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Designer biosensors can detect antibiotic molecules

Designer biosensors can detect antibiotic molecules | Amazing Science | Scoop.it

Researchers from North Carolina State University have engineered designer biosensors that can detect antibiotic molecules of interest. The biosensors are a first step toward creating antibiotic-producing “factories” within microbes such as E. coli.

 

Macrolides are a group of naturally occurring small molecules that can have antibiotic, antifungal or anticancer effects. The antibiotic erythromycin is one example – it is a macrolide produced by soil-dwelling bacteria. Researchers are interested in using these natural antibiotics and the microbes that produce them in order to develop new antibiotics; however, microbes that produce antibiotic macrolides only make small amounts of a limited variety of antibiotics.

 

“Our ultimate goal is to engineer microbes to make new versions of these antibiotics for our use, which will drastically reduce the amount of time and money necessary for new drug testing and development,” says Gavin Williams, associate professor of bio-organic chemistry at NC State and corresponding author of a paper describing the research. “In order to do that, we first need to be able to detect the antibiotic molecules of interest produced by the microbes.”

 

Williams and his team used a naturally occurring molecular switch – a protein called MphR – as their biosensor. In E. coli, MphR can detect the presence of macrolide antibiotics being secreted by microbes that are attacking E. coli. When MphR senses the antibiotic, it turns on a resistance mechanism to negate the antibiotic’s effects.

 

The researchers created a large library of MphR protein variants and screened them for the ability to switch on production of a fluorescent green protein when they were in the presence of a desired macrolide. They tested the variants against erythromycin, which MphR already recognizes, and found that some of the MphR variants improved their detection ability tenfold. They also successfully tested the variants against macrolides that were not closely related to erythromycin, such as tylosin.

 

“Essentially we have co-opted and evolved the MphR sensor system, increasing its sensitivity in recognizing the molecules that we’re interested in,” says Williams. “We know that we can tailor this biosensor and that it will detect the molecules we’re interested in, which will enable us to screen millions of different strains quickly. This is the first step toward high-throughput engineering of antibiotics, where we create vast libraries of genetically modified strains and variants of microbes in order to find the few strains and variants that produce the desired molecule in the desired yield.”

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CRISPR-Cas9 fixes Duchenne muscular dystrophy mutation in mice

CRISPR-Cas9 fixes Duchenne muscular dystrophy mutation in mice | Amazing Science | Scoop.it

Scientists at the University of California, Berkeley, have engineered a new way to deliver CRISPR-Cas9 gene-editing technology inside cells and have demonstrated in mice that the technology can repair the mutation that causes Duchenne muscular dystrophy, a severe muscle-wasting disease.

 

A new study shows that a single injection of CRISPR-Gold, as the new delivery system is called, into mice with Duchenne muscular dystrophy led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups.

 

Since 2012, when study co-author Jennifer Doudna, a professor of molecular and cell biology and of chemistry at UC Berkeley, and colleague Emmanuelle Charpentier, of the Max Planck Institute for Infection Biology, repurposed the Cas9 protein to create a cheap, precise and easy-to-use gene editor, researchers have hoped that therapies based on CRISPR-Cas9 would one day revolutionize the treatment of genetic diseases. Yet developing treatments for genetic diseases remains a big challenge in medicine. This is because most genetic diseases can be cured only if the disease-causing gene mutation is corrected back to the normal sequence, and this is impossible to do with conventional therapeutics.

 

CRISPR/Cas9, however, can correct gene mutations by cutting the mutated DNA and triggering homology-directed DNA repair. However, strategies for safely delivering the necessary components (Cas9, guide RNA that directs Cas9 to a specific gene, and donor DNA) into cells need to be developed before the potential of CRISPR-Cas9-based therapeutics can be realized. A common technique to deliver CRISPR-Cas9 into cells employs viruses, but that technique has a number of complications. CRISPR-Gold does not need viruses.

 

In the new study, research lead by the laboratories of Berkeley bioengineering professors Niren Murthy and Irina Conboy demonstrated that their novel approach, called CRISPR-Gold because gold nanoparticles are a key component, can deliver Cas9 – the protein that binds and cuts DNA – along with guide RNA and donor DNA into the cells of a living organism to fix a gene mutation.

 

“CRISPR-Gold is the first example of a delivery vehicle that can deliver all of the CRISPR components needed to correct gene mutations, without the use of viruses,” Murthy said.

 

The study was published October 2 in the journal Nature Biomedical Engineering.

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Biosensors detect harmful bugs in the lungs of cystic fibrosis patients

Biosensors detect harmful bugs in the lungs of cystic fibrosis patients | Amazing Science | Scoop.it

A team of Imperial researchers has developed a tool which 'lights up' when it detects the chemical signature of harmful bacteria in the lung.

 

In a clinical first, the group from the Department of Medicine used the tools, called cell-free biosensors, to test samples of sputum (phlegm) from patients with cystic fibrosis (CF).

 

Biosensors are based on engineered DNA circuits, designed to detect changes in their environment, such as the presence of chemicals, or changes in pH or temperature. These tools, which harness the biological machinery inside cells, can be used to quickly spot chemical traces of active microbial colonies in samples from the lung and could help to accurately diagnose bacterial infections in vulnerable patients.

 

In a small, proof-of-concept study, the team found that their biosensors could accurately detect markers of Pseudomonas bacteria – a leading cause of chest infections in people with weak immune systems or chronic conditions, such as CF – and were as sensitive as existing chemical diagnostic tests but could potentially be cheaper and easier to use.

 

The researchers are hopeful they could eventually develop their cell-free sensors into a range of rapid diagnostic tests which could be used either at home, GP surgeries or in hospital clinics or even in remote areas of the world with limited access to hospital diagnostics, at a fraction of the price of existing tests.

 

Professor Paul Freemont, co-founder and co-director of The Centre for Synthetic Biology and Innovation at Imperial, said: “The driving force behind this research is to show that these tools work and could be used to detect particular diagnostic markers associated with infection.”

 

He added: “By applying an engineering approach to biology, these systems could be altered to sense for any microbe we choose. The possibilities for public health and cost-savings for health systems could be considerable.”

 

Biosensors have emerged through the growing field of synthetic biology, with scientists tweaking living cells to respond to certain conditions, such as the presence of a chemical compound.

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Knotty Problems in DNA

Knotty Problems in DNA | Amazing Science | Scoop.it

If you have ever tried to untangle a pair of earbuds, you’ll understand how loops and cords can get twisted up. DNA can get tangled in the same way, and in some cases, has to be cut and reconnected to resolve the knots. Now a team of mathematicians, biologists and computer scientists has unraveled how E. coli bacteria can unlink tangled DNA by a local reconnection process. The math behind the research, recently published in Scientific Reports, could have implications far beyond biology.

 

E. coli bacteria can cause intestinal disease, but they are also laboratory workhorses. E. coli’s genome is a single circle of double-stranded DNA. Before an E. coli cell divides, that circle is copied. Opening up the double helix to copy it throws twisting strains elsewhere down the molecule — just as uncoiling a cord in one place will make it over-coil somewhere else. The process results in two twisted loops of DNA that pass through each other like a “magic rings” trick.

 

To separate the rings, E. coli uses an enzyme called topoisomerase IV, which precisely cuts a DNA segment, allows the loops to pass through the break and then reseals the break. Because topoisomerase IV is so important to bacteria, it’s a tempting target for antibiotics such as ciprofloxacin. But when topoisomerase IV is absent, another enzyme complex can step in to carry out this unlinking, although less efficiently. This complex introduces two breaks and unlinks by reconnecting the four loose ends.

 

“There are other ways to unlink the rings, but how do they do it?” said Mariel Vazquez, professor of mathematics and of microbiology and molecular genetics at the University of California, Davis.

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DNA Logic Gets Much Faster

DNA Logic Gets Much Faster | Amazing Science | Scoop.it

Scientists develop method for spatially organizing DNA molecules in regular intervals on a DNA origami surface.

 

Microsoft has taken quite an interest in the potential of DNA in computing over the years. Last year Microsoft researchers set a record for DNA data storage. (Its record was beaten this year). Now Microsoft is turning its attention to the other half of DNA computing, the processor. Researchers at Microsoft have teamed up with scientists at the University of Washington to find a way toward creating super fast computations using DNA molecules.

 

In research described in the journal Nature Nanotechnology,  the scientists have developed a method for spatially organizing DNA molecules in regular intervals on a DNA origami surface. That surface is essentially a bunch of DNA strands that have been folded in ways similiar to the techniques of the Japanese art of paper folding. The results offer a new approach to creating DNA logic gates and and the interconnects that link them. These nanoscale computational circuits are made from synthetic DNA, dubbbed “DNA domino” circuits. These are made from several different strands of synthetic DNA. For example a transmission line consists of hairpin loops of DNA strands with one end afixed to the origami surface. When “input” and “fuel” DNA strands are poured on, they break the loops in the transmission line strands and force them to bend over and link up with their neighbor strand—one after another like dominoes falling—until they form a line of DNA on the substrate. 

 

They used these transmission lines and other structures to make elementary AND and OR gates with two inputs. The researchers were able to to make more complex circuits by linking these elementary gates together. “The molecular components of the device are spatially positioned in close proximity to one another,” explained Andrew Phillips, the head of biological computation group at Microsoft, in an e-mail interview with IEEE Spectrum. “In our case, the molecular components are DNA strands, and they are fixed in place by attaching them to a DNA origami wafer, which acts as a sort of molecular breadboard.”

 

In the past, most computational DNA devices consisted mainly of freely-diffusing DNA strands in a chemical soup. Since all of the strands are freely diffusing, they can bump into each other at random and interfere with each other. “In our case, the components of the devices are positioned close to each other and held in place by a molecular breadboard, such that they are much more likely to interact with their immediate neighbors, and much less likely to interact with other components that are further away, which substantially reduces interference,” said Phillips.


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High-fidelity recording of molecular geometry with DNA “nanoscopy”

High-fidelity recording of molecular geometry with DNA “nanoscopy” | Amazing Science | Scoop.it

Nanotechnology that continuously creates DNA-based records of nearby features in molecular complexes, allowing for their computational reconstruction.

 

Researchers are constantly expanding their arsenal of methods to decipher the spatial organization of biological structures. Using microscopes, they can now visualize individual macromolecular components within DNA, protein, or other complexes.  However, this resolution typically requires sophisticated equipment applied to specially-processed samples, and it is difficult to simultaneously watch many types of molecules, especially at high density and throughput, or dynamic interactions.

 

Circumventing the need for expensive microscopes, some recent biochemical approaches attach barcoded DNA probes to molecular targets and then fuse those in nearby pairs together, often by DNA ligation. These DNA “records” are later read out for analysis. Because these methods destroy the DNA probes in the process of pairing, however, the information acquired from each molecular target cannot include more than one interaction, neither multiple at once nor one changing over time. Such methods can severely limit the quality of any subsequent computational reconstruction, and make reconstruction of individual complexes impossible.

 

To overcome these limitations, a team at Harvard’s Wyss Institute of Biologically Inspired Engineering led by Core Faculty member Peng Yin, Ph.D., has now developed a DNA nanotechnology-based method that allows for repeated, non-destructive recording of uniquely barcoded molecular pairings, rendering a detailed view of their components and geometries. In the future, the approach could help researchers understand how changes in molecular complexes control biological processes in living cells. The study is published in Nature Communications.


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DNA Origami

DNA Origami | Amazing Science | Scoop.it

Since DNA forms basepairs in a predictable way, by cleverly designing the sequences of several strands of DNA you can coax them to self-assemble into a particular shape.

 

Until recently, DNA origami has been constrained to two dimensional shapes like smiley faces, stars, and other things. These are entertaining, but this technology has potential applications besides aesthetic. Maybe one day we can build containers for drugs using DNA origami that carry medicine to particular cells, say chemotherapy drugs to cancer cells while sparing healthy cells from the same fate. Maybe one can take advantage of the stability of DNA by using it to build scaffolds on which tissues or whole organs can grow. These two applications clearly require taking DNA origami into three dimensions, which is just what Dongran Han and his colleagues did. In their designs they used one long piece of ssDNA, called the scaffold, and many small pieces of ssDNA, called staples. By choosing staples carefully, they were able to contort the scaffold into a desired shape. They began by building simple concentric circles in two dimensions with the scaffold weaving in and out between the rings. They then varied the parameters of their design to build three dimensional shapes with circular cross sections. They managed to build hemispheres, spheres, ellipsoids (stretched spheres), and flasks. They called their DNA flask the "nanoflask" in reference to its nanoscale size. The pictures of these shapes shown below are transmission electron micrographs in black and white and atomic force micrographs in yellow and red. Electron microscopes use a beam of electrons instead of light to focus on objects much smaller than the wavelength of visible light. Atomic force microscopes feel their way through a sample using a tiny needle tipped with a single atom.

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DNA interesting dates!

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Biohackers Encoded Malware in a Strand of DNA

Biohackers Encoded Malware in a Strand of DNA | Amazing Science | Scoop.it
Researchers planted a working hacker exploit in a physical strand of DNA.

 

When biologists synthesize DNA, they take pains not to create or spread a dangerous stretch of genetic code that could be used to create a toxin or, worse, an infectious disease. But one group of biohackers has demonstrated how DNA can carry a less expected threat—one designed to infect not humans nor animals but computers.

 

In new research they plan to present at the USENIX Security conference on Thursday, a group of researchers from the University of Washington has shown for the first time that it’s possible to encode malicious software into physical strands of DNA, so that when a gene sequencer analyzes it the resulting data becomes a program that corrupts gene-sequencing software and takes control of the underlying computer. While that attack is far from practical for any real spy or criminal, it's one the researchers argue could become more likely over time, as DNA sequencing becomes more commonplace, powerful, and performed by third-party services on sensitive computer systems. And, perhaps more to the point for the cybersecurity community, it also represents an impressive, sci-fi feat of sheer hacker ingenuity.

 

“We know that if an adversary has control over the data a computer is processing, it can potentially take over that computer,” says Tadayoshi Kohno, the University of Washington computer science professor who led the project, comparing the technique to traditional hacker attacks that package malicious code in web pages or an email attachment. “That means when you’re looking at the security of computational biology systems, you’re not only thinking about the network connectivity and the USB drive and the user at the keyboard but also the information stored in the DNA they’re sequencing. It’s about considering a different class of threat.”

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A breakthrough new method for 3D-printing living tissues

A breakthrough new method for 3D-printing living tissues | Amazing Science | Scoop.it

Scientists at the University of Oxford have developed a radical new method of 3D-printing laboratory-grown cells that can form complex living tissues and cartilage to potentially support, repair, or augment diseased and damaged areas of the body.

 

Printing high-resolution living tissues is currently difficult because the cells often move within printed structures and can collapse on themselves. So the team devised a new way to produce tissues in protective nanoliter droplets wrapped in a lipid (oil-compatible) coating that is assembled, layer-by-layer, into living cellular structures.

 

This new method improves the survival rate of the individual cells and allows for building each tissue one drop at a time to mimic the behaviors and functions of the human body. The patterned cellular constructs, once fully grown, can mimic or potentially enhance natural tissues.

 

“We were aiming to fabricate three-dimensional living tissues that could display the basic behaviors and physiology found in natural organisms,” explained Alexander Graham, PhD, lead author and 3D Bioprinting Scientist at OxSyBio (Oxford Synthetic Biology).

 

“To date, there are limited examples of printed tissues [that] have the complex cellular architecture of native tissues. Hence, we focused on designing a high-resolution cell printing platform, from relatively inexpensive components, that could be used to reproducibly produce artificial tissues with appropriate complexity from a range of cells, including stem cells.”

 

The researchers hope that with further development, the materials could have a wide impact on healthcare worldwide and bypass clinical animal testing. The scientists plan to develop new complementary printing techniques that allow for a wider range of living and hybrid materials, producing tissues at industrial scale.

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A new “atlas” of cancer genes could help personalize therapies for patients

A new “atlas” of cancer genes could help personalize therapies for patients | Amazing Science | Scoop.it

Researchers use a big-data approach to find links between different genes and patient survival.

 

Understanding the genetic changes in tumors that distinguish the most lethal cancers from more benign ones could help doctors better treat patients. Recently, Swedish researchers launched a new open-access catalog that maps many of those genetic changes. This “atlas” links thousands of specific genes involved in numerous cancers to patient survival and also reveals potential new drug targets.

 

The new atlas is one of several ongoing efforts to make sense of data that’s been collected by public databases—like the National Cancer Institute’s Cancer Genome Atlas—that act as repositories for tumor samples. The goal is to glean practical information, like markers of disease, that can be used to develop cancer drugs and diagnostics.

 

To generate the atlas, researchers led by Mathias Uhlén, a professor of microbiology at the Royal Institute of Technology in Sweden, used a supercomputer to analyze 17 major types of human cancers from nearly 8,000 tumor samples. Uhlén says his team was looking for “holistic changes across the genome caused by these mutations.”

 

They then mapped all the genes found in those cancer cells to find out how proteins made by these genes affect patient survival. Genes carry instructions for making proteins, and the level of gene expression increases or decreases the amount of protein that genes make. These resulting proteins can dramatically influence biological processes like cancer.


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First In Vivo Function Found for Animal Circular RNA

First In Vivo Function Found for Animal Circular RNA | Amazing Science | Scoop.it

Mice lacking the RNA had deregulated microRNAs in the brain, disrupted synaptic communication, and behavioral abnormalities associated with neuropsychiatric disorders.

 

Circular RNAs (circRNAs) have attracted growing attention in recent years, but their function in living organisms has long remained a mystery. Now, researchers report that one circRNA, Cdr1as, regulates microRNA levels in the mammalian brain, and that its removal results in abnormal neuronal activity and behavioral impairments in mice. The findings were published today (August 10) in Science. “There are few papers where you can really say it’s a breakthrough,” says Sebastian Kadener, a neuroscientist and circRNA researcher at Brandeis University who was not involved in the work. “But this paper is really exciting. It’s the first real demonstration of a function of these molecules in vivo in an animal.”

 

CircRNAs, or simply “circles,” are formed when one or more exons or introns are “back-spliced” into a loop instead of a linear transcript. Once thought to be the result of errors in gene expression, hundreds of circles are now known to be specifically expressed, and are conserved across animal species.

Cdr1as, a circRNA that is highly expressed in the mammalian brain, is one of the best characterized circles to date. When the Max Delbrück Center’s Nikolaus Rajewsky and colleagues described it in 2013, they noted the molecule’s potential to act as a microRNA “sponge”—it has more than 60 binding sites for the microRNA miR-7—although the role of this sponging remained unclear.

 

Cdr1as is also unusual in that it is transcribed from the antisense strand of DNA and has no well-expressed linear equivalent—a feature that makes it appealing for loss-of-function assays using DNA-editing tools such as CRISPR-Cas9. “This is an attractive case to study,” Rajewsky tells The Scientist. “It allows you to manipulate the DNA and hope that what you see at the functional level is really a response to the loss of the circular RNA.

 

In the current work, Rajewsky and his colleagues first took advantage of a technique they had previously developed to detect in vivo interactions between microRNAs and other molecules. Using mouse and human postmortem brains, the team showed that miR-7, and to a much lesser extent, another microRNA, miR-671, both bind to Cdr1as.Then, the researchers employed CRISPR-Cas9 to delete the locus in mice and create Cdr1as-deficient mutants. Although the knockout animals were outwardly normal—they were viable, fertile, and showed no obvious changes in brain anatomy—the team detected altered levels of free microRNA in areas of the brain where Cdr1as would normally have been expressed: miR-671 was slightly upregulated, while miR-7 levels were markedly lowered—a result that could reflect the circle’s role in preventing degradation of this microRNA by binding to it in wild-type animals, Rajewsky notes.


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Correction of a pathogenic gene mutation in human embryos using CRISPR

Correction of a pathogenic gene mutation in human embryos using CRISPR | Amazing Science | Scoop.it

Genome editing has potential for the targeted correction of germline mutations. Scientists now describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, the researchers were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

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Living computers: RNA circuits transform cells into nanodevices

Living computers: RNA circuits transform cells into nanodevices | Amazing Science | Scoop.it

The interdisciplinary nexus of biology and engineering, known as synthetic biology, is growing at a rapid pace, opening new vistas that could scarcely be imagined a short time ago.

 

In a new research, Alex Green, an assistant professor at ASU’s Biodesign Institute, demonstrates how living cells can be induced to carry out computations in the manner of tiny robots or computers. The results of the new study have significant implications for intelligent drug design and smart drug delivery, green energy production, low-cost diagnostic technologies and even the development of futuristic nanomachines capable of hunting down cancer cells or switching off aberrant genes. 

 

“We’re using very predictable and programmable RNA-RNA interactions to define what these circuits can do,” Green said. “That means we can use computer software to design RNA sequences that behave the way we want them to in a cell. It makes the design process a lot faster.”  The study appears in the advance online edition of the journal Nature.

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San Diego Startup Uses Algae Feedstock to Make Renewable Flip-Flops

San Diego Startup Uses Algae Feedstock to Make Renewable Flip-Flops | Amazing Science | Scoop.it

Every year, petroleum-based feedstocks are used worldwide to make roughly 3 billion flip-flops, the rubbery, flat-sole sandals held on the foot by a Y-shaped strap that fits between the first and second toes.

 

It might seem like a throwaway product—and it is, according to Stephen Mayfield, a UC San Diego professor of biology and director of the California Center for Algae Biotechnology. The petrochemicals used to produce flip-flops make them impervious to the elements—and they end up as non-biodegradable rubbish in rivers and oceans, and in landfills and trash heaps. Yet flip-flops also are the No. 1 shoe in the world. “These are the shoes of a fisherman and a farmer,” Mayfield says. “This is the No. 1 shoe in India, the No. 1 shoe in China, and the No. 1 shoe in Africa.”

 

So Mayfield and colleagues at UC San Diego recently unveiled prototype flip-flopsmade from algae-derived polymeric polyols instead of petroleum-based polyurethanes. The idea is to offer consumers more environmentally friendly flip-flops, made with renewable materials and perhaps even biodegradable after a year or two.

 

Mayfield, who was a scientific co-founder of the unsuccessful algal biofuel company Sapphire Energy, worked with UC San Diego chemists Michael Burkart and Robert “Skip” Pomeroy to make a pliable foam from algae-based polyols that could replace conventional polyurethanes. To advance the commercial prospects for biodegradable flip-flops, Mayfield, Burkart, and Pomeroy founded an industrial biotech, Algenesis Materials, in early 2016.

 

“Our goal is to get to 100 percent renewable, and 100 percent biodegradable,” said Mayfield, who is an environmentally conscious surfer and coastal enthusiast. “Burkart’s convinced that we’re going to throw these [flip-flops] in a compost pile, and in six months they’ll be gone. But we’re not there yet.”

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Twist Bioscience, Microsoft, and U Wash Preserve High-Quality Life Audio Recordings in DNA

Twist Bioscience, Microsoft, and U Wash Preserve High-Quality Life Audio Recordings in DNA | Amazing Science | Scoop.it

Twist Bioscience have successfully stored archival-quality audio recordings of two important music performances from the archives of Montreux Jazz Festival.

 

These selections are encoded and stored in nature’s preferred storage medium, DNA, for the first time. These tiny specks of DNA will preserve a part of UNESCO’s Memory of the World Archive, where valuable cultural heritage collections are recorded. This is the first time DNA has been used as a long-term archival-quality storage medium.

 

Quincy Jones, world-renowned Entertainment Executive, Music Composer and Arranger, Musician and Music Producer said, “With advancements in nanotechnology, I believe we can expect to see people living prolonged lives, and with that, we can also expect to see more developments in the enhancement of how we live. For me, life is all about learning where you came from in order to get where you want to go, but in order to do so, you need access to history! And with the unreliability of how archives are often stored, I sometimes worry that our future generations will be left without such access. So, it absolutely makes my soul smile to know that EPFL, Twist Bioscience and others are coming together to preserve the beauty and history of the Montreux Jazz Festival for our future generations, on DNA! I’ve been a part of this festival for decades and it truly is a magnificent representation of what happens when different cultures unite for the sake of music. Absolute magic. And I’m proud to know that the memory of this special place will never be lost.”

 

“Our partnership with EPFL in digitizing our archives aims not only at their positive exploration, but also at their preservation for the next generations,” says Thierry Amsallem, president of the Claude Nobs Foundation. “By taking part in this pioneering experiment which writes the songs into DNA strands, we can be certain that they will be saved on a medium that will never become obsolete!”

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New CRISPR tool targets RNA in mammalian cells

New CRISPR tool targets RNA in mammalian cells | Amazing Science | Scoop.it

Researchers from the Broad Institute of MIT and Harvard have shown that a CRISPR-based editing system can cut and bind RNA in mammalian cells. In a paper out this week in Nature, the team used CRISPR-Cas13, which the researchers had helped discover, to both reduce RNA levels and "tag" RNAs in order to view and track them within cells. The researchers previously used CRISPR-Cas13 to target RNA in bacterial cells, but proving that the system could work safely and effectively in mammalian cells was a critical step toward using the system to study human biology and disease.

 

Having this sort of programmable tool for modulating RNA in mammalian cells creates new opportunities for learning how cells function and, potentially, for designing safer therapeutics. Unlike editing DNA, which makes permanent changes to the genome of a cell, targeting RNA could enable researchers to make temporary changes that alter the amount of protein produced by a gene rather than stopping production entirely.

 

Even though we have good tools to delete genes, they still have many limitations that make the study of gene function difficult," explains co-first author Omar Abudayyeh, who is a graduate student in the lab of Broad core member and MIT associate professor Feng Zhang. "Cas13 allows you to bring down gene expression levels without completely eliminating them, which is useful for studying genes and may offer a less toxic therapeutic approach to correcting genetic diseases."

 

The team, led by scientists from Zhang's lab, tested Cas13 enzymes from fifteen different microbes to find the one, from Leptotrichia wadei (LwaCas13a), that was best-suited for the task. Using LwaCas13a enabled them to cut specific sites in targeted RNA with greater specificity than the current RNA-knockdown tool-of-choice, RNA-interference (RNAi). Although RNAi can be a useful tool, it often leads to unwanted off-target effects, making experiments difficult to interpret. Such off-target effects were significantly reduced with Cas13.

 

Zhang's team also demonstrated that a so-called "dead" variant of Cas13 that binds RNA but doesn't cut it can be combined with bright fluorescent "tags" to visually track target RNA as it moves within the cell. "Our engineering of Cas13 here to bind and image transcripts shows the promise of this platform for the development of a broader set of tools to monitor and manipulate RNA," adds co-first author Jonathan Gootenberg, who is also a graduate student in Zhang's lab as well as the lab of Broad core member Aviv Regev.


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Circular RNA linked to brain function

Circular RNA linked to brain function | Amazing Science | Scoop.it
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information -- like patients suffering from neuropsychiatric disorders.

 

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the current issue of Science, Nikolaus Rajewsky and his team at the Berlin Institute of Medical Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), as well as other collaborators within the MDC and Charité, present data that -- for the first time -- link a circular RNA to brain function.

 

RNA is much more than the mundane messenger between DNA and the protein it encodes. Indeed, there are several different kinds of non-coding RNA molecules. They can be long non-coding RNAs (lncRNAs) or short regulatory RNAs (miRs); they can interfere with protein production (siRNAs) or help make it possible (tRNAs). In the past 20 years, scientists have discovered some two dozen RNA varieties that form intricate networks within the molecular microcosm. The most enigmatic among them are circRNAs, an unusual class of RNAs whose heads are connected to their tails to form a covalently closed ring. These structures had for decades been dismissed as a rare, exotic RNA species. In fact, the opposite is true. Current RNA-sequencing analyses have revealed that they are a large class of RNA, which is highly expressed in brain tissues.


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Programming sites of meiotic crossovers using Spo11 fusion proteins

Programming sites of meiotic crossovers using Spo11 fusion proteins | Amazing Science | Scoop.it

Meiotic recombination shapes the genetic diversity transmitted upon sexual reproduction. However, its non-random distribution along the chromosomes constrains the landscape of potential genetic combinations. For a variety of purposes, it is desirable to expand the natural repertoire by changing the distribution of crossovers in a wide range of eukaryotes.

 

A group of scientists now changed the local stimulation of meiotic recombination at a number of chromosomal sites by tethering the natural Spo11 protein to various DNA-binding modules: full-length DNA binding proteins, zinc fingers (ZFs), transcription activator-like effector (TALE) modules, and the CRISPR-Cas9 system. In the yeast (Saccharomyces cerevisiae), each strategy is able to stimulate crossover frequencies in naturally recombination-cold regions. The binding and cleavage efficiency of the targeting Spo11 fusions (TSF) are variable, being dependent on the chromosomal regions and potential competition with endogenous factors. TSF-mediated genome interrogation distinguishes naturally recombination-cold regions that are flexible and can be warmed-up (gene promoters and coding sequences), from those that remain refractory (gene terminators and centromeres).

 

These results describe new generic experimental strategies to increase the genetic diversity of gametes, which should prove useful in plant breeding and other applications.


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Gene Therapy-Induced Antigen-Specific Tregs Reverse Multiple Sclerosis in Mice

Gene Therapy-Induced Antigen-Specific Tregs Reverse Multiple Sclerosis in Mice | Amazing Science | Scoop.it

The devastating neurodegenerative disease of multiple sclerosis (MS) could substantially benefit from an adeno-associated virus (AAV) immunotherapy designed to restore a robust and durable antigen-specific tolerance. However, developing a sufficiently potent and long-lasting immune-regulatory therapy that can intervene in an ongoing disease is a major challenge and has thus been elusive so far.

 

Researchers now addressed this problem by developing a highly effective and robust tolerance-inducing in vivo gene therapy. Using an animal model, they designed a liver-targeting gene transfer vector that expresses full-length myelin oligodendrocyte glycoprotein (MOG) in hepatocytes.

 

They were able to show that by harnessing the tolerant nature of the liver, this powerful gene immunotherapy restores immune tolerance by inducing functional MOG-specific regulatory T cells (Tregs) in vivo, independent of major histocompatibility complex (MHC) restrictions. Additionally, they could demonstrate that mice treated prophylactically are protected from developing disease and neurological deficits. More importantly even, they demonstrated that when given to mice with preexisting disease, ranging from mild neurological deficits to severe paralysis, the gene immunotherapy abrogated CNS inflammation and significantly reversed clinical symptoms of disease. This specialized approach for inducing antigen-specific immune tolerance has significant therapeutic potential for treating MS and other autoimmune disorders.

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Single-nucleus RNA sequencing, droplet by droplet

Single-nucleus RNA sequencing, droplet by droplet | Amazing Science | Scoop.it

DroNc-Seq — a technology that merges single-nucleus RNA sequencing with microfluidics — brings new scale to gene expression studies in complex tissues.

 

In 2016, Broad Institute researchers described a single-nucleus RNA sequencing method called sNuc-Seq. This system enabled researchers to study the gene expression profiles of difficult-to-isolate cell types as well as cells from archived tissues. Now a Broad-led team has overcome a key stumbling block to sNuc-Seq’s widespread use: scale.

 

In a recent paper published in Nature Methods, postdoctoral fellows Naomi Habib, Inbal Avraham-Davidi, and Anindita Basu; core institute members Feng Zhang and Aviv Regev; and their colleagues reveal DroNc-Seq, a single-cell expression profiling technique that merges sNuc-Seq with microfluidics, allowing massively parallel measurement of gene expression in structurally-complicated tissues.

 

Researchers struggled in the past to study expression in neurons and other cells from complex tissues, like the brain, at the single-cell level. This was because the procedures for isolating the cells affected their RNA content and did not always accurately capture the true proportions of the cell types present in a sample. Moreover, the procedures did not work for frozen archived tissues. sNuc-Seq bypassed those problems by using individual nuclei extracted from cells as a starting point instead.

 

sNuc-Seq, however, is a low-throughput technology, using 96- or 384-well plates to collect and run samples. To scale the method up to the level needed in order to efficiently study thousands of nuclei at a time, the team turned to microfluidics. Their inspiration: Drop-Seq, a single-cell RNA-seq (scRNAseq) technique that encapsulates single cells together with DNA barcoded-beads in microdroplets to greatly accelerate expression profiling experiments and reduce cost.

 

To test the new method’s accuracy and speed, the team successfully benchmarked DroNc-Seq against Drop-Seq, sNuc-Seq, and other lower throughput scRNAseq methods using a mouse cell line and mouse brain tissue. They also applied it to human brain tissue collected by the Genotype-Tissue Expression (GTEx) Project, finding that they could a) identify expression signatures unique to neurons, glial cells, and other cell types in the brain (including rare types), and b) differentiate between closely related cell subtypes.

 

DroNc-Seq’s robustness and accuracy suggest it could be a valuable addition to the stable of technologies being used as part of the Human Cell Atlas and other scRNAseq-based efforts.


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Fertile offspring from sterile sex chromosome trisomic mice

Fertile offspring from sterile sex chromosome trisomic mice | Amazing Science | Scoop.it

Having the correct number of chromosomes is vital for normal development and health. Sex chromosome trisomy (SCT) affects 0.1% of the human population and is associated with infertility. Scientists now show that during reprogramming to induced pluripotent stem cells (iPSC), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome, by a phenomenon we term trisomy-biased chromosome loss (TCL). Resulting euploid XY iPSCs can be differentiated into the male germ cell lineage and functional sperm that can be used in intracytoplasmic sperm injection to produce chromosomally normal, fertile offspring. Sex chromosome loss is comparatively infrequent during mouse XX and XY iPSC generation. TCL also applies to other chromosomes, generating euploid iPSCs from cells of a Down syndrome mouse model. It can also create euploid iPSCs from human trisomic patient fibroblasts. The findings have relevance to overcoming infertility and other trisomic phenotypes.

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Zebrafish implanted with a cancer patient’s tumor could guide cancer treatment

Zebrafish implanted with a cancer patient’s tumor could guide cancer treatment | Amazing Science | Scoop.it

Fish cancer “avatars” may be better than mice at revealing drugs’ effectiveness.

 

Eight years ago, developmental biologist Rita Fior learned that her mother, who needed cancer treatment at the time, would receive different drugs depending on nothing more than which hospital she chose. Fior was taken aback. “You don’t know if it’s better to take drug A or B,” she says. “This is a big problem.” Now she is addressing the problem—with a fish.

 

This week, Fior, who is at the Champalimaud Centre for the Unknown in Lisbon, and her colleagues reported growing implanted human tumor cells in zebrafish larvae. Each fish became a minuscule model of a patient’s cancer—and a testbed for treatments. Similar cancer “avatars” have been created with mice, but the piscine approach may be faster and cheaper, making it accessible for more patients. “Zebrafish could have a unique niche [in cancer treatment],” says Leonard Zon of Harvard Medical School in Boston, who has used the fish for more than a decade to study how cancer develops. 


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Scientists Record and Replay Movie Encoded in DNA

Scientists Record and Replay Movie Encoded in DNA | Amazing Science | Scoop.it

For the first time, a primitive movie has been encoded in – and then played back from – DNA in living cells. Scientists funded by the National Institutes of Health say it is a major step toward a “molecular recorder” that may someday make it possible to get read-outs, for example, of the changing internal states of neurons as they develop.

 

“We want to turn cells into historians,” explained neuroscientist Seth Shipman, Ph.D. , a post-doctoral fellow at Harvard Medical School, Boston. “We envision a biological memory system that’s much smaller and more versatile than today’s technologies, which will track many events non-intrusively over time.”

 

Shipman, Harvard’s Drs. George Church , Jeffrey Macklis  andJeff Nivala  report on their proof-of-concept for a futuristic “molecular ticker tape” online July 12, in the journal Nature. The work was funded by NIH’s National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and the National Human Genome Research Institute.

 

The ability to record such sequential events like a movie at the molecular level is key to the idea of reinventing the very concept of recording using molecular engineering, say the researchers. In this scheme, cells themselves could be induced to record molecular events – such as changes in gene expression over time – in their own genomes. Then the information could be retrieved simply by sequencing the genomes of the cells it is stored in.

 

“If we had those transcriptional steps, we could potentially use them like a recipe to engineer similar cells,” added Shipman. “These could be used to model disease – or even in therapies.”

 

For starters, the researchers had to show that DNA can be used to encode not just genetic information, but any arbitrary sequential information into a genome. For this they turned to the cutting-edge, NIH-funded gene editing technology CRISPR . They first demonstrated that they could encode and retrieve an image of the human hand in DNA inserted into bacteria. They then similarly encoded and reconstructed frames from a classic 1870s race horse in motion  sequence of photos – an early forerunner of moving pictures.

 

The researchers had previously shown that they could use CRISPR to store sequences of DNA in bacteria. CRISPR is a group of proteins and DNA that act as an immune system in some bacteria, vaccinating them with genetic memories of viral infections. When a virus infects a bacterium, CRISPR cuts out part of the foreign DNA and stores it in the bacteria’s own genome. The bacterium then uses the stored DNA to recognize the virus and defend against future attacks. “The sequential nature of CRISPR makes it an appealing system for recording events over time,” explained Shipman.

 

The researchers then similarly translated five frames from the race horse in motion photo sequence into DNA. Over the course of five days, they sequentially treated bacteria with a frame of translated DNA. Afterwards, they were able to reconstruct the movie with 90 percent accuracy by sequencing the bacterial DNA.

 

Although this technology could be used in a variety of ways, the researchers ultimately hope to use it to study the brain. “We want to use neurons to record a molecular history of the brain through development,” said Shipman. “Such a molecular recorder will allow us to eventually collect data from every cell in the brain at once, without the need to gain access, to observe the cells directly, or disrupt the system to extract genetic material or proteins.”

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Gene Editing Spurs Hope for Transplanting Pig Organs Into Humans

Gene Editing Spurs Hope for Transplanting Pig Organs Into Humans | Amazing Science | Scoop.it
Geneticists have created piglets free of retroviruses, an important step toward creating a new supply of organs for transplant patients.

 

Xenotransplantation is a promising strategy to alleviate the shortage of organs for human transplantation. In addition to the concern on pig-to-human immunological compatibility, the risk of cross-species transmission of porcine endogenous retroviruses (PERVs) has impeded the clinical application of this approach.

 

Earlier, a group of scientists demonstrated the feasibility of inactivating PERV activity in an immortalized pig cell line. Now, they confirmed that PERVs infect human cells, and observed the horizontal transfer of PERVs among human cells. Using CRISPR-Cas9, they inactivated all the PERVs in a porcine primary cell line and generated PERV-inactivated pigs via somatic cell nuclear transfer. This study clearly highlights the value of PERV inactivation to prevent cross-species viral transmission and demonstrated the successful production of PERV-inactivated animals to address the safety concern in clinical xenotransplantation.

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Scientists reveal source of human heartbeat in 3D

Scientists reveal source of human heartbeat in 3D | Amazing Science | Scoop.it

A pioneering new study is set to help surgeons repair hearts without damaging precious tissue.

 

A team of scientists from Liverpool John Moores University (LJMU), The University of Manchester, Aarhus University and Newcastle University, have developed a way of producing 3D data to show the cardiac conduction system -- the special cells that enable our hearts to beat -- in unprecedented detail. The findings were published in Scientific Reports.

 

The new data in this study gives them a much more accurate framework than previously available for computer models of the heartbeat and should improve our ability to make sense of troublesome heart rhythms like atrial fibrillation that affects 1.4 million people in the UK. The data reveals exactly where the cardiac conduction system is in a normal heart. For example, it shows just how close it runs to the aortic valve.

 

Professor Jonathan Jarvis who is based at the LJMU School of Sport and Exercise Sciences explained: "The 3D data makes it much easier to understand the complex relationships between the cardiac conduction system and the rest of the heart. We also use the data to make 3D printed models that are really useful in our discussions with heart doctors, other researchers and patients with heart problems.

 

"New strategies to repair or replace the aortic valve must therefore make sure that they do not damage or compress this precious tissue. In future work we will be able to see where the cardiac conduction system runs in hearts that have not formed properly. This will help the surgeons who repair such hearts to design operations that have the least risk of damaging the cardiac conduction system."

 

Co-author Dr Halina Dobrzynski, who is based in The University of Manchester's Cardiovascular Division, has been working on the anatomy of the cardiac conduction system for 20 years. She says: "This is just the beginning. The British Heart Foundation is supporting my group to visualize this system in 3D from aged and failing hearts. With my research assistant Andrew Atkinson and working with Professor Jonathan Jarvis, Robert Stephenson and others, we will produce families of data from aged and failing hearts in 3D."

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