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University of Athens Researchers Create Wooden Tongue Depressor with Biosensing Capabilities Capable of Identifying Biomarkers

Scientists believe the biodegradable device could someday help detect multiple saliva biomarkers. If true, it might provide a new type of test for clinical laboratories

When it comes to tongue depressors, it turns out you can teach an old dog new tricks. Researchers from National and Kapodistrian University of Athens Greece (NKUA) have taken this simple wooden medical tool and developed a high-tech biosensing device that may someday be useful at the point-of-care in hospitals and as a new type of test for clinical laboratories.

Using diode laser engraving, the researchers developed an “eco-friendly disposable sensor that can measure glucose levels and other biomarkers in saliva,” according to LabMedica.

This proof-of-principle biosensing device demonstrates the feasibility of “simultaneous determination of glucose and nitrite in artificial saliva,” according to the NKUA scientists who hope it will help doctors diagnose a variety of conditions.

The researchers published a paper on the development of their new wooden biosensor in the journal Analytical Chemistry titled, “Wooden Tongue Depressor Multiplex Saliva Biosensor Fabricated via Diode Laser Engraving.”

biosensing tongue depressor

In their published paper, the scientists at the University of Athens wrote that their wooden electrochemical biosensing tongue depressor (above) “is an easy-to-fabricate disposable point-of-care chip with a wide scope of applicability to other bioassays,” and that “it paves the way for the low-cost and straightforward production of wooden electrochemical platforms.” Might this and other similar biosensing devices eventually find their way to clinical laboratories for use in identifying and tracking certain biomarkers for disease? (Photo copyright: University of Athens.)


How to Make a High-Tech Tongue Depressor

Though wood is affordable and accessible, it doesn’t conduct electricity very well. The researchers’ first attempt to solve this problem was to use the wood as “a passive substrate” to which they coated “metals and carbon-based inks,” LabMedica reported. After that they tried using high-powered lasers to “char specific regions on the wood, turning those spots into conductive graphite.” But that process was complicated, expensive, and a fire hazard.

The researchers eventually turned to “low-power diode lasers” which have been used successfully “to make polyimide-based sensors but have not previously been applied to wooden electronics and electrochemical sensors,” LabMedica noted.

In their Analytical Chemistry paper, the researchers wrote, “A low-cost laser engraver, equipped with a low-power (0.5 W) diode laser, programmably irradiates the surface of the WTD [wooden tongue depressor], forming two mini electrochemical cells (e-cells). The two e-cells consist of four graphite electrodes: two working electrodes, a common counter, and a common reference electrode. The two e-cells are spatially separated via programmable pen-plotting, using a commercial hydrophobic marker pen.”

In other words, the researchers “used a portable, low-cost laser engraver to create a pattern of conductive graphite electrodes on a wooden tongue depressor, without the need for special conditions. Those electrodes formed two electrochemical cells separated by lines drawn with a water-repellent permanent marker,” states a press release from the American Chemical Society.

“The biosensor was then used to quickly and simultaneously measure nitrite and glucose concentrations in artificial saliva. Nitrite can indicate oral diseases like periodontitis, while glucose can serve as a diagnostic for diabetes. The researchers suggest that these low-cost devices could be adapted to detect other saliva biomarkers and could be easily and rapidly produced on-site at medical facilities,” LabMedica reported.

Benefits of Using Wood

One of the major benefits of using wood for their biosensing device is how environmentally friendly it is. “Since wood is a renewable, biodegradable naturally occurring material, the development of conductive patterns on wood substrates is a new and innovative chapter in sustainable electronics and sensors,” the researchers wrote in Analytical Chemistry.

Additionally, the tongue depressor features “An easy-to-fabricate disposable point-of-care chip with a wide scope of applicability to other bioassays, while it paves the way for the low-cost and straightforward production of wooden electrochemical platforms,” the researchers added.

This adds to a growing trend of developing bioassay products that keep the health of our planet in mind.

In “University of Pennsylvania Researchers Use Cellulose to Produce Accurate Rapid COVID-19 Test Results Faster and Cheaper than Traditional PCR Tests,” we covered how researchers at the University of Pennsylvania (UPenn) had developed a biodegradable rapid COVID-19 test that uses bacterial cellulose (BC) instead of printed circuit boards (PCBs) as its biosensor.

“This new BC test is non-toxic, naturally biodegradable and both inexpensive and scalable to mass production, currently costing less than $4.00 per test to produce. Its cellulose fibers do not require the chemicals used to manufacture paper, and the test is almost entirely biodegradable,” a UPenn blog post noted.

New Future Tool Use in Clinical Diagnostics

Who could have predicted that the lowly wooden tongue depressor would go high tech with technology that uses lasers to convert it to an electrochemical multiplex biosensing device for oral fluid analysis? This is yet another example of technologies cleverly applied to classic devices that enable them to deliver useful diagnostic information about patients.

And while a biosensing tongue depressor is certainly a diagnostic tool that may be useful for nurses and physicians in clinic and hospital settings, with further technology advancements, it could someday be used to collect specimens that measure more than glucose and nitrites.

—Kristin Althea O’Connor

Related Information:

Wooden Tongue Depressor Multiplex Saliva Biosensor Fabricated via Diode Laser Engraving

Say ‘Ahhh’: This Ecofriendly Tongue Depressor Checks Vitals

Biosensor-Fabricated Wooden Tongue Depressor Measures Glucose and Nitrite in Saliva

Researchers at Stanford University Discover Gene Variant That Appears to Protect Individuals from Both Alzheimer’s and Parkinson’s Disease

Study findings may lead to new clinical laboratory tests, as well as vaccines and immunotherapies for neurodegenerative diseases

Research into the human genome continues to produce useful new insights. This time, a study led by researchers at Stanford University identified a genetic variation that is believed to help “slow or even stall” progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s, according to a press release. Because these genetic variations are common, it is likely that diagnostic tests can be developed for use by clinical laboratories.

Researchers at Stanford Medicine led the study which discovered that approximately one in five individuals carry the gene variant, a protective allele identified as DR4 (aka, HLA-DR4). It’s one of a large number of alleles found in a gene known as DRB1.

DRB1 is part of a family of genes collectively known as the human lymphocyte antigen complex or HLA. The HLA-DRB1 gene plays a crucial role in the ability of the immune system to see a cell’s inner contents.

The Stanford scientists published their findings in the journal PNAS titled, “Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes.” Approximately 160 researchers from roughly 25 countries contributed to the work. 

Emmanuel Mignot, MD, PhD

“In an earlier study, we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Emmanuel Mignot, MD, PhD (above), Director of the Stanford Center for Narcolepsy, in a Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.” Clinical laboratories may soon have new vaccines for both neurodegenerative diseases. (Photo copyright: Stanford University.)


DR4 Found to Impact Both Parkinson’s and Alzheimer’s Diseases

To perform their research, the team examined a large collection of medical and genetic databases from 176,000 people who had either Alzheimer’s or Parkinson’s disease. The people involved in the study were from numerous countries located in East Asia, Europe, the Middle East and South America. Their genomes were then compared with people who did not have the diseases, focusing on the incidence and age of onset.

“In an earlier study we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Mignot in the Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.”

The team found that about 20% to 30% of people carry DR4, and that they have around a 10% risk reduction for developing the two diseases. 

“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Narcolepsy, in the Stanford Medicine press release. “The night after we found that out, I couldn’t sleep.”

The scientists also analyzed data from autopsied brains of more than 7,000 Alzheimer’s patients and discovered that individuals who carry DR4 had fewer neurofibrillary tangles and that those tangles are composed mainly of modified tau proteins, a common biomarker for Alzheimer’s.

The presence of these tangles corresponds with the severity of Alzheimer’s disease. They are not typically seen in Parkinson’s patients, but the Stanford team found that Parkinson’s patients who did carry DR4 experienced later onset of symptoms.

Mignot stated that tau, which is essential in Alzheimer’s, may also play a role in Parkinson’s, but that further research is required to prove its function.

Both diseases are characterized by the progressive loss of certain nerve cells or neurons in the brain and are linked to an accumulation of abnormal proteins. The Stanford researchers suggested that the DR4 gene variant may help protect individuals from Alzheimer’s and Parkinson’s by preventing the buildup of tau proteins.

“This is a very interesting study, providing additional evidence of the involvement of the immune system in the pathogenesis of Alzheimer’s and Parkinson’s,” neurologist Wassim Elyaman, PhD, Assistant Professor of Neurological Sciences in Neurology, the Taub Institute and the Institute for Genomic Medicine at Columbia University, told Live Science.

New Vaccines and Immunotherapies

According to the Alzheimer’s Association, more than six million Americans are currently living with Alzheimer’s disease and approximately one in three Americans die with Alzheimer’s or another dementia. 

The Parkinson’s Foundation states that nearly one million Americans are currently living with Parkinson’s disease, and that number is expected to rise to 1.2 million by 2030. Parkinson’s is the second-most common neurodegenerative disease after Alzheimer’s disease.

Even though the genetic analysis of the Stanford research is strong, more immune cell and blood-based research is needed to definitively establish how tau is connected to the two diseases.

This research could have implications for clinical laboratories by giving them biomarkers for a useful new diagnostic test, particularly for diagnosing Alzheimer’s and Parkinson’s.

Further, Mignot suggested that an effective vaccine could delay the onset or slow the progression of both diseases. He hopes to test his hypothesis on genetically modified mice and eventually human subjects.

—JP Schlingman

Related Information:

Stanford Medicine-led Study Finds Genetic Factor Fends Off Alzheimer’s and Parkinson’s

Gene Variant Carried by One in Five People May Guard Against Alzheimer’s and Parkinson’s, Massive Study Finds

Multiancestry Analysis of the HLA Locus in Alzheimer’s and Parkinson’s Diseases Uncovers a Shared Adaptive Immune Response Mediated by HLA-DRB1*04 Subtypes

Alzheimer’s Disease: Tau Biology and Pathology

Tau Protein and Alzheimer’s Disease: What’s the Connection?

C₂N Diagnostics Releases PrecivityAD, the First Clinical Laboratory Blood Test for Alzheimer’s Disease

Stanford Researchers Discover Junk DNA Affects Gene Expression

Research findings could lead to new biomarkers for genetic tests and give clinical laboratories new capabilities to diagnose different health conditions

New insights continue to emerge about “junk DNA” (aka, non-coding DNA). For pathologists and clinical laboratories, these discoveries may have value and eventually lead to new biomarkers for genetic testing.

One recent example comes from researchers at Stanford Medicine in California who recently learned how non-coding DNA—which makes up 98% of the human genome—affects gene expression, the function that leads to observable characteristics in an organism (phenotypes).

The research also could lead to a better understanding of how short tandem repeats (STRs)—the number of times a gene is copied into RNA for protein use—affect gene expression as well, according to Stanford.

Scientists at Stowers Institute for Medical Research and Duke University School of Medicine contributed to the study.

The researchers published their findings in the journal Science titled, “Short Tandem Repeats Bind Transcription Factors to Tune Eukaryotic Gene Expression.”

Polly Fordyce, PhD

“We’ve known for a while that short tandem repeats or STRs, aren’t junk because their presence or absence correlates with changes in gene expression. But we haven’t known how they exert these effects,” said study lead Polly Fordyce, PhD (above), Associate Professor of Bioengineering and Genetics at Stanford University, in a news release. The research could lead to new clinical laboratory biomarkers for genetic testing. (Photo copyright: Stanford University.)


To Bind or Not to Bind

In their Science paper, the Stanford researchers described an opportunity to explore a new angle to transcription factors binding to some sequences, also known as sequence motifs.

“Researchers have spent a lot of time characterizing these transcription factors and figuring out which sequences—called motifs—they like to bind to the most,” said the study lead Polly Fordyce, PhD, Associate Professor of Bioengineering and Genetics at Stanford University, in a Stanford Medicine news release.

“But current models don’t adequately explain where and when transcription factors bind to non-coding DNA to regulate gene expression. Sometimes, no transcription factor is attached to something that looks like a perfect motif. Other times, transcription factors bind to stretches of DNA that aren’t motifs,” the news release explains.

Transcription factors are “like light switches that can turn genes on or off depending on what cells need,” notes a King’s College London EDIT Lab blog post.

But why do transcription factors target some places in the genome and not others?

“To solve the puzzle of why transcription factors go to some places in the genome and not to others, we needed to look beyond the highly preferred motifs,” Fordyce added. “In this study, we’re showing that the STR sequence around the motif can have a really big effect on transcription factor binding, providing clues as to what these repeated sequences might be doing.”

Such information could aid in understanding certain hereditary conditions and diseases. 

“Variations in STR length have been associated with changes in gene expression and implicated in several complex phenotypes such as schizophrenia, cancer, autism, and Crohn’s disease. However, the mechanism by which STRs affect transcription remains unknown,” the researchers wrote in Science.

Special Assays Explore Binding

According to their paper, the research team turned to the Fordyce Lab’s previously developed microfluidic binding assays (MITOMI, kMITOMI, and STAMMP) to analyze the impact of different DNA sequences on transcription factor binding.

“In the experiment we asked, ‘How do these changes impact the strength of transcription factor binding?’ We saw a surprisingly large effect. Varying the STR sequence around a motif can have a 70-fold impact on the binding,” Fordyce wrote.

In an accompanying Science article titled, “Repetitive DNA Regulates Gene Expression,” Thomas Kuhlman, PhD, Assistant Professor, Physics and Astronomy, University of California, Riverside, wrote that the study “demonstrates that STRs exert their effects by directly binding transcription factor proteins, thus explaining how STRs might influence gene expression in both normal and diseased states.”

Junk DNA Affects Blood Pressure

In another study, researchers at The Hospital for Sick Children (SickKids), which is affiliated with the University of Toronto, Ontario, examined the possible effect of non-coding DNA on genes related to blood pressure.

“This research unveils, for the first time, the intricate connection between how variants in the non-coding genome affect genes that are associated with blood pressure and with hypertension. What we’ve created is a kind of functional map of the regulators of blood pressure genes, “said Philipp Maass, PhD, Lead Researcher and Assistant Professor Molecular Genetics, University of Toronto, in a news release.

The research team used massively parallel reporter assay (MPRA) technology to analyze 4,608 genetic variants associated with blood pressure.

In “Systematic Characterization of Regulatory Variants of Blood Pressure Genes,” published in the journal Cell Genomics, the SickKids scientists noted that high throughput technology identified “regulatory variants at blood pressure loci.”

The findings could aid precision medicine for cardiovascular health and may possibly be adopted to other conditions, according to The Hospital for Sick Children.

“The variants we have characterized in the non-coding genome could be used as genomic markers for hypertension, laying the groundwork for future genetic research and potential therapeutic targets for cardiovascular disease,” Maass noted.

Why All the ‘Junk’ DNA?

Clinical laboratory scientists may wonder why genetic research has primarily focused on 20,000 genes within the genome, leaving the “junk” DNA for later investigation. So did researchers at Harvard University.

“After the Human Genome Project, scientists found that there were around 20,000 genes within the genome, a number that some researchers had already predicted. Remarkably, these genes comprise only about 1-2% of the three billion base pairs of DNA. This means that anywhere from 98-99% of our entire genome must be doing something other than coding for proteins,” they wrote in a blog post.

“Imagine being given multiple volumes of encyclopedias that contained a coherent sentence in English every 100 pages, where the rest of the space contained a smattering of uninterpretable random letters and characters. You would probably start to wonder why all those random letters and characters were there in the first place, which is the exact problem that has plagued scientists for decades,” they added.

Not only is junk DNA an interesting study subject, but ongoing research may also produce useful new biomarkers for genetic diagnostics and other clinical laboratory testing. Thus, medical lab professionals may want to keep an eye on new developments involving non-coding DNA.   

—Donna Marie Pocius

Related Information:

Stanford Medicine-led Study Clarifies How “Junk DNA” Influences Gene Expression

Short Tandem Repeats Bind Transcription Factors to Tune Eukaryotic Gene Expression

J for Junk DNA Does Not Exist!

Repetitive DNA Regulates Gene Expression

Illuminating Genetic Dark Matter: How “Junk DNA” Influences Blood Pressure

Systematic Characterization of Regulatory Variants of Blood Pressure Genes

The 99 Percent of the Human Genome

In Early Weeks of Flu Season, COVID-19 Patients Show Milder Symptoms as SARS-CoV-2 Continues to Evolve

Doctors report difficulty differentiating COVID-19 from other viral infections, impacting clinical laboratory test orders

Because the SARS-CoV-2 coronavirus is in the same family of viruses that cause the common cold and influenza, virologists expected this virus—which caused the global COVID-19 pandemic—would evolve and mutate into a milder form of infection. Early evidence from this influenza season seems consistent with these expectations in ways that will influence how clinical laboratories offer tests for different respiratory viruses.

While new variants of the SARS-CoV-2 virus continue to appear, indications are that early in this flu season individuals infected with the more recent variants are experiencing milder symptoms when compared to the last few years. Doctors report they find it increasingly difficult to distinguish COVID-19 infections from allergies or the common cold because patients’ symptoms are less severe, according to NBC News.

This, of course, makes it challenging for doctors to know the most appropriate clinical laboratory tests to order to help them make accurate diagnoses.

Erick Eiting, MD

“It isn’t the same typical symptoms that we were seeing before. It’s a lot of congestion, sometimes sneezing, usually a mild sore throat,” Erick Eiting, MD, Vice Chair of Operations for Emergency Medicine at Mount Sinai Hospital in New York City, told NBC News. “Just about everyone who I’ve seen has had really mild symptoms. The only way that we knew that it was COVID was because we happened to be testing them.” Knowing which tests for respiratory viruses that clinical laboratories need to perform may soon be the challenge for doctors. (Photo copyright: Mt. Sinai.)

Milder COVID-19 Symptoms Follow a Pattern

Previous hallmarks of a COVID-19 infection included:

  • Loss of taste,
  • loss of smell,
  • dry cough,
  • fever,
  • sore throat,
  • diarrhea,
  • body aches,
  • headaches.

However, physicians now observe milder symptoms of the infection that follow a distinct pattern and which are mostly concentrated in the upper respiratory tract

Grace McComsey, MD, Vice President of Research and Associate Chief Scientific Officer at University Hospitals Health System (UH) in Cleveland, Ohio, told NBC News that some patients have described their throat pain as “a burning sensation like they never had, even with Strep in the past.”

“Then, as soon as the congestion happens, it seems like the throat gets better,” she added.

In addition to the congestion, some patients are experiencing:

  • headache,
  • fever,
  • chills,
  • fatigue,
  • muscle aches,
  • post-nasal drip. 

McComsey noted that fatigue and muscle aches usually only last a couple of days, but that the congestion can sometimes last a few weeks. She also estimated that only around 10-20% of her newest COVID patients are losing their sense of smell or taste, whereas early in the pandemic that number was closer to 60-70% of her patients. 

Doctors also noted that fewer patients are requiring hospitalization and that many recover without the use of antivirals or other treatments.

“Especially since July, when this recent mini-surge started, younger people that have upper respiratory symptoms—cough, runny nose, sore throat, fever and chills—99% of the time they go home with supportive care,” said Michael Daignault, MD, an emergency physician at Providence Saint Joseph Medical Center in Burbank, California.

Milder SARS-CoV-2 Variants Should Still be Taken Seriously

Doctors have varying opinions regarding why the current COVID-19 variants are milder. Some believe the recent variants simply aren’t as good at infecting the lungs as previous variants.

“Overall, the severity of COVID-19 is much lower than it was a year ago and two years ago,” Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, told NBC News. “That’s not because the variants are less robust. It’s because the immune responses are higher.”

McComsey added that she doesn’t think mild cases should be ignored as she is still seeing new cases of long COVID with rapid heart rate and exercise intolerance being among the most common lingering symptoms. Re-infections also add to the risks associated with long COVID.

“What we’re seeing in long COVID clinics is not just the older strains that continue to be symptomatic and not getting better—we’re adding to that number with the new strain as well,” McComsey said. “That’s why I’m not taking this new wave any less seriously.”

Clinical Laboratory COVID-19 Testing May Decrease

According to Andrew Read, PhD, Interim Senior Vice President for Research and Evan Pugh University Professor of Biology and Entomology at Pennsylvania State University, there is nothing unexpected or startling about the coronavirus acquiring new mutations.

“When a mutation confers an interesting new trick that’s got an advantage, it’s going to be popping up in many different places,” Read told the New York Times. “Everything we see is just consistent with how you imagine virus evolution proceeding in a situation where a new virus has jumped into a novel host population.”

Data from the Centers for Disease Control and Prevention’s COVID-19 Data Tracker—which reports weekly hospitalizations, deaths, emergency department (ED) visits, and COVID-19 test positivity results—shows infection trends fluctuating, but overall, they are decreasing.

  • For the week of October 21, 2023, there were 16,186 hospitalizations due to COVID-19 compared to the highest week recorded (January 15, 2022) with 150,674 hospitalizations nationwide.
  • The highest number of deaths reported in a single week were 25,974 for the week of January 8, 2021, while 637 patients perished from COVID-19 during the week of October 21, 2023.
  • In January of 2021, COVID accounted for 13.8% of all ED visits and in October 2023, COVID-19 was responsible for 1.3% of ED visits. 

“What I think we’re seeing is the virus continuing to evolve, and then leading to waves of infection, hopefully mostly mild in severity,” Barouch told The New York Times.

As severity of COVID-19 infections continues to fall, so, presumably, will demand for COVID-19 testing which has been a source of revenue for clinical laboratories for several years.

—JP Schlingman

Related Information:

Sore Throat, Then Congestion: Common COVID Symptoms Follow a Pattern Now, Doctors Say

COVID Continues to Rise, but Experts Remain Optimistic

What Is the Order of COVID Symptoms This Fall?

COVID Symptoms Now Follow a Distinct Pattern, Doctors Report

How are COVID-19 Symptoms Changing?

What Are the Mild Symptoms of COVID-19, and When Should You See a Doctor?

Doctors Admit They Can’t Tell COVID Apart from Allergies or the Common Cold Anymore—Highlighting How Mild Virus has Become

The Evolution of SARS-CoV-2

UCSF Researchers Identify Genetic Mutation That Promotes an Asymptomatic Response in Humans to COVID-19 Infection

Google DeepMind Says Its New Artificial Intelligence Tool Can Predict Which Genetic Variants Are Likely to Cause Disease

Genetic engineers at the lab used the new tool to generate a catalog of 71 million possible missense variants, classifying 89% as either benign or pathogenic

Genetic engineers continue to use artificial intelligence (AI) and deep learning to develop research tools that have implications for clinical laboratories. The latest development involves Google’s DeepMind artificial intelligence lab which has created an AI tool that, they say, can predict whether a single-letter substitution in DNA—known as a missense variant (aka, missense mutation)—is likely to cause disease.

The Google engineers used their new model—dubbed AlphaMissense—to generate a catalog of 71 million possible missense variants. They were able to classify 89% as likely to be either benign or pathogenic mutations. That compares with just 0.1% that have been classified using conventional methods, according to the DeepMind engineers.

This is yet another example of how Google is investing to develop solutions for healthcare and medical care. In this case, DeepMind might find genetic sequences that are associated with disease or health conditions. In turn, these genetic sequences could eventually become biomarkers that clinical laboratories could use to help physicians make earlier, more accurate diagnoses and allow faster interventions that improve patient care.

The Google engineers published their findings in the journal Science titled, “Accurate Proteome-wide Missense Variant Effect Prediction with AlphaMissense.” They also released the catalog of predictions online for use by other researchers.

Jun Cheng, PhD (left), and Žiga Avsec, PhD (right)

“AI tools that can accurately predict the effect of variants have the power to accelerate research across fields from molecular biology to clinical and statistical genetics,” wrote Google DeepMind engineers Jun Cheng, PhD (left), and Žiga Avsec, PhD (right), in a blog post describing the new tool. Clinical laboratories benefit from the diagnostic biomarkers generated by this type of research. (Photo copyrights: LinkedIn.)

AI’s Effect on Genetic Research

Genetic experiments to identify which mutations cause disease are both costly and time-consuming, Google DeepMind engineers Jun Cheng, PhD, and Žiga Avsec, PhD, wrote in a blog post. However, artificial intelligence sped up that process considerably.

“By using AI predictions, researchers can get a preview of results for thousands of proteins at a time, which can help to prioritize resources and accelerate more complex studies,” they noted.

Of all possible 71 million variants, approximately 6%, or four million, have already been seen in humans, they wrote, noting that the average person carries more than 9,000. Most are benign, “but others are pathogenic and can severely disrupt protein function,” causing diseases such as cystic fibrosis, sickle-cell anemia, and cancer.

“A missense variant is a single letter substitution in DNA that results in a different amino acid within a protein,” Cheng and Avsec wrote in the blog post. “If you think of DNA as a language, switching one letter can change a word and alter the meaning of a sentence altogether. In this case, a substitution changes which amino acid is translated, which can affect the function of a protein.”

In the Google DeepMind study, AlphaMissense predicted that 57% of the 71 million variants are “likely benign,” 32% are “likely pathogenic,” and 11% are “uncertain.”

The AlphaMissense model is adapted from an earlier model called AlphaFold which uses amino acid genetic sequences to predict the structure of proteins.

“AlphaMissense was fed data on DNA from humans and closely related primates to learn which missense mutations are common, and therefore probably benign, and which are rare and potentially harmful,” The Guardian reported. “At the same time, the program familiarized itself with the ‘language’ of proteins by studying millions of protein sequences and learning what a ‘healthy’ protein looks like.”

The model assigned each variant a score between 0 and 1 to rate the likelihood of pathogenicity [the potential for a pathogen to cause disease]. “The continuous score allows users to choose a threshold for classifying variants as pathogenic or benign that matches their accuracy requirements,” Avsec and Cheng wrote in their blog post.

However, they also acknowledged that it doesn’t indicate exactly how the variation causes disease.

The engineers cautioned that the predictions in the catalog are not intended for clinical use. Instead, they “should be interpreted with other sources of evidence.” However, “this work has the potential to improve the diagnosis of rare genetic disorders, and help discover new disease-causing genes,” they noted.

Genomics England Sees a Helpful Tool

BBC noted that AlphaMissense has been tested by Genomics England, which works with the UK’s National Health Service. “The new tool is really bringing a new perspective to the data,” Ellen Thomas, PhD, Genomics England’s Deputy Chief Medical Officer, told the BBC. “It will help clinical scientists make sense of genetic data so that it is useful for patients and for their clinical teams.”

AlphaMissense is “a big step forward,” Ewan Birney, PhD, Deputy Director General of the European Molecular Biology Laboratory (EMBL) told the BBC. “It will help clinical researchers prioritize where to look to find areas that could cause disease.”

Other experts, however, who spoke with MIT Technology Review were less enthusiastic.

“DeepMind is being DeepMind,” Insilico Medicine founder/CEO Alex Zhavoronkov, PhD, told the MIT publication. “Amazing on PR and good work on AI.”

Heidi Rehm, PhD, co-director of the Program in Medical and Population Genetics at the Broad Institute, suggested that the DeepMind engineers overstated the certainty of the model’s predictions. She told the publication that she was “disappointed” that they labeled the variants as benign or pathogenic.

“The models are improving, but none are perfect, and they still don’t get you to pathogenic or not,” she said.

“Typically, experts don’t declare a mutation pathogenic until they have real-world data from patients, evidence of inheritance patterns in families, and lab tests—information that’s shared through public websites of variants such as ClinVar,” the MIT article noted.

Is AlphaMissense a Biosecurity Risk?

Although DeepMind has released its catalog of variations, MIT Technology Review notes that the lab isn’t releasing the entire AI model due to what it describes as a “biosecurity risk.”

The concern is that “bad actors” could try using it on non-human species, DeepMind said. But one anonymous expert described the restrictions “as a transparent effort to stop others from quickly deploying the model for their own uses,” the MIT article noted.

And so, genetics research takes a huge step forward thanks to Google DeepMind, artificial intelligence, and deep learning. Clinical laboratories and pathologists may soon have useful new tools that help healthcare provider diagnose diseases. Time will tell. But the developments are certain worth watching.

—Stephen Beale

Related Information:

AlphaFold Is Accelerating Research in Nearly Every Field of Biology

A Catalogue of Genetic Mutations to Help Pinpoint the Cause of Diseases

Accurate Proteome-wide Missense Variant Effect Prediction with AlphaMissense

Google DeepMind AI Speeds Up Search for Disease Genes

DeepMind Is Using AI to Pinpoint the Causes of Genetic Disease

DeepMind’s New AI Can Predict Genetic Diseases

Florida Nurse Practitioner Convicted for Involvement in $200 Million Medicare Fraud Scheme Involving Clinical Laboratory Tests, Other Procedures

Federal prosecutors allege that this nurse practitioner ordered more genetic tests for Medicare beneficiaries than any other provider during 2020

Cases of Medicare fraud involving clinical laboratory testing continue to be prosecuted by the federal Department of Justice. A jury in Miami recently convicted a nurse practitioner (NP) for her role in a massive Medicare fraud scheme for millions of dollars in medically unnecessary genetic testing and durable medical equipment. She faces 75 years in prison when sentenced in December.  

In their indictment, federal prosecutors alleged that from August 2018 through June 2021 Elizabeth Mercedes Hernandez, NP, of Homestead, Florida, worked with more than eight telemedicine and marketing companies to sign “thousands of orders for medically unnecessary orthotic braces and genetic tests, resulting in fraudulent Medicare billings in excess of $200 million,” according to a US Department of Justice (DOJ) news release announcing the conviction.

“Hernandez personally pocketed approximately $1.6 million in the scheme, which she used to purchase expensive cars, jewelry, home renovations, and travel,” the press release noted.

Hernandez was indicted in April 2022 as part of a larger DOJ crackdown on healthcare fraud related to the COVID-19 outbreak.

Luis Quesada

“Throughout the pandemic, we have seen trusted medical professionals orchestrate and carry out egregious crimes against their patients all for financial gain,” said Assistant Director Luis Quesada (above) of the FBI’s Criminal Investigative Division, in a DOJ press release. Clinical laboratory managers would be wise to monitor these Medicare fraud cases. (Photo copyright: Federal Bureau of Investigation.)

Nurse Practitioner Received Kickbacks and Bribes

Federal prosecutors alleged that the scheme involved telemarketing companies that contacted Medicare beneficiaries and persuaded them to request genetic tests and orthotic braces. Hernandez, they said, then signed pre-filled orders, “attesting that she had examined or treated the patients,” according to the DOJ news release.

In many cases, Hernandez had not even spoken with the patients, prosecutors said. “She then billed Medicare as though she were conducting complex office visits with these patients, and routinely billed more than 24 hours of ‘office visits’ in a single day,” according to the news release.

In total, Hernandez submitted fraudulent claims of approximately $119 million for genetic tests, the indictment stated. “In 2020, Hernandez ordered more cancer genetic (CGx) tests for Medicare beneficiaries than any other provider in the nation, including oncologists and geneticists,” according to the news release.

The indictment noted that because CGx tests do not diagnose cancer, Medicare covers them only “in limited circumstances, such as when a beneficiary had cancer and the beneficiary’s treating physician deemed such testing necessary for the beneficiary’s treatment of that cancer. Medicare did not cover CGx testing for beneficiaries who did not have cancer or lacked symptoms of cancer.”

In exchange for signing the orders, Hernandez received kickbacks and bribes from companies that claimed to be in the telemedicine business, the indictment stated.

“These healthcare fraud abuses erode the integrity and trust patients have with those in the healthcare industry … the FBI, working in coordination with our law enforcement partners, will continue to investigate and pursue those who exploit the integrity of the healthcare industry for profit,” said Assistant Director Luis Quesada of the Federal Bureau of Investigation’s Criminal Investigative Division, in the DOJ press release.

Conspirators Took Advantage of COVID-19 Pandemic

Prosecutors alleged that as part of the scheme, she and her co-conspirators took advantage of temporary amendments to rules involving telehealth services—changes that were enacted by Medicare in response to the COVID-19 pandemic.

The indictment noted that prior to the pandemic, Medicare covered expenses for telehealth services only if the beneficiary “was located in a rural or health professional shortage area,” and “was in a practitioner’s office or a specified medical facility—not at a beneficiary’s home.”

But in response to the pandemic, Medicare relaxed the restrictions to allow coverage “even if the beneficiary was not located in a rural area or a health professional shortage area, and even if the telehealth services were furnished to beneficiaries in their home.”

Hernandez was convicted of:

  • One count of conspiracy to commit healthcare fraud and wire fraud.
  • Four counts of healthcare fraud.
  • Three counts of making false statements.

Medscape noted that she was acquitted of two counts of healthcare fraud. The trial lasted six days, Medscape reported.

Hernandez’s sentencing hearing is scheduled for Dec. 14.

Co-Conspirators Plead Guilty

Two other co-conspirators in the case, Leonel Palatnik and Michael Stein, had previously pleaded guilty and received sentences, the Miami Herald reported.

Palatnik was co-owner of Panda Conservation Group LLC, which operated two genetic testing laboratories in Florida. Prosecutors said that Palatnik paid kickbacks to Stein, owner of 1523 Holdings LLC, “in exchange for his work arranging for telemedicine providers to authorize genetic testing orders for Panda’s laboratories,” according to a DOJ press release. The kickbacks were disguised as payments for information technology (IT) and consulting services.

“1523 Holdings then exploited temporary amendments to telehealth restrictions enacted during the pandemic by offering telehealth providers access to Medicare beneficiaries for whom they could bill consultations,” the press release states. “In exchange, these providers agreed to refer beneficiaries to Panda’s laboratories for expensive and medically unnecessary cancer and cardiovascular genetic testing.”

Palatnik pleaded guilty to his role in the kickback scheme in August 2021 and was sentenced to 82 months in prison, a DOJ press release states.

Stein pleaded guilty in April and was sentenced to five years in prison, the Miami Herald reported. He was also ordered to pay $63.3 million in restitution.

These federal cases involving clinical laboratory genetic testing and other tests and medical equipment indicate a commitment on the DOJ’s part to continue cracking down on healthcare fraud.

—Stephen Beale

Related Information:

Nurse Practitioner Convicted of $200M Health Care Fraud Scheme

Florida Nurse Practitioner Convicted in $200 Million Medicare Scheme

Florida Nurse Convicted for Fraudulent Orders Billing Medicare for $200M

South Florida Nurse Convicted of Medicare Scheme for Approving $200 Million in Bogus Products

Justice Department Announces Nationwide Coordinated Law Enforcement Action to Combat COVID-19 Health Care Fraud

Laboratory Owner Pleads Guilty to $73 Million Medicare Kickback Scheme

Laboratory Owner Sentenced to 82 Months in Prison for COVID-19 Kickback Scheme

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