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Fred Hutch Researchers Identify Oral Bacteria That Appear to Play a Role in Certain Colon Cancers

Discovery highlights how ongoing microbiome research points to new opportunities that can lead to development of more effective cancer screening clinical laboratory tests

New research from the Fred Hutchinson Cancer Center in Seattle once again demonstrates that the human microbiome plays a sophisticated role in many biological processes. Microbiologists and anatomic pathologists who diagnose tissue/biopsies will find this study’s findings intriguing.

This breakthrough in colon cancer research came from the discovery that a “subspecies” of a common type of a bacteria that resides in the mouth and causes dental plaque also “shields tumor cells from cancer treatment,” according to NBC News.

The scientists inspected colorectal cancer (CRC) tumors and found that 50% of those examined featured a subspecies of Fusobacterium nucleatum (F. nucleatum or Fn) and that this anaerobic bacterium was “shielding tumor cells from cancer-fighting drugs,” NBC News noted. Many of these tumors were considered aggressive cases of cancer. 

“The discovery, experts say, could pave the way for new treatments and possibly new methods of screening,” NBC News reported.

The Fred Hutchinson Cancer Center scientists published their findings in the journal Nature titled, “A Distinct Fusobacterium Nucleatum Clade Dominates the Colorectal Cancer Niche.”

“Patients who have high levels of this bacteria in their colorectal tumors have a far worse prognosis,” Susan Bullman, PhD (above), who jointly supervised the Fred Hutch research team and who is now Associate Professor of Immunology at MD Anderson Cancer Center, told NBC News. “They don’t respond as well to chemotherapy, and they have an increased risk of recurrence,” she added. Microbiologists and clinical laboratories working with oncologists on cancer treatments will want to follow this research as it may lead to new methods for screening cancer patients. (Photo copyright: Fred Hutchinson Cancer Center.)

Developing Effective Treatments

Susan Bullman, PhD, Associate Professor of Immunology at MD Anderson Cancer Center, who along with her husband and fellow researcher Christopher D. Johnston, PhD, Assistant Professor at Fred Hutchinson Cancer Center, jointly supervised an international team of scientists that examined the genomes of 80 F. nucleatum strains from the mouths of cancer-free patients and 55 strains from tumors in patients with colorectal cancer, according to the National Institutes of Health (NIH). The NIH funded the research.

The researchers targeted a subspecies of F. nucleatum called F. nucleatum animalis (Fna) that “was more likely to be present in colorectal tumors. Further analyses revealed that there were two distinct types of Fna. Both were present in mouths, but only one type, called Fna C2, was associated with colorectal cancer” the NIH wrote in an article on its website titled, “Gum Disease-related Bacteria Tied to Colorectal Cancer.”

“Tumor-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumor niche,” the Fred Hutch researchers wrote in their Nature paper.

“We have pinpointed the exact bacterial lineage that is associated with colorectal cancer, and that knowledge is critical for developing effective preventive and treatment methods,” Johnston told the NIH.

How Bacteria Got from Mouth to Colon Not Fully Understood

Traditionally, F. nucleatum makes its home in the mouth in minute quantities. Thus, it is not fully understood how these bacteria travel from the mouth to the colon. However, the Fred Hutch researchers showed that Fna C2 could survive in acidic conditions, like those found in the gut, longer than the other types of Fna. This suggests that the bacteria may travel along a direct route through the digestive tract.

The study, which focused on participants over 50, comes at a time when colorectal cancer rates are trending upward. Rates are doubling for those under 55, jumping from 11% in 1995 to 20% in 2019. CRC is the second-leading cancer death and over 53,000 will succumb to the disease in 2024, according to NBC News.

Many of the newer diagnoses are in later stages with no clear reason why, and the Fred Hutch scientists are trying to understand how their findings tie into the increase of younger cases of colon cancer.

Bullman says it will be important to look at “whether there are elevated levels of this bacterium in young onset colorectal cancer, which is on the rise globally for unknown reasons,” she told NBC News.

Possibility of More Effective Cancer Screening

There is hope that scientists equipped with this knowledge can develop new and more effective screening and treatment options for colon cancer, as well as studying the microbiome’s impact on other diseases.

On the prevention side, researchers have seen that in mice the addition of Fna “appeared to cause precancerous polyps to form, one of the first warning signs of colorectal cancer, though Bullman added that this causation hasn’t yet been proven in humans.” NBC reported.

Future research may find that screening for Fna could determine if colorectal tumors will be aggressive, NIH reported.

“It’s possible that scientists could identify the subspecies while it’s still in the mouth and give a person antibiotics at that point, wiping it out before it could travel to the colon,” Bullman told NBC News. “Even if antibiotics can’t successfully eliminate the bacteria from the mouth, its presence there could serve as an indication that someone is at higher risk for aggressive colon cancer.”

There is also the thought of developing antibiotics to target a specific subtype of bacteria. Doing so would eliminate the need to be “wiping out both forms of the bacteria or all of the bacteria in the mouth. Further, it’s relevant to consider the possibility of harnessing the bacteria to do the cancer-fighting work,” NBC noted.

“The subtype has already proven that it can enter cancer cells quite easily, so it might be possible to genetically modify the bacteria to carry cancer-fighting drugs directly into the tumors,” Bullman told NBC News.

Further studies and research are needed. However, the Fred Hutch researchers’ findings highlight the sophistication of the human microbiome and hint at the potential role it can play in the diagnosis of cancer by clinical laboratories and pathology groups, along with better cancer treatments in the future.

—Kristin Althea O’Connor

Related Information:

A New Type of Bacteria was Found in 50% Of Colon Cancers. Many Were Aggressive Cases.

Gum Disease-related Bacteria Tied to Colorectal Cancer

A Distinct Fusobacterium Nucleatum Clade Dominates the Colorectal Cancer Niche

Dutch Patient with Longest COVID-19 Case of 612 Days Had More than 50 SARS-CoV-2 Mutations Before He Died

Study of the 50 Omicron variants could lead to new approaches to clinical laboratory testing and medical treatments for long COVID

Patients infected with SARS-CoV-2 can usually expect the COVID-19 illness to subside within a couple of weeks. However, one Dutch patient remained infected with the coronavirus for 612 days and fought more than 50 mutations (aka, variants) before dying late last year of complications due to pre-existing conditions. This extreme case has given doctors, virologists, microbiologists, and clinical laboratories new insights into how the SARS-CoV-2 virus mutates and may lead to new treatments for long COVID.

According to Scientific American, when the 72-year-old male patient was admitted to the Amsterdam University Medical Center (Amsterdam UMC) in 2022 with the Omicron variant of SARS-CoV-2, he was also found to have myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN) overlap syndromes. Thus, the patient was determined to be immunocompromised.

“This was complicated by the development of a post-transplant lymphoma for which he received rituximab [a monoclonal antibody medication used to treat certain autoimmune diseases and cancers] that depletes all available B-cells, including those that normally produce the SARS-CoV-2 directed antibodies,” according to a press release.

The medication the patient was taking for his pre-existing conditions may have contributed to his body being unable to produce antibodies in response to three shots of the Moderna mRNA COVID vaccine he received.

Magda Vergouwe, MD, PhD candidate at the Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, who lead a study into the patient, theorized that some of the medications the patient was on for his pre-existing conditions could have destroyed healthy cells alongside the abnormal cancer-causing B cells the drugs were meant to target.

“This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals,” the researchers said prior to presenting their report about the case at a meeting of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in Barcelona, Spain, Time reported. “We emphasize the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections.”

“Chronic infections and viral evolution [are] commonly described in [the] literature, and there are other cases of immunocompromised patients who have had [COVID] infections for hundreds of days,” Magda Vergouwe, MD, PhD candidate (above), Center for Experimental and Molecular Medicine at Amsterdam UMC, told Scientific American. “But this is unique due to the extreme length of the infection … and with the virus staying in his body for so long, it was possible for mutations to just develop and develop and develop.” Microbiologists, virologists, and clinical laboratories involved in testing patients with long COVID may want to follow this story. (Photo copyright: LinkedIn.)

Risks to Immunocompromised Patients

Pre-existing conditions increase the risk factor for COVID-19 infections. A 2021 study published in the Journal of the American Board of Family Medicine (JABFM) titled, “Prevalence of Pre-existing Conditions among Community Health Center Patients with COVID-19,” found that about 61% of that study’s test group had a pre-existing condition prior to the outbreak of the COVID-19 pandemic.

When the Dutch man was admitted to Amsterdam UMC with common and serious COVID-19 symptoms, such as shortness of breath, a cough, and low blood oxygen levels, he was prescribed sotrovimab (a monoclonal antibody) along with other COVID treatments.

About a month after being admitted his COVID-19 symptoms decreased, so he was first discharged to a rehab facility and then finally to his home. However, he continued to test positive for the coronavirus and developed other infections that may have been complicated by the persistent case of COVID-19.

The Amsterdam UMC doctors emphasized that the man ultimately succumbed to his pre-existing conditions and not necessarily COVID-19.

“It’s important to note that in the end he did not die from his COVID-19,” Vergouwe told Scientific American. “But he did keep it with him for a very long period of time until then, and this is why we made sure to sample [the virus in his body] as much as we could.”

One in Five Adults Develop Long COVID

Long COVID does not necessarily indicate an active infection. However, in as many as one in five US adults COVID symptoms persist after the acute phase of the infection is over, according to a study published recently in JAMA Network Open titled, “Epidemiologic Features of Recovery from SARS-CoV-2 Infection.”

“In this cohort study, more than one in five adults did not recover within three months of SARS-CoV-2 infection. Recovery within three months was less likely in women and those with pre-existing cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave,” the JAMA authors wrote.

The origins of long COVID are not entirely clear, but according to the National Institutes of Health (NIH) it can develop when a patient is unable to sufficiently rest while battling off the initial virus. According to Vergouwe, the SARS-CoV-2 genome will always grow quicker when found in a patient with a compromised immune system.

Unique COVID-19 Mutations

More than 50 new mutations of the original Omicron variant were identified in the Dutch patient. According to Vergouwe, “while that number can sound shocking, mutations to the SARS-CoV-2 genome are expected to evolve more quickly in those who are immunocompromised (the average mutation rate of the virus is estimated to be two mutations per person per month),” Scientific American reported. “What does make these mutations unusual, she noted, is how their features differed vastly from mutations observed in other people with COVID. [Vergouwe] hypothesizes that the exceptional length of the individual’s infection, and his pre-existing conditions, allowed the virus to evolve extensively and uniquely.”

COVID-19 appears to be here to stay, and most clinical laboratory managers and pathologists understand why. As physicians continue to learn about the SARS-CoV-2 coronavirus, this is another example of how the knowledge about SARS-CoV-2 is growing as different individuals are infected with different variants of the virus.

—Ashley Croce

Related Information:

Longest-Ever COVID Infection Lasted More than 600 Days

COVID Patient’s Infection Lasts Record 613 Days—and Accumulated Over 50 Mutations

72-Year-Old Patient Had COVID for Record 613 Days, Accumulated over 50 Mutations from Virus Before It Killed Him

Prevalence of Preexisting Conditions among Community Health Center Patients with COVID-19: Implications for the Patient Protection and Affordable Care Act

The Risk Factors for Long COVID Have Finally Been Revealed

Prevalence of Pre-existing Conditions among Community Health Center Patients with COVID-19

Epidemiologic Features of Recovery from SARS-CoV-2 Infection

Genetic Testing of Wastewater Now Common in Detecting New Strains of COVID-19 and Other Infectious Diseases

Researchers Find That Antibiotic-Resistant Bacteria Can Persist in the Body for Years

Study results from Switzerland come as clinical laboratory scientists seek new ways to tackle the problem of antimicrobial resistance in hospitals

Microbiologists and clinical laboratory scientists engaged in the fight against antibiotic-resistant (aka, antimicrobial resistant) bacteria will be interested in a recent study conducted at the University of Basel and University Hospital Basel in Switzerland. The epidemiologists involved in the study discovered that some of these so-called “superbugs” can remain in the body for as long as nine years continuing to infect the host and others.

The researchers wanted to see how two species of drug-resistant bacteria—K. pneumoniae and E. coli—changed over time in the body, according to a press release from the university. They analyzed samples of the bacteria collected from patients who were admitted to the hospital over a 10-year period, focusing on older individuals with pre-existing conditions. They found that K. pneumoniae persisted for up to 4.5 years (1,704 days) and E. coli persisted for up to nine years (3,376 days).

“These patients not only repeatedly become ill themselves, but they also act as a source of infection for other people—a reservoir for these pathogens,” said Lisandra Aguilar-Bultet, PhD, the study’s lead author, in the press release.

“This is crucial information for choosing a treatment,” explained Sarah Tschudin Sutter, MD, Head of the Division of Infectious Diseases and Hospital Epidemiology, and of the Division of Hospital Epidemiology, who specializes in hospital-acquired infections and drug-resistant pathogens. Sutter led the Basel University study.

The researchers published their findings in the journal Nature Communications titled, “Within-Host Genetic Diversity of Extended-Spectrum Beta-Lactamase-Producing Enterobacterales in Long-Term Colonized Patients.”

“The issue is that when patients have infections with these drug-resistant bacteria, they can still carry that organism in or on their bodies even after treatment,” said epidemiologist Maroya Spalding Walters, MD (above), who leads the Antimicrobial Resistance Team in the Division of Healthcare Quality Promotion at the federal Centers for Disease Control and Prevention (CDC). “They don’t show any signs or symptoms of illness, but they can get infections again, and they can also transmit the bacteria to other people.” Clinical laboratories working with microbiologists on antibiotic resistance will want to follow the research conducted into these deadly pathogens. (Photo copyright: Centers for Disease Control and Prevention.)

COVID-19 Pandemic Increased Antibiotic Resistance

The Basel researchers looked at 76 K. pneumoniae isolates recovered from 19 patients and 284 E. coli isolates taken from 61 patients, all between 2008 and 2018. The study was limited to patients in which the bacterial strains were detected from at least two consecutive screenings on admission to the hospital.

“DNA analysis indicates that the bacteria initially adapt quite quickly to the conditions in the colonized parts of the body, but undergo few genetic changes thereafter,” the Basel University press release states.

The researchers also discovered that some of the samples, including those from different species, had identical mechanisms of drug resistance, suggesting that the bacteria transmitted mobile genetic elements such as plasmids to each other.

One limitation of the study, the authors acknowledged, was that they could not assess the patients’ exposure to antibiotics.

Meanwhile, recent data from the World Health Organization (WHO) suggests that the COVID-19 pandemic might have exacerbated the challenges of antibiotic resistance. Even though COVID-19 is a viral infection, WHO scientists found that high percentages of patients hospitalized with the disease between 2020 and 2023 received antibiotics.

“While only 8% of hospitalized patients with COVID-19 had bacterial co-infections requiring antibiotics, three out of four or some 75% of patients have been treated with antibiotics ‘just in case’ they help,” the WHO stated in a press release.

WHO uses an antibiotic categorization system known as AWaRe (Access, Watch, Reserve) to classify antibiotics based on risk of resistance. The most frequently prescribed antibiotics were in the “Watch” group, indicating that they are “more prone to be a target of antibiotic resistance and thus prioritized as targets of stewardship programs and monitoring.”

“When a patient requires antibiotics, the benefits often outweigh the risks associated with side effects or antibiotic resistance,” said Silvia Bertagnolio, MD, Unit Head in the Antimicrobial resistance (AMR) Division at the WHO in the press release. “However, when they are unnecessary, they offer no benefit while posing risks, and their use contributes to the emergence and spread of antimicrobial resistance.”

Citing research from the National Institutes of Health (NIH), NPR reported that in the US, hospital-acquired antibiotic-resistant infections increased 32% during the pandemic compared with data from just before the outbreak.

“While that number has dropped, it still hasn’t returned to pre-pandemic levels,” NPR noted.

Search for Better Antimicrobials

In “Drug-Resistant Bacteria Are Killing More and More Humans. We Need New Weapons,” Vox reported that scientists around the world are researching innovative ways to speed development of new antimicrobial treatments.

One such scientist is César de la Fuente, PhD, Presidential Assistant Professor at University of Pennsylvania, whose research team developed an artificial intelligence (AI) system that can look at molecules from the natural world and predict which ones have therapeutic potential.

The UPenn researchers have already developed an antimicrobial treatment derived from guava plants that has proved effective in mice, Vox reported. They’ve also trained an AI model to scan the proteomes of extinct organisms.

“The AI identified peptides from the woolly mammoth and the ancient sea cow, among other ancient animals, as promising candidates,” Vox noted. These, too, showed antimicrobial properties in tests on mice.

These findings can be used by clinical laboratories and microbiologists in their work with hospital infection control teams to better identify patients with antibiotic resistant strains of bacteria who, after discharge, may show up at the hospital months or years later.

—Stephen Beale

Related Information:

Resistant Bacteria Can Remain in The Body for Years

‘Superbugs’ Can Linger in the Body for Years, Potentially Spreading Antibiotic Resistance

Superbug Crisis Threatens to Kill 10 Million Per Year by 2050. Scientists May Have a Solution

Drug-Resistant Bacteria Are Killing More and More Humans. We Need New Weapons.

How the Pandemic Gave Power to Superbugs

WHO Reports Widespread Overuse of Antibiotics in Patients Hospitalized with COVID-19

NIH Scientists Develop New Clinical Laboratory Assay to Measure Effectiveness of ‘Good’ Cholesterol

Clinical studies show that new ‘cell-free’ test can predict cardiovascular disease risk better than standard HDL cholesterol test

Researchers from the National Institutes of Health (NIH) have developed a diagnostic assay that measures how well high-density lipoprotein (HDL)—the so-called “good” cholesterol—is working in the body. And their findings could lead to new clinical laboratory tests that supplement standard HDL level testing to better determine a person’s risk for heart disease.

Cholesterol tests are among the most commonly performed assays by clinical laboratories. A new test that reveals how well HDL is working in the body would certainly boost a medical laboratory’s test requisition volume.

The researchers are with the NIH’s National Heart, Lung, and Blood Institute (NHLBI).

“Measuring HDL function is limited to research labs and isn’t conducive to large-scale testing by routine clinical laboratories. To try to solve that problem, researchers from NHLBI’s Lipoprotein Metabolism Laboratory created a new diagnostic test,” noted an NHLBI news release.

“This is going to quicken the pace of basic research,” said Edward B. Neufeld, PhD, who along with guest researcher Masaki Sato, PhD, developed the test. “It increases the number of samples that you can study. It increases the number of experiments you can do.”

The researchers published their findings in The Journal of Clinical Investigation titled, “Cell-Free, High-Density Lipoprotein–Specific Phospholipid Efflux Assay Predicts Incident Cardiovascular Disease.” They have also patented their test and plan to work with a company on licensing and manufacturing it.

Such a new cholesterol test would quickly become one of the most commonly performed clinical lab tests because just about every American who has a physical gets cholesterol tests as part of that process.

“Other people may modify this or come up with better versions, which is fine with us,” Edward Neufeld, PhD (above), NHLBI Staff Scientist, said in a news release. “We just really wanted to tackle this problem of evaluating HDL function.” Clinical laboratories may soon have a new cholesterol test to supplement standard HDL level testing. (Photo copyright: ResearchGate.)

Faster Answers Needed about HDL 

According to the NIH, the goal should go beyond measuring level of HDL as part of a person’s annual physical. What is also needed is finding out whether HDL cholesterol is effectively doing certain tasks, such as removing extra cholesterol from arteries and transporting it to the liver.

The NHLBI’s new cell-free test may make it possible to step up large-scale clinical testing of HDL function, according to the news release. As it stands now, HDL function study has been limited to research labs where testing involves “harvesting cells in the lab [which] can take days to process,” according to NIH Record.

“Most studies to date that have assessed CAD (coronary artery disease) risk by HDL functionality still use the CEC (cellular cholesterol efflux capacity) in vitro assay and are based on the use of radioisotopes (3H-cholesterol) and cultured cells, which is very labor intensive and impractical to do in a clinical laboratory,” the researchers wrote in The Journal of Clinical Investigation. They also pointed out that CEC batch-to-batch variability does not fit clinical laboratories’ need for standardization.

Advantages of NHLBI’s Test  

To overcome these barriers, the NHLBI researchers created an HDL-specific phospholipid efflux (HDL-SPE) assay that has certain advantages over current HDL function assessments done in research labs.

According to the NIH, the HDP-SPE assay:

  • Is easy to replicate in clinical labs.
  • Is more suited to automation and large samples.
  • Offers up results in about an hour.
  • Is a better predictor of cardiovascular disease risk than HDL cholesterol testing for CAD risk.

“We developed a cell-free, HDL-specific phospholipid efflux assay for the assessment of CAD risk on the basis of HDL functionality in whole plasma or serum. One of the main advantages of the HDL-SPE assay is that it can be readily automated, unlike the various CEC assays currently in use,” the authors noted in their paper.

Here is how the test is performed, according to the NIH:

  • Plasma with HDL is separated from the patient’s blood.
  • “Plasma is added to donor particles coated with a lipid mixture resembling plaque and a fluorescent-tagged phospholipid” that only HDL can remove.
  • The fluorescent signal by HDL is then measured.
  • A bright signal suggests optimal HDL lipid removal function, while a dim light means reduced function.

The test builds on the scientists’ previous findings and data. In creating the new assay they drew on data from:

  • A study of 50 severe CAD and 50 non-CAD people.
  • A Japanese study of 70 CAD and 154 non-CAD participants.
  • Examined association of HDL-SPE with cardiovascular disease in a study of 340 patients and 340 controls.

“We have established the HDL-SPE assay for assessment of the functional ability of HDL to efflux phospholipids. Our combined data consistently show that our relatively simple HDL-SPE assay captures a pathophysiologically relevant parameter of HDL function that is at least equivalent to the CEC assay in its association with prevalent and incident CAD,” the researchers concluded in The Journal of Clinical Investigation

Test May Be Subject to New FDA Rule

While HDL cardiovascular-related research is moving forward, studies aimed at the therapeutic side need to pick up, NIH noted.

“Someday we may have a drug that modulates HDL and turns out to be beneficial, but right now we don’t have that,” said Alan Remaley MD, PhD, NHLBI Senior Investigator and Head of the Lipoprotein Metabolism Laboratory, in the news release.

It may be years before the HDL-SPE test is used in medical settings, the researchers acknowledged, adding that more studies are needed with inclusion of different ethnicities.

Additionally, in light of the recently released US Food and Drug Administration (FDA) final rule on regulation of laboratory developed tests (LDT), the company licensed to bring the test to market may need to submit the HDL-SPE assay to the FDA for premarket review and clearance. That could lengthen the time required for the developers to comply with the FDA before the test is used by doctors and clinical laboratories in patient care.

—Donna Marie Pocius

Related Information:

FDA Takes Action Aimed at Helping Ensure Safety and Effectiveness of Laboratory Developed Tests

Cell-free, High-Density Lipoprotein-Specific Phospholipid Efflux Assay Predicts Incident Cardiovascular Disease

An Updated Test Measures How Well “Good Cholesterol” Works

NHLBI Refines Test for Good Cholesterol Function

Research Consortium Identifies 188 New CRISPR Gene-Editing Systems, Some More Accurate than CRISPR

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.

Researchers from Broad Institute, Massachusetts Institute of Technology (MIT), and the federal National Institutes of Health (NIH) have uncovered 188 new CRISPR systems “in their native habitat of bacteria” with some showing superior editing capabilities, New Atlas reported.

“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.”

The research team published their findings in the journal Science titled, “Uncovering the Functional Diversity of Rare CRISPR-Cas Systems with Deep Terascale Clustering.”

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.

Soumya Kannan, PhD

“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.

—Kristin Althea O’Connor

Related Information:

Algorithm Identifies 188 New CRISPR Gene-Editing Systems

188 New Types of CRISPR Revealed by Algorithm

FLSHclust, a New Algorithm, Reveals Rare and Previously Unknown CRISPR-Cas Systems

Uncovering the Functional Diversity of Rare CRISPR-Cas Systems with Deep Terascale Clustering

Questions and Answers about CRISPR

Annotation and Classification of CRISPR-Cas Systems

SHERLOCK: Nucleic Acid Detection with CRISPR Nucleases

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