“Previously … CDC developed tests for emerging pathogens and then shared those tests with others, and then after that, commercial labs would develop their own tests,” Shah told CNN. “That process took time. Now with these new arrangements, commercial labs will be developing new tests for public health responses alongside CDC, not after CDC.”
In a news release announcing the contract, ARUP Laboratories also characterized the move as a shift for the agency.
“The new contract formalizes ARUP’s relationship with the CDC,” said Benjamin Bradley, MD, PhD, medical director of the ARUP Institute for Research and Innovation in Infectious Disease Genomic Technologies, High Consequence Pathogen Response, Virology, and Molecular Infectious Diseases. “We continue to expand our capabilities to address public health crises and are prepared to scale up testing for H5N1, or develop other tests quickly, should the need arise.”
“To be clear, we have no evidence so far that this [bird flu] virus can easily infect human beings or that it can spread between human beings easily in a sustained fashion,” Jennifer Nuzzo, DrPH (above), Director of the Pandemic Center and Professor of Epidemiology at Brown University School of Public Health, told CNN. “If it did have those abilities, we would be in a pandemic.” Clinical laboratory leaders will recall the challenges at the CDC as it developed its SARS-CoV-2 test early in the COVID-19 pandemic. (Photo copyright: Brown University.)
Missouri Case Raises Concerns
The first human infection of HPAI was reported in late March following a farmer’s “exposure to dairy cows presumably infected with bird flu,” the CDC stated in its June 3, 2024, bird flu Situation Summary. That followed confirmation by the USDA’s Animal and Plant Health Inspection Service (APHIS) of an HPAI outbreak in commercial poultry flocks in February 2022, and the CDC’s confirmation of the first known infections in dairy herds reported on March 25, 2024.
Concerns about the outbreak were heightened in September following news that a person in Missouri had been infected with the virus despite having no known contact with infected animals. CNN reported that it was the 14th human case in the US this year, but all previous cases were in farm workers known to be exposed to infected dairy cattle or poultry.
In a news release, the Missouri Department of Health and Senior Services (DHSS) revealed that the patient, who was not identified, was hospitalized on Aug. 22. This person had “underlying medical conditions,” DHSS reported, and has since recovered and was sent home. Both DHSS and the CDC conducted tests to determine that the virus was the H5 subtype, the news release states.
At present, the CDC states that the public health risk from the virus is low. However, public health experts are concerned that risks could rise as the weather gets cooler, creating opportunities for the virus to mutate “since both cows and other flu viruses will be on the move,” CNN reported.
Concerns over CDC Testing and FDA Oversight
In the months immediately following the first human case of the bird flu virus, Nuzzo was among several public health experts sounding an alarm about the country’s ability to ramp up testing in the face of new pathogens.
“We’re flying blind,” she told KFF Health News in June, due to an inability to track infections in farmworkers. At that time, tests had been distributed to approximately 100 public health labs, but Nuzzo and other experts noted that doctors typically order tests from commercial laboratories and universities.
KFF reported that one diagnostics company, Neelyx Labs, ran into obstacles as it tried to license the CDC’s bird flu test. Founder, CEO, and lead scientist Shyam Saladi, PhD, told KFF that the federal agency had promised to cooperate by facilitating a license and a “right to reference” CDC data when applying for FDA authorization but was slow to come through.
While acknowledging the need for testing accuracy, Greninger contended that the CDC was prioritizing caution over speed, as it did in the early days of the COVID-19 pandemic. “The CDC should be trying to open this up to labs with national reach and a good reputation,” he told KFF.
Another problem, KFF reported, related to the FDA’s new oversight of laboratory developed tests (LDTs), which is causing labs to move cautiously in developing their own tests.
Jennifer Nuzzo, DrPH (above), Director of the Pandemic Center and Professor of Epidemiology at the Brown University School of Public Health co-authored a June 2024 analysis in Health Affairs that called on the CDC to develop “a better testing playbook for biological emergencies.” The authors’ analysis cited earlier problems with the responses to the COVID-19 and mpox (formerly known as monkeypox) outbreaks.
If global surveillance networks have detected a novel pathogen, the authors advise, the US should gather information and “begin examining the existing testing landscape” within the first 48 hours.
Once the pathogen is detected in the US, they continued, FDA-authorized tests should be distributed to public health laboratories and the CDC’s Laboratory Response Network (LRN) laboratories within 48 hours.
Advocates of this approach suggest that within the first week diagnostics manufacturers should begin developing their own tests and the federal government should begin working with commercial labs. Then, within the first month, commercial laboratories should be using FDA-authorized tests to provide “high throughput capacity.”
This may be good advice. Experts in the clinical laboratory and healthcare professions believe there needs to be improvement in how novel tests are developed and made available as novel infectious agents are identified.
Results of an earlier study in which locks of Beethoven’s hair underwent genetic analysis showed the composer ‘had a predisposition for liver disease and became infected with hepatitis B’
Here is an example of modern technologies being used with “historical biospecimens” to solve long-standing mysteries or questions about the illnesses of famous historical figures. Clinical laboratory scientists at the Mayo Clinic have used modern-day chemical analysis techniques to answer a 200-year-old question: What caused Ludwig van Beethoven’s deafness and other health problems?
“Such lead levels are commonly associated with gastrointestinal and renal ailments and decreased hearing but are not considered high enough to be the sole cause of death,” the authors wrote.
Beethoven’s death at age 56 has been attributed to kidney and liver disease, CNN reported. Even if the lead concentrations were not the sole cause, they would nevertheless be regarded as lead poisoning, lead study author Nader Rifai, PhD, told CNN.
“If you walk into any emergency room in the United States with these levels, you will be admitted immediately and you will undergo chelation therapy,” he said.
“It is believed that Beethoven died from liver and kidney disease at age 56. But the process of understanding what caused his many health problems has been a much more complicated puzzle, one that even Beethoven himself hoped doctors could eventually solve,” CNN reported, adding, “The composer expressed his wish that his ailments be studied and shared so ‘as far as possible at least the world will be reconciled to me after my death.’” Mayo clinical laboratory scientists are using chemical analysis on authenticated locks of Beethoven’s hair to do just that. (Photo copyright: Joseph Karl Stieler/Public Domain.)
Mass Spectrometry Analysis
Mayo Clinic’s metals laboratory, led by chemist Paul Jannetto, PhD, an associate professor in the Department of Laboratory Medicine and Pathology and Laboratory Director at the Mayo Clinic, performed the analysis on two authenticated locks of Beethoven’s hair, using inductively coupled plasma mass spectrometers.
The researchers found that one lock had 258 micrograms of lead/gram and the other had 380 micrograms. Normally they would expect to find less than four micrograms.
“These are the highest values in hair I’ve ever seen,” Jannetto told The New York Times. “We get samples from around the world and these values are an order of magnitude higher.”
The researchers also found that the composer’s hair had four times the normal level of mercury and 13 times the normal amount of arsenic.
Rifai and other researchers noted that Beethoven drank large amounts of plumbed wine, and at the time it was common to sweeten wine with lead acetate, CNN reported.
The composer also could have been exposed to lead in glassware. He likely absorbed high levels of arsenic and mercury by eating fish caught from the Danube River in Vienna.
David Eaton, PhD, a toxicologist, pharmacologist, and Professor Emeritus, Department of Environmental and Occupational Health Sciences at the University of Washington, told The New York Times that high levels of lead could have impaired Beethoven’s hearing through their effect on the nervous system. Additionally, he said the composer’s gastrointestinal ailments “are completely consistent with lead poisoning.”
Rifai told CNN that he’d like to study locks of hair from other 19th century Vienna residents to see how their lead levels compared with Beethoven’s.
Beethoven’s Genome and Genetic Predisposition for Liver Disease
Additional research published in May built on an earlier genomic analysis of Beethoven’s hair, which appeared in March 2023 in the journal Current Biology.
The international team included geneticists, archeologists, and immunologists who analyzed eight locks of hair attributed to the composer. They determined that five were authentic. One, known as the Stumpff Lock, appeared to be the best preserved. They used this lock to sequence Beethoven’s DNA.
“Although we could not identify a genetic explanation for Beethoven’s hearing disorder or gastrointestinal problems, we found that Beethoven had a genetic predisposition for liver disease,” the authors wrote. “Metagenomic analyses revealed furthermore that Beethoven had a hepatitis B infection during at least the months prior to his death. Together with the genetic predisposition and his broadly accepted alcohol consumption, these present plausible explanations for Beethoven’s severe liver disease, which culminated in his death.”
One surprising discovery was the likelihood of an extramarital affair on the composer’s father’s side, CNN reported. The researchers learned this in part by comparing his genetic profile with those of living relatives.
“Through the combination of DNA data and archival documents, we were able to observe a discrepancy between Ludwig van Beethoven’s legal and biological genealogy,” study coauthor Maarten Larmuseau, PhD, told CNN. Larmuseau is assistant professor, Faculty of Medicine, and head of the Laboratory of Human Genetic Genealogy at KU Leuven in Belgium.
The Mayo Clinic team used two locks authenticated in the 2023 study—the Bermann Lock and Halm-Thayer Lock—to perform their chemical analysis, CNN reported.
Beethoven’s Wishes
The earlier study noted that Beethoven wanted his health problems to be made public. In 1802, he wrote a document known as the Heiligenstadt Testament in which he asked that his physician, surgeon/ophthalmologist Johann Adam Schmidt, MD, discuss his disease after he died.
“For almost two years I have ceased to attend any social functions, just because I find it impossible to say to people: I am deaf,” Beethoven wrote at age 30, The New York Times reported. “If I had any other profession, I might be able to cope with my infirmity, but in my profession, it is a terrible handicap. And if my enemies, of whom I have a fair number, were to hear about it, what would they say?”
The authors of the Current Biology paper wrote, “Genomic sequence data from authenticated locks of Beethoven’s hair provide Beethoven studies with a novel primary source, already revealing several significant findings relating to Beethoven’s health and genealogy, including substantial heritable risk for liver disease, infection with HBV [Hepatitis B], and EPP [extra pair paternity]. This dataset additionally permits numerous future lines of scientific inquiry.
“The further development of bioinformatics methods for risk stratification and continued progress in medical genetic research will allow more precise assessments both for Beethoven’s disease risk and for the genetic inference of additional phenotypes of interest.
“This study illustrates the contribution and further potential of genomic data as a novel primary source in historical biography,” the scientists concluded.
The work of the clinical laboratory professionals at Mayo Clinic also demonstrates how advances in various diagnostic technologies can enable pathologists and lab scientists to participate in solving long-standing health questions about historical figures, especially if their hair or other types of specimens survived and can be used in the analysis.
The ASBMB story notes that nanopore technology depends on differences in charges on either side of the membrane to force DNA or RNA through the hole. This is one reason why proteins pose such a challenge.
“Think of a cell as a miniature city, with proteins as its inhabitants. Each protein-resident has a unique identity, its own characteristics, and function. If there was a database cataloging the fingerprints, job profiles, and talents of the city’s inhabitants, such a database would undoubtedly be invaluable!” said Behzad Mehrafrooz, PhD (above), Graduate Research Assistant at University of Illinois at Urbana-Champaign in an article he penned for the university website. This research should be of interest to the many clinical laboratories that do protein testing. (Photo copyright: University of Illinois.)
How the Maglia Process Works
In a Groningen University news story, Maglia said protein is “like cooked spaghetti. These long strands want to be disorganized. They do not want to be pushed through this tiny hole.”
His technique, developed in collaboration with researchers at the University of Rome Tor Vergata, uses electrically charged ions to drag the protein through the hole.
“We didn’t know whether the flow would be strong enough,” Maglia stated in the news story. “Furthermore, these ions want to move both ways, but by attaching a lot of charge on the nanopore itself, we were able to make it directional.”
The researchers tested the technology on what Maglia described as a “difficult protein” with many negative charges that would tend to make it resistant to flow.
“Previously, only easy-to-thread proteins were analyzed,” he said in the news story. “But we gave ourselves one of the most difficult proteins as a test. And it worked!”
Maglia now says that he intends to commercialize the technology through a new startup called Portal Biotech.
Detecting Post-Translational Modifications in the UK
In another recent study, researchers at the University of Oxford reported that they have adapted nanopore technology to detect post-translational modifications (PTMs) in protein chains. The term refers to changes made to proteins after they have been transcribed from DNA, explained an Oxford news story.
“The ability to pinpoint and identify post-translational modifications and other protein variations at the single-molecule level holds immense promise for advancing our understanding of cellular functions and molecular interactions,” said contributing author Hagan Bayley, PhD, Professor of Chemical Biology at University of Oxford, in the news story. “It may also open new avenues for personalized medicine, diagnostics, and therapeutic interventions.”
Bayley is the founder of Oxford Nanopore Technologies, a genetic sequencing company in the UK that develops and markets nanopore sequencing products.
The news story notes that the new technique could be integrated into existing nanopore sequencing devices. “This could facilitate point-of-care diagnostics, enabling the personalized detection of specific protein variants associated with diseases including cancer and neurodegenerative disorders,” the story states.
In another recent study, researchers at the University of Washington reported that they have developed their own method for protein sequencing with nanopore technology.
“This opens up the possibility for barcode sequencing at the protein level for highly multiplexed assays, PTM monitoring, and protein identification!” Motone wrote.
Single-cell proteomics, enabled by nanopore protein sequencing technology, “could provide higher sensitivity and wider throughput, digital quantification, and novel data modalities compared to the current gold standard of protein MS [mass spectrometry],” they wrote. “The accessibility of these tools to a broader range of researchers and clinicians is also expected to increase with simpler instrumentation, less expertise needed, and lower costs.”
There are approximately 20,000 human genes. However, there are many more proteins. Thus, there is strong interest in understanding the human proteome and the role it plays in health and disease.
Technology that makes protein testing faster, more accurate, and less costly—especially with a handheld analyzer—would be a boon to the study of proteomics. And it would give clinical laboratories new diagnostic tools and bring some of that testing to point-of-care settings like doctor’s offices.
Studying gut bacteria continues to intrigue investors, but can the results produce viable diagnostic data for healthcare providers?
Even as microbiologists and clinical pathologists closely watch research into the human microbiome and anticipate study findings that could lead to new medical laboratory tests based on microbiome testing, there are entrepreneurs ready to tout the benefits of microbiome testing to consumers. That’s the impetus behind an announced deal between a microbiome testing company and a national pharmacy chain.
That deal involves health startup Viome Life Sciences, which recently closed a $86.5 million Series C funding round to support research and development of its consumer health at-home test kits, and CVS, which will sell Viome’s Gut Intelligence Test at 200 of the pharmacy company’s retail locations nationwide, according to an August press release.
“Founded seven years ago by serial entrepreneur Naveen Jain, Viome sells at-home kits that analyze the microbial composition of stool samples and provide food recommendations, as well as supplements and probiotics. Viome says it is the first company to sell gut tests at CVS, both online and in-store. The tests will sell for $179,” GeekWire reported.
Investors appear to be intrigued by these types of opportunities. To date, Viome has raised a total of $175 million.
“In a world where healthcare has often been reactive, treating symptoms and targeting diseases only after they manifest, Viome is pioneering a transformative shift by harnessing the innate power of food and nutrition,” stated Naveen Jain (above), Founder and CEO of Viome, in a press release. “Our mission is not just to prolong life but to enrich it, enabling everyone to thrive in health and vitality.” But some microbiologists and clinical laboratory scientists would consider that the current state of knowledge about the human microbiome is not well-developed enough to justify offering direct-to-consumer microbiology tests that encourage consumers to purchase nutritional products. (Photo copyright: Viome Life Sciences.)
Empowering People to Make Informed Decisions about Their Health
Established in 2016, Bellevue, Washington-based Viome produces and sells, among other tests, its Gut Intelligence at-home test kit, which analyzes the microbial composition of stool samples. This kit relies on RNA sequencing to detect bacteria and other elements present in the gut, such as yeasts and viruses.
The genetic data is then entered into an artificial intelligence (AI) algorithm to provide individuals with information regarding their personal gut health. Viome partnered with Los Alamos National Laboratory to create their AI platform. The company has collected more than 600,000 test samples to date.
“We are the only company that looks at the gene expression and what these microbes are doing,” said Naveen Jain, Founder and CEO of Viome in the press release.
Viome uses technology combined with science to determine the optimal outcomes for each individual consumer based on his or her unique human and microbial gene expression. The data derived from the microbiome is also utilized to offer nutritional recommendations and supplement advice to test takers.
“At Viome, we’re empowering our customers with an individualized nutrition strategy, cutting through the noise of temporary trends and one-size-fits-all advice,” Jain added. “We’re on a journey to redefine aging itself, and we’re invigorated by the support of our investors and customers. Together, we’re building pathways to wellness that hold the potential to enhance the lives of billions of fellow humans across the globe.”
Manipulating Microbiome through Diet
Some scientists, however, are not sold on the idea of microbiome test kits and the data they offer to healthcare providers for treating illnesses.
“The best thing anybody can do for their microbiome is to eat a healthy diet. That’s the best way of manipulating your microbiome,” David Suskind, MD, a gastroenterologist at Seattle Children’s Hospital and Professor of Pediatrics at the University of Washington, told GeekWire.
Verdu, GeekWire reported, added that “there needs to be standardization of protocols and better understanding of microbiome function in health and disease.”
“Recommendations for such commercial kits would have to be based on evidence-based guidelines, which currently do not exist,” she told GeekWire.
Nevertheless, Jain remains positive about the value of microbiome testing. “The future of medicine will be delivered at home, not at the hospital. And the medicines of the future are going to come from a farm, not a pharmacy,” he told GeekWire.
Other Viome At-home Tests
According to a paper published in the journal Therapeutic Advances in Gastroenterology titled, “Role of the Gut Microbiota in Health and Chronic Gastrointestinal Disease: Understanding a Hidden Metabolic Organ,” the human gut contains trillions of microbes, and no two people share the exact same microbiome composition. This complex community of microbial cells influences human physiology, metabolism, nutrition and immune function, and performs a critical role in overall health.
CVS currently sells Viome’s “Gut Intelligence Health Insights Plus Personalized Nutrition Plan” on its website for $149.99. Prices may vary from online to in-store. The test is intended for individuals who want to monitor and address gut imbalances or health symptoms, such as:
Constipation
Diarrhea
Stomach pain
Bloating
Heartburn
Itchy skin
Trouble maintaining a healthy weight
Viome sells the Gut Intelligence Test for $179 on its own website, as well as the following health tests:
Viome also sell precision probiotics and prebiotics, as well as supplements and oral health lozenges.
Gut microbiome testing kits, such as the one from Viome, typically require the collection of a stool sample. Healthcare consumers have in the past been reluctant to perform such testing, but as more information regarding gut health is published, that reluctance may diminish.
Clinical laboratories also have a stake in the game. Dynamic direct to consumer at-home testing has the potential to generate revenue for clinical laboratories, while helping consumers who want to monitor different aspects of their health. But this would be an adjunct to the primary mission of medical laboratories to provide testing services to local physicians and their patients.
Another study in the United Kingdom that also used genomic analysis to understand drug-resistant Shigella produced findings that may be useful for microbiologists and medical laboratory scientists
From the onset of an infectious disease outbreak, public health officials, microbiologists, and clinical laboratory managers find it valuable to trace the origin of the spread back to the “index case” or “patient zero”—the first documented patient in the disease epidemic. Given the decreased cost of genomic analysis and improved accuracy of gene sequencing, infectious disease researchers are finding that task easier and faster than ever.
One recent example is a genomic study conducted at University of Washington (UW) in Seattle that enabled researchers to “retrace” the origin and spread of a “multidrug-resistant Shigellosis outbreak” from 2017 to 2022. “The aim of the study was to better understand the community transmission of Shigella and spread of antimicrobial resistance in our population, and to treat these multi-drug resistant infections more effectively,” the UW scientists stated in a new release.
Shigellosis (aka, bacillary dysentery) is a highly contagious disease of the intestines that can lead to hospitalization. Symptoms include fever, stomach cramps, diarrhea, dysentery, and dehydration.
“Additional analysis of the gut pathogen and its transmission patterns helped direct approaches to testing, treatment, and public health responses,” the UW news release states.
Usually prevalent in countries with public health and sanitation limitations, the “opportunistic” Shigella pathogen is now being seen in high-income countries as well, UW reported.
“You can’t really expect an infectious disease to remain confined to a specific at-risk population. [Shigella infections are] very much an emerging threat and something where our public health tools and therapeutic tools have significant limitations,” infectious disease specialist Ferric Fang, MD (above) told CIDRAP News. Fang is a UW professor of Microbiology and Clinical Laboratory Medicine and a corresponding author of the UW study. (Photo copyright: University of Washington.)
Generally, Shigella infects children, travelers, and men who have sex with men (MSM), the CDC noted.
The UW researchers were motivated to study Shigella when they noticed an uptick in drug-resistant shigellosis cases in Seattle’s homeless population in 2020 at the beginning of the COVID-19 pandemic, Center for Infectious Disease Research and Policy News (CIDRAP News) reported.
“Especially during the pandemic, a lot of public facilities were closed that homeless people were used to using,” infectious disease specialist Ferric Fang, MD, told CIDRAP News. Fang is Professor of Microbiology and Laboratory Medicine at University of Washington and corresponding author of the UW study.
The researchers studied 171 cases of Shigella identified from 2017 to 2022 by clinical laboratories at Harborview Medical Center and UW Medical Center in Seattle. According to CIDRAP News, the UW researchers found that:
46% were men who have sex with men (MSM).
51% were people experiencing homelessness (PEH).
Fifty-six patients were admitted to the hospital, with eight to an intensive care unit.
51% of isolates were multi-drug resistant (MDR).
Whole-Genome Sequencing Reveals Origin
The UW scientists characterized the stool samples of Shigella isolates by species identification, phenotypic susceptibility testing, and whole-genome sequencing, according to their Lancet Infectious Diseases paper. The paper also noted that 143 patients received antimicrobial therapy, and 70% of them benefited from the treatment for the Shigella infection.
Whole-genome sequencing revealed that two strains of Shigella (S. flexneri and S. sonnei) appeared first in Seattle’s MSM population before infecting the PEM population.
The genomic analysis found the outbreak of drug-resistant Shigella had international links as well, according to CIDRAP News:
One S. flexneri isolate was associated with a multi-drug resistant (MDR) strain from China, and
S. sonnei isolates resembled a strain characteristic of a current outbreak of MDR Shigella in England.
“The most prevalent lineage in Seattle was probably introduced to Washington State via international travel, with subsequent domestic transmission between at-risk groups,” the researchers wrote.
“Genomic analysis elucidated not only outbreak origin, but directed optimal approaches to testing, treatment, and public health response. Rapid diagnostics combined with detailed knowledge of local epidemiology can enable high rates of appropriate empirical therapy even in multidrug-resistant infection,” they continued.
UK Shigella Study Also Uses Genomics
Another study based in the United Kingdom (UK) used genomic analysis to investigate a Shigella outbreak as well.
Motivated by a UK Health Security Agency report of an increase in drug-resistance to common strains since 2021, the UK researchers studied Shigella cases from September 2015 to June 2022.
According to a paper they published in Lancet Infectious Diseases, the UK researchers “reported an increase in cases of sexually transmitted S. flexneri harboring blaCTX-M-27 (an antibiotic-resistant gene) in England, which is known to confer resistance to third-generation cephalosporins (antibiotics),” the researchers wrote.
Their analysis of plasmids (DNA with genes having antibiotic resistance) revealed a link in two drug-resistant Shigella strains at the same time, CIDRAP News explained.
“Our study reveals a worsening outlook regarding antimicrobial-resistant Shigella strains among MSM and highlights the value of continued integration of genomic analysis into surveillance and research,” the UK-based scientists wrote.
Current challenges associated with Shigella, especially as it evades treatment, may continue to demand attention from microbiologists, clinical laboratory scientists, and infectious disease specialists. Fortunately, use of genomic analysis—due to its ongoing improvements that have lowered cost and improved accuracy—has made it possible for public health researchers to better track the origins of disease outbreak and spread.
