Tag Archives: DNA

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/

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/

All of Human Knowledge in a Tablespoon of DNA

A tiny strand of DNA has an amazing ability to store some pretty big data. In fact, researchers estimate that all of the world’s digital data could fit into just 20 grams (a little more than a tablespoon) of DNA.

Every time we do anything on the internet, such as upload a photo or send an email, we generate data — which means we generate a lot of data. Most of our data is stored in the “cloud” — which really just means massive data centers around the worldLast year, all of Wikipedia was stored in a few strands of DNA.

However, these centers take up a lot of space, are costly to maintain, and account for nearly 2% of U.S. energy consumption. Plus, we’re going to keep generating more and more.) data, and existing centers won’t be able to store it all. We’ll either need to start discarding a bunch of potentially useful information, or we’ll need to think smaller and figure out how to store more information in less space.

Information in DNA is consistently sequenced, synthesized, copied, and stored… just like the information on your phone or computer’s hard drive. However, when it comes to storage, DNA has some considerable advantages. Aside from being extremely dense, it’s also extremely durable: it can survive passively for millennia. We were able to decode information from the DNA found in the 5,300-year-old corpse of Otzi the Iceman.

That’s clearly not the case with silicon microchips or magnetic tape, which tend to degrade and need replacing every few years. Last year, researchers announced that they had stored the English-version of Wikipedia (yes, all of it!) into a few strands of DNA. This year, we’ve used DNA to store the Wizard of Oz and an episode of Biohackers (a Netflix series). There’ve also been other random works of art saved, too: War and Peace, Shakespeare sonnets, and an OK Go music video.

While you and I won’t be buying synthetic DNA hard drives, considerable efforts are underway to make this a viable storage system for those who need to store a bunch of important, but rarely accessed, archival data (i.e., governments and big corporations). Researchers expect that more consumer-friendly options are at least a decade away.

In order to retrieve the information, you’ll need a DNA sequencing machine (the same machines used for sequencing human genomes), and that’s one of the hurdles to making this a household technology. As CNET points out, one of the machines “would fit easily in your house if you first got rid of your refrigerator, oven and some counter space.”

Another hurdle is the time it takes to retrieve the information. Last year, it took 21 hours to retrieve the word “Hello” (roughly 5 bytes of data) from DNA. If we’re going to use DNA as a storage system, we’ll have to make it many orders of magnitude faster.

Source: https://www.freethink.com/

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/

Scientists Successfully Stored ‘Wizard of Oz’ Into DNA

A team of interdisciplinary researchers has discovered a new technique to store information in DNA – in this case “The Wizard of Oz, translated into Esperanto – with unprecedented accuracy and efficiency. The technique harnesses the information-storage capacity of intertwined strands of DNA to encode and retrieve information in a way that is both durable and compact The technique is described in a paper in this week’s Proceedings of the National Academy of Sciences

The key breakthrough is  an encoding algorithm that allows accurate retrieval of the information even when the DNA strands are partially damaged during storage,” said Ilya Finkelstein, an associate professor of molecular biosciences and one of the authors of the study. 

Humans are creating information at exponentially higher rates than we used to, contributing to the need for a way to store more information efficiently and in a way that will last a long time. Companies such as Google and Microsoft are among those exploring using DNA to store information 

We need a way to store this data so that it is available when and where it’s needed in a format that will be readable,” said Stephen Jones, a research scientist who collaborated on the project with Finkelstein; Bill Press, a professor jointly appointed in computer science and integrative biology; and Ph.D. alumnus John Hawkins. “This idea takes advantage of what biology has been doing for billions of years: storing lots of information in a very small space that lasts a long time. DNA doesn’t take up much space, it can be stored at room temperature, and it can last for hundreds of thousands of years.”  

Source: https://news.utexas.edu/

New Cancer Drug Halts Tumour Growth

A drug that could stop cancer cells repairing themselves has shown early signs of working. More than half of the 40 patients given berzosertib had the growth of their tumours halted. Berzosertib was even more effective when given alongside chemotherapy, the trial run by the Institute of Cancer Research (ICR) and the Royal Marsden NHS Trust in UK suggested. The trial was designed to test the safety of the drug. The drug is the first to be trialled of a new family of treatments, which block a protein involved in DNA repairBlocking this protein prevents cancers from mending damage to their cells. It’s part of a branch of treatment known as “precision medicine“, which targets specific genes or genetic changes.

The study involved patients with very advanced tumours, for whom no other treatment had worked. This was what is known as a “phase onetrial, which is only designed to test the safety of a treatment. But the ICR said the researchers did find some early indications that berzosertib could stop tumours growing. One of the study’s authors, Prof Chris Lord, a professor of cancer genomics at the ICR, said these early signs were “very promising”, adding that it was unusual in phase one trials to see a clinical response. Further trials will be needed to demonstrate the drug’s effectiveness, though.

This study involved only small numbers of patients…Therefore, it is too early to consider berzosertib a game changer in cancer treatment,” said Dr Darius Widera at the University of Reading. “Nevertheless, the unusually strong effects of berzosertib, especially in combination with conventional chemotherapy, give reasons to be optimistic regarding the outcomes of follow-up studies.”

One patient in the trial, with advanced bowel cancer, had his tumours completely disappear after treatment with berzosertib, and has remained cancer-free for two years. Another, whose ovarian cancer returned following a different course of treatment, saw her tumours shrink after combination treatment with the drug and chemotherapyChemotherapy works by damaging cancer cells’ DNA, so using it in conjunction with this new treatment, which stops the cells from repairing themselves, appears to give an even greater benefit. And berzosertib is able to target tumour cells without affecting other healthy cells, Prof Lord said.

Our new clinical trial is the first to test the safety of a brand-new family of targeted cancer drugs in people, and it’s encouraging to see some clinical responses even in at this early stage,” said Professor Johann de Bono, head of drug development at the ICR and the Royal Marsden.

Source: https://www.bbc.com/

Breakthrough Against COVID-19

A team of scientists from Stanford University is working with researchers at the Molecular Foundry, a nanoscience user facility located at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab), to develop a gene-targeting, antiviral agent against COVID-19. Last year, Stanley Qi, an assistant professor in the departments of bioengineering, and chemical and systems biology at Stanford University and his team had begun working on a technique called PAC-MAN – or Prophylactic Antiviral CRISPR in human cells – that uses the gene-editing tool CRISPR to fight influenza.

But that all changed in January, when news of the COVID-19 pandemic emerged. Qi and his team were suddenly confronted with a mysterious new virus for which no one had a clear solution.

Lipitoids, which self-assemble with DNA and RNA, can serve as cellular delivery systems for antiviral therapies that could prevent COVID-19 and other coronavirus infections.

So we thought, ‘Why don’t we try using our PAC-MAN technology to fight it?’” said Qi.

Since late March, Qi and his team have been collaborating with a group led by Michael Connolly, a principal scientific engineering associate in the Biological Nanostructures Facility at Berkeley Lab’s Molecular Foundry, to develop a system that delivers PAC-MAN into the cells of a patient.

Like all CRISPR systems, PAC-MAN is composed of an enzyme – in this case, the virus-killing enzyme Cas13 – and a strand of guide RNA, which commands Cas13 to destroy specific nucleotide sequences in the coronavirus’s genome. By scrambling the virus’s genetic code, PAC-MAN could neutralize the coronavirus and stop it from replicating inside cells.

Qi said that the key challenge to translating PAC-MAN from a molecular tool into an anti-COVID-19 therapy is finding an effective way to deliver it into lung cells. When SARS-CoV-2, the coronavirus that causes COVID-19, invades the lungs, the air sacs in an infected person can become inflamed and fill with fluid, hijacking a patient’s ability to breathe.

But my lab doesn’t work on delivery methods,” he said. So on March 14, they published a preprint of their paper, and even tweeted, in the hopes of catching the eye of a potential collaborator with expertise in cellular delivery techniques. Soon after, they learned of Connolly’s work on synthetic molecules called lipitoids at the Molecular Foundry. Lipitoids are a type of synthetic peptide mimic known as a “peptoid” first discovered 20 years ago by Connolly’s mentor Ron Zuckermann. In the decades since, Connolly and Zuckermann have worked to develop peptoid delivery molecules such as lipitoids. And in collaboration with Molecular Foundry users, they have demonstrated lipitoids’ effectiveness in the delivery of DNA and RNA to a wide variety of cell lines.

Today, researchers studying lipitoids for potential therapeutic applications have shown that these materials are nontoxic to the body and can deliver nucleotides by encapsulating them in tiny nanoparticles just one billionth of a meter wide – the size of a virus. Now Qi hopes to add his CRISPR-based COVID-19 therapy to the Molecular Foundry’s growing body of lipitoid delivery systems.

Source: https://newscenter.lbl.gov/

How To Reverse Cellular Aging Process

Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice. Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.

This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.

One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.

Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Boston Children’s Hospital’s Suneet Agarwal, senior investigator on the new study. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.

Source: https://news.harvard.edu/
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New DNA-based Strategy To Fight Aggressive Cancers

Researchers from the University of Copenhagen have discovered that our cells replicate their DNA much more loosely than previously thought. The new knowledge might be useful for developing novel treatments against aggressive forms of cancers. This was found by inhibiting the essential gene DNA polymerase alpha, or POLA1, which initiates DNA replication during cell division. The discovery gives researchers new insights into DNA replication and may potentially be used for a new type of cancer treatment.

If we are visionaries, I would say that we might be at the birth of a whole new set of molecules that could be used in fighting cancer’, states  Research Leader and Associate Professor Luis Toledo of the Center for Chromosome Stability at the Department of Cellular and Molecular Medicine. ‘Basically, if we turn the finding on its head, this novel strategy aims at exploiting an in-built weakness in cancer cells and make them crash while they divide.

When a cell divides, the double DNA strand is opened lengthwise like a zipper that is unzipped. The new double strands are built at each of the separated strands, so that you gradually end up with two new “zippers”.

Before the new halfs of the zipper are made, a bit of DNA is temporally exposed in single stranded form. This process is required for the new zippers to form. Nevertheless, large amounts of single-stranded DNA have traditionally been considered by researchers to be a sign of pathological stress during cell proliferation. However, the researchers behind the new study discovered that DNA unzippers act more loosely than expected. This can generate large amounts of single-stranded DNA, which the researchers now show is no more than a form of natural stress that cells can actually tolerate in high quantities. Still, for this tolerance to exist, cells require a sufficient amount of the protective protein RPA to cover the single-stranded DNA parts.

We have seen that cells can duplicate their genome, even with large amounts of single stranded DNA. They can divide and go on living healthily because they have a large excess of RPA molecules that acts as a protective umbrella.’ says the study’s first author and former postdoc at the University of Copenhagen Amaia Ercilla, adding: ‘But there is a flip side of the coin. When we make the cells generate single strand DNA faster than what they can protect, chromosomes literally shatter in hundreds of pieces, a phenomenon we call replication catastrophe. We always thought that we could use this for instance to kill cancer cells“.

Source: https://news.ku.dk/

How To Uncloak Cancer Cells And Reveal Them To The Immune System

Scientists at Johns Hopkins report they have designed and successfully tested an experimental, super small package able to deliver molecular signals that tag implanted human cancer cells in mice and make them visible for destruction by the animals’ immune systems. The new method was developed, say the researchers, to deliver an immune system “uncloaking” device directly to cancer cells.

Conventional immune therapies generally focus on manipulating patients’ immune system cells to boost their cancer-killing properties or injecting drugs that do the same but often have toxic side effectsA hallmark of cancer biology is a tumor cell’s ability to essentially hide from the immune system cells whose job is to identify and destroy cancer cells. Current cellular immunotherapies, notably CAR-T, require scientists to chemically alter and enhance a patient’s own harvested immune system T-cells — an expensive and time-consuming process, say the researchers. Other weapons in the arsenal of immunotherapies are drugs, including so-called checkpoint inhibitors, which have broad effects and often lead to unwanted immune-system-associated side effects, including damage to normal tissue.

By contrast, the Johns Hopkins team sought an immune system therapy that can work like a drug but that also individually engineers a tumor and its surrounding environment to draw the immune system cells to it, says Jordan Green, Ph.D, professor of biomedical engineering at the Johns Hopkins University School of Medicine.

A microscopic image of the nanoparticles used in the study. The black scale bar is 100 nm in size
 And our process happens entirely within the body,” Green says, “requiring no external manipulation of a patient’s cells.

To develop the new system, Green and his team, including Stephany Tzeng, Ph.D., a research associate in the Department of Biomedical Engineering at Johns Hopkins, took advantage of a cancer cell’s tendency to internalize molecules from its surroundings. “Cancer cells may be easier to directly genetically manipulate because their DNA has gone haywire, they divide rapidly, and they don’t have the typical checks and balances of normal cells,” says Green.

The team created a polymer-based nanoparticle — a tiny case that slips inside cells. They guided the nanoparticles to cancer cells by injecting them directly into the animals’ tumors. “The nanoparticle method we developed is widely applicable to many solid tumors despite their variability on an individual and tumor type level,” says Green, also a member of the Johns Hopkins Kimmel Cancer Center. Once inside the cell, the water-soluble nanoparticle slowly degrades over a day. It contains a ring of DNA, called a plasmid, that does not integrate into the genome and is eventually degraded as the cancer cell divides, but it stays active long enough to alter protein production in the cell.

The additional genomic material from the plasmid makes the tumor cells produce surface proteins called 4-1BBL, which work like red flags to say, “I’m a cancer cell, activate defenses.” The plasmid also forces the cancer cells to secrete chemicals called interleukins into the space around the cells. The 4-1BBL tags and interleukins are like magnets to immune system cells, and they seek to kill the foreign-looking cancer cells.

Results of the proof-of-concept experiments were published online in the Proceedings of the National Academy of Sciences.

Source: https://www.hopkinsmedicine.org/