Tag Archives: DNA

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/

Nano-Transistor From DNA-like Material

Computer chips use billions of tiny switches, called transistors, to process information. The more transistors on a chip, the faster the computer. A material shaped like a one-dimensional DNA helix might further push the limits on a transistor’s size. The material comes from a rare earth element called tellurium.

Researchers found that the material, encapsulated in a nanotube made of boron nitride, helps build a field-effect transistor with a diameter of two nanometers. Transistors on the market are made of bulkier silicon and range between 10 and 20 nanometers in scale.  Engineers at Purdue University performed the work in collaboration with Michigan Technological University, Washington University in St. Louis, and the University of Texas at Dallas.

Over the past few years, transistors have been built as small as a few nanometers in lab settings. The goal is to build transistors the size of atomsPeide Ye’s lab at Purdue is one of many research groups seeking to exploit materials much thinner than silicon to achieve both smaller and higher-performing transistors.

These silver, wiggling lines are strings of atoms in tellurium behaving like DNA. Researchers have not seen this behavior in any other material.

This tellurium material is really unique. It builds a functional transistor with the potential to be the smallest in the world,” said Ye, Purdue’s Richard J. and Mary Jo Schwartz Professor of Electrical and Computer Engineering.

The research is published in the journal Nature Electronics.

Source: https://www.purdue.edu/

How To Reengineer Viruses To Cure Bacterial Infections

The world is in the midst of a global “superbug crisis. Antibiotic resistance has been found in numerous common bacterial infections, including tuberculosis, gonorrhoea and salmonellosis, making them difficult – if not impossibleto treat. We’re on the cusp of a post-antibiotic era, where there are fewer treatment options for such antibiotic-resistant strains. Given estimates that antibiotic resistance will cause 10 million deaths a year by 2050, finding new methods for treating harmful infections is essential.

Strange as it might sound, viruses might be one possible alternative to antibiotics for treating bacterial infections. Bacteriophages (also known as phages) are viruses that infect bacteria.

They’re estimated to be the most abundant organisms on Earth, with probably more than 1031 bacteriophages on the planet. They can survive in many environments, including deep sea trenches and the human gut. While phages are efficient killers of bacteria, they don’t infect human cells and are harmless to humans.

Although phage therapy was used in the 1930s, it has since become a forgotten cure in the west. Although the treatment became commonplace in the former Soviet Union, it wasn’t adopted by western countries largely because of the discovery of antibiotics, which became widespread after World War II.

Bacteriophages are effective against bacteria because they’re able to attach themselves to the cell if they recognise specific molecules called receptors. This is the first step in the “infection” process. After attaching to the bacterial cell, the phage then injects its DNA inside the bacteria.

This causes one of two things to happen. After being injected with the phage’s DNA, the virus will take over the bacterial cell’s replication mechanism and start producing more phages. This process is known as a “lytic infection”. This disintegrates the cell, allowing the newly produced viruses to leave the host cell to infect other bacterial cells.

But sometimes, the phage DNA gets incorporated into the bacterial host’s chromosome instead, becoming a “prophage. It usually remains dormant but environmental factors, such as UV radiation or the presence of certain chemicals such as those found in sunscreen, can cause the phage to “wake up”, start a lytic infection, take over the host cell and destroy it.

Lytic bacteriophages are preferred for treatment because they don’t integrate into the bacterial host’s chromosome. But it’s not always possible to develop lytic bacteriophages that can be used against all types of bacteria. As each type of phage is only able to infect specific types of bacteria, they can’t infect a bacterial cell unless the bacteriophage can find specific receptors on the bacterial cell surface.

However, engineering techniques can remove the bacteriophage’s ability to integrate into the host’s genome, making them useful for treatment. Engineered phages have even successfully treated a drug-resistant Mycobacterium abscessus infection in a 15-year-old girl.

Source: https://www.realclearscience.com/

Aggressive cancers in ‘evolutionary arms race’ with the immune system

Aggressive and highly-mutated cancers are engaged in an “evolutionary arms race” with the immune system, new research suggests. Gullet and stomach cancers with faults in their systems for repairing DNA build up huge numbers of genetic mutations which make them resistant to treatments like chemotherapy. But these numerous mutations mean they appear foreign to the immune system, leaving them vulnerable to attack, and susceptible to new immunotherapies.

Scientists at the Institute of Cancer Research, London (ICR), found that these “hyper-mutant” tumours rapidly evolve strategies to disguise themselves from the immune system and evade attack. They hope that in the future, the findings could help optimise treatment with immunotherapy, and other drugs such as chemotherapy.

Dr Marco Gerlinger, team Leader in translational oncogenomics at the ICR, said: “Our new study has shown that in highly mutated tumours, cancer and the immune system are engaged in an evolutionary arms race in which they continually find new ways to outflank one another.

Watching hyper-mutated tumours and immune cells co-evolve in such detail has shown that the immune system can keep up with changes in cancer, where current cancer therapies can become resistant – and that we could use immunotherapies to shift the balance of this arms race, extending patients’ lives.

“Next, we plan to study the evolutionary link between hyper-mutant tumours and the immune system as part of a new clinical trial looking at the possible benefit of immunotherapy in bowel cancer.

The study has been published in Nature Communications.

Source: https://www.sciencefocus.com/

Human Genetic Enhancement Might Soon Be Possible

The first genetically edited children were born in China in late 2018.Twins Lulu and Nana had a particular gene – known as CCR5modified during embryonic development. The aim was to make them (and their descendants) resistant to HIV. By some definitions, this would be an example of human enhancement.

Although there is still a long way to go before the technology is safe, this example has shown it’s possible to edit genes that will continue being inherited by genetic offspring for generations. However, we don’t yet know what effect these genetic changes will have on the overall health of the twins throughout life. Potential unintended changes to other genes is a grave concern which is limiting our use of gene editing technology at the moment – but this limit won’t always be present.

As we increasingly become less limited by what is scientifically achievable in the realm of gene editing for enhancement, we rely more heavily on ethical – rather than practical – limits to our actions. In fact, the case of Lulu and Nana might never have happened if both scientific and ethical limits had been more firmly established and enforced.

But in order to decide these limits, the expert community needs one important contribution: public opinion. Without the voice of the people, regulations are unlikely to be followed. In a worst-case scenario, a lack of agreed-upon regulations could mean the emergence of dangerous black markets for genetic enhancements. These come with safety and equity issues. In the meantime, experts have called for a temporary international ban on the use of gene editing technologies until a broad societal consensus has been established.

What should this broad consensus be? Current guidance in the UK is theoretically in favour of gene editing for treatment purposes in the future – if certain requirements regarding safety and the intentions of editing are met. This includes eliminating unintentional changes to other genes as a result of genetic enhancements, and that edits serve the welfare of the individuals involved. But when it comes to enhancement, ethical limits are harder to determine as people have different views on what’s best for ourselves and society.

One thing to consider with a technology like gene editing is that it affects more people than just the individual whose genes have been edited – and in some cases, those with edited genes could be unfairly better off than those who haven’t had their genes enhanced.

For example, if it were possible to enhance genes to improve facial symmetry or make a person more confident, it might mean these people are more likely to find employment in a competitive market, compared to those who haven’t had their genes edited for these characteristics. Future generations will also inherit and carry these enhancements in their DNA. In these ethical dilemmas, in order for one person to win, many people must (often unwittingly) lose.

Source: https://theconversation.com/

The Rising Of Gene Therapy

After false starts, drugs that manipulate the code of life are finally changing lives. The idea for gene therapy—a type of DNA-based medicine that inserts a healthy gene into cells to replace a mutated, disease-causing variant—was first published in 1972. After decades of disputed results, treatment failures and some deaths in experimental trials, the first gene therapy drug, for a type of skin cancer, was approved in China in 2003. The rest of the world was not easily convinced of the benefits, however, and it was not until 2017 that the U.S. approved one of these medicines. Since then, the pace of approvals has accelerated quickly. At least nine gene therapies have been approved for certain kinds of cancer, some viral infections and a few inherited disorders. A related drug type interferes with faulty genes by using stretches of DNA or RNA to hinder their workings. After nearly half a century, the concept of genetic medicine has become a reality.

These treatments use a harmless virus to carry a good gene into cells, where the virus inserts it into the existing genome, canceling the effects of harmful mutations in another gene.

GENDICINE: China’s regulatory agency approved the world’s first commercially available gene therapy in 2003 to treat head and neck squamous cell carcinoma, a form of skin cancer. Gendicine is a virus engineered to carry a gene that has instructions for making a tumor-fighting protein. The virus introduces the gene into tumor cells, causing them to increase the expression of tumor-suppressing genes and immune response factors.The drug is still awaiting FDA approval.

GLYBERA: The first gene therapy to be approved in the European Union treated lipoprotein lipase deficiency (LPLD), a rare inherited disorder that can cause severe pancreatitis. The drug inserted the gene for lipoprotein lipase into muscle cells. But because LPLD occurs in so few patients, the drug was unprofitable. By 2017 its manufacturer declined to renew its marketing authorization; Glybera is no longer on the market.

IMLYGIC: The drug was approved in China, the U.S. and the E.U. to treat melanoma in patients who have recurring skin lesions following initial surgery. Imlygic is a modified genetic therapy inserted directly into tumors with a viral vector, where the gene replicates and produces a protein that stimulates an immune response to kill cancer cells.

KYMRIAH: Developed for patients with B cell lymphoblastic leukemia, a type of cancer that affects white blood cells in children and young adults, Kymriah was approved by the FDA in 2017 and the E.U. in 2018. It works by introducing a new gene into a patient’s own T cells that enables them to find and kill cancer cells.

LUXTURNA: The drug was approved by the FDA in 2017 and in the E.U. in 2018 to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy. The disease affects between 1,000 and 2,000 patients in the U.S. who have a mutation in both copies of a particular gene, RPE65. Luxturna delivers a normal copy of RPE65 to patients’ retinal cells, allowing them to make a protein necessary for converting light to electrical signals and restoring their vision.

STRIMVELIS: About 15 patients are diagnosed in Europe every year with severe immunodeficiency from a rare inherited condition called adenosine deaminase deficiency (ADA-SCID). These patients’ bodies cannot make the ADA enzyme, which is vital for healthy white blood cells. Strimvelis, approved in the E.U. in 2016, works by introducing the gene responsible for producing ADA into stem cells taken from the patient’s own marrow. The cells are then reintroduced into the patient’s bloodstream, where they are transported to the bone marrow and begin producing normal white blood cells that can produce ADA.

YESCARTA: Developed to treat a cancer called large B cell lymphoma, Yescarta was approved by the FDA in 2017 and in the E.U. in 2018. It is in clinical trials in China. Large B cell lymphoma affects white blood cells called lymphocytes. The treatment, part of an approach known as CAR-T cell therapy, uses a virus to insert a gene that codes for proteins called chimeric antigen receptors (CARs) into a patient’s T cells. When these cells are reintroduced into the patient’s body, the CARs allow them to attach to and kill cancer cells in the bloodstream.

ZOLGENSMA: In May 2019 the FDA approved Zolgensma for children younger than two years with spinal muscular atrophy, a neuromuscular disorder that affects about one in 10,000 people worldwide. It is one of the leading genetic

causes of infant mortality. Zolgensma delivers a healthy copy of the human SMN gene to a patient’s motor neurons in a single treatment.

ZYNTEGLO: Granted approval in the E.U. in May 2019, Zynteglo treats a blood disorder called beta thalassemia that reduces a patient’s ability to produce hemoglobin, the protein in red blood cells that contains iron, leading to life-threatening anemia. The therapy has been approved for individuals 12 years and older who require regular blood transfusions. It employs a virus to introduce healthy copies of the gene for making hemoglobin into stem cells taken from the patient.The cells are then reintroduced into the bloodstream and transported to the bone marrow, where they begin producing healthy red blood cells that can manufacture hemoglobin.

The approach called ‘Gene Interference‘ uses a synthetic strand of RNA or DNA (called an oligonucleotide) that, when introduced into a patient’s cell, can attach to a specific gene or its messenger molecules, effectively inactivating them. Some treatments use an antisense method, named for one DNA strand, and others rely on small interfering RNA strands, which stop instruction molecules that go from the gene to the cell’s protein factories.

Source: https://www.nature.com/

Alzheimer’s May Be Caused By Dental Infection

In a new study scientists reveal yet another reason to keep up on dental hygiene. Bacteria that cause a common yet largely preventable gum infection may also play a role in Alzheimer’s disease. The discovery also offers hope for a treatment that could slow neurodegeneration.

There were many clues in the [features of Alzheimer’s disease] that an infection is at work,” said Casey Lynch, an entrepreneur and co-founder of Cortexyme, a biotech company headquartered at the Verily Life Sciences campus in South San Francisco, who led the new research. “Many of the genetic risk factors for Alzheimer’s are related to immune system function,” she added, which suggests “immune system dysfunction might put people more at risk.

Alzheimer’s disease, an irreversible and progressive brain disorder that leads to memory loss and diminished thinking skills, affects at least 5 million Americans. Clumps of a brain protein known as amyloid plaques are a hallmark sign of the disease. Billions of research dollars have gone towards finding a treatment that destroys these mind-robbing masses. But there’s still no cure.

Not enough people are asking what is upstream of the plaques … and [brain] inflammation,” said Lynch, who has a background in Alzheimer’s research and was frustrated by the string of failed therapies for the disease. Nearly six years ago, Lynch received a call from Stephen Dominy, a psychiatrist at the University of California, San Francisco, who had studied the link between HIV and dementia.

I think I’ve found a bacterial cause of Alzheimer’s,” Dominy, who co-founded Cortexyme with Lynch and now serves as the company’s Chief Scientific Officer, told her. Dominy had spent about 15 years searching for infections that might lead to Alzheimer’s until evidence for a bacterium known as P. gingivalis became “undeniable,” according to Lynch. P. gingivalis causes periodontitis, an infection that destroys the gums and can lead to tooth loss.

When the team examined the brains and cerebrospinal fluid of Alzheimer’s patients, they found DNA from the bacterium. They also discovered bacterial enzymes called gingipains that destroy brain cells were present, too. And when they watched P. gingivalis infections play out in mice, it triggered neurodegeneration in the hippocampus, a brain structure central to memory. It also led to Alzheimer’s hallmark amyloid beta plaque production and inflammation, the researchers discovered.

The scientists then designed and created a new molecule that blocks the gingipain enzymes. The antibiotic reduced the amount of bacteria in infected mice and stopped the formation of amyloid beta plaques while reducing inflammation, the team reports Wednesday in the journal Science Advances.

Source: https://www.discovermagazine.com/

Bacteria That Eat Carbon Dioxide

Bacteria in the lab of Prof. Ron Milo of the Weizmann Institute of Science have not just sworn off sugar – they have stopped eating all of their normal solid food, existing instead on carbon dioxide (CO2) from their environment. That is, they were able to build all of their biomass from air. This feat, which involved nearly a decade of rational design, genetic engineering and a sped-up version of evolution in the lab, was reported this week in Cell. The findings point to means of developing, in the future, carbon-neutral fuels.

The study began by identifying crucial genes for the process of carbon fixation – the way plants take carbon from CO2 for the purpose of turning it into such biological molecules as protein, DNA, etc. The research team added and rewired the needed genes. They found that many of the “parts” for the machinery that were already present in the bacterial genome could be used as is. They also inserted a gene that allowed the bacteria to get energy from a readily available substance called formate that can be produced directly from electricity and air and which is apt to “give up” electrons to the bacteria.

Just giving the bacteria the “means of production” was not enough, it turned out, for them to make the switch. There was still a need for another trick to get the bacteria to use this machinery properly, and this involved a delicate balancing act. Together with Roee Ben-Nissan, Yinon Bar-On and other members of Milo’s team in the Institute’s Plant and Environmental Sciences Department, Gleizer used lab evolution, as the technique is known; in essence, the bacteria were gradually weaned off the sugar they were used to eating. At each stage, cultured bacteria were given just enough sugar to keep them from complete starvation, as well as plenty of CO2 and formate. As some “learned” to develop a taste for CO2 (giving them an evolutionary edge over those that stuck to sugar), their descendants were given less and less sugar until after about a year of adapting to the new diet some of them eventually made the complete switch, living and multiplying in an environment that served up pure CO2.

The researchers believe that the bacteria’s new “health kick” could ultimately be healthy for the planet. Milo points out that today, biotech companies use cell cultures to produce commodity chemicals. Such cells – yeast or bacteria – could be induced to live on a diet of CO2 and renewable electricity, and thus be weaned from the large amounts of corn syrup they live on today. Bacteria could be further adapted so that rather than taking their energy from a substance such as formate, they might be able to get it straight up — say electrons from a solar collector – and then store that energy for later use as fuel in the form of carbon fixed in their cells. Such fuel would be carbon-neutral if the source of its carbon was atmospheric CO2.

Our lab was the first to pursue the idea of changing the diet of a normal heterotroph (one that eats organic substances) to convert it to autotrophism (‘living on air’),” says Milo. “It sounded impossible at first, but it has taught us numerous lessons along the way, and in the end we showed it indeed can be done. Our findings are a significant milestone toward our goal of efficient, green scientific applications.

Source: https://wis-wander.weizmann.ac.il/
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https://newatlas.com/

Devices Made Of DNA Detect Cancer

A new cancer-detecting tool uses tiny circuits made of DNA to identify cancer cells by the molecular signatures on their surfaceDuke University researchers fashioned the simple circuits from interacting strands of synthetic DNA that are tens of thousands of times finer than a human hair. Unlike the circuits in a computer, these circuits work by attaching to the outside of a cell and analyzing it for proteins found in greater numbers on some cell types than others. If a circuit finds its targets, it labels the cell with a tiny light-up tag. Because the devices distinguish cell types with higher specificity than previous methods, the researchers hope their work might improve diagnosis, and give cancer therapies better aim.

A team led by Duke computer scientist John Reif and his former Ph.D. student Tianqi Song described their approach in a recent issue of the Journal of the American Chemical Society.

The cell membrane is studded with proteins that researchers can use to discriminate between tumor cells and normal cells, or among cancer cells of different types or disease stages.

Similar techniques have been used previously to detect cancer, but they’re more prone to false alarmsmisidentifications that occur when mixtures of cells sport one or more of the proteins a DNA circuit is designed to screen for, but no single cell type has them all. For every cancer cell that is correctly detected using current methods, some fraction of healthy cells also get mislabeled as possibly cancerous when they’re not. Each type of cancer cell has a characteristic set of cell membrane proteins on its cell surface. To cut down on cases of mistaken identity, the Duke team designed a DNA circuit that must latch onto that specific combination of proteins on the same cell to work. As a result they’re much less likely to flag the wrong cells, Reif said.

The technology could be used as a screening tool to help rule out cancer, which could mean fewer unnecessary follow-ups, or to develop more targeted cancer treatments with fewer side effects.

Source: https://today.duke.edu/

How To Starve Cancer Tumors and Beef Up The Immune Cells

Tumors are hogs, gobbling nutrients to fuel their runaway growth, and for decades researchers have tried to develop drugs that cut off their food supply. A study out today shows that an updated version of a failed cancer drug can not only prevent tumor cells from using an essential nutrient, but also spur immune cells to attack the growths.

T lymphocyte cells attacking a cancer cell, computer illustration. T lymphocytes are a type of white blood cell that recognise a specific site (antigen) on the surface of cancer cells or pathogens and bind to it. Some T lymphocytes then signal for other immune system cells to eliminate the cell. The genetic changes that cause a cell to become cancerous lead to the presentation of tumour antigens on the cell’s surface.

It’s a pretty striking paper,” says cancer biologist Ralph DeBerardinis of the University of Texas Southwestern Medical Center in Dallas, who wasn’t connected to the study. “With a single drug, you can in effect starve the tumor and beef up the immune cells.”

Cancer cells eat to obtain molecules vital for survival and replication, but their gluttony also turns their surroundings into an acidic, oxygen-deprived moat that stymies immune cells trying to eliminate them. One of the nutrients many tumors need in abundance is the amino acid glutamine, which provides the building blocks for fabricating molecules such as DNA, proteins, and lipids. “Glutamine is incredibly important for cellular metabolism,” says immunologist Jonathan Powell of the Johns Hopkins School of Medicine in Baltimore, Maryland.

Starting in the 1950s, researchers tried to turn tumors’ glutamine dependence against them, developing drugs to block its metabolism. A bacteria-derived compound called DON, for instance, kills tumors by inhibiting several enzymes that allow cancer cells to use glutamine. In clinical trials, however, the drug provoked severe nausea and vomiting, and it was never approved.

Now, Powell and colleagues have crafted a new version of DON that may be easier to stomach. It carries two chemical groups that keep it inert until it reaches the tumor’s neighborhood. There, enzymes that normally loiter around tumors remove these molecular handcuffs, unleashing the drug on the cancerous cells. With this approach, “the vast majority of the active drug is where we want,” Powell says.

To test their new compound, he and colleagues injected four types of cancer cells into mice, inducing tumors. They then dosed some of the animals with their next-generation DON. The drug worked against all four kinds of tumors, the scientists report today in Science. In untreated mice, for example, colon cancer tumors had grown more than five times larger after about 3 weeks. But in rodents that received DON, the tumors shrank and almost disappeared. The researchers found that the drug wasn’t just throttling glutamine metabolism. It was also disrupting other aspects of the cellsbiochemistry, such as their ability to use the sugar glucose.

Source: https://www.sciencemag.org/