But now it appears that selfish genetic elements might not be so selfish after all. According to new research conducted by scientists at the University of California, San Diego, a certain kind of selfish genetic element—an intron containing a homing endonuclease—can give its host, a phage, a survival advantage over the phage’s peers.

Detailed findings recently appeared in Science, in an article titled, “An intron endonuclease facilitates interference competition between coinfecting viruses.”

“[We] studied intron-encoded homing endonuclease gp210 in bacteriophage ΦPA3 and found that it contributes to viral competition by interfering with the replication of a coinfecting phage, ΦKZ,” the article’s authors wrote. “We show that gp210 targets a specific sequence in ΦKZ, which prevents the assembly of progeny viruses.

“This is the first time a selfish genetic element has been demonstrated to confer a competitive advantage to the host organism it has invaded,” said study co-first author Erica Birkholz, a postdoctoral scholar in the Department of Molecular Biology. “Understanding that selfish genetic elements are not always purely ‘selfish’ has wide implications for better understanding the evolution of genomes in all kingdoms of life.”

In the new study, which focused on investigating “jumbo” phages, the researchers analyzed the dynamics as two phages co-infect a single bacterial cell and compete against each other. The researchers looked closely at the endonuclease, an enzyme that serves as a DNA cutting tool. The endonuclease from one phage’s mobile intron, the studies showed, interferes with the genome of the competing phage. The endonuclease therefore is now regarded as a combat tool since it has been documented cutting an essential gene in the competing phage’s genome. This sabotages the competitor’s ability to appropriately assemble its own progeny and reproduce.

“We were able to clearly delineate the mechanism that gives an advantage and how that happens at the molecular level,” said Biological Sciences graduate student Chase Morgan, the paper’s co-first author. “This incompatibility between selfish genetic elements becomes molecular warfare.”

The results of the study are important as phage viruses emerge as therapeutic tools in the fight against antibiotic resistant bacteria. Since doctors have been deploying cocktails of phage to combat infections in this growing crisis, the new information is likely to come into play when multiple phage are implemented. Knowing that certain phage are using selfish genetic elements as weapons against other phage could help researchers understand why certain combinations of phage may not reach their full therapeutic potential.

“The phages in this study can be used to treat patients with bacterial infections associated with cystic fibrosis,” said Biological Sciences Professor Joe Pogliano. “Understanding how they compete with one another will allow us to make better cocktails for phage therapy.”

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This achievement and other advances, which Qubit says raise hopes of a near-term practical application of hybrid high performance computing (HPC)-quantum computing to drug discovery, has led to the company and the Sorbonne receiving €8 ($8.7) million in funding under the France 2030 national plan for the further development of Hyperion-1.

With this proof of concept, the teams note that they have demonstrated that the routine use of quantum computers coupled with high-performance computing platforms for chemistry and drug discovery is much closer than previously thought. Nearly five years could be gained, they add, bringing researchers significantly closer to the era when quantum computers (noisy or perfect) could be used in production within hybrid supercomputers combining HPC, AI, and quantum. The use of these new computing powers will improve the precision, speed, and carbon footprint of calculations, the researchers point out.

Soon to be deployed on noisy machines

To achieve this breakthrough, teams from Qubit Pharmaceuticals and Sorbonne University developed new algorithms that break down a quantum calculation into its various components, some of which can be calculated precisely on conventional hardware. This strategy enables calculations to be distributed using the best hardware (quantum or classical), while automatically improving the complexity of the algorithms needed to calculate the molecules’ properties. In this way, explain the researchers, all calculations not enhanced by quantum computers are performed on classical GPUs.

As the physics used allows the number of qubits required for the calculations, the team, by optimizing the approach to the extreme, has managed to limit GPU requirements to a single card in some cases, according to the scientists. As this hybrid classical/quantum approach is generalist, it can be applied to any type of quantum chemistry calculation, and is not restricted to molecules of pharmaceutical interest, but also to catalysts (chemistry, energy) or materials, notes Robert Marino, PhD, CEO of Qubit Pharmaceuticals.

“This work clearly demonstrates the need to progress simultaneously on hardware and software development,” says Jean-Philip Piquemal, PhD, professor at Sorbonne University and director of the theoretical chemistry laboratory (Sorbonne University/CNRS), co-founder and CSO of Qubit Pharmaceuticals. “It is by making breakthroughs on both fronts that we will be able to enter the era of quantum utility for drug discovery in the very short term.”

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The preclinical study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing the muscle wasting sometimes associated with inflammatory diseases—including bacterial infections—Alzheimer’s disease and long COVID.

“We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses,” said senior author Aaron Johnson, PhD, an associate professor of developmental biology. “Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally.”

Johnson and colleagues reported on their findings in Science Immunology, in a paper titled “Infection and chronic disease activate a systemic brain-muscle signaling axis.” In their report the team concluded, “Our study argues that infections and chronic diseases activate a conserved IL-6–mediated systemic brain-muscle signaling axis, which could be a therapeutic target to improve muscle outcomes in affected patients.”

“Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show non-neural symptoms including muscle pain and muscle fatigue,” the authors wrote. “The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood.”

To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases—an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species (ROS) build up. The reactive oxygen species cause brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which travels throughout the body via the bloodstream.

Johnson added, “Flies and mice that had COVID-associated proteins in the brain showed reduced motor function—the flies didn’t climb as well as they should have, and the mice didn’t run as well or as much as control mice.” We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments.” Reporting on their experiments, the team further stated, “Using genetic rescue experiments and pharmacological treatments, we conclude cytokine signaling from the CNS is sufficient to impair motor function and that IL-6 could be a therapeutic target to treat muscle dysfunction in response to infections and chronic disease. Brain muscle-communication is thus a central regulator of muscle performance.”

Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD—who did this work as a postdoctoral researcher in Johnson’s lab—make the case that the same processes are likely relevant in people. The bacterial brain infection meningitis is known to increase IL-6 levels and can be associated with muscle issues in some patients, for instance. Among COVID-19 patients, inflammatory SARS-CoV-2 proteins have been found in the brain during autopsy, and many long COVID patients report extreme fatigue and muscle weakness even long after the initial infection has cleared. Patients with Alzheimer’s disease also show increased levels of IL-6 in the blood as well as muscle weakness.

The study pinpoints potential targets for preventing or treating muscle weakness related to brain inflammation. Several therapeutics already approved by the Food and Drug Administration for other diseases can block this JAK-STAT pathway, the team pointed out. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory conditions. “IL-6 inhibitors have been used to treat autoimmune diseases such as rheumatoid arthritis, and clinical trials are ongoing to expand the inflammatory disorders that can be targeted with IL-6 inhibitors,” the researchers stated.

“We’re not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories,” Johnson said. “If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body.

“In the meantime, we hope our study encourages more clinical research into this pathway and whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he said. Acknowledging limitations of their study, and noting results from previous clinical studies using IL-6 inhibitors or JAK inhibitors, the team further concluded, “These clinical results argue that systemic treatment with IL-6 and JAK inhibitors could inhibit changes to muscle performance induced by the brain-muscle signaling axis and prevent muscle dysfunction associated with chronic and infectious diseases.”

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Characterizing clonal evolution in blood cancers like acute myeloid leukemia (AML) is critical for understanding their mutational histories and how cell populations change during disease development.

In this GEN webinar, Robert Bowman, PhD, will discuss his lab’s approaches for modeling clonal evolution in mouse models of disease. His group deploys multi-recombinase models to study the stepwise acquisition of mutations seen in AML. These approaches allow for the evaluation of how mutation order impacts disease development. They have characterized the hierarchy of cellular differentiation using flow cytometry and single cell RNA sequencing, recently integrating the ScaleBio Single Cell RNA Kit into their workflow. He will discuss a specific study focusing on FLT3-mutant AML, present data comparing genetic deletion versus chemical inhibition with FDA-approved tyrosine kinase inhibitors, and finally, his plans to further deploy models of oncogene-dependency.

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelist.

Webinar produced with support from:

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“This has been a 20-year effort among four labs and multiple highly talented researchers,” Andrew F. Stewart, MD, director of the Diabetes Obesity and Metabolism Institute at Mount Sinai told GEN.

The new study, titled, “Harmine and exendin-4 combination therapy safely expands human b cell mass in vivo in a mouse xenograft system,” was published in Science Translational Medicine.

Diabetes is a worldwide medical concern for more than 500 million people, nearly 10% of all adults. Current diabetes treatments address the symptoms of the disease, replacing insulin or increasing the body’s ability to utilize insulin. However, these treatments do not increase beta cell numbers, leaving a significant gap in reversing diabetes.

Stewart and his team in New York with California collaborators, including Adolfo Garcia-Ocaña, PhD, chair in gene regulation and drug discovery research at City of Hope, strategized that the best way to treat diabetes is to reverse the fundamental cause of the disease. “Beta cell deficiency underlies diabetes treatment strategies such as pancreas transplant, islet transplant, and new attempts at growing new beta cells from human stem cells,” remarked Stewart.

Together, they designed and implemented the first drug screens, followed by cell culture experiments, and as presented in the current study, animal transplant and drug treatment models.

The initial drug screening experiments identified a small molecule called harmine that can induce beta cell replication, which was published in 2015. This is a natural compound found in some plants that works by inhibiting the enzyme DYRK1A. Five years later, Stewart’s team showed that any of the GLP1 receptor agonists currently on the market synergize with any DYRK1A inhibitor to produce much higher rates of beta-cell replication.

The researchers’ earlier studies demonstrated that inhibiting DYRK1A in beta cells could induce short-term cell proliferation in vitro. They utilized an advanced laser microscopy technique called iDISCO⁺ to visualize and quantify beta-cell survival, function, and proliferation. iDISCO⁺ makes tissue transparent, allowing for 3D visualization of immunolabeled tissues.

Taken together, these data suggested that beta cells might grow in response to a combination treatment of harmine and GLP1. Further experimentation showed that the beta cells could survive in culture and the current study moved from tissue culture to studies in mice.

The researchers next took immunodeficient mice, typically used as models for diabetes research, with implanted human beta cells, and administered a combined treatment of harmine and GLP1. The results were profoundly positive, showing up to 700% increase in human beta cells over the three-month experimental duration. Stewart added, “In addition to beta cell mass expansion, diabetes reverses rapidly.”

“This is the first time that scientists have developed a drug treatment that is proven to increase adult human beta cell numbers in vivo,” said Garcia-Ocaña. “This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes.”

Stewart told GEN, “We had hoped that we would observe a small increase in human beta cell mass in vivo. But we never expected to see a 300–700% increase. This should be more than enough to ‘fill up the beta cell tank’ and reverse most types of human diabetes.”

Concurrent with this study, the Mount Sinai team has also completed a Phase I clinical trial of harmine to assess its safety and tolerability in healthy individuals. “We had hoped that we would observe no drug safety issues with drug treatment, and this is what we observed,” Stewart said of the trial.

Collaborators are also working on developing next-generation DYRK1A inhibitors as part of their continued research with the aim toward imminent clinical trials.

“Our studies pave the way for moving [other] DYRK1A inhibitors into human clinical trials and it’s very exciting to be close to seeing this novel treatment used in patients,” Garcia-Ocaña said. “There is nothing like this available to patients right now.”

Stewart concluded, “The steady progression from the most basic human beta cell biology, through robotic drug screening and now moving to human studies, illustrates the essential role for physician-scientists in academia and pharma.”

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The findings are published in Nature in an article titled, “CryoET of β-amyloid and tau within post-mortem Alzheimer’s disease brain,” and led by scientists at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge.

“A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures,” the scientists wrote. “In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain.”

The study zoomed in on two proteins that cause dementia—”β-amyloid,” a protein that forms microscopic sticky plaques, and “tau”—another protein that in Alzheimer’s disease forms abnormal filaments that grow inside cells and spread throughout the brain.

Rene Frank, PhD, lead author and associate professor in the University of Leeds’s School of Biology, said: “This first glimpse of the structure of molecules inside the human brain offers further clues to what happens to proteins in Alzheimer’s disease but also sets out an experimental approach that can be applied to better understand a broad range of other devastating neurological diseases.”

This study carried out at the University of Leeds in collaboration with scientists at Amsterdam UMC, Zeiss Microscopy, and the University of Cambridge, is part of new efforts by structural biologists to study proteins directly within cells and tissues, their native environment—and how proteins work together and affect one another, particularly in human cells and tissues ravaged by disease. In the longer term, it is hoped that observing this interplay of proteins within tissues will accelerate the identification of new targets for next-generation mechanism-based therapeutics and diagnostics.

The post Deep Dive into Brain’s Molecular Structures Affected by Alzheimer’s Disease appeared first on GEN - Genetic Engineering and Biotechnology News.

Following their success against COVID-19 infections, interest in RNA-based therapeutics is growing rapidly. And as demand for RNA drugs continues to grow and “additional products come to market, we will exceed the current global supply of acetonitrile, the organic solvent used in chemical RNA synthesis methods,” said co-first author Jonathan Rittichier, PhD, a former postdoctoral fellow at the Wyss and HMS. 

Besides reducing the creation of toxic synthesis byproducts, the technology that Rittichier and his collaborators, which includes George Church, PhD, Wyss core faculty member and HMS professor of genetics, have developed incorporates common molecular modifications found in RNA drugs today and can be used with novel RNA chemistries to develop new therapies. “Delivering RNA drugs to the world at these scales requires a paradigm shift to a renewable, aqueous synthesis, and we believe our proprietary enzymatic technology will enable that shift,” Rittichier said.

The starting point for the technology is an enzyme from Schizosaccharomyces pombe, a strain of yeast, that is used to form RNA strands. The scientists engineered a more efficient version of the enzyme that can also incorporate nonstandard nucleotides into RNA—a necessary improvement since every FDA-approved RNA drug includes modified nucleotides that increase their stability in the body or equip them with new functions. Their approach also uses milder methods to remove protecting groups which are added to nucleotides to protect them during the synthesis process. 

Furthermore, the researchers modified the nucleotides by attaching a chemical group called a “blocker” that ensures that nucleotides are added to the RNA chain one at a time. Once the desired nucleotide has been added to the link, the blocker is removed to allow the next nucleotide in the sequence to bind. This two-step process is simpler and uses fewer reagents than the typical four-step chemical synthesis. According to the scientists, their process is also 95% efficient and can build RNA molecules as long as 23 nucleotides. However, they noted that “overall yields in bulk phase were lower than those in standard RNA oligonucleotide synthesis” likely due to “multiple rounds of purification after both extension and deblocking.”

“Enzymatic nucleotide synthesis technologies offer many advantages as an alternative to chemical-based methods,” Church said in a statement. “This platform can help unlock the immense potential of RNA therapeutics in a sustainable way, especially manufacturing high-quality guide RNA molecules for CRISPR/Cas gene editing.” 

Rittichier, Church, and others launched EnPlusOne Biosciences in 2022 to commercialize the technology with funding from Northpond Ventures, Breakout Ventures, and Coatue. The company is currently using the technology to manufacture small interfering RNAs that could be used to treat various diseases. 

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The multi-product facility, which doubles Rentschler Biopharma’s global cGMP capacity, is focusing mainly on commercial production of highly complex molecules. The original Milford site went from a single-product commercial facility to producing multiple products in an up to 500L bioreactor setup.

The new production line has added 22,000 square feet of manufacturing cleanroom space and houses four new 2,000L single-use bioreactors, bringing the total of production lines at the site up to three.

“The completion of our new production line is an important milestone for our company and emphasizes Rentschler Biopharma’s strong capabilities in the U.S.,” said Benedikt von Braunmühl, CEO of Rentschler Biopharma. “Indeed, in 2023, Rentschler Biopharma was proud to contribute to nearly 25% of the biopharmaceuticals approved by the FDA.”

The post Rentschler Biopharma’s New Production Line in Massachusetts Now Fully Operational appeared first on GEN - Genetic Engineering and Biotechnology News.

Kappler said the bacterium had a unique ability to “talk” to and deactivate the immune system, convincing it there was no threat. “These bacteria are especially damaging to vulnerable groups, such as those with cystic fibrosis, asthma, the elderly, and Indigenous communities,” Kappler said. “In some conditions, such as asthma and chronic obstructive pulmonary disease, they can drastically worsen symptoms. Our research shows the bacterium persists by essentially turning off the body’s immune responses, inducing a state of tolerance in human respiratory tissues.”

The researchers reported on their studies, and results, in PLOS Pathogens, in a paper titled “Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model.”

Respiratory tract infections are highly debilitating, and Haemophilus influenzae is a bacterial pathogen that is associated with persistent acute and chronic respiratory tract infections, particularly among vulnerable individuals, the authors explained. “Haemophilus influenzae is a human-adapted pathobiont that inhabits the nasopharynx as a commensal but causes disease in other parts of the respiratory tract.” What are classed as nontypeable strains of H. influenzae (NTHi) are the most common type of clinical isolate, the team continued. In addition to causing acute diseases such as pneumonia, these strains are a major cause of exacerbations of chronic lung diseases, including in patients recovering from COVID-19. Interactions between the bacteria and the respiratory epithelia represent a key factor in NTHi virulence,” the team continued. “Despite this, insights into the molecular interactions that allow NTHi to persist in contact with human epithelia are lacking, but likely hold the key to uncovering both bacterial and host processes that are crucial for infection.”

For their newly reported studies the team generated primary normal human nasal epithelia (NHNE), derived from cells from five healthy donors, and monitored the effects on tissue gene expression of NTHi infection. They first prepared the human nasal tissue in the lab, growing it to resemble the surfaces of the human respiratory tract. They then monitored post infection (p.i.) gene expression changes over a 14-day period of “infection” with the NTHi. “Persistent infections rely on close molecular interactions between the human respiratory cells and the bacterial pathogen,” the team noted, “… and here we have investigated changes in host and bacterial cells during persistent, long-term infections with H. influenzae.”

Their found very limited production of inflammation molecules over time, which normally would be produced within hours of bacteria infecting human cells. “We then applied both live and dead Haemophilus influenzae, showing the dead bacteria caused a fast production of the inflammation makers, while live bacteria prevented this,” professor Kappler said.  “This proved that the bacteria can actively reduce the human immune response.”

In their paper the authors wrote, “… Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, ‘unproductive’ inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state.”

This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, they stated. “In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation.”

Co-author and pediatric respiratory physician emeritus professor Peter Sly, MD, at UQ’s Faculty of Medicine, said the results show how Haemophilus influenzae can cause chronic infections, essentially living in the cells that form the surface of the respiratory tract.

“This is a rare behavior that many other bacteria don’t possess,” professor Sly said.
“If local immunity drops, for example during a viral infection, the bacteria may be able to ‘take over’ and cause a more severe infection.” The findings will lead to future work towards new treatments to prevent these infections by helping the immune system to recognize and kill these bacteria. “We’ll look at ways of developing treatments that enhance the immune system’s ability to detect and eliminate the pathogen before it can cause further damage,” Kappler added.

In their paper the authors concluded, “… our data provide first evidence that NTHi infections can delay strong inflammatory responses in human epithelia and induce an apparent tolerance of NTHi infection that had not been previously observed, but could be a driver of NTHi persistence in the human respiratory tract. This state of ‘peaceful’ coexistence of NHNE and NTHi required infection with live NTHi, which indicates an active immunomodulatory role for NTHi.”

They pointed out that further research is needed to investigate whether bacterial effector proteins or metabolites are involved in triggering NHNE tolerance of NTHi infection, and what mechanisms within human epithelia cause differences in tolerance of NTHi infections.

The post Respiratory Bacteria “Talk” Immune System into Tolerating Infection appeared first on GEN - Genetic Engineering and Biotechnology News.

Novel or next-generation biologics such as bispecific antibodies (bsAbs) and fusion proteins present unique development and manufacturing process challenges due to complex formats, suboptimal stability, product aggregation, or low productivity. These issues impact product quality and consistency, as well as the ability to develop efficient and scalable processes. Successfully addressing these challenges while reducing the cost of goods (COGs) requires the strategic utilization of advanced technologies, appropriate analytical methods, extensive experience, as well as adopting a proactive approach to de-risk the biotherapeutics development.

In this GEN webinar, our speakers will present WuXi Biologics’ suite of advanced solutions for overcoming obstacles associated with the development and manufacturing of complex biologics.

In this webinar you’ll learn:

• The evolving landscape of new modalities and the holistic challenges in CMC development for complex biotherapeutics

• Technical strategies to address specific challenges in bispecific antibody (bsAb) development

• Solutions to achieve efficient and successful fusion protein development in mammalian protein expression systems

• Case studies and experience sharing on strategies to reduce COGs for complex biologic modalities

A live Q&A session will follow the presentation, offering you a chance to pose questions to our expert panelists.

Webinar produced with support from:

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