With more study, the technique could lead to new precision medicine pathology diagnostics and clinical laboratory tests
Researchers at Yale University have devised a new pathology tool that utilizes barcode technology to map the spatial relationships of ribonucleic acid (RNA) and proteins. This will be of interest to histopathologists who are responsible for examining clinical laboratory tissue samples and helping physicians diagnose disease.
Called Patho-DBiT (pathology-compatible deterministic barcoding in tissue), the Yale scientists claim their new tool can completely examine RNA and possibly aid in the diagnoses and treatment of cancer.
The technology, according to a Yale news release, “is unique in that it has microfluidic devices that deliver barcodes into the tissue from two directions creating a unique 2D ‘mosaic’ of pixels, providing spatial information that could be used to inform the creation of patient-specific targeted therapies.”
“It’s the first time we can directly ‘see’ all kinds of RNA species, where they are and what they do, in clinical tissue samples,” said Rong Fan, PhD, Harold Hodgkinson professor of biomedical engineering and pathology at Yale and senior author of the study.
“I think it’s going to completely transform how we study the biology of humans in the future,” said Rong Fan, PhD (above), Harold Hodgkinson professor of biomedical engineering and pathology at Yale and senior author of the study, in a Yale news release. The discovery could lead to new clinical laboratory screening tests and diagnostics for cancer. (Photo copyright: Yale University.)
More Precise Cancer Diagnoses
“As a physician who has been diagnosing cancer, I was surprised by how much more I can see using this pathology tool,” said Mina Xu, MD, professor of pathology at Yale School of Medicine and one of the authors of the study. “I think this deep molecular dive is going to advance our understanding of tumor biology exponentially. I really look forward to delivering more precise and actionable diagnoses.”
According to the Yale study, the Patho-DBiT tool has many beneficial capabilities. They include:
Dissecting spatiotemporal dynamics of lymphomagenesis at the single-cell level.
FFPE tissue involves the fixation of tissues by utilizing formalin and embedding tissue samples in paraffin wax. This method allows for the long-term preservation of tissue morphology and cellular details and is commonly used in histopathology.
In the past, the RNA within FFPE samples have been susceptible to fragmentation during the paraffin-embedding process and degradation issues. These samples may also experience chemical modifications which could result in resistance to the enzymatic reactions necessary for proper sequencing.
“There are millions of these tissues that have been archived for so many years, but up until now, we didn’t have effective tools to investigate them at spatial level,” said the study’s first author Zhiliang Bai, PhD, a postdoctoral associate in Rong Fan’s lab at Yale. “RNA molecules in these tissues we’re looking at are highly fragmented and traditional methods can’t capture all the important information about them. It’s why we’re very excited about Patho-DBiT.”
Targeted Therapies
The team is encouraged by their research and the future potential for Patho-DBiT. They believe the technology may be useful in creating targeted therapies and helping understand the metamorphosis of low-grade tumors to more aggressive ones. They conceive their tool may assist in developing ways to prevent the progression of cancers.
“It is very exciting that Patho-DBiT-seq is also capable of generating spatial maps of noncoding RNA expression,” said Jun Lu, PhD, associate professor of genetics at Yale and another of the study’s authors. “Noncoding RNAs are often in regions of our genomes that were previously thought of as junk DNA, but now they are recognized as treasured players in biology and diseases such as cancer.”
The research included faculty members from several departments at Yale and was supported by the National Institutes of Health (NIH). The technology is now licensed to biotechnology company AtlasXomics of New Haven, Ct., for further development.
More research and studies are needed to validate the findings of this research, but the Patho-DBiT tool could prove to be useful for the preservation of tissue samples and become essential in the diagnoses and treatment of cancers.
Clinical laboratories should closely watch the Trump administration as it contemplates a court appeal, a revised LDT rulemaking, or abandoning the rule altogether
With a US District Court judge’s decision to vacate the Food and Drug Administration’s (FDA) rule on laboratory-developed tests (LDTs), perhaps the most intriguing aspect for clinical laboratories is what the next move will be by the federal government.
It’s hard to predict whether the administration of President Donald Trump will either appeal the judge’s decision, direct the FDA to come up with a new version of the rule that passes legal muster, or simply back off further scrutiny of LDTs.
Let’s look more closely at the options for clinical laboratory professionals to monitor.
US District Court Judge Sean Jordan, JD (above), vacated the federal Food and Drug Administration’s final rule to regulate laboratory-developed tests (LDTs) on March 31, 2025. In a lawsuit, the Association for Molecular Pathologists and the American Clinical Laboratory Association accused the FDA of overstepping its legal authority in issuing the LDT rule in 2024. The outcome of this ruling will affect clinical laboratories’ future development their own tests. (Photo copyright: Jackson Walker LLP.)
Will the Trump Administration Appeal the LDT Decision?
The FDA’s final rule—which came out in 2024 and was about to hit its first compliance milestone on May 6, 2025—had been discussed for at least 10 years prior, covering multiple presidential administrations. Because the final rule was published by the FDA under former President Joe Biden, it surprised some observers to see Trump’s Department of Justice defend the FDA’s right to implement the rule during oral arguments in February before Judge Sean Jordan in US District Court for the Eastern District of Texas.
That hearing was the culmination of a combined lawsuit from American Clinical Laboratory Association (ACLA) and the Association for Molecular Pathology (AMP) challenging the LDT rule. The suit sought summary judgment on the matter, which Jordan granted on March 31 in his decision to vacate the FDA’s rule.
“The Court vacates and sets aside, in its entirety, the FDA’s final rule titled Medical Devices; Laboratory Developed Tests,” Jordan wrote. “The Court remands this matter to the secretary of Health and Human Services for further consideration.”
Trump’s legal team set a precedent early in the president’s second term to aggressively challenge any court decisions that buck his authority. From that perspective, an appeal of the LDT judgment seems probable, although there is no official word yet about that.
Trump ran on an anti-regulatory, smaller government platform. In that sense, the DOJ’s defense of the FDA’s standing to carry out the LDT rule was a surprise.
Will the FDA Create a Revised Version of the LDT Rule?
The court sent the rule back to the FDA, which leaves the door open for the agency to construct and issue a new rule.
The clinical laboratory industry argued that LDTs should not be classified as medical devices, which the rule instead emphasized. That could be an area where a new version of the rule bends.
Congress could also step in here. For many years, a proposed bill known as the VALID Act (formally the Verifying Accurate Leading-Edge IVCT Development Act) was filed in the House of Representatives to increase LDT oversight.
But then—after the FDA’s LDT rule came out—the VALID Act looked to be the lesser of two evils to lab professionals. It’s possible labs and lawmakers could work out a new version of the VALID Act to avoid another potentially onerous FDA-issued rulemaking.
Will Trump and the FDA Do Nothing?
Even though it would go against the current pattern of challenging court decisions, the Trump administration could simply step back and choose to do nothing with the FDA’s vacated rule.
In that case, presumably LDTs would continue to be overseen by the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The medical lab industry has long preferred to see CLIA reform as the pathway to regulating LDTs in the future rather than formal FDA involvement. The FDA referred to this arrangement as “enforcement discretion,” as LDT oversight has always been on the books at the FDA, but the agency deferred to CLIA for many years.
Of related interest was a news release last week from the federal Department of Health and Human Services (HHS) announcing a sweeping number of layoffs under its individual agencies. The FDA is slated to lose 3,500 employees, although the “reduction will not affect drug, medical device, or food reviewers, nor will it impact inspectors,” HHS noted in a fact sheet.
Revisiting an LDT rule that will require more reviewers and inspectors seems at odds with a shrinking FDA.
Clinical Labs Must Monitor the Near-term Future of LDTs
After coming out ahead in one of the biggest court showdowns in clinical lab history, medical laboratory scientists and industry leaders now must keep their eyes on the various avenues that LDT regulation could head down in the near future.
Watch for further analysis of the business implications of this court decision in The Dark Report.
Robert Michel, founder of TDIG and editor-in-chief of The Dark Report, explained that the acquisition serves as step one to winding down his long career.
“First and most important, this starts my path toward retirement,” Michel said in the March 10 issue of The Dark Report. “I’ve served in the clinical laboratory industry for 34 years now. That’s one-third of a century!”
More Options Ahead for Dark Daily Readers
In purchasing the assets of TDIG, LabX Media Group adds to its powerhouse of resources for clinical laboratory leaders, including Today’s Clinical Lab, G2 Intelligence, and Lab Manager.
The deal will give readers of Dark Daily further options from which to get their laboratory science and operations information, as Today’s Clinical Lab provides free content in areas such as pathology and clinical laboratory technology.
Additionally, “The lab science coverage in Today’s Clinical Lab complements the business intelligence of The Dark Report, allowing LabX Media to offer a more comprehensive range of information for clinical lab professionals,” Today’s Clinical Lab wrote last week.
“The good news for all the clients and long-time readers of The Dark Report is that LabX has both the capital and the specialized expertise required to keep The Dark Report, Dark Daily, and the Executive War College at the top of their games going forward,” said Robert Michel (above), founder of The Dark Intelligence Group, which sold its assets to LabX Media Group. (Photo copyright: LabX.)
Statement on LabX Purchase of The Dark Intelligence Group
In a statement about this transaction, LabX Media Group CEO Bob Kafato said: “We are excited to formally recognize these new additions to the LMG family. TDIG’s flagship publication, The Dark Report, has a 30-year track record of delivering timely business intelligence to the leaders of North America’s most successful clinical laboratories, genetic testing companies, and anatomic pathology groups. During these same 30 years, the Executive War College has become the biggest and the highest-profile laboratory management conference in North America.”
Michel will serve as an advisor to LabX Media Group to ensure a smooth transition while continuing to provide strategic consulting services to the lab industry.
Who is LabX Media Group?
LabX Media Group is a leading business-to-business science media company delivering award-winning editorial coverage, essential industry news, analysis, and insights for members of the scientific research and life science communities. LabX Media Group connects laboratory professionals with resources to help them make smarter buying decisions through powerful, market-leading brands.
One interesting final fact: TDIG and LabX Media Group both were founded in 1995 and are celebrating their respective 30-year anniversaries, Michel noted.
Pathologists and clinical laboratories will play a key role in collecting the data needed to create a person’s digital twin
Digital twins is a promising new technology that is making a big impact in healthcare. This development is significant because clinical laboratory test results will be among the most important sets of data to go into the creation of a patient’s “digital twin.”
A digital twin is defined by IBM as “a virtual representation of an object or system designed to reflect a physical object accurately. It spans the object’s lifecycle, is updated from real-time data, and uses simulation, machine learning, and reasoning to help make decisions.”
“We define a digital twin for healthcare as a virtual representation of a person which allows dynamic simulation of potential treatment strategy, monitoring and prediction of health trajectory, and early intervention and prevention, based on multi-scale modeling of multi-modal data such as clinical, genetic, molecular, environmental, and social factors, etc.,” wrote the authors of a review article published in NPJ Digital Medicine titled, “Digital Twins for Health: A Scoping Review.”
“The concept of digital twin for health (DT4H) holds great promise to revolutionize the entire healthcare system, including management and delivery, disease treatment and prevention, and health well-being maintenance, ultimately improving human life,” wrote study lead Eva Katsoulakis, MD (above), clinical informaticist and radiation oncologist at Tampa General Hospital in Florida, et al, in a review article she and her team published in NPJ Digital Medicine. Clinical laboratory test data will be a key element in the creation of a patient’s digital twin. (Photo copyright: Tampa General Hospital.)
Development of Digital Twins
Something akin to digital twins was first used in 1960 at NASA when replicas of spacecrafts currently on a mission in space were duplicated and studied on Earth. In 1991, Michael Grieves introduced the concept to manufacturing while at University of Michigan’s College of Engineering. The technology was later coined “digital twins” by John Vickers, a principal technologist in advanced manufacturing at NASA in 2010, IBM noted.
The increased use of digital twins in healthcare has brought some brilliant advancements. Examples, as reported by Computer Weekly, include:
Surgery and treatment: Boston Children’s Hospital uses digital twins to examine the complexities of heart procedures in reference to oxygen, blood flow, and valve pressure. Real-time analysis helps with surgeries and treatments, allowing clear visualization at all angles.
Metabolic analysis to tackle kidney failures: Digital twins are being used in Singapore to “Replicate metabolic fluxes to predict chronic kidney disease in type 2 diabetes mellitus.” Doctors there hope to curb the spike of chronic kidney disease found in type 2 diabetes mellitus. Their country has seen cases double in the last 40 years.
Bacterial predictions, E. coli: Bacteria behavior is being analyzed in computational simulations as part of a Simulating Microbial Systems (SMS) program. Run by the US Defense Advanced Research Projects Agency, the “SMS seeks interdisciplinary, comprehensive, and integrated workflows to generate unknown parameters from new data to inform computational models that can predict E. coli.”
Full body data: Precisely personalized care is the goal of European Virtual Human Twins Initiative, a project from the European Commission. The group creates digital twins and updates them with an individual’s personal conditions and health information that shifts as they age, keeping prevention as a focal point.
Respiratory viral pathogens: The complexities and variety of causes behind respiratory infections makes it an ideal area for digital twins. Its use in hospital ICUs can help doctors consider pneumonia treatment outlooks and develop plans for spread of infection.
Pharmaceuticals: Many pharma companies are opting to use digital twins since drug development is highly expensive and animal testing does not always provide clear data compared to human testing. Examples include Orion Pharma, which paired with AstraZeneca and Bayer to create digital twins that “capture genetic and molecular interactions that causally drive clinical and physiological outcomes.” Immunology company, Sanofi, also is using digital twins as “an essential first step to improve efficacy and safety.”
Future of Digital Twins in Healthcare
While digital twin development within healthcare is still in early stages, it promises to pioneer much change.
“When you have this model, you can personalize with certain features, certain anatomy, then you can try things. In heart surgery, you can’t try 20 different things, you only have one shot,” Ellen Kuhl PhD, professor of engineering and bioengineering at Stanford University, told Computer Weekly.
As technology advances and personalized healthcare continues to trend, it is likely digital twins will have a long-term place in medical practices. Astute clinical laboratory professionals will watch the expansion of this trend, since lab data will play such a key role in its development.
Research could lead to new biomarkers for clinical laboratory tests that spot disease early in patients
As we have covered in previous Dark Daily ebriefs, there are ongoing efforts to develop diagnostic assays that use human breath as the specimen. One early example was the breath specimen for Helicobacter pylori (H. pylori) testing—the bacteria that causes peptic ulcers—in the 1990s. Thus, a new sensor developed by scientists at Zhejiang University in China that can detect the presence of lung cancer in human breath will be of interest to medical laboratory scientists and clinical laboratories working on such testing.
In a proof-of-concept study, the Zhejiang University researchers “developed ultrasensitive nanoscale sensors that in small-scale tests distinguished a key change in the chemistry of the breath of people with lung cancer,” according to an American Chemical Society (ACS) news release.
The new research exemplifies how instruments are becoming increasingly sensitive to detection of smaller specimen quantities, making it possible to even use exhaled breath to diagnose lung cancer, noted a review article published in Science Direct.
“This study presents a novel Pt@InNiOx [platinum (Pt), indium (In), nickel (Ni)] nanoflake isoprene sensor that achieves an exceptionally low limit of detection at two parts per billion (2ppb)—the lowest reported for isoprene sensor to date,” wrote study lead author, Pingwei Liu, PhD (above), distinguished research fellow, Zhejiang University, et al, in ACS Sensors. “Our work not only provides a breakthrough in low-cost, noninvasive cancer screening through breath analysis but also advances the rational design of cutting-edge gas sensing materials.” Clinical laboratories working with breath sample biomarkers will be intrigued by this new advancement in the technology. (Photo copyright: Zhejiang University.)
Finding the Breakthrough Sensor
The Zhejiang University researchers were motivated by the potential for rapid gas sensing in diagnostics. Many gases, including carbon dioxide, are exhaled. But one particular gas, isoprene, they found “can indicate the presence of lung cancer,” the news release states.
However, while breath is readily available, it is not easy to isolate breath biomarkers. That is because a detector needs to “differentiate between volatile chemicals, withstand the natural humidity of exhaled breath, and detect tiny quantities of specific chemicals,” New Atlas explained.
To detect small specimen quantities of isoprene, a highly sensitive sensor needed to be developed—one that would be a step up from standard indium oxide-based breath sensors.
The scientists experimented with a series of indium (III) oxide (In203)-based nanoflake sensors until they found the sensor that performed consistently in nine experiments. They called it Pt@InNiOx for the platinum (Pt), indium (In), and nickel (Ni) it contained.
According to the news release, the Pt@InNiOx sensor:
Had “sensitivity that far surpassed earlier sensors” as evidenced by detection of isoprene as low as 2ppb.
Emphasized isoprene attraction over other volatile compounds in breath.
Has advanced sensitivity due to “Pt nanoclusters uniformly anchored on the nanoflakes” activating the isoprene sensing.
Gadget Review described the innovation as a “significant advance in diagnostic capability” that uses nanoscale technology along with “indium oxide nanoflakes with platinum-based nanoclusters.”
Developing the Lung Cancer Diagnostic Device
The scientists put their Pt@InNiOx nanoflakes into a portable sensing device for breath analysis. They then inserted breath samples from 13 people including five who had lung cancer. They found that:
In samples from people with cancer, the device enabled detection of isoprene levels lower than 40 ppb.
In samples from cancer-free participants, the device found isoprene levels more than 60 ppb.
“We integrate these ultrasensitive Pt@InNiOx nanoflakes into a miniaturized portable electronic device that successfully distinguishes lung cancer patients with expiratory isoprene below 40ppb, from the healthy population with isoprene above 60 ppb, enabling an accurate diagnosis in clinics,” wrote study lead author, Pingwei Liu, PhD, distinguished research fellow, Zhejiang University, et al, in ACS Sensors.
“As the isoprene hits the nanoflakes, electron release is sparked in a way that can be measured,” MSN Health reported, adding that the nanoflakes were also able to find isoprene in other chemicals and operate even in humid conditions.
Breath as Lab Test Biomarker for Cancer
In the United States, more people die from lung cancer than any other form of cancer, according to US Centers for Disease Control and Prevention statistics. The CDC data show there were 209,500 new lung and bronchus cancer cases in 2022, the most recent year for available data.
The Zhejiang University scientists reportedly plan to continue their research on the sensing materials and link between isoprene and lung cancer.
Studies continue to show many components in human breath can be used as clinical laboratory test biomarkers. Assays that use the breath as specimen may one day play an important role in early diagnosis of lung cancer and other diseases.
Researchers find neanderthal blood did not evolve and may have contributed to their demise
Researchers out of France have identified a unique antigen in red blood cells that may have contributed to the downfall of Neanderthals, according to an article in Live Science. These findings will be of interest to clinical laboratorians in hospitals who operate blood banks and blood bankers who do daily testing for blood groups and specific antigens.
“We showed that all Neanderthal shared the same blood group profile,” Mazières told Discover magazine. “Such low diversity is the signal of small populations.” He added, “the study shows how different blood types can help fight against infectious disease,” and that, “it emphasizes the importance of monitoring blood during both transfusions and pregnancies. The presence of some rare subtypes that originated with the Neanderthals but outlived them can lead to complications,” Discover reported.
Clinical laboratories and pathologists will appreciate these new findings, as this unique look into Neanderthal physiology illustrates how the importance of proper blood typing has endured throughout time.
“For any case of inbreeding of a Neanderthal female with a Homo sapiens or Denisova male, there is a high risk of hemolytic disease of the newborn. The condition can lead to jaundice, severe anemia, brain damage and death. This could have contributed to the demise of the Neanderthal population,” Stéphane Mazières, PhD (above), a population geneticist at Aix-Marseille University who led the study into why Neanderthals did not survive, told Live Science. Clinical laboratories that run blood banks and perform blood type testing will find the study results interesting. (Photo copyright: X, formerly Twitter.)
‘Incompatible Blood Type
Mazières’ team studied ancient genomes to further understand the evolution from Neanderthals and Denisovans to Homo Sapiens. Genome sequencing was used to look at blood groups from “dozens of people who lived between 120,000 and 20,000 years ago.” This uncovered “a rare blood group that could have been fatal to their newborns,” Live Science reported.
The rare blood type discovered was not compatible with either Denisovans or early Homo Sapiens. Additionally, the more diverse blood found in Homo Sapiens may have attributed to a more robust immunity, Discover reported.
“Nowadays, certain blood groups confer an advantage against pathogens such as cholera, malaria, one of the gastroenteritis viruses and, as we’ve seen recently, COVID. We can therefore imagine that the blood groups found in the first Sapiens may have equipped them with a new arsenal to face the new environments encountered as they spread across the world,” Mazières told Discover.
“The contribution of this study is twofold. It enlightens the expansion patterns of Homo Sapiens and recalls the anthropological effectiveness of genetic polymorphisms currently being surveyed for transfusion safety and pregnancy monitoring,” the researchers wrote in Scientific Reports.
Knowing a patient’s blood type is key to ensure immune system acceptance of the blood, leading to successful blood transfusions and preventing fatalities. Focus is given to Rh (Resus) factor’s positive and negative typing and on the antigens responsible for segregating A, B, and O blood types. In the case of Neanderthals, a look at red blood cells was key, Live Science noted.
Modern-day Rh incompatibility, which can occur when an Rh-negative woman is pregnant with an Rh positive fetus, can be discovered during pregnancy and treated with prenatal administration of lab-made immunoglobulin to prevent hemolytic disease of the newborn, Live Science reported. It’s a whole system of healthcare that was certainly not available in Neanderthal times.
“Neanderthals have an Rh blood group that is very rare in modern humans. This Rh variant—a type of RhD, another red blood cell antigen—is not compatible with the variants the team found in the Denisovans or the early Homo Sapiens in their study,” Mazières told Live Science.
Looking Ahead
While this research may not change the way blood is handled today, the new findings serve as a reminder of just how important and varied antigens in human blood type can be and how significant the variances impact individuals. It also provides a window into how subtle differences shape the way civilization grows.
The complexity of red blood cells remains an area worthy of continued research, especially since many of these surface and internal antigens are passed down through generations, Live Science noted.
Also, study results may further the decades-long attempt to create artificial blood that has both an extensive shelf life and is accepted by the immune systems of many different patients. However, that will be a daunting challenge. Over the decades, blood bankers and clinical laboratory scientists have watched many attempts to develop artificial blood come close but fail to demonstrate safety while delivering benefits to patients.
