor cells from cancer-fighting drugs,” NBC News noted. Many of these tumors were considered aggressive cases of cancer.
“The discovery, experts say, could pave the way for new treatments and possibly new methods of screening,” NBC News reported.
“Patients who have high levels of this bacteria in their colorectal tumors have a far worse prognosis,” Susan Bullman, PhD (above), who jointly supervised the Fred Hutch research team and who is now Associate Professor of Immunology at MD Anderson Cancer Center, told NBC News. “They don’t respond as well to chemotherapy, and they have an increased risk of recurrence,” she added. Microbiologists and clinical laboratories working with oncologists on cancer treatments will want to follow this research as it may lead to new methods for screening cancer patients. (Photo copyright: Fred Hutchinson Cancer Center.)
Developing Effective Treatments
Susan Bullman, PhD, Associate Professor of Immunology at MD Anderson Cancer Center, who along with her husband and fellow researcher Christopher D. Johnston, PhD, Assistant Professor at Fred Hutchinson Cancer Center, jointly supervised an international team of scientists that examined the genomes of 80 F. nucleatum strains from the mouths of cancer-free patients and 55 strains from tumors in patients with colorectal cancer, according to the National Institutes of Health (NIH). The NIH funded the research.
The researchers targeted a subspecies of F. nucleatum called F. nucleatum animalis (Fna) that “was more likely to be present in colorectal tumors. Further analyses revealed that there were two distinct types of Fna. Both were present in mouths, but only one type, called Fna C2, was associated with colorectal cancer” the NIH wrote in an article on its website titled, “Gum Disease-related Bacteria Tied to Colorectal Cancer.”
“Tumor-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumor niche,” the Fred Hutch researchers wrote in their Nature paper.
“We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods,” Johnston told the NIH.
How Bacteria Got from Mouth to Colon Not Fully Understood
Traditionally, F. nucleatum makes its home in the mouth in minute quantities. Thus, it is not fully understood how these bacteria travel from the mouth to the colon. However, the Fred Hutch researchers showed that Fna C2 could survive in acidic conditions, like those found in the gut, longer than the other types of Fna. This suggests that the bacteria may travel along a direct route through the digestive tract.
The study, which focused on participants over 50, comes at a time when colorectal cancer rates are trending upward. Rates are doubling for those under 55, jumping from 11% in 1995 to 20% in 2019. CRC is the second-leading cancer death and over 53,000 will succumb to the disease in 2024, according to NBC News.
Many of the newer diagnoses are in later stages with no clear reason why, and the Fred Hutch scientists are trying to understand how their findings tie into the increase of younger cases of colon cancer.
Bullman says it will be important to look at “whether there are elevated levels of this bacterium in young onset colorectal cancer, which is on the rise globally for unknown reasons,” she told NBC News.
Possibility of More Effective Cancer Screening
There is hope that scientists equipped with this knowledge can develop new and more effective screening and treatment options for colon cancer, as well as studying the microbiome’s impact on other diseases.
On the prevention side, researchers have seen that in mice the addition of Fna “appeared to cause precancerous polyps to form, one of the first warning signs of colorectal cancer, though Bullman added that this causation hasn’t yet been proven in humans.” NBC reported.
Future research may find that screening for Fna could determine if colorectal tumors will be aggressive, NIH reported.
“It’s possible that scientists could identify the subspecies while it’s still in the mouth and give a person antibiotics at that point, wiping it out before it could travel to the colon,” Bullman told NBC News. “Even if antibiotics can’t successfully eliminate the bacteria from the mouth, its presence there could serve as an indication that someone is at higher risk for aggressive colon cancer.”
There is also the thought of developing antibiotics to target a specific subtype of bacteria. Doing so would eliminate the need to be “wiping out both forms of the bacteria or all of the bacteria in the mouth. Further, it’s relevant to consider the possibility of harnessing the bacteria to do the cancer-fighting work,” NBC noted.
“The subtype has already proven that it can enter cancer cells quite easily, so it might be possible to genetically modify the bacteria to carry cancer-fighting drugs directly into the tumors,” Bullman told NBC News.
Further studies and research are needed. However, the Fred Hutch researchers’ findings highlight the sophistication of the human microbiome and hint at the potential role it can play in the diagnosis of cancer by clinical laboratories and pathology groups, along with better cancer treatments in the future.
Study of the 50 Omicron variants could lead to new approaches to clinical laboratory testing and medical treatments for long COVID
Patients infected with SARS-CoV-2 can usually expect the COVID-19 illness to subside within a couple of weeks. However, one Dutch patient remained infected with the coronavirus for 612 days and fought more than 50 mutations (aka, variants) before dying late last year of complications due to pre-existing conditions. This extreme case has given doctors, virologists, microbiologists, and clinical laboratories new insights into how the SARS-CoV-2 virus mutates and may lead to new treatments for long COVID.
The medication the patient was taking for his pre-existing conditions may have contributed to his body being unable to produce antibodies in response to three shots of the Moderna mRNA COVID vaccine he received.
Magda Vergouwe, MD, PhD candidate at the Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, who lead a study into the patient, theorized that some of the medications the patient was on for his pre-existing conditions could have destroyed healthy cells alongside the abnormal cancer-causing B cells the drugs were meant to target.
“This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals,” the researchers said prior to presenting their report about the case at a meeting of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in Barcelona, Spain, Time reported. “We emphasize the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections.”
“Chronic infections and viral evolution [are] commonly described in [the] literature, and there are other cases of immunocompromised patients who have had [COVID] infections for hundreds of days,” Magda Vergouwe, MD, PhD candidate (above), Center for Experimental and Molecular Medicine at Amsterdam UMC, told Scientific American. “But this is unique due to the extreme length of the infection … and with the virus staying in his body for so long, it was possible for mutations to just develop and develop and develop.” Microbiologists, virologists, and clinical laboratories involved in testing patients with long COVID may want to follow this story. (Photo copyright: LinkedIn.)
Risks to Immunocompromised Patients
Pre-existing conditions increase the risk factor for COVID-19 infections. A 2021 study published in the Journal of the American Board of Family Medicine (JABFM) titled, “Prevalence of Pre-existing Conditions among Community Health Center Patients with COVID-19,” found that about 61% of that study’s test group had a pre-existing condition prior to the outbreak of the COVID-19 pandemic.
When the Dutch man was admitted to Amsterdam UMC with common and serious COVID-19 symptoms, such as shortness of breath, a cough, and low blood oxygen levels, he was prescribed sotrovimab (a monoclonal antibody) along with other COVID treatments.
About a month after being admitted his COVID-19 symptoms decreased, so he was first discharged to a rehab facility and then finally to his home. However, he continued to test positive for the coronavirus and developed other infections that may have been complicated by the persistent case of COVID-19.
The Amsterdam UMC doctors emphasized that the man ultimately succumbed to his pre-existing conditions and not necessarily COVID-19.
“It’s important to note that in the end he did not die from his COVID-19,” Vergouwe told Scientific American. “But he did keep it with him for a very long period of time until then, and this is why we made sure to sample [the virus in his body] as much as we could.”
One in Five Adults Develop Long COVID
Long COVID does not necessarily indicate an active infection. However, in as many as one in five US adults COVID symptoms persist after the acute phase of the infection is over, according to a study published recently in JAMA Network Open titled, “Epidemiologic Features of Recovery from SARS-CoV-2 Infection.”
“In this cohort study, more than one in five adults did not recover within three months of SARS-CoV-2 infection. Recovery within three months was less likely in women and those with pre-existing cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave,” the JAMA authors wrote.
The origins of long COVID are not entirely clear, but according to the National Institutes of Health (NIH) it can develop when a patient is unable to sufficiently rest while battling off the initial virus. According to Vergouwe, the SARS-CoV-2 genome will always grow quicker when found in a patient with a compromised immune system.
Unique COVID-19 Mutations
More than 50 new mutations of the original Omicron variant were identified in the Dutch patient. According to Vergouwe, “while that number can sound shocking, mutations to the SARS-CoV-2 genome are expected to evolve more quickly in those who are immunocompromised (the average mutation rate of the virus is estimated to be two mutations per person per month),” Scientific American reported. “What does make these mutations unusual, she noted, is how their features differed vastly from mutations observed in other people with COVID. [Vergouwe] hypothesizes that the exceptional length of the individual’s infection, and his pre-existing conditions, allowed the virus to evolve extensively and uniquely.”
COVID-19 appears to be here to stay, and most clinical laboratory managers and pathologists understand why. As physicians continue to learn about the SARS-CoV-2 coronavirus, this is another example of how the knowledge about SARS-CoV-2 is growing as different individuals are infected with different variants of the virus.
New biomarker may lead to new clinical laboratory testing and treatments for long COVID
Researchers studying long COVID at the University Hospital of Zurich (UZH) and the Swiss Institute of Bioinformatics (SIB), both in Switzerland, have discovered a protein biomarker in blood that indicates a component of the body’s innate immune system—called the complement system—remains active in some individuals long after the infection has run its course. The scientists are hopeful that further studies may provide clinical laboratories with a definitive test for long COVID, and pharma companies with a path to develop therapeutic drugs to treat it.
Ever since the COVID-19 pandemic began, a subset of the population worldwide continues to experience lingering symptoms even after the acute phase of the illness has passed. Patients with long COVID experience symptoms for weeks, even months after the initial viral infection has subsided. And because these symptoms can resemble other illnesses, long COVID is difficult to diagnose.
This new biomarker may lead to new clinical laboratory diagnostic blood tests for long COVID, and to a greater understanding of why long COVID affects some patients and not others.
“Those long COVID patients used to be like you and me, totally integrated [into] society with a job, social life, and private life,” infectious disease specialist Michelè van Vugt, MD (above), Senior Fellow and Professor at Amsterdam Institute for Global Health and Development (AIGHD), told Medical News Today. “After their COVID infection, for some of them, nothing was left because of their extreme fatigue. And this happened not only in one patient but many more—too many for only [a] psychological cause.” Clinical laboratories continue to perform tests on patients experiencing symptoms of COVID-19 even after the acute illness has passed. (Photo copyright: AIGHD.)
Role of the Complement System
To complete their study, the Swiss scientists monitored 113 patients who were confirmed through a reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) test to have COVID-19. The study also included 39 healthy control patients who were not infected.
The researchers examined 6,596 proteins in 268 blood samples collected when the sick patients were at an acute stage of the virus, and then again six months after the infection. They found that 40 of the patients who were sick with COVID-19 eventually developed symptoms of long COVID. Those 40 patients all had a group of proteins in their blood showing that the complement system of their immune system was still elevated even after recovering from the virus.
“Complement is an arm of the immune system that ‘complements’ the action of the other arms,” Amesh Adalja, MD, Adjunct Assistant Professor at Johns Hopkins Bloomberg School of Public Health, told Prevention, “Activities that it performs range from literally attacking the cell membranes of a pathogen to summoning the cells of other immune systems to the site of infection.”
In addition to helping bodies heal from injury and illness, the complement immune system also activates inflammation in the body—and if the complement system is activated for too long the patient is at risk for autoimmune disease and other inflammatory conditions.
Conducted by genetic scientists at Trinity College Dublin and St. James’ Hospital in Dublin, Ireland, the study “analyzed blood samples—specifically, serum and plasma—from 76 patients who were hospitalized with COVID-19 in March or April 2020, along with those from 25 people taken before the pandemic. The researchers discovered that people who said they had brain fog had higher levels of a protein in their blood called S100β [a calcium-binding protein] than people who didn’t have brain fog,” Prevention reported.
“S100β is made by cells in the brain and isn’t normally found in the blood. That suggests that the patients had a breakdown in the blood-brain barrier, which blocks certain substances from getting to the brain and spinal cord, the researchers noted,” Prevention reported.
“The scientists then did MRI scans with dye of 22 people with long COVID (11 of them who reported having brain fog), along with 10 people who recovered from COVID-19. They found that long COVID patients who had brain fog had signs of a leaky blood-brain barrier,” Prevention noted.
“This leakiness likely disrupts the integrity of neurons in the brain by shifting the delicate balance of materials moving into and out of the brain,” Matthew Campbell, PhD, Professor and Head of Genetics at Trinity College Dublin, told Prevention.
Interactions with Other Viruses
According to Medical News Today, the Swiss study results also suggest that long COVID symptoms could appear because of the reactivation of a previous herpesvirus infection. The patients in the study showed increased antibodies against cytomegalovirus, a virus that half of all Americans have contracted by age 40.
The link between long COVID and these other viruses could be key to developing treatment for those suffering with both illnesses. The antiviral treatments used for the herpesvirus could potentially help treat long COVID symptoms as well, according to Medical News Today.
“Millions of people across the planet have long COVID or will develop it,” Thomas Russo MD, Professor and Chief of Infectious Disease at the University at Buffalo in New York, told Prevention. “It’s going to be the next major phase of this pandemic. If we don’t learn to diagnose and manage this, we are going to have many people with complications that impact their lives for the long term.”
Long COVID won’t be going away any time soon, much like the COVID-19 coronavirus. But these two studies may lead to more effective clinical laboratory testing, diagnoses, and treatments for millions of people suffering from the debilitating condition.
Pathology groups and clinical laboratories are among the beneficiaries if the Accelerating Medicines Partnership achieves its goals
Power players in healthcare are about to invest nearly a quarter of a billion dollars to accelerate the time it takes for new medical discoveries to gain regulatory approval and enter clinical use. The emphasis will be on both therapeutic drugs and diagnostics, making this an important development for in vitro diagnostics companies and medical laboratories.
