New gene-editing systems could provide markedly improved accuracy for DNA and RNA editing leading to new precision medicine tools and genetic therapies
In what may turn out to be a significant development in genetic engineering, researchers from three institutions have identified nearly 200 new systems that can be used for editing genes. It is believed that a number of these new systems can provide comparable or better accuracy when compared to CRISPER (Clustered Regularly Interspaced Short Palindromic Repeats), currently the most-used gene editing method.
CRISPR-Cas9 has been the standard tool for CRISPR gene editing and genetic engineering. However, publication of these new research findings are expected to give scientists better, more precise tools to edit genes. In turn, these developments could lead to new clinical laboratory tests and precision medicine therapies for patients with inherited genetic diseases.
“Best known as a powerful gene-editing tool, CRISPR actually comes from an inbuilt defense system found in bacteria and simple microbes called archaea. CRISPR systems include pairs of ‘molecular scissors’ called Cas enzymes, which allow microbes to cut up the DNA of viruses that attack them. CRISPR technology takes advantage of these scissors to cut genes out of DNA and paste new genes in,” according to Live Science.
In its article, New Atlas noted that the researchers looked to bacteria because “In nature, CRISPR is a self-defense tool used by bacteria.” They developed an algorithm—called FLSHclust—to conduct “a deep dive into three databases of bacteria, found in environments as diverse as Antarctic lakes, breweries, and dog saliva.”
In their paper, the researchers wrote, “We developed fast locality-sensitive hashing–based clustering (FLSHclust), a parallelized, deep clustering algorithm with linearithmic scaling based on locality-sensitive hashing. FLSHclust approaches MMseqs2, a gold-standard quadratic-scaling algorithm, in clustering performance. We applied FLSHclust in a sensitive CRISPR discovery pipeline and identified 188 previously unreported CRISPR-associated systems, including many rare systems.”
“In lab tests [the newfound CRISPR systems] demonstrated a range of functions, and fell into both known and brand new categories,” New Atlas reported.
“Some of these microbial systems were exclusively found in water from coal mines,” Soumya Kannan, PhD (above), a Graduate Fellow at MIT’s Zhang Lab and co-first author of the study, told New Atlas. “If someone hadn’t been interested in that, we may never have seen those systems.” These new gene-editing systems could lead to new clinical laboratory genetic tests and therapeutics for chronic diseases. (Photo copyright: MIT McGovern Institute.)
Deeper Look at Advancement
The CRISPR-Cas9 made a terrific impact when it was announced in 2012, earning a Nobel Prize in Chemistry.
Though CRISPR-Cas9 brought huge benefits to genetic research, the team noted in their Science paper that “existing methods for sequence mining lag behind the exponentially growing databases that now contain billions of proteins, which restricts the discovery of rare protein families and associations.
“We sought to comprehensively enumerate CRISPR-linked gene modules in all existing publicly available sequencing data,” the scientist continued. “Recently, several previously unknown biochemical activities have been linked to programmable nucleic acid recognition by CRISPR systems, including transposition and protease activity. We reasoned that many more diverse enzymatic activities may be associated with CRISPR systems, many of which could be of low abundance in existing [gene] sequence databases.”
Among the previously unknown gene-editing systems the researchers found were some belonging to the Type 1 CRISPR systems class. These “have longer guide RNA sequences than Cas9. They can be directed to their targets more precisely, reducing the risk of off-target edits—one of the main problems with CRISPR gene editing,” New Atlas reported.
“The authors also identified a CRISPR-Cas enzyme, Cas14, which cuts RNA precisely. These discoveries may help to further improve DNA- and RNA-editing technologies, with wide-ranging applications in medicine and biotechnology,” the Science paper noted.
Testing also showed these systems were able to edit human cells, meaning “their size should allow them to be delivered in the same packages currently used for CRISPR-Cas9,” New Atlas added.
Another newfound gene-editing system demonstrated “collateral activity, breaking down nucleic acids after binding to the target, New Atlas reported. SHERLOCK, a tool used to diagnose single samples of RNA or DNA to diagnose disease, previously utilized this system.
Additionally, New Atlas noted, “a type VII system was found to target RNA, which could unlock a range of new tools through RNA editing. Others could be adapted to record when certain genes are expressed, or as sensors for activity in cells.”
Looking Ahead
The strides in science from the CRISPR-Cas9 give a hint at what can come from the new discovery. “Not only does this study greatly expand the field of possible gene editing tools, but it shows that exploring microbial ecosystems in obscure environments could pay off with potential human benefits,” New Atlas noted.
“This study introduces FLSHclust as a tool to cluster millions of sequences quickly and efficiently, with broad applications in mining large sequence databases. The CRISPR-linked systems that we discovered represent an untapped trove of diverse biochemical activities linked to RNA-guided mechanisms, with great potential for development as biotechnologies,” the researchers wrote in Science.
How these newfound gene-editing tools and the new FLSHclust algorithm will eventually lead to new clinical laboratory tests and precision medicine diagnostics is not yet clear. But the discoveries will certainly improve DNA/RNA editing, and that may eventually lead to new clinical and biomedical applications.
Level 3 bio labs handle Ebola, smallpox and other deadly diseases, and may play a role in research into the human genome
Because of the COVID-19 pandemic, there is a concerted effort to improve public health laboratories and increase the growth of bioresearch. Clinical laboratories across the country are required by law to send specimens of certain infectious diseases to public health labs for testing and analysis. The results of those tests are then reported to the federal Centers for Disease Control and Prevention (CDC), which is working to foster robust connections and relationships between clinical labs and public health labs.
A land transaction for a 1.6-acre purchase between Dallas County and TXRE Properties closed in April. The development of the lab is expected to cost $52 million and should be completed by late 2025 with occupancy as early as January 2026.
The graphic above is an artist rendering of what the new Dallas County Health and Human Services Public Health Laboratory may look like. For some time now, Dallas County has been working to create a hub centered around infrastructure and buildings to be used for bio development and research, public health labs, and even clinical laboratories. (Graphic copyright: 5G Studio Collaborative.)
Continuing Support for HHS
“The large-scale response required for COVID-19 demonstrated the need for the acquisition that will permit the continued support of the HHS efforts in response to the ongoing safety, containment, incident response to emerging and high consequence diseases that could operate at the peak of a crisis without hindering or being hindered by other county operations,” states a Dallas County Commissioners Court Order, D Magazine reported.
“The county currently utilizes owned facilities to provide laboratory services, testing services, and other initiatives,” according to the court order. “These facilities have performance and design shortcomings and have required significant capital expenditure for their ongoing use.
“To avoid leasing space and avoid additional capital investment into deferred and ongoing maintenance, the county has been searching for a suitable location/acquisition to collocate uses/departments into a centralized, efficient, and suitable laboratory,” the court order continued.
Lab Will Conduct Research into Potentially Fatal Diseases
The facility will pursue becoming a Biological Safety Level-3 laboratory. BSL-3 labs typically conduct research or work on microbes that can cause serious and potentially fatal disease through inhalation. These labs are required to be easily decontaminated. They must also have additional safety measures, including interlocked doors, sealed windows, floors, and walls, and filtered ventilation systems.
“The core diagnostic functions are—along with safety—related to identification, containment, security, and incident response to emerging and high consequence diseases,” the court order notes.
A Georgetown University article published last year concluded there are 148 institutions with BSL-3 laboratories in the US. This number was established by identifying and totaling the number of BSL-3 facilities that published research between 2006 and 2021 using PubMed Central, a full-text archive of biomedical and life sciences journal literature at the US National Institutes of Health’s National Library of Medicine (NIH/NLM).
The creation of this new biosafety lab in Dallas is consistent with the trend of investment dollars being poured into research into the human genome. This type of research, along with the creation of new facilities, can directly lead to new biomarkers that can be utilized in clinical laboratory testing and disease prevention.
Not the first smart diaper to come along, but consumers seem unready for diapers that can flag urinary tract infections and other biomarkers usually tested by clinical laboratories
Will wonders never cease? For centuries, parents had only their own senses to determine when infants needed diaper changing. Today, however, caregivers can rely on “smart diapers” to send alerts when a diaper is soiled. Crying, smelly babies may no longer be the gold standard in diaper management. But are smart diapers practical?
The sensor array is “so cheap and simple” it “could clear the way for wearable, self-powered health monitors for use not only in ‘smart diapers’ but also to predict major health concerns like cardiac arrest and pneumonia,” a Penn State new release noted.
However, clinical laboratory managers following similar developments probably know that this is not the first scientific effort to develop a smart diaper that uses some type of sensor to detect a biomarker and issue an alert to the wearer or caregivers.
“Our team has been focused on developing devices that can capture vital information for human health,” said Huanyu “Larry” Cheng, PhD (above), the James L. Henderson, Jr. Memorial Associate Professor of Engineering Science and Mechanics at Penn State in a news release. “The goal is early prediction for disease conditions and health situations, to spot problems before it is too late.” This is yet another example of how researchers are working to take more testing out of clinical laboratories and offer unique assays that can be used as wearables—whether as a diaper, a skin patch, or a smart watch. (Photo copyright: Penn State University.)
This Smart Diaper Is as Simple to Use as Paper and Pencil
The Penn State sensor array takes advantage of how paper naturally reacts to wetness and utilizes the graphite in pencil marking to interact with the water molecules and sodium chloride.
Once the water molecules are absorbed by the paper, the sodium chloride solution becomes ionized and electrons start to stream towards the graphite. This movement sets off the sensor, which is extremely sensitive to humidity. According to the study, the sensor can provide accurate readings over a wide range of humidity levels, from 5.6% to 90%.
“We wanted to develop something low-cost that people would understand how to make and use, and you can’t get more accessible than pencil and paper,” said Li Yang, PhD, a professor in the School of Artificial Intelligence at China’s Hebei University of Technology and one of the authors of the study, in the Penn State news release.
“You don’t need to have some piece of multi-million-dollar equipment for fabrication. You just need to be able to draw within the lines of a pre-drawn electrode on a treated piece of paper. It can be done simply and quickly.”
The diaper is connected to a tiny lithium battery. When the sensor recognizes an increase in humidity the battery powers transmission of the change to a smartphone via Bluetooth technology. This notification informs caregivers that it is time to change the diaper.
“That application was actually born out of personal experience,” explained Huanyu “Larry” Cheng, PhD, James L. Henderson, Jr. Memorial Associate Professor of Engineering Science and Mechanics at Penn State, one of the authors of the study and father to two young children. “There’s no easy way to know how wet is wet, and that information could be really valuable for parents. The sensor can provide data in the short-term, to alert for diaper changes, but also in the long-term, to show patterns that can inform parents about the overall health of their child.”
Do Consumers Want Smart Diapers?
Research into such wearable sensors has been gaining momentum in the scientific community as a novel way to detect and deal with several medical conditions. The Penn State team hopes that devices such as their smart diaper can be used in the future to alert caregivers about the overall health of their children and clients.
“Our team has been focused on developing devices that can capture vital information for human health,” Cheng said. “The goal is early prediction for disease conditions and health situations, to spot problems before it is too late.”
Previous research teams have had similar smart diaper goals.
However, these types of products have yet to gain significant popularity with consumers. Regardless, sales projections for smart diapers remain positive.
According to a MarketsandMarkets report, the smart diaper market, estimated to be $646 million (US) in 2021, is expected to surpass $1.5 billion by 2026. The demand for smart diapers, the report notes, is increasing due to:
Growing elderly populations,
Rising disposable incomes,
Increasing personal hygiene awareness,
Growing populations in emerging countries, and
Expanding preference for advanced technology when it comes to health.
So, it’s uncertain if consumers are now ready for a device in their baby’s diaper telling them it’s time for a change. Regardless, researchers will likely continue developing tools that combine new diagnostics with existing products to help people better understand and monitor their health and the health of their loved ones.
Meanwhile, clinical laboratory managers and pathologists can remain on the alert for future published studies and press releases announcing new wearable items containing sensors, such as smart diapers. The unanswered question is whether both consumers and healthcare professionals will consider these novel inventions useful devices in the care of young and old alike.
NIH program could lead to new diagnostic biomarkers for clinical laboratory tests across a more diverse segment of US population
In another milestone in the US National Institutes of Health’s (NIH) plan to gather diverse genetic information from one million US citizens and then use that data to inform clinical care in ways consistent with Precision Medicine, the NIH’s All-of-Us Research Program announced in a news release it has “begun returning personalized health-related DNA results” to more than 155,000 study participants.
In addition, those participants who request them will receive genetic reports that detail whether they “have an increased risk for specific health conditions and how their body might process certain medications.”
The All-of-Us program, which began enrolling people in 2018, is one of the world’s largest—if not the largest—project of its kind. It could result in more than a million human whole genome sequences to drive medical research and speed discoveries. Study findings, for example, may produce new biomarkers for clinical laboratory tests and diagnostics.
In 2020, the All-of-Us program “had begun releasing genetic results for ancestry and a small number of nonclinical genetic traits,” according to GenomeWeb. Now, the program is taking on the greater challenge of sharing health-related genetic test results directly with its participants.
“We really wanted to make sure that we are providing a responsible return to our participants,” Anastasia Wise, PhD, All-of-Us Program Director for the Genetic Counseling Resource, told GenomeWeb. “They might get information that’s unexpected,” she explained.
So far, about 10,000 people received the NIH’s invitation and 56% have shown interest in receiving their genetic test results, GenomeWeb noted.
“Knowledge is powerful,” said Josh Denny, MD (above), Chief Executive Officer, NIH All-of-Us Research Program, in an NIH news release. “By returning health-related DNA information to participants, we are changing the research paradigm, turning it into a two-way street—fueling both scientific and personal discovery that could help individuals navigate their own health,” he added. The NIH’s research could lead to new clinical laboratory precision medicine diagnostics for chronic diseases across a more diverse segment of the US population. (Photo copyright: National Institutes of Health.)
Two Types of Genetic Health Reports
Study participants who provided a blood sample and gave their consent to receiving genomic information may also receive a Hereditary Disease Risk report that includes 59 genes and genetic variants linked to serious and “medically actionable” health conditions.
About 3% to 5% of participants will have findings suggesting a high risk for a genetic disease such as breast and ovarian cancers as indicated by BRCA1 and BRCA2 genes, Medical Xpress reported.
“I kind of shudder to think about what could happen if I hadn’t known this [finding that she has the BRCA2 gene],” said Rachele Peterson, All-of-Us Chief of Staff, who spoke to the Associated Press about her receiving own Hereditary Disease Risk report.
Participants can also choose to receive an All-of-Us Medicine and Your DNA report with insights on seven genes that affect how specific medications are metabolized. This pharmacogenetics report is important for those who could learn, for example, that they have a 50% to 60% greater risk of a second heart attack when they continue to take the standard medication, as opposed to a different medication, Medical Xpress noted.
“The information on metabolizing medication can be particularly important for people who need treatment after a heart attack,” Josh Denny, MD, Chief Executive Officer, NIH All-of-Us Research Program, told Medical Xpress.
“Such transparency of genetic information about a massive group—as well as the genetic information on individuals—can be used to improve patient care and clinical outcomes,” said Robert Michel, Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
“The program provides a roadmap for other healthcare organizations to follow. And this is useful strategic knowledge for clinical laboratory leaders to understand and incorporate into their plans to support precision medicine with genetic testing and whole human genome sequencing,” Michel added.
Rich Genetic Data Across a More Diverse Population
As to its goal to reflect national diversity, NIH reported about 80% of All-of-Us participants reside in communities that have been unrepresented in medical research, and that 50% are part of a racial or ethnic minority group.
By combining this information into a single database, the MVP promises to advance knowledge about the complex links between genes and health, according to an MVP news release.
Researchers tapping All-of-Us and MVP data may ultimately produce enlightening and impactful study findings, which could enable clinical laboratories to perform new diagnostic precision medicine tests that identify diseases early and save lives.
Encouraging patients—even children—to be more directly involved in their own medical care may reduce the burden on healthcare workers and might even help those clinical laboratories struggling to hire enough phlebotomists to collect specimens
Researchers at Emory University School of Medicine have concluded a study which found that school-aged children can successfully use a nasal swab to obtain their own SARS-CoV-2 test specimens. This may come as a surprise to hospital and clinical laboratory personnel who have performed nasal swabbing for COVID-19 tests. Some people, adults included, find the procedure so uncomfortable it brings tears.
And yet, after being shown a 90-second how-to video and given a handout with written instructions and pictures, 197 Atlanta children who had COVID-19 symptoms between July and August of 2021 performed their own self-swabbing. A healthcare worker then collected a second swabbed sample. All samples were submitted to a clinical laboratory for PCR analysis.
The Emory study provides another example of how the healthcare system is engaging patients to be directly involved in their own medical care. Results of the study could positively impact clinical laboratories facing a shortage of personnel, as well as schools where children have to take repeated COVID-19 tests with the assistance of trained professionals.
In a study with 197 school-age children, researchers at Emory University School of Medicine found that children could self-swab themselves for COVID-19 testing after watching a 90-second instructional video. Clinical laboratory leaders who are short on personnel may find these results intriguing. (Photo copyright: Emory University.)
How Did the Children Do?
The self-collected swabs and those collected by a healthcare worker agreed 97.8% of the time for a positive result and 98.1% of the time for a negative result. The analysis showed that both collection methods identified the 44% of symptomatic kids who were positive for COVID-19.
“Seeing how closely the results line up between the children and trained healthcare workers is a strong indicator that these age groups are fully capable of swabbing themselves if given proper instruction,” said Jesse Waggoner, MD, an Assistant Professor of Infectious Diseases with the Emory University School of Medicine and one of the lead authors on the study, in an Emory University press release.
A higher percentage of children age eight and under needed assistance, such as more instruction before correctly completing self-collection—21.8% compared to 6.1% for children older—but SARS-CoV-2 detection among the two age groups did not differ.
Does FDA Approve of Self-Swabbing?
The US Food and Drug Administration (FDA) has not authorized COVID-19 tests that include self-swabbing by children under age 14. However, data from the Emory study, published in JAMA, is now available to test manufacturers seeking authorization for pediatric self-collection.
“Pediatric self-swabbing will support expanded testing access and should make it even easier to test school age populations with fewer resources,” said Tim Stenzel, MD, PhD, Director of the Office of In Vitro Diagnostics at the FDA, in the Emory statement. “This study furthers our knowledge of test accuracy with these types of samples and provides test manufacturers with data to support their EUA (Emergency Use Authorization) requests to the FDA.”
Self-swabbing versus Clinical Laboratory Worker
While it has been longstanding medical practice to have healthcare workers collect samples for respiratory tract infection testing, the Emory researchers suggest that allowing children to collect their own COVID-19 samples could be one way to reduce the burden of a shortage of healthcare workers.
The researchers also believe pediatric self-swabbing would expand access to diagnostic tests and make it easier to test school-age populations.
“Every minute of a healthcare worker’s time is at a premium,” said senior study author Wilbur Lam, MD, Professor of Pediatrics and Biomedical Engineering, Emory University and Georgia Tech, in a National Institutes of Health (NIH) press release. “Why not allow a kid to self-swab? It’s a win-win! They would rather do it themselves and it frees up the healthcare worker to do other things,” he added.
In 2020, a Stanford University School of Medicine study published in JAMA showed test samples collected by adults who swabbed their own nasal passages were as accurate as those collected by healthcare workers. This study involved 30 participants who had previously tested positive for COVID-19.
Though the Emory University and Stamford University studies were small, they agreed in their findings which is significant. Clinical laboratory executives and pathologists should expect this trend toward direct-to-consumer and other forms of self-testing to continue, even among young patients.
