Journal Club

Cells can communicate with one another to coordinate essential processes such as development, growth, and repair through the release of signaling intermediates. One class of signaling intermediates are extracellular vesicles (EVs) that contain nucleic acids and proteins that mediate cell-cell communication. In cancer, the cargo of these EVs is altered in order to promote tumor progression, improving the ability to proliferate, invade, metastasize, and develop drug resistance, among other cancer characteristics. While most EVs range in diameter from 50 nanometers to one micron, there has been an increasing interest in smaller particles that might also be released from cells and contribute to cancer. Only recently has technology evolved enough to detect these previously undiscernible nanoparticles. Qin Zhang, PhD, Robert Coffey, MD, and colleagues were motivated by previous advances in the lab regarding the role of EVs in cancer to determine if smaller particles existed with similar functions. Dr. Coffey and his team discovered a new nanoparticle, termed the supermere, with functional relevance not only to cancer but to many other diseases, resulting in a publication at the end of 2021 in Nature Cell Biology (Zhang Q et al. 2021).

Continue reading

This blog originated as a press release from Nagoya University. Thanks to them for allowing us to repost it here.

Researchers at Nagoya University in Japan have developed a new chemical-only process that may represent an important breakthrough in creating customized mRNA vaccines for a variety of diseases and allow for the inexpensive preparation of mRNA in large quantities.

During the COVID-19 pandemic, mRNA vaccines were successfully used to boost immunity. These vaccines teach cells how to make a protein that triggers the body’s immune response, allowing its natural defenses to recognize the invading virus. However, current vaccines that use biological processes do not allow for the precise molecular design of mRNA, which limits their use in creating new vaccines as variants emerge.

As published in ACS Chemical Biology, a research group led by Professor Hiroshi Abe and Associate Professor Naoko Abe of the Graduate School of Science at Nagoya University has developed the first completely chemical synthesis method for mRNA.

In their study, the group synthesized a part of the mRNA called the cap. The cap is important because it promotes the translation of mRNA into proteins and protects mRNA from degradation. To prepare synthetic mRNA, such as that used in vaccines, the two currently used biological methods rely on enzymes to incorporate the cap structure into the mRNA. However, the researchers found that their technique could synthesize a variety of chemically modified mRNA strands with a cap structure.

According to Professor Abe, “our research suggests that it is possible to make mRNAs with precisely introduced chemical modifications with complete control over the process. The molecular design reported in our study exhibits five times higher translational activity than that of enzyme-produced natural-type mRNA. This means that mRNA can be synthesized in large quantities at low cost using chemical synthesis.”

Chemically modified mRNA could be used to create customized vaccines against a variety of infectious diseases including viruses and cancers. Professor Abe explains, “By introducing these chemical modifications, the mRNA becomes stable. This could allow for the creation of long-lasting and effective mRNA vaccines. In addition, it could allow mRNA to be administered directly instead of using lipid nanoparticles, which are used for delivery in current vaccines.”

“One of the exciting implications of this research is that this could be used in the next generation of vaccines,” the researchers said. “We hope that the capping method reported here will be of great use in the development of RNA therapeutics.”

The study, “Complete Chemical Synthesis of Minimal Messenger RNA by Efficient Chemical Capping Reaction,” was published in ACS Chemical Biology on May 24, 2022.

Authors:
Naoko Abe, Akihiro Imaeda, Masahito Inagaki, Zhenmin Li, Daisuke Kawaguchi, Kaoru Onda, Yuko Nakashima, Satoshi Uchida, Fumitaka Hashiya, Yasuaki Kimura, and Hiroshi Abe

The study was supported by the AMED LEAP project ‘Innovation of Chemistry-Based Molecular Design and Production Methods for mRNA and its Application to Vaccines’, which started in FY2021.

Reference

Abe N et al. Complete chemical synthesis of minimal messenger RNA by efficient chemical capping reaction. ACS Chem Biol AOP 2022-05-24. doi: 10.1021/acschembio.1c00996 PMID: 35608277.

This blog originated as a press release from the Johns Hopkins Kimmel Cancer Center. Thanks to them for allowing us to repost it here.

It may be possible to identify the presence of an aggressive brain tumor in children by studying their cerebrospinal fluid, according to new research led by Johns Hopkins Kimmel Cancer Center investigators.

Comparing cerebrospinal fluid samples from 40 patients with medulloblastoma — the most common malignant brain tumor in children, accounting for 10% to 15% of pediatric central nervous system tumors — and from 11 healthy children without the disease, investigators identified 110 genes, 10 types of RNA–the machinery that translates proteins–called circular RNAs, 14 lipids and several metabolites that were expressed differently between the two groups. While these details were not specific enough to distinguish among the four subtypes of medulloblastoma, they could be used to identify the presence of cancer versus normal fluid. A description of the work was published in the journal Acta Neuropathologica Communications.

Continue reading

Extracellular vesicles (EVs) are small membrane-bound particles that are loaded with various proteins, RNA, DNA, and lipids, and secreted by cells. Interest in these vesicles has grown in recent years with mounting evidence that EVs act as intercellular communication systems, transferring their selected cargo to other cells to confer specific effects on target cell biology. However, the processes that direct specific RNAs and proteins into these specialized vesicles remain largely unknown. In the April 25th, 2022 edition of Developmental Cell, Alissa Weaver, M.D., Ph.D. and her research team at the Vanderbilt Center for Extracellular Vesicle Research have uncovered subcellular hubs of EV formation that selectively assemble RNA-containing EVs. These hubs are located at membrane contact sites (MCS) where the endoplasmic reticulum (ER) interacts with EV biogenesis membranes, including late endosomal multivesicular bodies (MVBs) (ER-MVB MCS). Shedding much needed mechanistic light, the group further pinpointed the ER MCS membrane tether protein VAP-A and its binding partner ceramide transfer protein (CERT) as key drivers in this process.

Continue reading

This blog originated as a press release from the Swiss National Centre of Competence in Research SYNAPSY. Thanks to them for allowing us to repost it here.

A research team from Synapsy has shown that the severity of the clinical symptoms of schizophrenia is strongly linked to blood biomarkers related to the deregulation of neuronal mitochondria.

Psychotic symptoms are a characteristic clinical manifestation of schizophrenia. They go hand-in-hand with an increase in oxidative stress, which results in damage to a particular type of neurons called parvalbumin neurons. This deterioration leads to dysfunction in the activity of the prefrontal cortex, a region of the brain that is involved in cognition. A study conducted at the Centre for Psychiatric Neuroscience of the Lausanne University (UNIL) and the Lausanne University Hospital (CHUV), and supported by the National Centre of Competences in Research Synapsy (Synapsy), has shown, in an animal model, that the cellular mechanism for recycling mitochondria is deficient in parvalbumin neurons. The study – published in the journal Molecular Psychiatry – investigated the underlying biochemical mechanisms, pinpointing two key molecules, miR-137 and COX6A2, that can be detected in blood. When used as biomarkers in patients diagnosed with psychosis, they unveil two distinct clinical sub-groups with different severity of symptoms, cognitive deficits, and functioning in everyday life. This discovery represents a major breakthrough for stratifying individuals suffering from schizophrenia, whose heterogeneity of symptoms currently restricts diagnosis and treatment.

Mouse parvalbumin neuronsMouse parvalbumin neurons – Parvalbumin neurons are affected by oxidative stress in mouse model of schizophrenia. Markers of this neuropathological process can be detected in the blood of human patients, helping to diagnose and potentially treat them with antioxidant compounds. © Inès Khadimallah / CHUV UNIL.

Continue reading

This blog originated as a press release from the UCSD Jacobs School of Engineering. Thanks to them for allowing us to repost it here.

Nanoengineers at the University of California San Diego have developed a new and potentially more effective way to deliver messenger RNA (mRNA) into cells. Their approach involves packing mRNA inside nanoparticles that mimic the flu virus –– a naturally efficient vehicle for delivering genetic material such as RNA into cells.

The new mRNA delivery nanoparticles are described in a paper published recently in the journal Angewandte Chemie International Edition.

The work addresses a major challenge in the field of drug delivery: getting large biological drug molecules safely into cells and protecting them from organelles called endosomes. These tiny acid-filled bubbles inside the cell serve as barriers that trap and digest large molecules that try to enter. In order for biological therapeutics to do their job once they are inside the cell, they need a way to escape the endosomes.

Continue reading

This blog originated as a press release from the German Center for Neurodegenerative Diseases. Thanks to them for allowing us to repost it here.

Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the University Medical Center Göttingen (UMG) have identified molecules in the blood that can indicate impending dementia. Their findings, which are presented in the scientific journal EMBO Molecular Medicine, are based on human studies and laboratory experiments. Various university hospitals across Germany were also involved in the investigations. The biomarker described by the team led by Prof. André Fischer is based on measuring levels of so-called microRNAs. The technique is not yet suitable for practical use; the scientists therefore aim to develop a simple blood test that can be applied in routine medical care to assess dementia risk. According to the study data, microRNAs could potentially also be targets for dementia therapy.

“When symptoms of dementia manifest, the brain has already been massively damaged. Presently, diagnosis happens far too late to even have a chance for effective treatment. If dementia is detected early, the odds of positively influencing the course of the disease increase,” says André Fischer, research group leader and spokesperson at the DZNE site in Göttingen and professor at the Department of Psychiatry and Psychotherapy at UMG. “We need tests that ideally respond before the onset of dementia and reliably estimate the risk of later disease. In other words, tests that give an early warning. We are confident that our current study results pave the way for such tests.”

Continue reading

This blog originated as a press release from the University of Houston. Thanks to them for allowing us to repost it here.

Economical, Ultra-sensitive Biosensing in Point-of-Care Applications

When it comes to cancer detection, size matters. Traditional diagnostic imaging cannot detect tumors smaller than a certain size, causing missed opportunities for early detection and treatment. Circulating tumor exosomes are especially small cancer biomarkers and easy to miss. These nanovesicles are composed of molecules that reflect the parental cells. But, because they are tiny (~30-150nm in diameter) and complex, the precise detection of exosome-carried biomarkers with molecular specificity has been elusive, until now.

Wei-Chuan Shih, professor of electrical and computer engineering at the University of Houston Cullen College of Engineering, reports the findings in IEEE Sensors Journal.

“This work demonstrates, for the first time, that the strong synergy of arrayed radiative coupling and substrate undercut can enable high-performance biosensing in the visible light spectrum where high-quality, low-cost silicon detectors are readily available for point-of-care application,” said Shih. “The result is a remarkable sensitivity improvement, with a refractive index sensitivity increase from 207 nm/RIU to 578 nm/RIU.”

Professor Wei0Chuan Shih, University of HoustonWei-Chuan Shih, professor of electrical and computer engineering at the University of Houston, is reporting rapid cancer detection as a cost-effective, high-performance platform for molecularly specific exosome biosensing.

Continue reading

This blog originated as a press release from MIT News. Thanks to them for allowing us to repost it here.

A new RNA-based control switch could be used to trigger production of therapeutic proteins to treat cancer or other diseases.

eToehold press releaseResearchers at MIT and Harvard University have designed a way to selectively turn on gene expression in target cells, including human cells. Their technology can detect specific mRNA sequences (represented in the center of the illustration), which triggers production of a specific protein (bottom right).
Image: Jose-Luis Olivares, MIT, with figures from iStockphoto

Researchers at MIT and Harvard University have designed a way to selectively turn on gene therapies in target cells, including human cells. Their technology can detect specific messenger RNA sequences in cells, and that detection then triggers production of a specific protein from a transgene, or artificial gene.

Because transgenes can have negative and even dangerous effects when expressed in the wrong cells, the researchers wanted to find a way to reduce off-target effects from gene therapies. One way of distinguishing different types of cells is by reading the RNA sequences inside them, which differ from tissue to tissue.

By finding a way to produce transgene only after “reading” specific RNA sequences inside cells, the researchers developed a technology that could fine-tune gene therapies in applications ranging from regenerative medicine to cancer treatment. For example, researchers could potentially create new therapies to destroy tumors by designing their system to identify cancer cells and produce a toxic protein just inside those cells, killing them in the process.

“This brings new control circuitry to the emerging field of RNA therapeutics, opening up the next generation of RNA therapeutics that could be designed to only turn on in a cell-specific or tissue-specific way,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study.

Continue reading

This blog originated as a press release from the Max Planck Institute for Medical Research in Heidelberg. Thanks to them for allowing us to repost it here.

Scientists create synthetic exosomes with natural functionalities and present their therapeutic application.

Scientists from the Max Planck Institute for Medical Research in Heidelberg and colleagues at the DWI Leibniz Institute for Interactive Materials in Aachen have engineered synthetic exosomes that regulate cellular signaling during wound closure. The synthetic structures are built to resemble naturally occurring extracellular vesicles (EV) that play a fundamental role in communication between cells during various processes in our bodies. The scientists uncovered key mechanisms in the regulation of wound healing and the formation of new blood vessels. They designed and built programmable fully-synthetic EVs from scratch rather than isolating natural EVs from cells. Inspired by the roles of the natural counterparts, the scientists demonstrate for the first time that fully synthetic exosomes with therapeutic functions can be constructed.

Continue reading