Neuroscience  

Scientists have carefully reverse engineered and created a 3D model of a synapse. The resulting model will serve as a reference source for neuroscientists of all specializations in the future, and will support future research.

Synapses are the contacts between nerve cells that allow the flow of information that makes our brains work. However, the molecular architecture of these highly complex structures has been largely  unknown until now.

"This 3D model of a synapse opens a new world for neuroscientists."

Now, a research team from Göttingen, led by Prof. Silvio O. Rizzoli from the DFG Research Center and Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) of the University Medical Center Göttingen, managed to determine the copy numbers and positions of all important building blocks of a synapse for the first time. This allowed them to reconstruct the first scientifically accurate 3D model of a synapse.

This effort has been made possible by a collaboration of specialists in electron microscopy, super-resolution light microscopy (STED), mass spectrometry, and quantitative biochemistry from the UMG, the Max Planck Institute for Biophysical Chemistry, Göttingen, and the Leibniz Institute for Molecular Pharmacology in Berlin.

The results have been published in the journal Science in an article titled, "Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins". Highlighting the impact of this work, the presented model has been selected as the cover of the respective issue of the Science journal.

The reverse engineering output, shown above displays a synapse in cross section. The small spheres are synaptic vesicles. The model shows 60 different proteins.

“This 3D model of a synapse opens a new world for neuroscientists,” says Rizzoli, senior author of the publication. Particularly the abundance and distribution of the building blocks have long been terra incognita, an undiscovered land. The model presented by Rizzoli and his team now shows several hundreds of thousands of individual proteins in correct copy numbers and at their exact localisation within the nerve cell.

“The new model shows, for the first time, that widely different numbers of proteins are needed for the different processes occurring in the synapse,” says Dr. Benjamin G. Wilhelm, first author of the publication. The new findings reveal: proteins involved in the release of messenger substances (neurotransmitters) from so called synaptic vesicles are present in up to 26,000 copies per synapse. Proteins involved in the opposite process, the recycling of synaptic vesicles, on the other hand, are present in only 1,000-4,000 copies per synapse.

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These details help to solve a long-lasting controversy in neuroscience: how many synaptic vesicles within the synapse can be used simultaneously? Apparently, more than enough proteins are present to ensure vesicle release, but the proteins for vesicle recycling are sufficient for only 7-11% of all vesicles in the synapse. This means that the majority of vesicles in the synapse cannot be used simultaneously.

The most important insight the new model reveals, is however that the copy numbers of proteins involved in the same process scale to an astonishingly high degree. The building blocks of the cell are tightly coordinated to fit together in number, comparable to a highly efficient machinery. This is a very surprising finding and it remains entirely unclear how the cell manages to coordinate the copy numbers of proteins involved in the same process so closely.

The new model will serve as a reference source for neuroscientists of all specializations in the future, and will support future research, since the copy number of proteins can be an important indicator for their relevance. But the research team led by Rizzoli does not plan to stop there: “Our ultimate goal is to reconstruct an entire nerve cell”. Combined with functional studies on the interaction of individual proteins this would allow to simulate cellular function in the future – the creation of a “virtual cell”.

An impressive video animation, below has been created from the obtained data to visualize the structure and protein distribution of a synapse.




SOURCE  Nanowerk

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 Computer Models  

Scientists have developed a sophisticated computer modelling simulation to explore how cells of the fruit fly react to changes in the environment.

Researchers have developed a sophisticated computer modelling simulation to explore how cells of the fruit fly react to changes in the environment. The research has been published in the science journal Cell, is part of an on-going study at The Universities of Manchester and Sheffield that is investigating how external environmental factors impact on health and disease.

The model shows how cells of the fruit fly communicate with each other during its development. Dr Martin Baron, who led the research, said:

"It is exciting that the computer model was able to make predictions that we could test by going back to the fly experiments to investigate the effects of different mutations which alter the components of the cells."

“The work is a really nice example of researchers from different disciplines of maths and biology working together to tackle challenging problems.”

The paper describes how the comptuer model provides a theoretical framework by which to explore how different environmental and other regulatory inputs can be integrated with the core signaling mechanism to result in adaptive—or, possibly, maladaptive—outcomes on the development, maintenance, and health of an organism.

The current phase of the study aims to understand how temperature interacts with cell signalling networks during development. Flies are able to develop normally across a wide range of temperatures and it is not understood how this is achieved.

The combined disciplines approach was undertaken because the complexity of development involves numerous components that are interconnected with each other in networks of cell to cell communication pathways, whose outcomes are difficult to predict without computer simulations.

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The fruit fly is a commonly used  in lab work because, although its development is relatively simple, around 75% of known human disease genes have a recognizable match in the genome of fruit flies which means they can be used to study the fundamental biology behind complex conditions such as neurodegeneration or cancer.

Baron said: “it is exciting that the computer model was able to make predictions that we could test by going back to the fly experiments to investigate the effects of different mutations which alter the components of the cells. It shows us that the model is working well and provides a solid basis on which to develop its sophistication further.”

The next phase will see the team research how the cell signalling network adjusts and responds to other environmental changes such as nutrition. Baron says "There is a lot of interest in how environmental inputs influence our health and disease by interacting with our genetic makeup. Our initial studies have already shown that changes to the adult fly's diet can also affect how cells inside a fly communicate with each other and produce responses in certain fly tissues. This is a promising avenue for future studies".

Baron explains that there are wider implications for understanding human health and disease: “Many different types of signal control normal development but when some of these signals are mis-activated they can result in the formation of tumors."

“What we’ve learnt from studying the flies” said Baron, “is that some communication signals can arise in different ways and this means that, in cancer, mis-activation of these signals can also occur by different routes. This is important because it can help us to understand how to stop mis-activation from occurring.”


SOURCE  University of Manchester

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 Cell Biology  

Another discovery has been made that will cause textbooks to be rewritten. New research reveals that when missing critical components, cells can adapt and make copies of their DNA in an other way.

New research shows that cells are more resilient in taking care of their DNA than scientists originally thought. Even when missing critical components, cells can adapt and make copies of their DNA in an alternative way.

In a study published in Cell Reports, a team of researchers at Michigan State University showed that cells can grow normally without a crucial component needed to duplicate their DNA.

“Our genetic information is stored in DNA, which has to be continuously monitored for damage and copied for growth,” said Kefei Yu, MSU Professor. “If the cell is unable to make copies of its DNA or if it overlooks mistakes in its structure, it can lead to cell death or the production of cancerous cells.”

The study shows that cells are much more flexible in managing their DNA — when they lack the gadgets required to replicate DNA, they adapt and use other tools instead.

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But the study shows that cells are much more flexible in managing their DNA than we thought. When they lack the gadgets required to replicate DNA, they adapt and use other tools instead.

These tools are a family of proteins called DNA Ligases, which are needed for a variety of processes associated with DNA. There are several forms of these ligases, and the consensus among scientists has been that they each have specific roles that don’t really overlap.

Belonging to this family of ligases is DNA Ligase I, which is thought to be critical for making copies of DNA and hence essential for growth. However, the researchers have shown that DNA Ligase I is actually not needed in some cells.

“This suggests that cells are much more flexible in the way they make more of their DNA,” Yu said. “It might be that these ligases can substitute for each other when one of them is missing.”

The researchers took out DNA Ligase I in a type of mouse cells and examined how the cells would respond to the challenge of losing a supposedly essential component for making copies of DNA.

To their surprise, they saw that these cells could grow just fine, indicating that they were still managing to make more DNA without DNA Ligase I. They even saw that these ‘handicapped’ cells were able to fix induced damages in the DNA as well.

“Our next question is whether this phenomenon is unique to this specific type of cell, or if it’s generally true to a variety of other cells, including those of humans,” Yu said. “We’re interested in finding out how exactly the cell’s adapting.”

If the replacement of DNA Ligase I is in fact a general rule among many types of cells, then textbooks will have to be rewritten, and scientists will have to start working toward a better explanation of how DNA is maintained and copied in the cell – two processes that are essential to the viability of life.


SOURCE  Michigan State University

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 Neuroscience  

Using optogenetics, researchers have mapped the signaling of touch sensations directly from cells into the skin.  The work could lead to the development of artificial skin and smarter prosthetics.

In a study published online in the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures.

Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision—rod and cone cells and light-sensitive receptors—have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch.

"These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us."

This study is the first to use optogenetics—a new method that uses light as a signaling system to turn neurons on and off on demand—on skin cells to determine how they function and communicate.

The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin’s neurons to create what we perceive as fine details and textures.

“These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us,” Dr. Lumpkin said.

The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception.

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Several conditions—including diabetes and some cancer chemotherapy treatments, as well as normal aging—are known to reduce sensitive touch. Merkel cells begin to disappear in one’s early 20s, at the same time that tactile acuity starts to decline. “No one has tested whether the loss of Merkel cells causes loss of function with aging—it could be a coincidence—but it’s a question we’re interested in pursuing,” Dr. Lumpkin said.

In the future, these findings could inform the design of new “smart” prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch.

The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception.

“The new findings should open up the field of skin biology and reveal how sensations are initiated,” Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin’s team applied to Merkel cells can now be applied to other skin cells to answer these questions.

“It’s an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them,” she said.




SOURCE  Columbia University Medical Center

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 Imaging  

A research team has developed a general method to image a broad spectrum of small biomolecules, such as small molecular drugs and nucleic acids, amino acids, lipids for determining where they are localized and how they function inside cells.

Researchers at Columbia University have made a significant step toward visualizing small biomolecules inside living biological systems with minimum disturbance, a longstanding goal in the scientific community. In a study published in Nature Methods, Assistant Professor of Chemistry Wei Min's research team has developed a general method to image a broad spectrum of small biomolecules, such as small molecular drugs and nucleic acids, amino acids, lipids for determining where they are localized and how they function inside cells.

When studying biological functions of a molecule in complex and mysterious cells, researchers typically label the molecules of interest with fluorophores, a kind of molecule that glows when illuminated. Using a fluorescence microscope, common in research labs, the fluorophore-tagged molecules can be located and tracked with high precision. The invention of green fluorescent protein (GFP), in 1994, compatible with imaging inside live cells and animals, has since made fluorescence microscopy even more popular.

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However, when it comes to small biomolecules, fluorophore tagging is problematic, because the fluorophores are almost always larger or comparable in size to the small molecules of interest. As a result, they often disturb the normal functions of these small molecules with crucial biological roles.

To address this problem, Min and his team departed from the conventional paradigm of fluorescence imaging of fluorophores, and pursued a novel combination of physics and chemistry. Specifically, they coupled an emerging laser-based technique called stimulated Raman scattering (SRS) microscopy with a small but highly vibrant alkyne tag (that is, C=C, carbon-carbon triple bond), a chemical bond that, when it stretches, produces a strong Raman scattering signal at a unique "frequency" (different from natural molecules inside cells).

This new technique, labeling the small molecules with this tiny alkyne tag, avoids perturbation that occurs with large fluorescent tags, while obtaining high detection specificity and sensitivity by SRS imaging. By tuning the laser colors to the alkyne frequency and quickly scanning the focused laser beam across the sample, point-by-point, SRS microscopy can pick up the unique stretching motion of the C=C bond carried by the small molecules and produce a three-dimensional map of the molecules inside living cells and animals.

In this way, Min's team demonstrated tracking alkyne-bearing drugs in mouse tissues and visualizing de novo synthesis of DNA, RNA, proteins, phospholipids and triglycerides through metabolic incorporation of alkyne-tagged small precursors in living cells.

"The major advantages of our technique lie in the superb sensitivity, specificity and biocompatibility with dynamics of live cells and animals for small molecule imaging," says the lead author Lu Wei, a Ph.D. candidate in chemistry.

Next, Min's team will apply this new technique to biomedical questions, such as detecting tumor cells and probing drug pharmacokinetics in animal models. They are also creating other alkyne-labeled biologically active molecules for more versatile imaging applications.

"Our new technique will open up numerous otherwise difficult studies on small biomolecules in live cells and animals," says Min. "In addition to basic research, our technique could also contribute greatly to translational applications. I believe SRS imaging of alkyne tags could do for small biomolecules what fluorescence imaging of fluorophores such as GFP has done for larger species."



SOURCE  Columbia University via EurekAlert

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 Cell Biology  

Researchers have deciphered the structure of part of the ribosome found in mitochondria, the power plants of the cell. The scientists were able to benefit from advancements in the field of electron microscopy and capture images of the mitochondrial ribosome at a level of resolution never achieved before.

The ribosome can be thought of as a decryption device housed within the cell. It is able to decipher the genetic code, which is delivered in the form of messenger ribonucleic acid (mRNA), and translate it into a specific sequence of amino acids. The final assembly of amino acids into long protein chains also takes place in these enzyme complexes. Without ribosomes, a cell would be unable to produce any proteins. Due to their central function, these enzyme complexes have long been the focus of attention of biologists.

In order to obtain a better understanding of ribosomes, which are found in all cells, it is imperative to know their exact composition and structure.

Over the past 15 years, Nenad Ban, professor at ETH Zurich, has made a significant contribution to not only the elucidation of the ribosome structure of bacteria, but also of higher organisms, termed eukaryotes, which include fungi, plants and animals.

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Until now, the molecular structure of the ribosomes found in mitochondria, the power plants of the cell, was still largely unknown. Mitochondrial ribosomes differ considerably from the ‘ordinary’ ribosomes found in the cytoplasm, which are composed of 60% ribonucleic acids (RNA) and 40% protein components.

In the case of mitochondrial ribosomes, RNA accounts for just under a third of the entire complex. One reason for this is that the RNA molecules have shortened significantly over the course of evolutionary history. Mitochondrial ribosomes in the cell are primarily localised at the inner membrane of mitochondria and are present within the cell in a far smaller number than the cytoplasmic ribosomes. This makes them more difficult to isolate, hampering progress of research in the field.

A team of researchers from the ETH research groups of Ban and Ruedi Aebersold have now succeeded in elucidating the structure of the large subunit of the mitochondrial ribosomes from mammalian cells to a resolution of 4.9 angstroms (less than 0.5 nanometres). Such a level of resolution allows, for example, the visualization of individual phosphate groups of the ribosomal RNA. The researchers’ findings were published in Nature as the cover story.

Image Source - Ban et al, Nature

The ETH researchers used the latest generation of high-resolution cryo-electron microscopes, which have only recently become available. The researchers captured more than a million images of the large subunit of the mitoribosome and reconstructed its three-dimensional structure by performing complex calculations on a computer cluster.

In order to interpret the calculated structure as precisely as possible and to determine the exact location of the RNA and protein molecules within the enzyme complex, the researchers used a method derived from Aebersold’s laboratory – a method called ‘chemical cross-linking combined with mass spectrometry.’ Here, the individual protein components of the ribosome are chemically cross-linked, fragmented into peptides for further analysis, and sequenced in the mass spectrometer.

From this data, it is then possible to determine the structure of a protein complex, such as the ribosome and its large subunit. A great deal of computer power is required, however, and so the research team used Brutus, ETH’s high-performance cluster.

The combination of these methods enabled the researchers to succeed in creating a high-resolution structural model of the large subunit of the mitochondrial ribosome with unprecedented precision.

Thanks to their new findings, the researchers can now explain why mitochondrial ribosomes are always located at the membrane of the mitochondrion. In the vicinity of the tunnel exit, through which freshly synthesised proteins leave the ribosome, the biologists were able to localise a protein with similarity to membrane anchor proteins. From this observation, they have been able to conclude that during the course of evolution an anchor protein of this kind was integrated in the ribosome in order to fix it to the mitochondrial membrane, thus allowing the freshly synthesised proteins to be targeted directly to their destination in the membrane.

On the basis of this ground-breaking work, the researchers also hope to gain new insights into the functioning and disorders of this important cellular organelle. Defects in the genetic material coding for the components of mitochondria can lead, for example, to muscle diseases and also play a role in cancer.

Cancer cells not only require high levels of nutrients in order to grow quickly, but also large amounts of energy. Their energy metabolism therefore is in an unusual state, to which the mitochondria probably also contribute. Ban makes clear, however, that no application-related questions are currently being addressed. “The structure of this ribosome provides an important foundation on which other researchers can build,” he says.



SOURCE  ETH Zurich

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 Organic Chemistry  

For the first time, chemists have successfully produced an artificial cell containing organelles capable of carrying out the various steps of a chemical reaction. This was done at the Institute for Molecules and Materials at Radboud University Nijmegen.

It is difficult for chemists to match the chemistry in living cells in their laboratories. After all, in cells all kinds of complex reactions are taking place simultaneously in a small area, in various compartments and incredibly efficiently. This is why chemists attempt to imitate the cell in various ways. In doing so, they also hope to learn more about the origin of life and the transition from chemistry to biology.

Now, a research team led by Jan van Hest from Radboud University Nijmegen and Sébastien Lecommandoux at the University of Bordeaux have created artificial organelles by filling tiny spheres with chemicals and placing these inside a water droplet.

The research has been published in Nature Chemistry and Angewandte Chemie.

The researchers then coated the water droplet with a polymer layer to make a cell wall. Using fluorescence, they were able to show that the planned cascade of reactions did in fact take place. This means that they are the first chemists to create a polymer cell with working organelles.

"Just like in the cells in our bodies, the chemicals are able to enter the cell plasma following the reaction in the organelles, to be processed elsewhere in the cell," Ruud Peters, PhD candidate on the project, explains.

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Creating cell-like structures is currently very popular in the field of chemistry, with various methods being tried at the Institute for Molecules and Materials (IMM). Professor Wilhelm Huck, for example, is making cells from tiny droplets of solutions very similar to cytoplasm, and Van Hest’s group is building cells using polymers.

"Competing groups are working closer to biology; making cells from fatty acids, for example. We would like to do the same in the future. Another step would be to make cells that produce their own energy supply. We are also working on ways of controlling the movement of chemicals within the cell, towards organelles," says Huck. "By simulating these things, we are able to better understand living cells. One day we will even be able to make something that looks very much like the real thing."



SOURCE  Radboud University Nijmegen

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 Imaging  

A new 3D imaging technique for live cells uses a conventional microscope to capture image slices throughout the depth of the cell, then computationally renders them into one three-dimensional image. The technique uses no dyes or chemicals, allowing researchers to observe cells in their natural state.

Living cells are ready for their close-ups, thanks to a new imaging technique that needs no dyes or other chemicals, yet renders high-resolution, three-dimensional, quantitative imagery of cells and their internal structures – all with conventional microscopes and white light.

Called white-light diffraction tomography (WDT), the imaging technique opens a window into the life of a cell without disturbing it and could allow cellular biologists unprecedented insight into cellular processes, drug effects and stem cell differentiation.

The team of University of Illinois researchers, led by electrical and computer engineering and bioengineering professor Gabriel Popescu, published their results in the journal Nature Photonics.

“One main focus of imaging cells is trying to understand how they function, or how they respond to treatments, for example, during cancer therapies,” Popescu said. “If you need to add dyes or contrast agents to study them, this preparation affects the cells’ function itself. It interferes with your study. With our technique, we can see processes as they happen and we don’t obstruct their normal behavior.”

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Because it uses white light, WDT can observe cells in their natural state without exposing them to chemicals, ultraviolet radiation, or mechanical forces – the three main methods used in other microscopy techniques. White light also contains a broad spectrum of wavelengths, thus bypassing the interference issues inherent in laser light – speckles, for example.

The 3D images are a composite of many cross-sectional images, much like an MRI or CT image. The microscope shifts its focus through the depth of the cell, capturing images of various focus planes. Then the computer uses the theoretical model and compiles the images into a coherent three-dimensional rendering.

The greatest potential of WDT, according to the researchers, is the ability to study cells in three dimensions over time. Since the cells are not altered, they can be imaged repeatedly, allowing researchers a glimpse into the dynamics of a cell as it goes about its life – or as it is treated with a new drug.

“As a cell grows we can see the change in all three dimensions,” said Taewoo Kim, a graduate student and first author of the paper. “We can see the dynamics of the cell in 3-D, which hasn’t been done in a quantitative manner. For example, we could see, in the span of a minute or over a cell’s lifetime, how it grows and how the things in the cell move around.”

“With this imaging we can tell at what scale things within the cell are transported randomly and at what scale processes are actually organized and deterministic,” Popescu said. “At first glance, the dynamics looks pretty messy, but then you look at it – we stare at movies for hours and hours – and you realize it all makes sense. Everything is organized perfectly at certain scales. That’s what makes a cell alive. Randomness is just nature’s way to try new things.”

WDT uses a component that adds onto a conventional phase contrast microscope, a common piece of equipment in biology labs, without altering the microscope itself. The researchers used conventional microscopes with the intention of making these new optics principles easily accessible for biologists. The researchers hope that this will allow rapid large-scale adoption of WDT, and Popescu founded a startup company, Phi Optics, to help achieve that goal.

In addition to biological applications, the WDT technique has implications in the broader field of optics as the researchers pushed the boundaries of physics by applying scattering theory to imaging optics.

“The physics behind this technique is another thing we were fascinated about,” Kim said. “Light propagation in general is studied with approximations, but we’re using almost no approximation. In a very condensed form, we can perfectly show how the light changes as it passes through the cell.”

“We started on this problem two years ago, trying to formulate mathematically the sectioning effect observed in spatial light interference light microscopy (SLIM),” said Renjie Zhou, a graduate student and co-first author of the paper. “We came up with equations which eventually described WDT. The final equation is beautiful and the theory opens opportunities for solving other optics problems in a new theoretical language.”

Next, the researchers hope to pursue cross-disciplinary collaborations to explore applications of WDT in biology as well as expansions of the imaging optics demonstrated in WDT. For example, they are using WDT to watch stem cells as they differentiate in hopes of better understanding how they turn into different cell types. Since stem cells are so sensitive, only a chemical-free, non-invasive, white-light technique such as WDT could be used to study them without adverse effects.



SOURCE  University of Illinois at Urbana-Champaign

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 Biological Computation  

Chemists from North Carolina State University have performed a DNA-based logic-gate operation within a human cell. The research may pave the way to more complicated computations in live cells, as well as new methods of disease detection and treatment.

Chemists from North Carolina State University have performed a DNA-based logic-gate operation within a human cell. The research may pave the way to more complicated computations in live cells, as well as new methods of disease detection and treatment.

Their results appear in the Journal of the American Chemical Society.

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Logic gates are the means by which computers “compute,” as sets of them are combined in different ways to enable computers to ultimately perform tasks like addition or subtraction. In DNA computing, these gates are created by combining different strands of DNA, rather than a series of transistors. However, thus far DNA computation events have typically taken place in a test tube, rather than in living cells.

NC State chemist Alex Deiters and graduate student James Hemphill wanted to see if a DNA-based logic gate could detect the presence of specific microRNAs in human cells. The researchers utilized a DNA-based logic gate known as an “AND” gate that was engineered to respond to the presence of two specific microRNAs – known as miRNA-21 and miRNA-122.

Just as computer operations utilize different inputs to create a particular output, the researchers’ DNA-based Boolean logic gate was activated only when both miRNA-21 and miRNA-122 “inputs” were present in cells. If they were present, the gate generated an “output” by releasing a fluorescent molecule.

Deiters believes that use of these logic gates could lead to more accurate tests and treatments for human disease, especially cancer.

“The fluorescent molecule we used in this logic-gate design could be useful as a marker that identifies a cancer cell,” he says. “Or, instead of directing the gate to release a fluorescent molecule in the presence of particular microRNAs, we could attach therapeutic agents that are released to treat the disease itself.”



SOURCE  \NC State

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