Lifeboat Foundation

Modified RNA CRISPR boosts gene knockdown in human cells.

In the latest of ongoing efforts to expand technologies for modifying genes and their expression, researchers in the lab of Neville Sanjana, PhD, at the New York Genome Center (NYGC) and New York University (NYU) have developed chemically modified guide RNAs for a CRISPR system that targets RNA instead of DNA. These chemically-modified guide RNAs significantly enhance the ability to target – trace, edit, and/or knockdown – RNA in human cells.

Longevity. Technology: In the study published in Cell Chemical Biology, the research team explores a range of different RNA modifications and details how the modified guides increase efficiencies of CRISPR activity from 2-to 5-fold over unmodified guides. They also show that the optimised chemical modifications extend CRISPR targeting activity from 48 hours to four days.

Continue reading “RNA CRISPR gene editing boosts gene knockdown in human cells” »

From the time of Aristotle, it has been known that the human liver has the greatest regenerative capacity of any organ in the body, being able to regrow even from a 70% amputation, which has enabled live-donor transplants. Although the liver regenerates fully upon injury, the mechanisms that regulate how to activate or stop the process and when regeneration is terminated, are still unknown. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden (Germany), at the Gurdon Institute (Cambridge, UK) and at the University of Cambridge (Biochemistry Department) have now found that a regulatory cell type—mesenchymal cell—can activate or stop liver regeneration. The mesenchymal cells do so by the number of contacts they establish with the regenerating cells (epithelial cells). This study suggests that mistakes in the regeneration process, which can give rise to cancer or chronic liver diseases, are caused by the wrong number of contacts between both populations. The work is described in a paper published in the journal Cell Stem Cell on 2nd August 2021.

The molecular mechanisms by which adult liver cells trigger the regenerative response remain largely unknown. Approximately 29 million people in Europe suffer from a chronic liver condition such as cirrhosis or liver cancer. They are a major cause of morbidity and mortality with liver diseases accounting for approximately two million deaths per year worldwide. Currently, there is no cure and liver transplants are the only treatment for liver failure. Scientists are therefore exploring new options for how to trigger the regenerative capacity of the liver as an alternative means to restore function.

Although visible signs of aging are usually unmistakable, unraveling what triggers them has been quite a challenge. Researchers at Baylor College of Medicine and collaborating institutions have discovered that a cellular phenomenon called cryptic transcription, which had been previously described and linked to aging in yeasts and worms, is elevated in aging mammalian stem cells.

The team reports in the journal Nature Aging that cryptic transcription occurs because a cellular mechanism that keeps it in check falls apart as cells get old. The findings suggest that strategies that control cryptic transcription could have pro-longevity effects.

“In previous work, we showed that cryptic transcription in yeasts and worms is not only a marker of aging but also a cause,” said corresponding author Dr. Weiwei Dang, assistant professor of molecular and human genetics and the Huffington Center on Aging at Baylor. “Reducing the amount of this aberrant transcription in these organisms prolonged their lifespan.”

A new discovery explains what determines the number and position of genetic exchanges that occur in sex cells, such as pollen and eggs in plants, or sperm and eggs in humans.

When sex cells are produced by a special cell division called meiosis, chromosomes exchange large segments of DNA. This ensures that each new cell has a unique genetic makeup and explains why, with the exception of identical twins, no two siblings are ever completely genetically alike. These exchanges of DNA, or crossovers, are essential for generating genetic diversity, the driving force for evolution, and their frequency and position along chromosomes are tightly controlled.

Co-first author of the study Dr. Chris Morgan explains the significance of this phenomenon: “Crossover positioning has important implications for evolution, fertility and selective breeding. By understanding the mechanisms that drive crossover positioning we are more likely to be able to uncover methods to modify crossover positioning to improve current plant and animal breeding technologies.”

In the latest of ongoing efforts to expand technologies for modifying genes and their expression, researchers have developed chemically modified guide RNAs for a CRISPR system that targets RNA instead of DNA. These chemically-modified guide RNAs significantly enhance the ability to target — trace, edit, and/or knockdown — RNA in human cells.

In a study published today in Cell Chemical Biology, the team explores a range of different RNA modifications and details how the modified guides increase efficiencies of CRISPR activity from 2-to 5-fold over unmodified guides. They also show that the optimized chemical modifications extend CRISPR targeting activity from 48 hours to four days. The researchers worked in collaboration with scientists at Synthego Corporation and New England BioLabs, bringing together a diverse team with expertise in enzyme purification and RNA chemistry. To apply these optimized chemical modifications, the research team targeted cell surface receptors in human T cells from healthy donors and a “universal” segment of the genetic sequence shared by all known variants of the RNA virus SARS-COV-2, which is responsible for the COVID-19 pandemic.

Increasing the efficiencies and “life” of CRISPR-Cas13 guides is of critical value to researchers and drug developers, allowing for better gene knockdown and more time to study how the gene influences other genes in related pathways.

“CRISPR RNA guide delivery can be challenging, with knockdown time limited due to rapid guide degradation. We were inspired by the guide modifications developed for other DNA-targeting CRISPRs and wanted to test if chemically modified guides could improve knockdown time for RNA-targeting CRISPR-Cas13 in human cells,” says Alejandro Méndez-Mancilla, PhD, a postdoctoral scientist in the lab and co-first author of the study.

Last week, a young woman with sickle cell anemia became the first person in the United States to have her cells altered with CRISPR gene editing technology. Here’s what that means for the future treatment of genetic diseases.

The longest-lived leaves in the plant kingdom can be found only in the harsh, hyperarid desert that crosses the boundary between southern Angola and northern Namibia. A desert is not, of course, the most hospitable place for living things to grow, let alone leafy greens, but the Namib Desert — the world’s oldest, with parts receiving less than 2 inches of precipitation a year — is where Welwitschia calls home. Sign up for The Morning newsletter from the New York Times In Afrikaans, the plant is.

“Balancing that, I clearly state that my goal is not longevity, not even modest longevity. It’s just reversal of diseases of aging, which really is classic medicine. Q: Which takes me to the next question: do we even know how to aim at life extension? I don’t think we do. I think if we get serious aging reversal, it’s something that we can continue to improve on, just like we improved on transportation from the first wheel to rocket ships,” I’ll be honest, I disagree as we have some improvement in humans indicated from TRIM and TAME and plasma filtering. Church’s work is very important though.

Professor of Genetics at Harvard Medical School and one of the most prominent geroscientists, George Church works on gene therapies that can potentially reverse age-related diseases. We had the opportunity to interview this prolific researcher and entrepreneur, who is involved in dozens of startups on topics ranging from the current state of gene therapy to his recent attempt to auction off his genome, one of the first sequenced human genomes in the world, as an NFT.

What have been the successes and the failures of gene therapy in recent years? What do you expect to happen in the next few years?

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“Our study raises the possibility of using therapeutic drugs, gene editing, or other strategies to make epigenetic modifications that tap into the latent regenerative capacity of inner ear cells as a way to restore hearing,” said Segil. “Similar epigenetic modifications may also prove useful in other non-regenerating tissues, such as the retina, kidney, lung, and heart.”

Scientists from the USC Stem Cell laboratory of Neil Segil have identified a natural barrier to the regeneration of the inner ear’s sensory cells, which are lost in hearing and balance disorders. Overcoming this barrier may be a first step in returning inner ear cells to a newborn-like state that’s primed for regeneration, as described in a new study published in Developmental Cell.

“Permanent hearing loss affects more than 60 percent of the population that reaches retirement age,” said Segil, who is a Professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology – Head and Neck Surgery. “Our study suggests new gene engineering approaches that could be used to channel some of the same regenerative capability present in embryonic inner ear cells.”

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