Once thought incapable of encoding proteins due to their simple monotonous repetitions of DNA, tiny telomeres at the tips of our chromosomes seem to hold a potent biological function that’s potentially relevant to our understanding of cancer and aging.
Reporting in the Proceedings of the National Academy of Science, UNC School of Medicine researchers Taghreed Al-Turki, PhD, and Jack Griffith, PhD, made the stunning discovery that telomeres contain genetic information to produce two small proteins, one of which they found is elevated in some human cancer cells, as well as cells from patients suffering from telomere-related defects.
Based on our research, we think simple blood tests for these proteins could provide a valuable screen for certain cancers and other human diseases. These tests also could provide a measure of ‘telomere health,’ because we know telomeres shorten with age.”
Jack Griffith, PhD, the Kenan Distinguished Professor of Microbiology and Immunology and Member of the UNC Lineberger Comprehensive Cancer Center
Telomeres contain a unique DNA sequence consisting of endless repeats of TTAGGG bases that somehow inhibit chromosomes from sticking to each other. Two decades ago, the Griffith laboratory showed that the end of a telomere’s DNA loops back on itself to form a tiny circle, thus hiding the end and blocking chromosome-to-chromosome fusions. When cells divide, telomeres shorten, eventually becoming so short that the cell can no longer divide properly, leading to cell death.
Scientist first identified telomeres about 80 years ago, and because of their monotonous sequence, the established dogma in the field held that telomeres could not encode for any proteins, let alone ones with potent biological function.
In 2011 a group in Florida working on an inherited form of ALS reported that the culprit was an RNA molecule containing a six-base repeat which by a novel mechanism could generate a series of toxic proteins consisting of two amino acids repeating one after the other. Al-Turki and Griffith note in their paper a striking similarity of this RNA to the RNA generated from human telomeres, and they hypothesized that the same novel mechanism might be in play.
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They conducted experiments – as described in the PNAS paper – to show how telomeric DNA can instruct the cell to produce signaling proteins they termed VR (valine-arginine) and GL (glycine-leucine). Signaling proteins are essentially chemicals that trigger a chain reaction of other proteins inside cells that then lead to a biological function important for health or disease.
Al-Turki and Griffith then chemically synthesized VR and GL to examine their properties using powerful electron and confocal microscopes along with state-of-the-art biological methods, revealing that the VR protein is present in elevated amounts in some human cancer cells, as well as cells from patients suffering from diseases resulting from defective telomeres.
“We think it’s possible that as we age, the amount of VR and GL in our blood will steadily rise, potentially providing a new biomarker for biological age as contrasted to chronological age,” said Al-Turki, a postdoctoral researcher in the Griffith lab. “We think inflammation may also trigger the production of these proteins.”
Griffith noted, “When you go against current thinking, you are usually wrong because you are bucking many people who’ve worked so diligently in their fields. But occasionally scientists have failed to put observations from two very distant fields together and that’s what we did. Discovering that telomeres encode two novel signaling proteins will change our understanding of cancer, aging, and how cells communicate with other cells.
“Many questions remain to be answered, but our biggest priority now is developing a simple blood test for these proteins. This could inform us of our biological age and also provide warnings of issues, such as cancer or inflammation.”
Al-Turki, T., et al. (2023) Mammalian Telomeric RNA (TERRA) can be translated to produce valine-arginine and glycine-leucine dipeptide repeat proteins. PNAS. doi.org/10.1073/pnas.2221529120.
Research findings published in Frontiers in Immunology show that cancer immunotherapy does not interfere with COVID-19 immunity in previously vaccinated patients. These findings support recommending vaccination for patients with cancer, including those receiving systemic therapies, say Saint Louis University scientists.
Immunotherapy is a treatment strategy that boosts a patient’s immune system to attack cancerous cells. In this novel study led by Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine, the Teague lab studied T cell responses and antibody responses against the SARS-CoV-2 spike protein in vaccinated and unvaccinated patients receiving immunotherapy.
Their research found data to support the clinical safety and efficacy of COVID-19 vaccination in patients receiving immune checkpoint inhibitors, a class of immunotherapy drugs.
It was thought that patients who had recently been vaccinated for or exposed to COVID-19 may have boosted inflammatory responses after immune checkpoint blockade treatment. The study found that immunotherapy did not tend to boost immune responses against COVID-19 in vaccinated patients, supporting the safety of receiving immune checkpoint inhibitors and the vaccine simultaneously.”
Ryan Teague, Ph.D., professor of molecular microbiology and immunology at Saint Louis University’s School of Medicine
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Teague notes that several timely factors came together to enable this research. In July 2022, the Teague lab published a study in Cancer Immunology Immunotherapy using a new technique known as Single-Cell RNA Sequencing, which allows researchers to study genetic information at the individual cell level to characterize immune responses after cancer treatment to identify biomarkers that could predict better patient outcomes.
Having collected blood from more than 100 patients with cancer during the COVID-19 pandemic, Teague recognized the opportunity to extend the benefit of this collection toward improving our understanding of patient immune responses against the vaccine.
“The COVID paper came from a unique window of time where we had a pandemic, and we had this valuable collection of patient samples that we could use to ask this timely question,” Teague said.
Additional authors include graduate students Alexander Piening, Emily Ebert, Niloufar Khojandi, and Assistant Professor Elise Alspach, Ph.D., from the Department of Molecular Microbiology and Immunology at SLU’s School of Medicine.
This work was supported by grant number NIH NCI R01 CA238705 from the National Institutes of Health.
Piening, A., et al. (2022) Immune responses to SARS-CoV-2 in vaccinated patients receiving checkpoint blockade immunotherapy for cancer. Frontiers in Immunology.doi.org/10.3389/fimmu.2022.1022732.
A groundbreaking Tel Aviv University study has discovered about 100,000 new types of previously unknown viruses – a ninefold increase in the number of RNA viruses known to science until now. These viruses were discovered in global environmental data from soil samples, oceans, lakes, and other ecosystems. This discovery may aid in the development of anti-microbial drugs and protect against agriculturally harmful fungi and parasites.
Doctoral student Uri Neri led the study under the guidance of Prof. Uri Gophna of the Shmunis School of Biomedicine and Cancer Research in the Wise Faculty of Life Sciences at Tel Aviv University. The research was conducted in collaboration with the US-based research bodies NIH and JGI, as well as the Pasteur Institute in France. The study was published in the prestigious journal Cell and comprised data collected by more than a hundred scientists worldwide.
Viruses are genetic parasites, meaning they must infect a living cell to replicate their genetic information, produce new viruses, and complete their infection cycle. Some viruses are disease-causing agents that can cause harm to humans (such as the coronavirus). Still, the vast majority of viruses do not harm us and infect bacterial cells – some even live inside our bodies without us being aware.
Uri Neri says that the study used new computational technologies to mine genetic information from thousands of different sampling points worldwide (oceans, soil, sewage, geysers, etc.). The researchers developed a sophisticated computational tool that distinguished between the genetic material of RNA viruses and that of the hosts and used it to analyze the big data. The discovery allowed the researchers to reconstruct how the viruses underwent diverse acclimation processes throughout their evolutionary development to adapt to different hosts.
In analyzing their findings, the researchers identified viruses suspected of infecting various pathogenic microorganisms, thus opening up the possibility of using viruses to control them.
“The system we developed makes it possible to perform in-depth evolutionary analyses and to understand how the various RNA viruses have developed throughout evolutionary history. One of the key questions in microbiology is how and why viruses transfer genes between them. We identified a number of cases in which such gene exchanges enabled viruses to infect new organisms. Furthermore, compared to DNA viruses, the diversity and roles of RNA viruses in microbial ecosystems are not well understood. In our study, we found that RNA viruses are not unusual in the evolutionary landscape and, in fact, that in some aspects, they are not that different from DNA viruses. This opens the door for future research and a better understanding of how viruses can be harnessed for use in medicine and agriculture,” said Prof. Gophna
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Overall, the results show a large expansion of the diversity of Orthornavira, especially that of RNA viruses associated with bacteria. In addition, they introduce relatively minor changes to the latest taxonomic scheme, supporting its overall robustness. Furthermore, RNA viruses are predicted to have multiple protein functions. This work generated a large number of sequences and derivatives, which can be accessed through the companion website (riboviria.org) or via the Zenodo deposit. Using this resource, researchers can gain meaningful context when describing new RNA viruses in future research. For example, by gaining insights into specific viral lineages’ ecological distributions or annotating their specific protein domains. Further, this resource may assist researchers in identifying key RNA virus genomes that can be further characterized experimentally.
Thought LeadersMatthew DunneDirector for Drug DiscoveryMicreos Pharamceuticals
For World Antimicrobial Awareness Week 2022, we speak to Matthew Dunne, Director for Drug Discovery at Micreos Pharmaceuticals, about the importance of creating new targeted antibacterial products.
Please can you introduce yourself and tell us about your role at Micreos?
My name is Matthew Dunne, and I am a Director for Drug Discovery at Micreos Pharmaceuticals in Switzerland. I provide strategic and technical leadership for R&D and preclinical activities within our newly established Division of Antimicrobial Vector Innovation. I joined Micreos in May of 2022 from the Swiss Federal Institute of Technology Zurich (ETH Zurich) at the same time as Dr. Samuel Kilcher, who sits alongside me as co-Director within the new division, which is developing a new class of medicines we have coined Antimicrobial Vectors.
In my capacity as Director, I work from Micreos’ state-of-the-art research facility in Switzerland, where I analyze data together with our growing team of genetic engineers and biologists. In addition to providing leadership of this new, highly innovative drug discovery division, I provide assistance with developing our regulatory affairs strategy, the management of external innovation development projects with industry partners and academia, as well as dealing with a variety of diverse tasks that are typical for a fast-growing biotech company.
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You are currently a Director of Drug Discovery at Micreos, a company working to develop the world’s first targeted antibacterial products. Can you tell us more about Micreos’ vision and the importance of finding alternatives to antibiotics?
Micreos is working towards providing innovative therapeutic solutions that deliver a profound and transformational impact to improve the standard of care for people living with devastating illnesses.
Antimicrobial resistance, or AMR is a naturally occurring process that cannot be eliminated; it can only be controlled. Unfortunately, decades of overprescribing antibiotics in combination with the use of antibiotics in agriculture and farming, such as growth factors for livestock (that has been banned in the EU since 2006), has driven the spread of antimicrobial resistance genes among bacterial pathogens. AMR is estimated to have caused 1.27 million deaths in 2019, with this number expected to keep on growing. Nevertheless, we are fighting back.
At Micreos, we are developing two classes of antimicrobials: Endolysins and Antimicrobial Vectors. Both have different modes of action compared to antibiotics, making them capable of killing all AMR bacteria. Both technologies provide other important advantages, too, such as their ability to precisely kill a specific pathogenic species while leaving commensal or “good” bacteria unaffected. Also, due to their alternative mechanisms of action, they are able to circumvent some of the harmful side effects of antibiotic use.
The drug discovery sector has seen considerable advances in the last decade, thanks largely to technology and increased collaboration. How do you feel this sector has changed in recent years and what has personally been the most exciting development that you have seen?
Global healthcare is rapidly transitioning towards precision medicine. Personally, I think the most impressive advancements over the last decade have been realized with nucleic acids. For example, antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that modulate gene expression are being designed for large indications, rare diseases, and even patients with ultrarare, “n-of-1” diseases.
In the last two years, we all witnessed another form of nucleic acid therapy, mRNA. In less than a year, scientists went from sequencing the SARS-CoV-2 virus to designing different mRNA vaccines for global distribution. I am sure there are going to be many more exciting developments within this space in the near future. I am especially interested to see how the mRNA field progresses with regard to gene therapy, where mRNA can be administered to compensate for a faulty gene or protein.
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Micreos has recently launched a new world-class antimicrobial vector engineering team to ramp up the fight against antimicrobial resistance (AMR). Can you tell us more about why this team was created and the work you are carrying out?
Bacteriophages are natural predators of bacteria that, for over 100 years, have sat on the sidelines of modern medicine. They have mostly been applied as an experimental treatment, reserved for patients suffering from chronic infections that are untreatable with conventional antibiotics. As the threat of AMR intensifies, there is a significant demand for developing and enhancing the capabilities of alternative therapeutics to treat bacterial infections, among many other chronic and rare diseases.
At Micreos Pharmaceuticals, we are heavily invested in harnessing the power of genetic information. In the Division of Antimicrobial Vectors, we use the genomes of bacterial viruses or bacteriophages as “blueprints” for engineering using CRISPR-Cas technology as well as various synthetic approaches. First, we isolate and sequence bacteriophages from different environments that are predisposed to target and kill certain pathogenic species. Next, the fun starts, as the team and I get to apply our knowledge and expertise in bacteriophages, biochemistry, and structural biology to reprogram these genetic “blueprints” to generate Antimicrobial Vector libraries.
We can engineer structural genes for improved stability, introduce heterologous payloads for improved potency, remove unneeded elements for better efficiency and safety, and reprogram their targeting capabilities to reach bacteria in niche locations, such as intracellular reservoirs or biofilms. The resulting libraries of Antimicrobial Vectors provide unique and therapeutically important functions when used against bacterial infections.
This new team combines individuals with a variety of knowledge across various sectors, including molecular microbiology, genetic engineering, and phage therapy. Why is having a multidisciplinary team vital when developing new ways to tackle infectious diseases?
We are fortunate to have assembled a multidisciplinary team of experts proficient in all aspects of the Antimicrobial Vector R&D process, from selecting and testing environmental bacteriophages, to designing genetic scaffolds for reprogramming, to early-stage production, efficacy assessment, manufacturing optimization, and preclinical testing.
Our team also works very closely with experts in clinical trial design and regulatory affairs. This not only makes for interesting coffee breaks, where ideas and alternative perspectives are thrown around, but it ensures that we have a drug development pipeline that runs as efficiently as possible. It is important to have frequent input regarding aspects of safety, translatability, and efficacy to ensure our medicines will translate as quickly as possible from bench to bedside.
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How can the technology developed at Micreos help to tackle AMR through the creation of precision antimicrobials?
We are seeing more and more biologics and recombinant protein-based therapies in development to accompany small-molecule antibiotics in the fight against AMR. Micreos has already established itself as the global experts in engineering of endolysins, which has led to an array of precision protein-based antimicrobials capable of targeted killing of harmful S. aureus pathogen while leaving beneficial bacteria intact and without triggering resistance development.
During my PhD studies at EMBL Hamburg, I solved the atomic structures of these cell wall degrading enzymes and witnessed firsthand how miniscule amounts of endolysin could eradicate entire monocultures of specific bacteria in minutes with no off-target effects against “good” bacteria, such as those found on our skin or in our guts. Unlike the development of AMR against antibiotics, scientists do not expect to see similar resistance mechanisms emerge for endolysins due to their targeting of essential cell wall components that are extremely difficult for bacteria to modify.
Currently, our pharmaceutical grade endolysins are being developed for atopic dermatitis, diabetic foot ulcers, cutaneous T-cell lymphoma (based on excessive skin colonization by S. aureus) and bloodstream infections.
At the right time, and following extensive preclinical testing, we are all excited to witness our Antimicrobial Vector technology follow in the footsteps of our endolysins as it translates from discovery to clinical trials and onto improving the standard of care for people suffering from infections and many other devastating disorders.
Every year, the world celebrates World Antimicrobial Awareness Week (WAAW), dedicated to spreading awareness about AMR. The theme for 2022 is ‘Preventing Antimicrobial Resistance Together‘. What does this message mean to you, and how can international collaboration help to tackle this global health threat?
In 2019, nearly 5 million people died from illnesses involving AMR bacteria. Based on the current trajectory, these numbers are only going to keep rising – and at quicker and quicker rates – with predictions estimating AMR will cause 10 million deaths by the year 2050. The solution to controlling antimicrobial resistance is to work together internationally to implement more effective governance surrounding antimicrobials, improve public awareness surrounding antibiotics, and fund the development of new classes of antimicrobials to bolster our arsenal of available medicines.
It is important that drug developers, researchers, health authorities, and academics all play a part, no matter how big (e.g., establishing initiatives and investment funds) or small (e.g., tweets, chats among friends in the pub), to help raise public awareness surrounding AMR. Events such as those taking place during WAAW and their ability to disseminate information about AMR and its threat to our everyday lives are incredibly important. The public needs to know that AMR could impact our normal way of life. We risk reversing nearly a century of progress in public health if we allow normally innocuous infections to again become untreatable.
In addition to WAAW, we are seeing an expansion in other AMR initiatives, the introduction of innovation funds, and a growing number of collaborative organizations providing much-needed platforms for engagement and collaboration between industry, researchers, non-profit organizations, charities, and governments around the world.
Micreos has always focused on forging strong collaborations with other industry partners, clinicians, and academia to help advance the development of our precision antimicrobials. For instance, our proprietary endolysin technology was created together with ETH Zurich, which remains an important partner to us moving forwards with our Antimicrobial Vector technology.
Image Credit: The World Health Organization
Despite AMR being described as one of the top 10 threats to humanity, many people still do not understand its wide-reaching effects. Why is this, and why is it therefore so critical to continue to raise awareness?
I believe this is due to poor public communication and education regarding what antibiotics are, how they work, and what AMR really means. In 2015, when the WHO asked 10,000 people from 12 different countries about antibiotics, 76% of respondents believed that antibiotic resistance happens when the body becomes resistant to antibiotics – rather than bacteria becoming resistant to the antibiotics. Moreover, 44% of people believed they are not at risk of antibiotic-resistant infections if they simply take antibiotics as prescribed and of course, that is not correct.
Governments, academics, drug developers, and health professionals must do better at communicating a clearer message about what antibiotics are and – most importantly – why they are a precious resource that we cannot continue to take for granted.
What do you believe the future of antimicrobials to look like? Is it possible to one day see a world without resistance?
Another imminent threat to human existence is climate change, which shares many similarities, such as urgency, severity, and global effects, as we are seeing with the spread of AMR. What gives me hope for the future of antimicrobials and tackling AMR is witnessing the growth in public conversation and awareness surrounding climate change; the same will happen with AMR.
Improving awareness for AMR is about educating and mobilizing audiences so they are driven to take their own actions and make their own decisions toward confronting this growing crisis. I am hopeful that everyone will play a part through communication, the sharing of novel solutions, and advocating for change that will be shaped by our different experiences, cultures, and underlying values.
Originally from Macclesfield in the Northwest of England, Matthew studied Biochemistry at the University of Birmingham before obtaining a Ph.D. in Biochemistry and Structural Biology from the European Molecular Biology Laboratory (EMBL) in Hamburg and the University College Cork, Ireland, where he characterized the atomic structure and function of endolysins.
For the last eight years, Matthew has worked as a Postdoc and then Senior Scientist at the Swiss Institute of Technology in Zurich (ETH Zurich), where he investigated the molecular-level interactions of bacteriophages against a wide variety of foodborne and clinical pathogens, produced novel bacterial diagnostics, and developed genetic engineering tools that have been used to produce different types of bacteriophage-based therapeutics and diagnostic elements. Matthew maintains a research group within the lab of Prof. Martin Loessner at ETH Zurich, where he is actively involved in using genetic engineering to further explore how bacteriophages interact with their hosts, as well as lead a team of researchers developing bacteriophages to treat urinary tract infections for assessment in future clinical trials.
Matthew lives in Zurich with his wife, Alyssa Hill, also a Senior Scientist in Pharmaceutical Chemistry at ETH Zurich. In his free time, you will find Matthew swimming in the lakes and rivers dotted around the city, coaching and playing field hockey for the Red Sox HC, or skiing, hiking, and exploring Switzerland with Alyssa.
Eichenseher F, Herpers BL, Badoux P, Leyva-Castillo JM, Geha RS, van der Zwart M, McKellar J, Janssen F, de Rooij B, Selvakumar L, Röhrig C, Frieling J, Offerhaus M, Loessner MJ, Schmelcher M. Linker-Improved Chimeric Endolysin Selectively Kills Staphylococcus aureus In Vitro, on Reconstituted Human Epidermis, and in a Murine Model of Skin Infection. Antimicrob Agents Chemother. 2022 May 17;66(5):e0227321. doi: 10.1128/aac.02273-21. Epub 2022 Apr 13. PMID: 35416713; PMCID: PMC9112974.
Microbiome: From Research and Innovation to Market
