Though they are a mystery, once solved, Obelisks could lead to new biomarkers for clinical laboratory testing
Microbiologists and clinical laboratories know that human microbiota play many important roles in the body. Now, scientists from Stanford University have discovered an entirely new class of “viroid-like” lifeforms residing inside the human body. The researchers detected their presence in both the gut microbiome and saliva samples. Most interesting of all, the researchers are not sure what the lifeforms actually are.
The Stanford researchers, led by PhD student Ivan Zheludev, called the new discovery “Obelisks” due to their RNA structures, which are short and can fold into structures that resemble rods.
The scientists believe the Obelisks went undetected until now in the human microbiome due to their compact genetic elements, which are only around 1,000 characters or nucleotides in size. A typical human DNA structure consists of around three billion nucleotides.
In an article they published on the biology preprint server bioRxiv titled, “Viroid-like Colonists of Human Microbiomes,” the Stanford researchers wrote, “Here, we describe the ‘Obelisks,’ a previously unrecognized class of viroid-like elements that we first identified in human gut metatranscriptomic data. … Obelisks comprise a class of diverse RNAs that have colonized and gone unnoticed in human and global microbiomes.”
The researchers discovered that Obelisks “form their own distinct phylogenetic group with no detectable sequence or structural similarity to known biological agents.”
This is yet another example of how researchers are digging deeper into human biology and finding things never before identified or isolated.
“I am really impressed by the approach. The authors were really creative,” computational biologist Simon Roux, PhD (above) of the Department of Energy (DEO) Joint Genome Institute at Lawrence Berkeley National Laboratory told Science in response to the Stanford researcher’s published findings. “I think this [work] is one more clear indication that we are still exploring the frontiers of this viral universe. This is one of the most exciting parts of being in this field right now. We can see the picture of the long-term evolution of viruses on Earth start to slowly emerge.” How these findings might eventually spark new biomarkers for clinical laboratory testing remains to be seen. (Photo copyright: Berkeley Lab.)
Researchers Bewildered by Obelisks
In their study, “Zheludev and team searched 5.4 million datasets of published genetic sequences and identified almost 30,000 different Obelisks. They appeared in about 10% of the human microbiomes the team examined,” Science reported.
The Stanford researchers found that various types of Obelisks seem to inhabit different areas of the body. In one dataset, the Obelisks were found in half of the oral samples.
The function of Obelisks is unknown, but their discovery is bewildering experts.
Rod-like secondary structures encompassing the entire genome, and
Open reading frames coding for a novel protein superfamily, which the researchers dubbed “Oblins.”
At least half of the genetic material of the Obelisks was taken up by these Oblins. The researchers suspect those proteins may be involved in the replication process of the newly-discovered lifeforms.
The Oblins are also significantly larger than other genetic molecules that live inside cells and they do not have the genes to create protein shells that RNA viruses live within when they are outside of cells.
“Obelisks, therefore, need some kind of host. The researchers managed to identify one: A bacterium called Streptococcus sanguinis that lives mostly in dental plaque in our mouths. Exactly which other hosts obelisks inhabit is yet another mystery, as are what they do to their host and how they spread,” Vice reported.
“While we don’t know the ‘hosts’ of other Obelisks, it is reasonable to assume that at least a fraction may be present in bacteria,” the researchers noted in their bioRxiv paper.
Researchers are Stumped
The Stanford scientists were unable to identify any impact the Obelisks were having on their bacterial hosts—either negative or positive—or determine how they could spread between cells.
“These elements might not even be ‘viral’ in nature and might more closely resemble ‘RNA plasmids,’” they concluded in their paper.
The Stanford scientists are uncertain as to where or what the hosts of the Obelisks are, but they suspect that at least some of them are present in bacteria. However, Obelisks do not appear to be similar to any biological agents that could provide a link between genetic molecules and viruses.
And so, Obelisks are a true mystery—one the Stanford researchers may one day solve. If they do, new biomarkers for clinical laboratory testing may not be far behind.
The antibodies target portions of the SARS-CoV-2 spike protein that resist mutation, potentially leading to better treatments and vaccines
One challenge in the battle against COVID-19 is the emergence of SARS-CoV-2 variants, especially the Delta variant, which may be more resistant to neutralizing antibodies compared with the original coronavirus. But now, scientists led by researchers at the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle say they have identified antibodies that could be broadly protective against multiple sarbecoviruses, the subgenus that contains SARS-CoV-2 as well as SARS-CoV-1, the virus responsible for the 2002-2004 severe acute respiratory syndrome (SARS) outbreak.
In “SARS-CoV-2 RBD Antibodies That Maximize Breadth and Resistance to Escape,” the researchers described how they compared 12 antibodies obtained from patients infected with either SARS-CoV-2 or SARS-CoV-1. They pointed to one antibody in particular—S2H97—that could lead to development of new vaccines and therapies against current and future variants. It might even protect against sarbecoviruses that have not yet been identified, they wrote.
Unsaid in the news release about these research findings is the fact that these particular antibodies could eventually become useful biomarkers for clinical laboratory tests designed to help physicians determine which patients have these antibodies—and the protection from infection they represent—and which do not.
So far, however, S2H97 has only been tested in hamsters. But results are promising.
“This antibody, which binds to a previously unknown site on the coronavirus spike protein, appears to neutralize all known sarbecoviruses—the genus of coronaviruses that cause respiratory infections in mammals,” said Jay Nix, PhD, an affiliate in Berkeley Lab’s Biosciences Area and Beamline Director of the Molecular Biology Consortium at Berkeley Lab’s Advanced Light Source (ALS), in a Berkeley Lab news release. “And, due to the unique binding site on mutation-resistant part of the virus, it may well be more difficult for a new strain to escape,” he added.
Scientists have long known that the SARS-CoV-2 virus uses the spike protein to attach to human cells. The federal Centers for Disease Control and Prevention (CDC) notes that the variants have mutations in their spike proteins that make some of them more transmissible.
The Delta variant, the CDC notes, was the predominant variant in the US as of August 28, 2021. It “has been shown to have increased transmissibility, potential reduction in neutralization by some monoclonal antibody treatments, and reduction in neutralization by post-vaccination sera,” the agency states.
The key to S2H97, the researchers wrote, is that it targets a portion of the spike protein that is common among sarbecoviruses, and that is likely to be resistant to mutations.
The researchers used a variety of techniques to analyze how the 12 antibodies bind to the virus. They “compiled a list of thousands of mutations in the binding domains of multiple SARS-CoV-2 variants,” Nature reported. “They also catalogued mutations in the binding domain on dozens of SARS-CoV-2-like coronaviruses that belong to a group called the sarbecoviruses. Finally, they assessed how all these mutations affect the 12 antibodies’ ability to stick to the binding domain.”
William Schaffner, MD (above), Professor of Preventive Medicine in the Department of Health Policy as well as Professor of Medicine in the Division of Infectious Diseases at the Vanderbilt University School of Medicine in Nashville, believes that “people who test positive for SARS-CoV-2 and who are at risk of progressing to severe disease—including those who are over the age of 65 years and those who have weakened immune systems—should talk with a doctor about receiving monoclonal antibody treatment,” Medical News Today reported. “[The monoclonal antibody treatment is] designed to prevent the evolution of the infection from a mild infection into a serious one,” he noted. “In other words, you’ve just [contracted the virus], but we can now give you a medication that will help prevent [you] being hospitalized and getting seriously ill.” (Photo copyright: Vanderbilt University.)
Earlier Antibody Treatment Receives an EUA from the FDA
In issuing the EUA for sotrovimab, the FDA cited “an interim analysis from a phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in 583 non-hospitalized adults with mild-to-moderate COVID-19 symptoms and a positive SARS-CoV-2 test result. Of these patients, 291 received sotrovimab and 292 received a placebo within five days of onset of COVID-19 symptoms.”
Among these patients, 21 in the placebo group were hospitalized or died compared with three who received the therapy, an 85% reduction.
“While preventive measures, including vaccines, can reduce the total number of cases, sotrovimab is an important treatment option for those who become ill with COVID-19 and are at high risk—allowing them to avoid hospitalization or worse,” stated Adrienne E. Shapiro, MD, PhD, of the Fred Hutchinson Cancer Research Center in a GSK news release. Shapiro was an investigator in the clinical trial.
The EUA allows use of sotrovimab in patients who have tested positive for SARS-CoV-2, have mild-to-moderate symptoms, and “who are at high risk for progression to severe COVID-19, including hospitalization or death. This includes, for example, individuals who are 65 years of age and older or individuals who have certain medical conditions.” It is not authorized for patients who are hospitalized or for those who require oxygen therapy.
The therapy was originally known as VIR-7831. The companies say they have developed a similar treatment, VIR-7832, with modifications designed to enhance T cell function against the disease.
The antibody, they wrote, targets a region of the SARS-CoV-1 spike protein that is “highly conserved” among sarbecoviruses. Clinical laboratory testing, they wrote, also indicated that the therapy was likely to be effective against known SARS-CoV-2 variants.
“Our distinctive scientific approach has led to a single monoclonal antibody that, based on an interim analysis, resulted in an 85% reduction in all-cause hospitalizations or death, and has demonstrated, in vitro, that it retains activity against all known variants of concern, including the emerging variant from India,” stated Vir Biotechnology CEO George Scangos, PhD, in the GSK news release. “I believe that sotrovimab is a critical new treatment option in the fight against the current pandemic and potentially for future coronavirus outbreaks, as well.”
Pathologists and clinical laboratory managers working with rapid molecular tests and antibody tests for COVID-19 will want to monitor the development of monoclonal antibody treatments, as well as further research studies that focus on these specific antibodies.
Exogen uses crowdfunding to both collect needed specimens and raise capital to pursue FDA clearance for its proposed medical laboratory test that would identify an individual’s damaged DNA
It might be coming soon to a pharmacy or other retail store near you: a medical laboratory test kit allows consumers to test themselves for damaged DNA. This bold new world for genetic testing is the vision of a new company in San Francisco called Exogen Biotechnology.
This startup business was co-founded by Sylvain Costes, Ph.D., a nuclear engineer who serves as Exogen’s Chief Executive Officer, and Jonathan Tang, Ph.D., a bioengineer. Their team is developing a blood test that will enable consumers to monitor their own DNA damage and take actions to reverse the damage. (more…)
