Imagine being able to have your genes edited to eradicate errors and to greatly lengthen quality of life and life span. There are some people that are still active and independent at the age of 100 and live well beyond that. Generally those people also had long lived parents. What if the same genetic traits they inherited and more could be given to anyone?

Researchers at the Joint Institute of Metrology and Biology (JIMB) have recently developed MAGESTIC, a new CRISPR platform that is similar to a word processor which makes gene editing using barcodes. CRISPR which snips at DNA has been a clumsy tool making precision medicine or ?clipping? disease causing genetic mutations in patients virtually impossible. MAGESTIC or ?multiplexed accurate genome editing with short, trackable, integrated cellular barcodes? is being compared to a word processer that enables efficient search and replace functions for genetic material. This new platform was also able to produce an increase of sevenfold in survival of cells during the process of editing.

Previously, CRISPR required a very extensive understanding of how repair cuts with cells at a variety of sites across the genome could be controlled as needed. Because DNA strands are able to rejoin in very unpredictable ways, random mutations are likely to occur at the cut sites in the DNA of the cells. Additionally, many cells will not survive the process of editing at all. It has been extremely challenging building very accurate predictions of gene editing. Researchers want a more reliable way for programming CRISPR to be able to cut at targeted locations in the genome and then be able to direct cells for designed edits at the cut sites of the DNA. This can be accomplished by providing a donor DNA for the cell which the cell?s DNA repair machinery is able to use as a template for replacing the original sequence at the original cut site. However, the cell?s DNA repair system is complex and will not always behave predictably.

The cell searching for a DNA donor suitable for repairing a cut site is a huge challenge for the cell. The repair machinery of the DNA has to search through millions and even billions of DNA base pair sequences to be able to find the correct donor DNA. MAGESTIC has provided a significant advance in gene-editing technology by helping the cell search by artificially recruiting the DNA designed donor through a process called active donor recruitment which will recruit the donor DNA right to the cut site. This recruitment resulted in a sevenfold increase in the cell?s survival which was a change that resulted in increased effectiveness and efficiency.

The other feature that was different from CRISPR, was MAGESTIC?S new version of cellular barcode. Previously, researchers used small bits of circular DNA also known as plasmids to guide DNAs and to store barcodes for tracking designed mutations to each cell. The plasmids will multiply with cell growth and are inherited by both cells following cell division. With MAGESTIC the barcodes are integrated into chromosomes as opposed to single barcode per item correspondence which can vary widely in number resulting in 10 to 40 appearing in every cell.

Scientists do not know much about the function of the 0.l% of code that will vary between individuals in any population and is responsible for differences in susceptibility of disease. MAGESTIC helps to address the gap in understanding natural genetic variation through enabling individual genetic variant to be edited very precisely and compared to other genetic variants one by one. This results in help in uncovering which genetic differences will have cellular impact function. MAGESTIC will also edit all at one time in just a single test tube with every edit happening in any one of a million otherwise cells that are identical.

The researchers have reached a state where they have achieved sequencing the order of genome base pairs and are also able to change them. Additional research is needed to understand the edit sequencing.

To view the original scientific study click here: Multiplexed precision genome editing with trackable genomic barcodes in yeast

A study published in Nature Genetics and led by scientists at Van Andel Research Institute (VARI) and Cedars Sinai, have developed a new computational, straightforward method to measure cellular age. The findings may lead to simpler, better screening and a way to measure the success of anti-aging therapies.

The findings reveal a measurable, progressive loss of specific chemical tags that regulate gene activity and can be detected at the earliest stays of development. These changes will continue throughout a person?s life and will correlate with cellular rather than chronological age.

The study builds on a 2011 long time collaboration and discovery by Benjamin Berman, Ph. D. of Cedars-Sinai and Peter Laird, Ph.D. and Hui Shen, Ph.D. of VARI. The 2011 discovery first determined loss of these DNA marks (called methyl groups) occurs in specific areas of the genome. However, at the time the techniques used could not detect this process occurring in normal cells. Our cellular clock begins ticking the moment our cells start dividing. This method allowed the researchers to track the history of the past divisions and measure age-related changes to the genetic code that may contribute to both dysfunction and normal aging.

Every cell in the nearly 40 trillion cells in the human body can trace its lineage back to a single, fertilized egg cell which contains the original copy of a person?s DNA. Throughout a person?s lifetime, the cells divide and replace damaged or old cells at different rates based on factors such as their function in the body, would healing and environmental insults.

Even though undergoing elaborate biological quality control checks, each cell division chips away at the genome?s integrity which leaves behind an accumulating number of changes. Principal among these is a dramatic shift in the location and number of methyl groups on the genome which is part of a process that begins during fetal development and continues through a lifetime.

What the researchers found striking about the results from their new method is that they push back the start of that process to the earliest stages of in utero development. Until recently mechanisms behind loss of DNA methyl groups (known as hypomethylation) have largely been unknown. It appears to be more profound in tissues with a high turnover rate such as skin and the epithelium. Typically, tissues with high turnover rates are more susceptible because there are more chances for errors to accumulate. What is being seen is a normal process of cellular aging.

The research project encompassed more than 200 mouse datasets and 340 human datasets the most in-depth study of its kind. The study would not have been possible without massive swaths of accessible data from large-scale sequencing projects.

Reference: Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen, Peter W. Laird, Benjamin P. Berman. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nature Genetics, 2018; DOI: 10.1038/s41588-018-0073-4

Researchers have identified a previously unknown feature of human anatomy with implications for the function of all organs, most tissues and the mechanisms of most major diseases.

Published March 27 in Scientific Reports, a new study co-led by an NYU School of Medicine pathologist reveals that layers of the body long thought to be dense, connective tissues below the skin’s surface, lining the digestive tract, lungs and urinary systems, and surrounding arteries, veins, and the fascia between muscles are instead interconnected, fluid-filled compartments.

This series of spaces, supported by a meshwork of strong (collagen) and flexible (elastin) connective tissue proteins, may act like shock absorbers that keep tissues from tearing as organs, muscles, and vessels squeeze, pump, and pulse as part of daily function.

Importantly, the finding that this layer is a highway of moving fluid may explain why cancer that invades it becomes much more likely to spread. Draining into the lymphatic system, the newfound network is the source of lymph, the fluid vital to the functioning of immune cells that generate inflammation. Furthermore, the cells that reside in the space, and collagen bundles they line, change with age, and may contribute to the wrinkling of skin, the stiffening of limbs, and the progression of fibrotic, sclerotic and inflammatory diseases.

The field has long known that more than half the fluid in the body resides within cells, and about a seventh inside the heart, blood vessels, lymph nodes, and lymph vessels. The remaining fluid is “interstitial,” and the current study is the first to define the interstitium as an organ in its own right, and as one of the largest of the body, say the authors.

The researchers say that no one saw these spaces before because of the medical field’s dependence on the examination of fixed tissue on microscope slides, believed to offer the most accurate view of biological reality. Scientists prepare tissue this examination by treating it with chemicals, slicing it thinly, and dying it to highlight key features. The “fixing” process makes vivid details of cells and structures, but drains away any fluid. The current research team found that the removal of fluid as slides are made causes the connective protein meshwork surrounding once fluid-filled compartments to pancake, like the floors of a collapsed building.

“This fixation artifact of collapse has made a fluid-filled tissue type throughout the body appear solid in biopsy slides for decades, and our results correct for this to expand the anatomy of most tissues,” says co-senior author Neil Theise, MD, professor in the Department of Pathology at NYU Langone Health. “This finding has potential to drive dramatic advances in medicine, including the possibility that the direct sampling of interstitial fluid may become a powerful diagnostic tool.”

The study findings are based on newer technology called probe-based confocal laser endomicroscopy, which combines the slender camera-toting probe traditionally snaked down the throat to view the insides of organs (an endoscope) with a laser that lights up tissues, and sensors that analyze the reflected fluorescent patterns. It offers a microscopic view of living tissues instead of fixed ones.

Using this technology in the fall of 2015 at Beth Israel Medical Center, endoscopists and study co-authors David Carr-Locke, MD, and Petros Benias, MD, saw something strange while probing a patient’s bile duct for cancer spread. It was a series of interconnected cavities in this submucosal tissue level that not match any known anatomy.

Faced with a mystery, the endoscopists walked the images into the office of their partnering pathologist in Theise. Strangely, when Theise made biopsy slides out of the same tissue, the reticular pattern found by endomicroscopy disappeared. The team would later confirm that very thin spaces seen in biopsy slides, traditionally dismissed as tears in the tissue, were instead the remnants of collapsed, previously fluid-filled compartments.

For the current study, the team collected tissue specimens of bile ducts during twelve cancer surgeries that were removing the pancreas and the bile duct. Minutes prior to clamping off blood flow to the target tissue, patients underwent confocal microscopy for live tissue imaging.

Once the team recognized this new space in images of bile ducts, they quickly recognized it throughout the body, wherever tissues moved or were compressed by force. The cells lining the space are also unusual, perhaps responsible for creating the supporting collagen bundles around them, say the authors. The cells may also be mesenchymal stem cells, says Theise, which are known to be capable of contributing to the formation of scar tissue seen in inflammatory diseases. Lastly, the protein bundles seen in the space are likely to generate electrical current as they bend with the movements of organs and muscles, and may play a role in techniques like acupuncture, he says.

Reference: Petros C. Benias, Rebecca G. Wells, Bridget Sackey-Aboagye, Heather Klavan, Jason Reidy, Darren Buonocore, Markus Miranda, Susan Kornacki, Michael Wayne, David L. Carr-Locke, Neil D. Theise. Structure and Distribution of an Unrecognized Interstitium in Human Tissues. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-23062-6