Tag Archives: cells

How To Protect Cells From Premature Aging

Molecules that accumulate at the tip of chromosomes are known to play a key role in preventing damage to our DNA. Now, researchers at EPFL (Ecole Polytechnique Fédérale de Lausanne in Switzerland) have unraveled how these molecules home in on specific sections of chromosomes—a finding that could help to better understand the processes that regulate cell survival in aging and cancer.

Much like an aglet of a shoelace prevents the end of the lace from fraying, stretches of DNA called telomeres form protective caps at the ends of chromosomes. But as cells divide, telomeres become shorter, making the protective cap less effective. Once telomeres get too short, the cell stops dividing. Telomere shortening and malfunction have been linked to cell aging and age-related diseases, including cancer.

A new study by EPFL researchers shows how RNA species called TERRA muster at the tip of chromosomes, where they help to prevent telomere shortening and premature cell aging

Scientists have known that RNA species called TERRA help to regulate the length and function of telomeres. Discovered in 2007 by postdoc Claus Azzalin in the team of EPFL Professor Joachim Lingner, TERRA belongs to a class of molecules called noncoding RNAs, which are not translated into proteins but function as structural components of chromosomes. TERRA accumulates at chromosome ends, signaling that telomeres should be elongated or repaired.

However, it was unclear how TERRA got to the tip of chromosomes and remained there. “The telomere makes up only a tiny bit of the total chromosomal DNA, so the question is ‘how does this RNA find its home?’”, Lingner says. To address this question, postdoc Marianna Feretzaki and others in the teams of Joachim Lingner at EPFL and Lumir Krejci at Masaryk University set out to analyze the mechanism through which TERRA accumulates at telomeres, as well as the proteins involved in this process. The findings are published in Nature.

By visualizing TERRA molecules under a microscope, the researchers found that a short stretch of the RNA is crucial to bring it to telomeres. Further experiments showed that once TERRA reaches the tip of chromosomes, several proteins regulate its association with telomeres. Among these proteins, one called RAD51 plays a particularly important role, Lingner says.

RAD51 is a well-known enzyme that is involved in the repair of broken DNA molecules. The protein also seems to help TERRA stick to telomeric DNA to form a so-called “RNA-DNA hybrid molecule”. Scientists thought this type of reaction, which leads to the formation of a three-stranded nucleic acid structure, mainly happened during DNA repair. The new study shows that it can also happen at chromosome ends when TERRA binds to telomeres. “This is paradigm-shifting,” Lingner says.

The researchers also found that short telomeres recruit TERRA much more efficiently than long telomeres. Although the mechanism behind this phenomenon is unclear, the researchers hypothesize that when telomeres get too short, either due to DNA damage or because the cell has divided too many times, they recruit TERRA molecules. This recruitment is mediated by RAD51, which also promotes the elongation and repair of telomeres. “TERRA and RAD51 help to prevent accidental loss or shortening of telomeres,” Lingner says. “That’s an important function.”

Source: https://actu.epfl.ch/

Nobel Chemistry Prize Awarded For CRISPR ‘NanoScissors’

A humbling lesson of science is that, even when it comes to many of humanity’s most brilliant inventions, nature got there first. The 2020 selection for the Nobel Prize in Chemistry goes to two scientists who share credit for identifying and developing a revolutionary method of genome editing — one that has allowed researchers to modify and investigate the genomes of microbial, plant and animal cells with an ease, precision and effectiveness that would have been unfathomable even a decade ago. Yet the technology that came out of their work, revolutionary as it is, springs from an innovation that first evolved in bacteria, probably more than a billion years ago, and went unnoticed until recently.

Emmanuelle Charpentier (right) and Jennifer Doudna (left) have been awarded the 2020 Nobel Prize in Chemistry for their development of CRISPR/Cas9 genetic editing.

Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens Institute for Infection Biology and Jennifer Doudna of the University of California, Berkeley have been recognized for their work on CRISPR/Cas9 genome editing — a technique routinely called CRISPR for short and often referred to as “genetic scissors.” This award marks the first time that two women have been award a Nobel Prize for science.

In a seminal 2012 paper, Charpentier and Doudna showed that key components of the ancient immune system found in bacteria and archaea could be retooled to edit DNA, to essentially “rewrite the code of life,” as the Nobel committee put it this morning.

In the eight years since, the discovery has transformed the life sciences, making genome editing commonplace in laboratories around the world. It has enabled researchers to probe the functions of genes at will, pushing the field of molecular biology ahead by leaps and bounds; to innovate new methods of plant breeding; and to develop promising new gene therapies, some now in clinical trials, for conditions such as sickle cell disease.

The Nobel committee’s selection will undoubtedly be greeted as controversial because of well-publicized disputes about the intellectual property associated with CRISPR. Virginijus Šikšnys of Vilnius University in Lithuania independently developed the idea of using these genetic features of bacteria as a genome-editing tool at about the same time as Charpentier and Doudna, and he has sometimes been honored alongside them. Two other scientists, Feng Zhang of the Massachusetts Institute of Technology and George Church of Harvard University, are also often credited as early co-discoverers and developers of CRISPR technology, and their exclusion will fuel arguments. However, no one in the scientific community would dispute that Charpentier and Doudna’s work laid the foundation for CRISPR’s prolific and game-changing use today.

Source: https://www.quantamagazine.org/

Secure Nano-Carrier Delivers Medications Directly To Cells

Medications often have unwanted side-effects. One reason is that they reach not only the unhealthy cells for which they are intended, but also reach and have an impact on healthy cells. Researchers at the Technical University of Munich (TUM), working together with the KTH Royal Institute of Technology in Stockholm, have developed a stable nano-carrier for medications. A special mechanism makes sure the drugs are only released in diseased cells.

The human body is made up of billions of cells. In the case of cancer, the genome of several of these cells is changed pathologically so that the cells divide in an uncontrolled manner. The cause of virus infections is also found within the affected cells. During chemotherapy for example, drugs are used to try to destroy these cells. However, the therapy impacts the entire body, damaging healthy cells as well and resulting in side effects which are sometimes quite serious.

A team of researchers led by Prof. Oliver Lieleg, Professor of Biomechanics and a member of the TUM Munich School of BioEngineering, and Prof. Thomas Crouzier of the KTH has developed a transport system which releases the active agents of medications in affected cells only.

The drug carriers are accepted by all the cells,” Lieleg explains. “But only the diseased cells should be able to trigger the release of the active agent.”

The scientists have now shown that the mechanism functions in tumor model systems based on cell cultures. First they packaged the active ingredients. For this purpose, they used so-called mucins, the main ingredient of the mucus found for example on the mucus membranes of the mouth, stomach and intestines. Mucins consist of a protein background to which sugar molecules are docked. “Since mucins occur naturally in the body, opened mucin particles can later be broken down by the cells,” Lieleg says.

Another important part of the package also occurs naturally in the body: deoxyribonucleic acid (DNA), the carrier of our genetic information. The researchers synthetically created DNA structures with the properties they desired and chemically bonded these structures to the mucins. If glycerol is now added to the solution containing the mucin DNA molecules and the active ingredient, the solubility of the mucins decreases, they fold up and enclose the active agent. The DNA strands bond to one another and thus stabilize the structure so that the mucins can no longer unfold themselves.

The DNA-stabilized particles can only be opened by the rightkey” in order to once again release the encapsulated active agent molecules. Here the researchers use what are called microRNA molecules. RNA or ribonucleic acid has a structure very similar to that of DNA and plays a major role in the body’s synthesis of proteins; it can also regulate other cell processes.

Cancer cells contain microRNA strands whose structure we know precisely,” explains Ceren Kimna, lead author of the study. “In order to use them as keys, we modified the lock accordingly by meticulously designing the synthetic DNA strands which stabilize our medication carrier particles.” The DNA strands are structured in such a way that the microRNA can bind to them and as a result break down the existing bonds which are stabilizing the structure. The synthetic DNA strands in the particles can also be adapted to microRNA structures which occur with other diseases such as diabetes or hepatitis.

Source: https://www.tum.de/

Why RNA Is A Better Measure Of A Patient’s Current Health Than DNA

By harnessing the combined power of NGS, machine learning and the dynamic nature of RNA we’re able to accurately measure the dynamic immune response and capture a more comprehensive picture of what’s happening at the site of the solid tumor. In the beginning, there was RNA – the first genetic molecule.

In the primordial soup of chemicals that represented the beginning of life, ribonucleic acid (RNA) had the early job of storing information, likely with the support of peptides. Today, RNA’s cousin – deoxyribonucleic acid – or DNA, has taken over most of the responsibilities of passing down genetic information from cell-to-cell, generation-to-generation. As a result, most early health technologies were developed to analyze DNA. But, RNA is a powerful force. And its role in storing information, while different from its early years, has no less of an impact on human health and is gaining more mindshare in our industry.

RNA is often considered a messenger molecule, taking the information coded in our DNA and transcribing it into cellular directives that result in downstream biological signals and proteinslevel changes.  And for this reason, RNA is becoming known not only as a drug target but perhaps more importantly, as a barometer of health.

3d illustration of a part of RNA chain from which the deoxyribonucleic acid or DNA is composed

How and why is RNA so useful? First, RNA is labile — changing in both sequence and abundance in response to genetic and epigenetic changes, but also external factors such as disease, therapy, exercise, and more. This is in contrast to DNA, which is generally static, changing little after conception.

Next, RNA is a more accurate snapshot of disease progression. When mutations do occur at the DNA level, these do not always result in downstream biological changes. Often, the body is able to compensate by repairing the mutation or overcome it by using redundancies in the pathway in which the gene resides. By instead evaluating RNA, we get one step closer to understanding the real impact disease is imparting on our body.

Finally, RNA is abundant. In most human cells, while only two copies of DNA are present, hundreds of thousands of mRNA molecules are present,representing more than 10,000 different species of RNA. Because even rare transcripts are present in multiple copies, biological signals can be confidently detected in RNA when the right technology is used.

Source: https://medcitynews.com/

3D Mapping of Coronavirus Genome

The novel coronavirus uses structures within its RNA to infect cells. Scientists have now identified these configurations, generating the most comprehensive atlas to date of SARS-CoV-2’s genome. Although contained in a long, noodle-like molecule, the new coronavirus’s genome looks nothing like wet spaghetti. Instead, it folds into stems, coils, and cloverleafs that evoke molecular origami.

A team led by RNA scientist Anna Marie Pyle has now made the most comprehensive map to date of these genomic structures. In two preprints posted in July 2020 to bioRxiv.org, Pyle’s team mapped structures across the entire RNA genome of the coronavirus SARS-CoV-2, using living cells and computational analyses.

SARS-CoV-2 relies on its unique RNA structures to infect people and cause the illness COVID-19. But these structures’ contribution to infection and disease is often underappreciated, even among scientists, says Pyle, a Howard Hughes Medical Institute Investigator at Yale University.

Colorized scanning electron micrograph of a cell (blue) heavily infected with SARS-CoV-2 virus particles (red), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland

The general wisdom is that if we just focus on the proteins encoded in the virus’s genome, we’ll understand how SARS-CoV-2 works,” Pyle says. “But for these types of viruses, RNA structures in the genome can influence their ability to function as much as encoded proteins.”

Researchers can now begin to tease out just how these structures aid the virus—information that could ultimately lead to new treatments for COVID-19. Once scientists have identified RNA structures that carry out key tasks, for instance, it may be possible to devise ways to disrupt them—and interfere with infection.

Source: https://www.hhmi.org/
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https://phys.org/

How To Stimulate Broken Bone Cells To Heal Much More Quickly

It was just a couple of months ago that we heard about an implantable material that electrically stimulates bone cells, causing them to reproduce. Now, scientists have created a similar substance that utilizes magnetism. There are already a number of experimental materials that have a three-dimensional scaffolding-like microstructure, which simulates the structure of natural bone. After a piece of such a material has been implanted at a bone wound site, cells from the body’s adjacent bone tissue gradually migrate into it. Those cells reproduce over time, while the scaffolding simultaneously dissolves. Eventually, all that’s left is newly-grown bone, in the shape and location of the implant.

One of the challenges of the technology involves getting the bone cells to migrate and reproduce quickly. Although growth-boosting chemicals are often added to the material, scientists at the University of Connecticut took another approach with a scaffolding that they announced this June – it generates a weak electrical field in response to externally applied ultrasound pulses, and that field in turn prompts the bone cells to reproduce.

More recently, though, a team at Spain’s University of the Basque Country developed a material that instead incorporates magnetic nanoparticles. These are dispersed within a 3D matrix of a biocompatible silk-derived protein known as fibroin.

When we apply a magnetic field, we bring about a response by these nanoparticles, which vibrate and thus deform the structure, they stretch it and transmit the mechanical stress to the cells,” says the lead scientist, Dr. José Luis Vilas-Vilela. In in vitro lab tests, that stress stimulated bone cells to reproduce much more quickly than would have otherwise been the case. In fact, the technology could conceivably be used to regrow more than just bone.

We are developing various types of materials, stimuli and processes so that we can have the means to achieve the regeneration of different tissue,” says Vilas-Vilela. “In addition, the idea would be to use the stem cells of the patients themselves and be capable of differentiating them towards the type of cell we want to form the tissue with, be it bone, muscle, heart or whatever might be needed.”

The research – which also involved scientists from Portugal’s University of Minho and biotech firm BCMaterials – is described in a paper that was recently published in the journal Materialia.

Source: https://www.sciencedirect.com/
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https://newatlas.com/

Antibodies + Immunotherapy Result In Complete Elimination Of Tumors

Immunotherapy has revolutionized cancer treatment by stimulating the patient’s own immune system to attack cancer cells, yielding remarkably quick and complete remission in some cases. But such drugs work for less than a quarter of patients because tumors are notoriously adept at evading immune assault.

A new study in mice by researchers at Washington University School of Medicine in St. Louis has shown that the effects of a standard immunotherapy drug can be enhanced by blocking the protein TREM2, resulting in complete elimination of tumors. The findings, which are published in the journal Cell, point to a potential new way to unlock the power of immunotherapy for more cancer patients.

Immune cells infiltrate a human tumor in the four colorized images above. In a mouse study, researchers at Washington University School of Medicine in St. Louis have found that an antibody that targets the protein TREM2 empowers tumor-destroying immune cells and improves the effectiveness of cancer immunotherapy.

Essentially, we have found a new tool to enhance tumor immunotherapy,” said senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “An antibody against TREM2 alone reduces the growth of certain tumors, and when we combine it with an immunotherapy drug, we see total rejection of the tumor. The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we’d be able to move into clinical trials fairly easily because there are already a number of antibodies available.”

T cells, a kind of immune cell, have the ability to detect and destroy tumor cells. To survive, tumors create a suppressive immune environment in and around themselves that keeps T cells subdued. A type of immunotherapy known as checkpoint inhibition wakes T cells from their quiescence so they can begin attacking the tumor. But if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be enough to eliminate the tumor.

An expert on the immune system, Colonna has long studied a protein called TREM2 in the context of Alzheimer’s disease, where it is associated with underperforming immune cells in the brain. Colonna and first author Martina Molgora, PhD, a postdoctoral researcher, realized that the same kind of immune cells, known as macrophages, also were found in tumors, where they produce TREM2 and promote an environment that suppresses the activity of T cells.

When we looked at where TREM2 is found in the body, we found that it is expressed at high levels inside the tumor and not outside of the tumor,” Colonna said. “So it’s actually an ideal target, because if you engage TREM2, you’ll have little effect on peripheral tissue.”

Colonna and Molgora — along with colleagues Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor; and William Vermi, MD, an immunologist at the University of Brescia — set out to determine whether inhibiting TREM2 could reduce immunosuppression and boost the tumor-killing powers of T cells. As part of this study, the researchers injected cancerous cells into mice to induce the development of a sarcoma.

The mice were divided into four groups. In one group, the mice received an antibody that blocked TREM2; in another group, a checkpoint inhibitor; in the third group, both; and the fourth group, placebo. In the mice that received only placebo, the sarcomas grew steadily. In the mice that received the TREM2 antibody or the checkpoint inhibitor alone, the tumors grew more slowly and plateaued or, in a few cases, disappeared. But all of the mice that received both antibodies rejected the tumors completely. The researchers repeated the experiment using a colorectal cancer cell line with similarly impressive results.

Source: https://medicine.wustl.edu/

Nanotubes In the Eye That Help Us See

Researchers  find a new structure by which cells in the retina communicate with each other, regulating blood supply to keep vision intact. A new mechanism of blood redistribution that is essential for the proper functioning of the adult retina has just been discovered in vivo by researchers at the University of Montreal Hospital Research Centre (CRCHUM).

For the first time, we have identified a communication structure between cells that is required to coordinate blood supply in the living retina,” said Dr. Adriana Di Polo, a neuroscience professor at Université de Montréal and holder of a Canada Research Chair in glaucoma and age-related neurodegeneration, who supervised the study.

We already knew that activated retinal areas receive more blood than non-activated ones,” she said, “but until now no one understood how this essential blood delivery was finely regulated.”

The study was conducted on mice by two members of Di Polo’s lab: Dr. Luis Alarcon-Martinez, a postdoctoral fellow, and Deborah Villafranca-Baughman, a PhD student. Both are the first co-authors of this study.

In living animals, as in humans, the retina uses the oxygen and nutrients contained in the blood to fully function. This vital exchange takes place through capillaries, the thinnest blood vessels in all organs of the body. When the blood supply is dramatically reduced or cut off—such as in ischemia or stroke—the retina does not receive the oxygen it needs. In this condition, the cells begin to die and the retina stops working as it should.

The study has been published in Nature.

https://www.chumontreal.qc.ca/

New NanoDrug Kills Aggressive Breast Cancer Cells

Researchers at the University of Arkansas have developed a new nano drug candidate that kills triple negative breast cancer cells.

Triple negative breast cancer is one of the most aggressive and fatal types of breast cancer. The research will help clinicians target breast cancer cells directly, while avoiding the adverse, toxic side effects of chemotherapy.

Researchers led by Hassan Beyzavi, assistant professor in the Department of Chemistry and Biochemistry, linked a new class of nanomaterials, called metal-organic frameworks, with the ligands of an already-developed photodynamic therapy drug to create a nano-porous material that targets and kills tumor cells without creating toxicity for normal cells.

Metal-organic frameworks are an emerging class of nanomaterials designed for targeted drug delivery. Ligands are molecules that bind to other molecules.

With the exception of skin cancers, breast cancer is the most common form of cancer in American women,” said Beyzavi. “As we know, thousands of women die from breast cancer each year. Patients with triple negative cells are especially vulnerable, because of the toxic side effects of the only approved treatment for this type of cancer. We’ve addressed this problem by developing a co-formulation that targets cancer cells and has no effect on healthy cells.”

Researchers in Beyzavi’s laboratory focus on developing new, targeted photodynamic therapy drugs. As an alternative to chemotherapy – and with significantly fewer side effectstargeted photodynamic therapy, or PDT, is a noninvasive approach that relies on a photosensitizer that, upon irradiation by light, generates so-called toxic reactive oxygen species, which kill cancer cells. In recent years, PDT has garnered attention because of its ability to treat tumors without surgery, chemotherapy or radiation.

The study was published in June issue of Advanced Therapeutics.

Source: https://news.uark.edu/

Key Protein Behind Cancer Progression Can Be Reversed

Reports show that cancer is the second-highest leading cause of death globally, with the possibility that every one in four to five people in Singapore may develop cancer in their lifetime. A recent study by scientists from Duke-NUS Medical School provides new evidence supporting the presence of a key mechanism behind progression and relapse in cancer. The study, published in Proceedings of the National Academy of Sciences (PNAS), discusses the role of MBNL1 protein as a biomarker for cancer prognosis, which can lead to the development of new treatment strategies for cancer.

Cancer cases have been rising over the years and according to the statistics, the number of people living with cancer will continue to increase. Despite decades of research, cancer treatments are still inefficient and have unacceptable side effects that continue to prompt an urgent need for new approaches to prevention and treatment. Uncovering novel mechanisms associated with cancer would fill current knowledge gaps and help meet this need.

We discovered a mechanism involving MBNL1 protein that predicts several characteristics of cancer such as progression and relapse,” said Dr Debleena Ray, Senior Research Fellow at Duke-NUSCancer and Stem Cell Biology (CSCB) programme, the lead author of this study. ”We found that MBNL1 protein is present in low amounts in many of the common cancers in the world, including breast, colorectal, stomach, lung and prostate cancers, which when combined account for about 49 per cent of all cancers diagnosed in 2018. This can cause poor overall survival in many of these commonly-occurring cancers.”

The team also found that this mechanism can be reversed by blocking the JNK protein, a well-known target in cancer treatment, in cancer cells with low levels of MBNL1.

While JNK inhibitors have been tested as a cancer drug previously, currently there are no clinical trials for the same. However, if in the future there is a JNK inhibitor against cancer, MBNL1 could be used as a biomarker to select patients for the treatment,” said Adjunct Associate Professor David Epstein at the Duke-NUSCSCB programme and the co-corresponding author of this study.

Cancer is a global health challenge and Singapore is no exception. This study provides important information about novel targets and biomarkers that are implicated in several major cancers, which could lead to the development of new treatment strategies that can improve the lives of patients,” said Prof Patrick Casey, Senior Vice Dean for Research at Duke-NUS.

Over the next year, the team will be investigating the role of MBNL1 in colorectal cancer and exploring the potential of anti-JNK therapeutic for cancer using antisense technology, a tool that is used for the inhibition of gene expression.

 

Reference: Debleena Ray, Yu Chye Yun, Muhammad Idris, Shanshan Cheng, Arnoud Boot, Tan Bee Huat Iain, Steven G. Rozen, Patrick Tan and David M. Epstein (2020). A tumor associated splice-isoform of MAP2K7 drives de- differentiation in MBNL1-low cancers via JNK activation. PNAS. Complete research paper available at this link: https://www.pnas.org/content/early/2020/06/25/2002499117

Source: Duke-NUS