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Archive - Jul 27, 2019


New CRISPR Platform (RESCUE) Expands RNA Editing Capabilities; Enables Cytosine to Uridine Changes; Zhang Team Shows That Technique Can Be Used to Convert APOE4 Alzheimer’s Risk Variant to APOE2 Non-Risk Variant

CRISPR-based tools have revolutionized our ability to target disease-linked genetic mutations. CRISPR technology comprises a growing family of tools that can manipulate genes and their expression, including by targeting DNA with the enzymes Cas9 and Cas12, and by targeting RNA with the enzyme Cas13. This collection offers different strategies for tackling mutations. Targeting disease-linked mutations in RNA, which is relatively short-lived, would avoid making permanent changes to the genome. In addition, some cell types, such as neurons, are difficult to edit using CRISPR/Cas9-mediated editing, and new strategies are needed to treat devastating diseases that affect the brain. McGovern Institute Investigator and Broad Institute of MIT and Harvard core member Feng Zhang (photo), PhD, and his team have now developed one such strategy, called RESCUE (RNA Editing for Specific C to U Exchange), which they describe in an article published in the July 26, 2019 issue of Science. The article is titled “A Cytosine Deaminase for Programmable Single-Base RNA Editing.” Dr. Zhang and his team, including first co-authors Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, (both now McGovern Fellows), made use of a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel, evolved, programmable enzyme to convert unwanted cytosine into uridine -- thereby directing a change in the RNA instructions. RESCUE builds on REPAIR, a technology developed by Zhang's team that changes adenine bases into inosine in RNA. RESCUE significantly expands the landscape that CRISPR tools can target RNA coding for modifiable positions in proteins, such as phosphorylation sites. Such sites act as on/off switches for protein activity and are notably found in signaling molecules and cancer-linked pathways.

Scientists Find New Cause of Cellular Aging--Cells Stop Making Nucleotides--Findings May Have Major Implications for Cancer and Age-Related Conditions

New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works. The findings potentially pave the way for better cancer treatments and revolutionary new drugs that could vastly improve human health in the twilight years. The work, from Assistant Professor of Chemical Engineering and Materials Science Nick Graham, PhD, and his team in collaboration with Scott Fraser, PhD, Provost Professor of Biological Sciences and Biomedical Engineering, and Pin Wang, PhD, Zohrab A. Kaprielian Fellow in Engineering, was published online on May 28, 2019 in the Journal of Biological Chemistry. The article is titled “Inhibition of Nucleotide Synthesis Promotes Replicative Senescence of Human Mammary Epithelial Cells.” "To drink from the fountain of youth, you have to figure out where the fountain of youth is, and understand what the fountain of youth is doing," Dr. Graham said. "We're doing the opposite; we're trying to study the reasons cells age, so that we might be able to design treatments for better aging." To achieve this, lead author Alireza Delfarah, a graduate student in the Graham lab, focused on senescence, a natural process in which cells permanently stop creating new cells. This process is one of the key causes of age-related decline, manifesting in diseases such as arthritis, osteoporosis, and heart disease. "Senescent cells are effectively the opposite of stem cells, which have an unlimited potential for self-renewal or division," Delfarah said. "Senescent cells can never divide again. It's an irreversible state of cell cycle arrest." The research team discovered that the aging, senescent cells stopped producing nucleotides, which are the building blocks of DNA.

Newly Identified Pluripotent Liver Cell May Ultimately Provide Alternative to Liver Transplants; Single-Cell RNA Sequencing Key to This Major Discovery

Researchers at King's College London have used single cell RNA sequencing to identify a type of cell that may be able to regenerate liver tissue, treating liver failure without the need for transplants. In a paper published online on July 26, 2019 in Nature Communications, the scientists describe identying a new type of cell called a hepatobiliary hybrid progenitor (HHyP), that forms during our early development in the womb. The open-access article is titled “Single Cell Analysis of Human Foetal Liver Captures the Transcriptional Profile of Hepatobiliary Hybrid Progenitors.” Surprisingly, HHyP also persist in small quantities in adults and these cells can grow into the two main cell types of the adult liver (hepatocytes and cholangiocytes) giving HHyPs stem cell like properties. The team examined HHyPs and found that they resemble mouse stem cells which have been found to rapidly repair mice liver following major injury, such as occurs in cirrhosis. Senior author Dr. Tamir Rashid (photo) from the Centre for Stem Cells & Regenerative Medicine at King's College London said: "For the first time, we have found that cells with true stem-cell-like properties may well exist in the human liver. This in turn could provide a wide range of regenerative medicine applications for treating liver disease, including the possibility of bypassing the need for liver transplants." Liver disease is the fifth biggest killer in the UK and the third most common cause of premature death, and the number of cases is continuing to rise. It can be caused by lifestyle issues such as obesity, viruses, alcohol misuse, or by non-lifestyle issues such as autoimmune and genetic-mediated disease.

Unexpected Developmental Hierarchy Revealed in New Study of Highly Unusual Disease (Langerhans Cell Histiocytosis)--Epigenomics and Single-Cell Sequencing Were Key

Langerhans cell histiocytosis (LCH) is a very unusual disease: Often classified as a cancer because of uncontrolled cell growth in different parts of the body, it also has features of an autoimmune disease, as LCH lesions attract immune cells and show characteristic tissue inflammation. LCH is clinically variable and often difficult to diagnose. Skin involvement in babies with LCH can look like a nappy rash, whereas bone involvement can be mistaken as sarcoma in an X-ray picture. In its most aggressive form, LCH can present as leukemia-like disease and lead to organ failure. These diverse manifestations and the enormous clinical heterogeneity of LCH continue to puzzle medical doctors and scientists around the world. Studying LCH lesions under the microscope, Caroline Hutter, MD, PhD-- a pediatric oncologist at St. Anna Children's Hospital Research Center (CCHR) in Vienna, Austria, principal investigator at CCRI and co-lead investigator of this study -- observed striking heterogeneity among LCH cells. To investigate this diversity in full molecular detail, she assembled an interdisciplinary team including experimental and computational researchers from CCRI and CeMM (Research Center in Molecular Medicine—Vienna Austria), as well as medical doctors from St. Anna Children's Hospital and Vienna General Hospital. Her aim was to answer two fundamental questions: What are the mechanisms behind LCH, and how can we improve treatment of children affected by this disease? Utilizing state-of-the-art technology in the laboratory of co-lead investigator Christoph Bock (CeMM), PhD, LCH lesions were analyzed for their molecular composition at single-cell resolution.