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Scientists Are Amazed How Easy It Is To Tweak Genes In Human Embryos

Scientists Are Amazed How Easy It Is To Tweak Genes In Human Embryos | Amazing Science | Scoop.it
“This is not the beginning of designer babies,” said one bioethicist. But good luck getting people to believe that.

 

Researchers have erased a genetic glitch that causes heart defects in dozens of human embryos with surprising success, fixing the problem 72% of the time. It is the first study to use the controversial CRISPR gene-editing technology in a large number of normal human embryos.

 

The hottest invention in biology, CRISPR allows scientists to cut out and replace genes. About 40 nations, including the US and the UK, effectively prohibit or outlaw using the method to genetically engineer babies.

 

But the new study, published in Nature, suggests that CRISPR might work as an aid to fertility clinic screening for dangerous inherited diseases, relying on a previously unknown ability of human embryos to swiftly repair their genes. “I’m very surprised,” study coauthor Jin-Soo Kim of Seoul National University said in a briefing for reporters on the already widely discussed and speculated-about study, a collaboration between US, Chinese, and South Korean researchers.

 

Kim and his colleagues injected the CRISPR gene fix into dozens of donor eggs, alongside sperm from a man who is a carrier for a heart defect linked to cardiomyopathy. The genetic defect corrected in the study is the leading cause of sudden heart attacks in young people, carried by about 1 in 500. If you inherit the glitch, you have a 50% chance of passing it along to your children.

 

Unlike past experiments that attempted CRISPR days after embryos had developed, this one did it at the time of fertilization. And it worked in 72% of the embryos, replacing the defective gene with a healthy one. In those, the gene-editing technique replaced the gene in every one of the embryo’s cells, preventing the “mosaicism” — when some cells are fixed and others are not — that happened in previous studies. And CRISPR didn’t target any other genes — collateral damage that plagued similar Chinese studies in 2015.

 

Even in the 28% of embryos where CRISPR did not correct the defective sperm gene, it still erased it. The biggest discovery was that the genetic defect originating in sperm was corrected not with the replacement gene that the researchers had inserted, but instead with a healthy gene from the donor egg. That suggests that the CRISPR process inadvertently triggered a powerful and unexpected form of natural DNA repair in human embryos, one not seen before in studies of mice or other creatures.

 

“Overall, this is a very cool and surprising result, especially that it worked as well as it did,” stem cell scientist Paul Knoepfler of the University of California, Davis stated. “But I’m skeptical this will end up in clinical use,” Knoepfler added. Fertility clinics can already screen embryos for the 50-50 chance genetic defects like the one in the study, he noted, and then not use the defective ones in IVF procedures.

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First-of-its-Kind Chemical Oscillator Using DNA Components Offers New Level of Molecular Control

First-of-its-Kind Chemical Oscillator Using DNA Components Offers New Level of Molecular Control | Amazing Science | Scoop.it

UT researchers successfully constructed a first-of-its-kind chemical oscillator that uses DNA components.

 

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors. Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit computation within molecular systems designed for applications in health care, advanced materials and nanotechnology. The findings are published in the Dec. 15 issue of the journal Science.

 

Chemical oscillators have long been studied by engineers and scientists. The researchers who discovered the chemical oscillator that controls the human circadian rhythm —responsible for our bodies’ day and night rhythm — earned the 2017 Nobel Prize in physiology or medicine.

 

Though understanding of chemical oscillators and other biological chemical processes has evolved significantly, scientists do not know enough to control the chemical activities of living cells. This is leading engineers and scientists to turn to synthetic oscillators that work in test tubes rather than in cells.

 

In the new study, David Soloveichik and his research team in the Cockrell School of Engineering at The University of Texas at Austin show how to program synthetic oscillators and other systems by building DNA molecules that follow specific instructions.

Soloveichik, an assistant professor in the Cockrell School’s Department of Electrical and Computer Engineering, along with Niranjan Srinivas, a graduate student at the California Institute of Technology, and the study’s co-authors, have successfully constructed a first-of-its-kind chemical oscillator that uses DNA components — and no proteins, enzymes or other cellular components — demonstrating that DNA alone is capable of complex behavior.

 

According to the researchers, their discovery suggests that DNA can be much more than simply a passive molecule used solely to carry genetic information. “DNA can be used in a much more active manner,” Soloveichik said. “We can actually make it dance — with a rhythm, if you will. This suggests that nucleic acids (DNA and RNA) might be doing more than we thought, which can even inform our understanding of the origin of life, since it is commonly thought that early life was based entirely on RNA.”


Via Integrated DNA Technologies
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DNA origami structures created that are larger than ever before

DNA origami structures created that are larger than ever before | Amazing Science | Scoop.it

A collection of large, complex objects sculpted out of DNA have been unveiled by three separate research groups, expanding the range of nanometre-scale structures that DNA self-assembly can make. Groups led by California Institute of Technology’s (Caltech’s) Lulu Qian, Harvard’s Peng Yin, and Technical University of Munich’s (TU Munich’s) Hendrik Dietz have each developed complementary methods.

 

Shawn Douglas from University of California, San Francisco, who wasn’t involved in these studies, emphasizes that the largest DNA structures now weigh billions of Daltons, and are a thousand times heavier than the largest were a decade ago. The tubes Dietz’s team constructs can also be up to 1000 nanometers long, ten times as big as the largest DNA structures were previously.

 

Remarkably, DNA construction is already at least 26 years old, from when New York University’s Ned Seeman published his group’s assembly of cubes from ten DNA strands in 1991. In the years since, researchers have built progressively bigger and more intricate DNA objects, and used them for computational and mechanical functions. One key underlying technology, known as DNA origami, relies on forcing one long scaffold strand of DNA into a desired shape using dozens of other, shorter, staple strands.

 

Dietz’s team was inspired by viruses, whose outer shells contain just a few types of protein subunit closed into regular shapes. They explored whether DNA origami subunits might do the same, trying different designs and studying their properties using cryo-electron microscopy. They discovered that these first-level subunits needed to form precise shapes and be rigid to successfully self-assemble at second and third levels.

 

‘The subunit needs to withstand collisions from solution molecules – the faces have certain relative angles and if they fluctuate too much they’ll never form a closed object,’ Dietz explains. They also shouldn’t bind too tightly, because they’ll get stuck in partially formed states. ‘If we have sufficiently weak interactions then subunits can associate but also dissociate. If you have some erroneously stuck subunits they fall off again.’

 

The TU Munich team’s final designs used V-shaped first-level DNA origami subunits, which could link up into second-level 350 nanometer diameter rings or ‘reactive vertices’. Depending on their shape, the reactive vertices could link up and close onto each other in third level virus-sized cages that were tetrahedral, hexahedral or dodecahedral. The largest weighed 1.2 billion Daltons and contained 220 DNA origami units. Similarly, the rings can link up into third level, 1000 nanometre-long tubes.

 

While TU Munich’s approach means all assemblies have to be symmetrical, the Caltech team’s multi-level assembly approach creates custom designs. They produce two-dimensional images from a jigsaw of 64 DNA origami tiles, reaching up to 8,704 pixels and 700 micrometres wide. ‘Once we have synthesized each individual tile, we place each one into its own test tube for a total of 64 tubes,’ explains Qian’s grad student Philip Petersen. ‘First, we combine the contents of certain tubes together to get 16 two-by-two squares. Then those are combined in a certain way to get four tubes each with a four-by-four square, and then the final four tubes are combined to create one large, eight-by-eight square composed of 64 tiles. We design the edges of each tile so that we know exactly how they will combine.’

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Gene circuit switches on inside cancer cells, triggers immune attack

Gene circuit switches on inside cancer cells, triggers immune attack | Amazing Science | Scoop.it

Researchers at MIT have developed a synthetic gene circuit that triggers the body’s immune system to attack cancers when it detects signs of the disease. The circuit, which will only activate a therapeutic response when it detects two specific cancer markers, is described in a paper published today in the journal Cell.

 

Immunotherapy is widely seen as having considerable potential in the fight against a range of cancers. The approach has been demonstrated successfully in several recent clinical trials, according to Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science at MIT and a member of MIT's Koch Institute for Integrative Cancer Research.

 

“There has been a lot of clinical data recently suggesting that if you can stimulate the immune system in the right way you can get it to recognize cancer,” says Lu, who is head of the Synthetic Biology Group in MIT’s Research Laboratory of Electronics. “Some of the best examples of this are what are called checkpoint inhibitors, where essentially cancers put up stop signs that prevent T-cells from killing them. There are antibodies that have been developed now that basically block those inhibitory signals and allow the immune system to act against the cancers.”

 

However, despite this success, the use of immunotherapy remains limited by the scarcity of tumor-specific antigens — substances that can trigger an immune system response to a particular type of cancer. The toxicity of some therapies, when delivered as a systemic treatment to the whole body, for example, is another obstacle.

 

What’s more, the treatments are not successful in all cases. Indeed, even in some of the most successful tests, only 30-40 percent of patients will respond to a given therapy, Lu says.

As a result, there is now a push to develop combination therapies, in which different but complementary treatments are used to boost the immune response. So, for example, if one type of immunotherapy is used to knock out an inhibitory signal produced by a cancer, and the tumor responds by up-regulating a second signal, an additional therapy could then be used to target this one as well, Lu says.

 

“Our belief is that there is a need to develop much more specific, targeted immunotherapies that work locally at the tumor site, rather than trying to treat the entire body systemically,” he says. “Secondly, we want to produce multiple immunotherapies from a single package, and therefore be able to stimulate the immune system in multiple different ways.”

 

To do this, Lu and a team including MIT postdocs Lior Nissim and Ming-Ru Wu, have built a gene circuit encoded in DNA designed to distinguish cancer cells from noncancer cells. The circuit, which can be customized to respond to different types of tumor, is based on the simple AND gates used in electronics. Such AND gates will only switch on a circuit when two inputs are present.

 

Cancer cells differ from normal cells in the profile of their gene expression. So the researchers developed synthetic promoters — DNA sequences designed to initiate gene expression but only in cancer cells. The circuit is delivered to cells in the affected area of the body using a virus. The synthetic promotors are then designed to bind to certain proteins that are active in tumor cells, causing the promoters to turn on. “Only when two of these cancer promoters are activated, does the circuit itself switch on,” Lu says.

 

This allows the circuit to target tumors more accurately than existing therapies, as it requires two cancer-specific signals to be present before it will respond. Once activated, the circuit expresses proteins designed to direct the immune system to target the tumor cells, including surface T cell engagers, which direct T cells to kill the cells. The circuit also expresses a checkpoint inhibitor designed to lift the brakes on T cell activity. When the researchers tested the circuit in vitro, they found that it was able to detect ovarian cancer cells from amongst other noncancerous ovarian cells and other cell types.

 

They then tested the circuit in mice implanted with ovarian cancer cells, and demonstrated that it could trigger T cells to seek out and kill the cancer cells without harming other cells around them.

Finally, the researchers showed that the circuit could be readily converted to target other cancer cells. “We identified other promoters that were selective for breast cancer, and when these were encoded into the circuit, it would target breast cancer cells over other types of cell,” Lu says.

 

Ultimately, they hope they will also be able to use the system to target other diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases.


Via Gerd Moe-Behrens, ComplexInsight
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The Human Cell Atlas: an ambitious project to map all the cells in the human body gets officially under way

The Human Cell Atlas: an ambitious project to map all the cells in the human body gets officially under way | Amazing Science | Scoop.it

Our knowledge of the cells that make up the human body, and how they vary from person to person, or throughout development and in health or disease, is still very limited. Recently, a year after project planning began, more than 130 biologists, computational scientists, technologists and clinicians are reconvening in Rehovot, Israel, to kick the Human Cell Atlas initiative1 into full gear. This international collaboration between hundreds of scientists from dozens of universities and institutes — including the UK Wellcome Trust Sanger Institute, RIKEN in Japan, the Karolinska Institute in Stockholm and the Broad Institute of MIT and Harvard in Cambridge, Massachusetts — aims to create comprehensive reference maps of all human cells as a basis for research, diagnosis, monitoring and treatment.

 

On behalf of the Human Cell Atlas organizing committee, we outline here some of the key challenges faced in building such an atlas — and our proposed strategies. For more details on how the atlas will be built as an open global resource, see the white paper2 posted on the Human Cell Atlas website.

 

Cells have been characterized and classified with increasing precision since Robert Hooke first identified them under the microscope in the seventeenth century. But biologists have not yet determined all the molecular constituents of cells, nor have they established how all these constituents are associated with each other in tissues, systems and organs. As a result, there are many cell types we don’t know about. We also don’t know how all the cells in the body change from one state to another, which other cells they interact with or how they are altered during development.

Technology revolution 

New technologies offer an opportunity to build a systematic atlas at unprecedented resolution. These tools range from single-cell RNA sequencing to techniques for assessing a cell’s protein molecules and profiling the accessibility of the chromatin. For example, we can now determine the RNA profiles for millions of individual cells in parallel (see ‘From one to millions’). Protein composition and chromatin features can be studied in hundreds or thousands of individual cells, and mutations or other markers tracked to reconstruct cell lineages. We can also profile multiple variants of RNA and proteins in situ to map cells and their molecules to their locations in tissues.

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MIT Researchers Develop Nanoparticles that Deliver the CRISPR genome-editing system

MIT Researchers Develop Nanoparticles that Deliver the CRISPR genome-editing system | Amazing Science | Scoop.it
In a new study, MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system and specifically modify genes in mice.

The team used nanoparticles to carry the CRISPR components, eliminating the need to use viruses for delivery.

Using the new delivery technique, the researchers were able to cut out certain genes in about 80 percent of liver cells, the best success rate ever achieved with CRISPR in adult animals.

“What’s really exciting here is that we’ve shown you can make a nanoparticle that can be used to permanently and specifically edit the DNA in the liver of an adult animal,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

One of the genes targeted in this study, known as Pcsk9, regulates cholesterol levels. Mutations in the human version of the gene are associated with a rare disorder called dominant familial hypercholesterolemia, and the FDA recently approved two antibody drugs that inhibit Pcsk9.

However these antibodies need to be taken regularly, and for the rest of the patient’s life, to provide therapy. The new nanoparticles permanently edit the gene following a single treatment, and the technique also offers promise for treating other liver disorders, according to the MIT team.
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Lamb3 Mutation Correction to Heal a Kid with Junctional Epidermolysis Bullosa

Lamb3 Mutation Correction to Heal a Kid with Junctional Epidermolysis Bullosa | Amazing Science | Scoop.it
When a genetic skin-peeling disease threatened the life of a 7-year-old boy, doctors turned to an experimental mashup of stem cells and gene therapy.

 

The baby was still in diapers when the first blister appeared, ballooning red and angry from his pale, newborn skin. Soon, they became a regular feature on the map of his body, along with deep creases in his face when he howled out in pain. A doctor told the parents his LAMB3 gene had a glitch—his body wasn’t making enough of a protein to anchor the outer layer of his skin to the inner ones. For seven years they kept the blisters at bay. But by summer of 2015, the wounds were winning—and the boy had lost 60 percent of his skin.

 

In June, the child arrived at the burn unit of the Ruhr University Children’s Hospital in Bochum, Germany, hot with fever and septic from a strain of staph. His doctors began pumping him full of antibiotics and painkillers, bathing him in iodine, and dressing the wounds with ointments. Nothing worked. The father gave his son skin from his own body. It didn’t take. After five weeks in the intensive care unit, the boy was dying. But there was one more thing left to try. A genetic experiment never attempted before.

 

The doctors snipped out a tiny square of the boy’s skin and shipped it to a laboratory in Modena, Italy. Scientists there used a virus to inject a functioning LAMB3 gene into all the cells that made up that patch of skin, including some stem cells. Then they grew them and grew them and grew them until there were enough to seed onto nine square feet of gauze and protein gel. An adult-sized skin suit would take about 22 square feet, but for a kid, it was more than enough.

 

In October, the Italians sent the new skin back to Germany, and the boy’s doctors carefully laid them into areas they’d scoured of any dead or infected flesh, first to his arms and legs. When another batch arrived in November they did his chest and back. In January they touched up any spots they’d missed. Seven and a half months after he was admitted, the boy walked out the hospital doors, wound-free—the recipient of the largest-ever infusion of transgenic stem cells. A few weeks later he returned to elementary school. Today, the boy spends his free time playing soccer and bruising like a normal kid. His new skin has never seen a blister.

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Novel CRISPR-derived ‘base editors’ surgically alter DNA or RNA, offering new ways to fix mutations

Novel CRISPR-derived ‘base editors’ surgically alter DNA or RNA, offering new ways to fix mutations | Amazing Science | Scoop.it

Since the start of the CRISPR craze 5 years ago, scientists have raced to invent ever-more-versatile or efficient variations of this powerful tool, which vastly simplifies the editing of DNA. Two studies published in Science and Nature this week broaden CRISPR's reach further still, honing a subtler approach to modifying genetic material that's called base editing. One study extends a strategy for editing DNA, whereas the other breaks new ground by base editing its molecular cousin, RNA.

 

Both open new avenues for genetic research and even curing diseases. "One shouldn't view base editors as better than CRISPR—they're just different," says David Liu, a chemist at Harvard University who pioneered DNA base editing in a paper in Nature last year and co-authored the latest Nature paper. "It's like, what's better, a boat or a car?"

 

CRISPR, adapted from a primitive bacterial immune system, does its handiwork by first cutting the double-stranded DNA at a target site in a genome. Base editing, in contrast, does not cut the double helix, but instead uses enzymes to precisely rearrange some of the atoms in one of the four bases that make up DNA or RNA, converting the base into a different one without altering the bases around it. That ability greatly increases the options for altering genetic material. "It's a very worthwhile addition and it's here to stay," says CRISPR researcher Erik Sontheimer of the University of Massachusetts Medical School in Worcester.

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Scientists Are Rewriting the History of Photosynthesis

Scientists Are Rewriting the History of Photosynthesis | Amazing Science | Scoop.it

Researchers have caught their best glimpse yet into the origins of photosynthesis, one of nature’s most momentous innovations. By taking near-atomic, high-resolution X-ray images of proteins from primitive bacteria, investigators at Arizona State University and Pennsylvania State University have extrapolated what the earliest version of photosynthesis might have looked like nearly 3.5 billion years ago. If they are right, their findings could rewrite the evolutionary history of the process that life uses to convert sunlight into chemical energy.


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Scientists Can Now Repaint Butterfly Wings

Scientists Can Now Repaint Butterfly Wings | Amazing Science | Scoop.it
Thanks to CRISPR, scientists are studying animal evolution in ways that were previously thought to be impossible.

 

When the butterfly emerged from its pupa, Robert Reed was stunned. It was a Gulf fritillary—a bright-orange species with a few tigerlike stripes. But this butterfly had no trace of orange anywhere. It was entirely black and silver. “It was the most heavy-metal butterfly I’ve ever seen,” Reed says. “It was amazing to see that thing crawl out of the pupa.”

 

Reed’s team at Cornell University had created the metal butterfly by deleting just one of its genes, using the revolutionary gene-editing technique known as CRISPR. And by performing the same feat across several butterfly species, the team showed that this one gene, known as optix, controls all kinds of butterfly patterns. Red becomes black. Matte becomes shiny. Another gene, known asWntA, produces even wilder variations when it’s deleted. Eyespots disappear. Boundaries shift. Stripes blur.

 

These experiments prove what earlier studies had suggested—that optix andWntA are “paintbrush genes,” says Anyi Mazo-Vargas, one of Reed’s students. “Wherever you put them, you’ll have a pattern.”

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Grafting human cancer cells into mice alters tumor evolution

Grafting human cancer cells into mice alters tumor evolution | Amazing Science | Scoop.it

An analysis of more than 1,000 mouse models of cancer has challenged their ability to predict patients’ response to therapy.

The study, published today in Nature Genetics1, catalogues the genetic changes that occur in human tumors after they have been grafted into mouse hosts. Such models, called patient-derived xenografts (PDXs), are used in basic research and as ‘avatars’ for individual patients. Researchers use these avatar mice to test a bevy of chemotherapies against a person's tumor, in the hope of tailoring a treatment plan for the patient's specific cancer.

 

But fresh data from geneticists at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, suggest that transplanting human cancer cells into a mouse alters the cells' evolution, reshaping the tumor's genome in ways that could affect responses to chemotherapy.

 

“The assumption is that what grows out in the PDX is reflective of the bulk of the tumor in the patient,” says cancer geneticist Todd Golub, a lead author on the study. “But there’s quite dramatic resculpting of the tumor genome.” No animal model is perfect, and researchers have long acknowledged that PDXs have their limitations. To avoid an immune assault on the foreign tumor, for example, PDXs are typically grafted into mice that lack a functioning immune system. This compromises scientists' ability to study how immune cells interact with the tumor — an area of increasing interest given the success of cancer therapies that unleash the immune system. PDXs can also take months to generate, making them too slow to serve as avatars for those patients who need to make immediate decisions about their therapy.

 

But previous research had suggested that the PDXs were reasonably faithful reproductions of the human tumors they are meant to model, offering researchers a chance to explore the tumor’s interaction with its environment in ways that are not possible using cells grown in a Petri dish. The US National Cancer Institute has developed a library of more than 100 PDXs for distribution to researchers, and European scientists have launched EurOPDX, a consortium that boasts more than 1,500 models for more than 30 tumor types. One company, Champions Oncology of Hackensack, New Jersey, creates and tests mouse avatars for individual patients and for pharmaceutical companies to use in research.

 
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GMO Apples That Don’t Brown to Reach U.S. Shelves This Fall

GMO Apples That Don’t Brown to Reach U.S. Shelves This Fall | Amazing Science | Scoop.it
Can genetic modification appeal to consumers? A new apple will test the market.

 

The so-called Arctic apples are genetically altered to suppress browning and may be offered for sale as bagged slices in up to 400 stores in the Midwest and Southern California, according to the company. The launch is the first significant test of a GMO whose modification is meant to appeal to consumers, rather than help farmers increase production, since a slow-ripening tomato called the Flavr Savr flopped in the 1990s.

 

The modified Golden Delicious apples were developed by Okanagan Specialty Fruits, a privately owned company acquired for $41 million in 2015 by the Maryland biotech Intrexon. Other divisions of that company are already marketing genetically modified salmon, cloned cattle, and self-destructing mosquitoes.

 

The company plans to sell the apples as bags of pre-sliced fruit but say they will not be labeled as “produced with genetic engineering” and will not come with any other packaging identifying them as GMOs. Instead, as allowed under a 2016 labeling law, there will be a QR code that links to a Web page with detailed information on how the apples were made.

“We didn’t want put ‘GMO’ and a skull and crossbones on the package,” Neal Carter, Okanagan’s founder, said this week, during a presentation in San Francisco.

 

A package of golden delicious apple slices. The fruit has been genetically modified so they don't turn brown. The GM apple is notable partly because Carter, an apple grower and farming innovator, independently developed it and won regulatory approval to sell it. Most GMOs have been developed and marketed as seeds by large corporations like Monsanto or DuPont and involve large-acre crops like soybeans and corn. Using a technique called gene silencing, Carter and his research team engineered the apple’s DNA to produce less polyphenol oxidase, or PPO, the enzyme that causes the flesh to turn brown. Carter says slices of the engineered apples can stay free of browning as long as three weeks.To some, genetic slowing of the browning process could seem like a solution in search of a problem.

 

Commercial apple slices are already preserved with a mixture of calcium and vitamin C, which keeps them from browning long enough to be ordered via Amazon. At home, many cooks know a squirt of lemon juice does the trick, at least for a few hours.Groups opposing GMOs have protested the introduction of Okanagan’s apples and pressured food companies including Burger King not to sell them. Friends of the Earth told the Independent that the Arctic apple is “understudied, unlabeled, and unnecessary.” Because of widespread opposition, genetically modified foods are subject to an array of labeling rules and even outright bans around the world.  

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Tech Showcase: Ribocomputing

Tech Showcase: Ribocomputing | Amazing Science | Scoop.it
A novel method of programming cells to operate like computers, called Ribocomputing, will be aided by Twist Bioscience's streamlined DNA manufacturing process.

 

One goal of synthetic biology is to engineer life to recognize desired inputs and in turn respond with desired outputs. Biocomputing is the management of this input/output system, designing genetic parts that allow life to perform logic based decisions in a manner not dissimilar to the computer you're using to read this article. 
 
Researchers at the Wyss Institute for Biologically Inspired Engineering and Arizona State University, in a recent article in Nature, demonstrated a novel method of programming cells to operate like computers. They call their method ribocomputing because their engineered cells carry out complex logic-based computations exclusively using ribonucleic acids, more commonly known as RNA.
 
Unlike the digital computers ubiquitous in the modern world, which use electricity to accomplish all higher-order functions, these ribocomputers perform logical operations on biological materials, such as proteins, toxins, and immune system molecules. Adding programmability to cells opens up exciting new possibilities for ways to control cells and their interactions with organisms and their environment. The ribocumputing researchers propose that using this new technique, cells and microorganisms can be programmed to accomplish tasks ranging from disease diagnostics and therapeutic drug delivery to green energy production and environmental cleanup.
 
In their ribocomputing demonstration, the research team engineered the bacteria E. coli to sense the presence of 12 different molecules, and then use a computational circuit encoded in RNA to calculate the correct level of green fluorescent protein (GFP) to express. GFP is commonly used as a marker in biological experiments, as its green glow makes it simple for researchers to assess the behavior of genes or pathways in question. 
 
In the ribocomputing experiment, the researchers first designed an RNA circuit to map different combinations and levels of input molecules to specific GFP intensities, as controlled by expression levels. Next, the researchers introduced controlled levels of the input molecules into the engineered E. coli’s cellular environments, and then checked whether GFP was lighting up at the specified levels. By confirming that GFP was behaving in a manner that they expected, the researchers demonstrated the viability of their RNA circuits to carry out computations.
 
In general, the principles in this experiment can be applied to other kinds of bio-computation. Using the same methodology, cells can be engineered to respond with specified behavior to any number of the diverse chemical arrangements they encounter in their complicated environments.
 
The demonstration of successful RNA-based computing represents a significant advancement for cellular computing technology. Although such computing had been described in publications almost two decades ago, the conventional methods required resources and included drawbacks that made the techniques unattractive to pursue for commercial, industrial, and clinical applications. In previous experiments, researchers used combinations of DNA, RNA, proteins, and other molecules to design biological circuits. Incorporating these disparate computing elements into a circuit design is more error-prone: successful operation of the circuit would hinge on the precise coordination of these multifarious components. Each component adds a source of noise to the logical circuit, degrading the results. As the computational load increases, it can limit the effectiveness and applicability of the method. By using RNA only, various sources of noise can be muted.
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Single-stranded DNA and RNA origami go live

Single-stranded DNA and RNA origami go live | Amazing Science | Scoop.it

Self-folding of an information-carrying polymer into a defined structure is foundational to biology and offers attractive potential as a synthetic strategy. Although multicomponent self-assembly has produced complex synthetic nanostructures, unimolecular folding has seen limited progress. This new work describes a framework to design and synthesize a single DNA or RNA strand to self-fold into a complex yet unknotted structure that approximates an arbitrary user-prescribed shape. The scientists experimentally constructed diverse multikilobase single-stranded structures, including a ~10,000-nucleotide (nt) DNA structure and a ~6,000-nt RNA structure. They were able to demonstrate facile replication of the strand in vitro and in living cells. The work here thus establishes unimolecular folding as a general strategy for constructing complex and replicable nucleic acid nanostructures, and expands the design space and material scalability for bottom-up nanotechnology.

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Scientists modify CRISPR to epigenetically treat diabetes, kidney disease and muscular dystrophy

Scientists modify CRISPR to epigenetically treat diabetes, kidney disease and muscular dystrophy | Amazing Science | Scoop.it

Most CRISPR/Cas9 systems work by creating "double-strand breaks" (DSBs) in regions of the genome targeted for editing or for deletion, but many researchers are opposed to creating such breaks in the DNA of living humans. As a proof of concept, the Salk group used their new approach to treat several diseases, including diabetes, acute kidney disease, and muscular dystrophy, in mouse models.

 

"Although many studies have demonstrated that CRISPR/Cas9 can be applied as a powerful tool for gene therapy, there are growing concerns regarding unwanted mutations generated by the double-strand breaks through this technology," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and senior author of the new paper, published in Cell on December 7, 2017. "We were able to get around that concern."

 

In the original CRISPR/Cas9 system, the enzyme Cas9 is coupled with guide RNAs that target it to the right spot in the genome to create DSBs. Recently, some researchers have started using a "dead" form of Cas9 (dCas9), which can still target specific places in the genome, but no longer cuts DNA. Instead, dCas9 has been coupled with transcriptional activation domains—molecular switches—that turn on targeted genes. But the resulting protein—dCas9 attached to the activator switches—is too large and bulky to fit into the vehicle typically used to deliver these kinds of therapies to cells in living organisms, namely adeno-associated viruses (AAVs). The lack of an efficient delivery system makes it very difficult to use this tool in clinical applications.


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Programming cells with computer-like logic

Programming cells with computer-like logic | Amazing Science | Scoop.it

Synthetic biologists are converting microbial cells into living devices that are able to perform useful tasks ranging from the production of drugs, fine chemicals and biofuels to detecting disease-causing agents and releasing therapeutic molecules inside the body. To accomplish this, they fit cells with artificial molecular machinery that can sense stimuli such as toxins in the environment, metabolite levels or inflammatory signals. Much like electronic circuits, these synthetic biological circuits can process information and make logic-guided decisions. Unlike their electronic counterparts, however, biological circuits must be fabricated from the molecular components that cells can produce, and they must operate in the crowded and ever-changing environment within each cell.

 

Similar to how computer scientists use logical language to have their programs make accurate AND, OR and NOT decisions towards a final goal, “Ribocomputing Devices” (stylized here in yellow) developed by a team at the Wyss Institute can now be used by synthetic biologists to sense and interpret multiple signals in cells and logically instruct their ribosomes (stylized in blue and green) to produce different proteins.

 

So far, synthetic biological circuits can only sense a handful of signals, giving them an incomplete picture of conditions in the host cell. They are also built out of several moving parts in the form of different types of molecules, such as DNAs, RNAs, and proteins, that must find, bind and work together to sense and process signals. Identifying molecules that cooperate well with one another is difficult and makes development of new biological circuits a time-consuming and often unpredictable process.

 

As reported in Nature, a team at Harvard’s Wyss Institute for Biologically Inspired Engineering is now presenting an all-in-one solution that imbues a molecule of ‘ribo’ nucleic acid or RNA with the capacity to sense multiple signals and make logical decisions to control protein production with high precision. The study’s approach resulted in a genetically encodable RNA nano-device that can perform an unprecedented 12-input logic operation to accurately regulate the expression of a fluorescent reporter protein in E. coli bacteria only when encountering a complex, user-prescribed profile of intra-cellular stimuli. Such programmable nano-devices may allow researchers to construct more sophisticated synthetic biological circuits, enabling them to analyze complex cellular environments efficiently and to respond accurately.

 

“We demonstrate that an RNA molecule can be engineered into a programmable and logically acting “Ribocomputing Device,” said Wyss Institute Core Faculty member Peng Yin, Ph.D., who led the study and is also Professor of Systems Biology at Harvard Medical School. “This breakthrough at the interface of nanotechnology and synthetic biology will enable us to design more reliable synthetic biological circuits that are much more conscious of the influences in their environment relevant to specific goals.”

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This robot made of algae can swim through your body—thanks to magnets

This robot made of algae can swim through your body—thanks to magnets | Amazing Science | Scoop.it

Biohybrid bot could one day deliver drugs or do surgery.

 

For decades, engineers have been trying to build medical robots that can deliver drugs or do surgery inside the human body—a somewhat less fantastic version of the 1966 sci-fi film Fantastic Voyage. Now, scientists have manipulated spirulina, a microscopic plant and food supplement, to travel through people in response to magnetic signals. The biohybrid robot could one day carry drugs to specific parts of the body, minimizing side effects. What’s more, the robot—and its magnetic coat—appear to kill cancer cells.

 

Spirulina, an alga, looks like a tiny coiled spring at the microscopic level. Researchers had been trying, and succeeding to various degrees, to build bots out of rods, tubes, spheres, and even cages no bigger than a cell. Outfitting these tiny devices with an ample power supply has been quite a challenge, as most potential fuels are toxic to humans. Another problem is steering such a microrobot through the body’s maze of proteins and other molecules, which requires both a way to control its movements and to see where it is.

 

So Li Zhang, a materials scientist at the Chinese University of Hong Kong in Shatin, turned to magnetism—and living organisms. Magnetic fields created outside the body can penetrate living tissue without harm, allowing researchers to move magnetized objects around inside. For maximum mobility, a helical body propelled by twirling works best. Enter Spirulina. “It’s surprising that you can find in nature such a convenient structure and that it can behave so nicely,” says Peer Fischer, a physical chemist at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany, who was not involved in the study.

 

Several years ago, Zhang and his colleagues used the alga as inspiration for a synthetic microbot, which worked to some degree. This time, the scientists decided to use the alga itself. They needed a way to track the robot in the body, and the alga produces a fluorescent glow. The researchers wondered whether they could follow the robot's course near the body surface by detecting this fluorescence, and then use a commonly used medical imaging technology called nuclear magnetic resonance (NMR) to track it in deeper parts of the body. NMR works by detecting magnetic particles given to a patient before the imaging takes place.

 

They developed a one-step method to magnetize the alga, coating millions of Spirulina with iron oxide nanoparticles. A longer dip time allows for more control, but a shorter dip time allows researchers to detect the fluorescence more readily. When the bot is too deep for that technique to work, NMR can still follow the robot’s course because of the coating, the researchers report today in Science Robotics. Using NMR, they observed the microrobots swarm in a rat’s stomach as directed by the magnetic field.

 

“It’s a step forward that you can track these swimmers in the body,” says Joseph Wang, a nanoengineer at the University of California, San Diego, who is developing a different sort of medical microbot. “And it’s biocompatible and low cost.”

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Algae. Another amazing tool afforded by Nature!
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Can data storage in DNA solve our massive data storage problem in the future?

Can data storage in DNA solve our massive data storage problem in the future? | Amazing Science | Scoop.it

The latest in high-density ultra-durable data storage has been perfected over billions of years by nature itself.

 

Now ‘Smoke on the Water’ is making history again. This September, it was one of the first items from the Memory Of the World archive to be stored in the form of DNA and then played back with 100% accuracy. The project was a joint effort between the University of Washington, Microsoft and Twist Bioscience, a San Francisco-based DNA manufacturing company.

 

The demonstration was billed as a ‘proof of principle’ – which is shorthand for successful but too expensive to be practical. At least for now. Many pundits predict it’s just a matter of time till DNA pips magnetic tape as the ultimate way to store data. It’s compact, efficient and resilient. After all, it has been tweaked over billions of years into the perfect repository for genetic information. It will never become obsolete, because as long as there is life on Earth, we will be interested in decoding DNA. “Nature has optimised the format,” says Twist Bioscience’s chief technology officer Bill Peck.

 

Players like Microsoft, IBM and Intel are showing signs of interest. In April, they joined other industry, academic and government experts at an invitation-only workshop (cosponsored by the U.S. Intelligence Advanced Research Projects Activity (IARPA)) to discuss the practical potential for DNA to solve humanity’s looming data storage crisis.

 

It’s a big problem that’s getting bigger by the minute. According to a 2016 IBM Marketing Cloud report, 90% of the data that exists today was created in just the past two years. Every day, we generate another 2.5 quintillion (2.5 × 1018) bytes of information. It pours in from high definition video and photos, Big Data from particle physics, genomic sequencing, space probes, satellites, and remote sensing; from think tanks, covert surveillance operations, and Internet tracking algorithms. EVERY DAY, WE GENERATE ANOTHER 2.5 QUINTILLION BYTES OF INFORMATION.

 

Right now all those bits and bytes flow into gigantic server farms, onto spinning hard drives or reels of state-of-the-art magnetic tape. These physical substrates occupy a lot of space. Compare this to DNA. The entire human genome, a code of three billion DNA base pairs, or in data speak, 3,000 megabytes, fits into a package that is invisible to the naked eye – the cell’s nucleus. A gram of DNA — the size of a drop of water on your fingertip — can store at least the equivalent of 233 computer hard drives weighing more than 150 kilograms. To store the all the genetic information in a human body — 150 zettabytes — on tape or hard drives, you’d need a facility covering thousands, if not millions of square feet.

 

And then there’s durability. Of the current storage contenders, magnetic tape has the best lifespan, at about 10-20 years. Hard drives, CDs, DVDs and flash drives are less reliable, often failing within five to ten years. DNA has proven that it can survive thousands of years unscathed. In 2013, for example, the genome of an early horse relative was reconstructed from DNA from a 700,000-year-old bone fragment found in the Alaskan permafrost.


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Pigments on synthetic DNA circuits can harvest light energy

Pigments on synthetic DNA circuits can harvest light energy | Amazing Science | Scoop.it

Novel structures made with DNA scaffolds could be used to create solar-powered materials.

 

By organizing pigments on a DNA scaffold, an MIT-led team of researchers has designed a light-harvesting material that closely mimics the structure of naturally occurring photosynthetic structures.

 

The researchers showed that their synthetic material can absorb light and efficiently transfer its energy along precisely controlled pathways. This type of structure could be incorporated into materials such as glass or textiles, enabling them to harvest or otherwise control incoming energy from sunlight, says Mark Bathe, an associate professor of biological engineering at MIT.

 

“This is the first demonstration of a purely synthetic mimic of a natural light-harvesting circuit that consists of densely packed clusters of dyes that are precisely organized spatially at the nanometer scale, as found in bacterial systems,” Bathe says. One nanometer is one billionth of a meter, or 1/10,000 the thickness of a human hair.

 

Bathe is one of the senior authors of the new study, along with Alan Aspuru-Guzik, a professor of chemistry and chemical biology at Harvard University, and Hao Yan, a professor of chemistry and biochemistry at Arizona State University. Lead authors of the paper, which appears in the Nov. 13 issue of Nature Materials, are former MIT postdoc Etienne Boulais, Harvard graduate student Nicolas Sawaya, and MIT postdoc Rémi Veneziano. 


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Are we at the dawn of choosing human embryos by health, height, and future intelligence?

Are we at the dawn of choosing human embryos by health, height, and future intelligence? | Amazing Science | Scoop.it
Will you be among the first to pick your kids’ IQ? As machine learning unlocks predictions from DNA databases, scientists say parents could have choices never before possible.

 

 

Nathan Treff was diagnosed with type 1 diabetes at 24. It’s a disease that runs in families, but it has complex causes. More than one gene is involved. And the environment plays a role too.

So you don’t know who will get it. Treff’s grandfather had it, and lost a leg. But Treff’s three young kids are fine, so far. He’s crossing his fingers they won’t develop it later.

 

Now Treff, an in vitro fertilization specialist, is working on a radical way to change the odds. Using a combination of computer models and DNA tests, the startup company he’s working with, Genomic Prediction, thinks it has a way of predicting which IVF embryos in a laboratory dish would be most likely to develop type 1 diabetes or other complex diseases. Armed with such statistical scorecards, doctors and parents could huddle and choose to avoid embryos with failing grades.

 

IVF clinics already test the DNA of embryos to spot rare diseases, like cystic fibrosis, caused by defects in a single gene. But these “preimplantation” tests are poised for a dramatic leap forward as it becomes possible to peer more deeply at an embryo’s genome and create broad statistical forecasts about the person it would become.

 

The advance is occurring, say scientists, thanks to a growing flood of genetic data collected from large population studies. As statistical models known as predictors gobble up DNA and health information about hundreds of thousands of people, they’re getting more accurate at spotting the genetic patterns that foreshadow disease risk. But they have a controversial side, since the same techniques can be used to project the eventual height, weight, skin tone, and even intelligence of an IVF embryo.

 

In addition to Treff, who is the company’s chief scientific officer, the founders of Genomic Prediction are Stephen Hsu, a physicist who is vice president for research at Michigan State University, and Laurent Tellier, a Danish bioinformatician who is CEO. Both Hsu and Tellier have been closely involved with a project in China that aims to sequence the genomes of mathematical geniuses, hoping to shed light on the genetic basis of IQ.

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Suicide small RNA molecules can kill cancer cells

Suicide small RNA molecules can kill cancer cells | Amazing Science | Scoop.it

Small RNA molecules originally developed as a tool to study gene function trigger a mechanism hidden in every cell that forces the cell to commit suicide, reports a new Northwestern Medicine study, the first to identify molecules to trigger a fail-safe mechanism that may protect us from cancer.

 

The mechanism—RNA suicide molecules—can potentially be developed into a novel form of cancer therapy, the study authors said. Cancer cells treated with the RNA molecules never become resistant to them because they simultaneously eliminate multiple genes that cancer cells need for survival. "It's like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time," said Northwestern scientist and lead study author Marcus Peter. "You cannot survive." The inability of cancer cells to develop resistance to the molecules is a first, Peter said.

 

"This could be a major breakthrough," noted Peter, the Tom D. Spies Professor of Cancer Metabolism at Northwestern University Feinberg School of Medicine. Peter and his team discovered sequences in the human genome that when converted into small double-stranded RNA molecules trigger what they believe to be an ancient kill switch in cells to prevent cancer. He has been searching for the phantom molecules with this activity for eight years.

 

"We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old," he said. "It could be a fail safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer."

 

This study, which will be published Oct. 24, 2017, in eLife, and two other new Northwestern studies in Oncotarget and Cell Cycle by the Peter group, describe the discovery of the assassin molecules present in multiple human genes and their powerful effect on cancer in mice.


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As 'Flesh-Eating' Leishmania Come Closer, a Vaccine Against Them Does, Too

As 'Flesh-Eating' Leishmania Come Closer, a Vaccine Against Them Does, Too | Amazing Science | Scoop.it
A potentially deadly parasite that can ulcerate skin, nose, mouth and organs could someday meet its match in an experimental vaccine that has now worked in lab tests on humanized mice.

 

Parasites that ulcerate the skin, can disfigure the face, and can fatally mutilate internal organs are creeping closer to the southern edges of the United States. No vaccine is available against Leishmania yet, but researchers have now come closer to changing that. A new experimental vaccine, made with a proprietary biological particle developed at the Georgia Institute of Technology, has immunized laboratory mice that were genetically altered to mimic the human immune system.

 

The vaccine exploits a weakness in Leishmania’s tricky chemical camouflage, which normally hides it from the victim’s disease-fighting cells, to trigger a forceful immune response against the parasite, according to a new study.

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Major advance in nanopore detection of peptides and proteins

Major advance in nanopore detection of peptides and proteins | Amazing Science | Scoop.it

Nanopore technology, which is used to sequence DNA, is cheap, hand-held and works in the jungle and in space. The use of this technology to identify peptides or proteins is now a step closer. University of Groningen scientists have used a patented nanopore to identify the fingerprints of proteins and peptides, and it can even detect polypeptides differing by one amino acid. The results were published on 16 October in the journal Nature Communications.

 

Scientists have now been able to identify a number of peptides and proteins passing through a funnel-shaped nanopore. They have solved two main problems that have hampered attempts to analyze and sequence proteins with nanopores: getting polypeptides into the pore and identifying differences in proteins by recordings of current. 'Nanopores usually carry a charge, and the amino acids that make up polypeptides are also charged. Getting the polypeptide inside the pore and to pass through nanopores is therefore a challenge', explains associate professor of Chemical Biology Giovanni Maglia.

 

Maglia and his team used an electro-osmotic flow to pull the polypeptides into the pores. Under an applied potential across the nanopore, a flow of ions and water passes through the pore.' If the direction of the ion current can be controlled, a fluid flow strong enough to transport polypeptides can be generated. 'We did this by tuning the charges inside the pore wall. By changing the pH of the medium, it was possible to fine-tune the balance between the electro-osmotic flow and the force of the electric field which was applied across the pore.'

 

Maglia tested five different polypeptides ranging from 1 to 25 kilodalton. 'We used biomarker peptides linked to disease, with different charges and shapes', he says. The polypeptides entered the pore and the current across the pore produced a 'fingerprint' for each. He thus managed to distinguish two versions of the 21 amino acid peptide endothelin, which differ by just one amino acid (tryptophan or methionine).

 

Getting a good reading from a nanopore is complicated. Maglia used a new kind of pore that he characterized and patented. 'Pores used in the past are barrel-shaped, which means the shape and size of the pore has fundamental limitations. But our pore has an alpha helical funnel shape, and the size of the narrow end, which is where we do our measurements, means it should contain just one amino acid, so it is more easily tuned.'

 

Currently, the polypeptides pass through the pore too rapidly to identify the separate amino acids. This is needed for protein sequencing at the single-molecule scale. It would be a valuable tool for research, explains Maglia: 'Proteins can be chemically modified in many unique ways, and we have very little information on the exact composition of proteins in our body.' This can only be seen at the single-molecule level.

 

Reference: Gang Huang, Kherim Willems, Misha Soskine, Carsten Wloka & Giovanni Maglia: Electro-Osmotic Capture and Ionic Discrimination of Peptide and Protein Biomarkers with FraC Nanopores. Nature Communications, 16 October 2016

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CRISPR gene therapy could turn your skin into a glucose sensor

CRISPR gene therapy could turn your skin into a glucose sensor | Amazing Science | Scoop.it

Diabetics might ultimately have glucose sensors built into their bodies.

 

For diabetics, the constant finger pricks to obtain a blood drop and measure its glucose level is an annoyance. But it’s essential, too. Out-of-whack blood sugar can be fatal. That’s why engineers have tried for decades to create a noninvasive glucose sensor,  but developing one has proved difficult. It’s just not feasible to accurately measure sugar levels through the skin.

 

So why not, instead, redesign a person’s body to do the measuring instead? That’s the bright idea that Xiaoyang Wu and colleagues at the University of Chicago’s Ben May Department for Cancer Research had. 

 

In a fascinating mashup of technologies, the Chicago team says it has genetically edited skin cells from a mouse and turned them into a glucose detector that, once grafted onto the animals, works all the time and doesn’t need a battery.

 

It’s the first time living skin has been turned into a sensor, says Wu, adding that “a skin-based technology would have a lot of advantages” over finger pricks or even the continuous monitors some diabetics use.

 

Skin is one of the largest organs in the body, Wu and his colleagues point out in their report, which appeared last week on the publishing website bioRxiv. Skin is easy to get ahold of and—they say—easy to remove later if things go wrong. To make their biological invention, Wu and team first collected from mice some of the stem cells whose job it is to make new skin. Next, they used the gene-editing technique CRISPR to create their built-in glucose detector. That involved adding a gene from E. coli bacteria whose product is a protein that sticks to sugar molecules. 

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Scientists create genetically modified mosquitoes and bacteria in mosquitoes' guts to combat deadly malaria

Scientists create genetically modified mosquitoes and bacteria in mosquitoes' guts to combat deadly malaria | Amazing Science | Scoop.it
Scientists explore genetically modifying mosquitoes and bacteria in mosquitoes' guts to combat deadly malaria.

 

The first study focused on whether mosquitoes that have been genetically modified to be more resistant to the malaria-causing parasite would become weaker and less able to mate and breed.

If modified mosquitoes are going to be used against malaria, the transformed mosquitoes must be as fit as wild ones and able to pass on their genetic modification in large scale to future generations.

 

The study, led by mosquito vector biologist George Dimopoulos, found that one type of genetically modified mosquito not only bred well, but became more attractive to normal mosquitoes.

 

Dimopoulos took a group of genetically modified mosquitoes and a group of wild normal mosquitoes and locked them up together. To his surprise, the normal male mosquitoes preferred the genetically modified females, while the genetically modified males went wild over the normal females. Those mating preferences meant that within one generation, the mosquito population was becoming 90 percent genetically modified.

 

“We found the modification was changing the microbiome and bacteria of the genetically modified mosquitoes,” Dimopoulos said. “It made them smell different, better to their mates.”

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