RNA: The Unknotted Strand Of Life

RNA: The Unknotted Strand Of Life

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No one had checked before, but RNA, the nucleic acid involved in many cell functions including protein synthesis, appears to be the only “strand of life” not to have knots.

Over the years, advances in structural biology have firmly established that both proteins and DNA, although subject to evolutionary selection, do not escape the statistical law whereby a sufficiently long and compacted molecular strand will inevitably be entangled. However, no one to date had looked into the case of RNA.

Using the structural description provided for approximately 6,000 RNA chains entered in the Protein Data Bank, a public database that allows scientists to share information about the structure of proteins, DNA and RNA, Cristian Micheletti and Marco Di Stefano from SISSA, and Henri Orland from CEA in Saclay set out on a search for knots.

“We expected this long flexible molecule to behave like the others – DNA and proteins – forming knots with a certain frequency”, explains Micheletti. “Instead we were in for a surprise: out of 6,000 known structures only three cases showed ‘suspected’ knots”.

Suspected, because the three cases could in fact be artefacts. “The database contains multiple descriptions of the same molecule entered by separate research groups using different experimental techniques with varying resolution. Comparing the alternative descriptions of our ‘knotted RNA’ candidates we found no instances of knots. That the three cases may be artefacts is further confirmed by the fact that in all three instances the alternative, unknotted, descriptions were based on the most accurate technique, i.e., x-ray crystallography”.

Naturally occurring RNA is therefore a type of molecule that tends to take on particularly simple geometric configurations. “Computer predictions demonstrate that if we were to re-arrange naturally occurring RNA sequences randomly we would obtain far more entangled and complex structures”, explains Micheletti. “The underlying reasons for this disarming simplicity are probably manifold”, continues Di Stefano. “It is plausible that the chemical composition of naturally occurring RNAs evolved to ensure reliable and rapid folding into simple, faithfully reproducible forms allowing smooth processing by the molecular machinery that decodes them to synthesise proteins. Any knots would negatively influence the process”. Now further investigations are needed to better understand the anti-knot properties of RNA.

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The above story is based on materials provided by International School of Advanced Studies (SISSA). Note: Materials may be edited for content and length.

9 Overlooked Technologies That Could Transform The World

9 Overlooked Technologies That Could Transform The World

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We live in an era of accelerating change. Technology is changing and innovating faster than most of us can keep up. And at the same time, it’s easy to get so caught up in shiny visions of the future, and not notice the astounding things that are happening in science and technology today. So the next time people ask you where the future went, tell them it’s already here.

Here are nine underrated or overlooked technologies that could transform the world before you know it.

Top image composed by Dylan Cole.

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1. Cheap and fast DNA sequencing

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Most of us know about DNA sequencing — but you probably don’t realize just how fast and cheap it’s getting. In fact, some experts suggest that it’s following along a Moore’s Law of its own. As Adrienne Burke has pointed out, the speed of genome sequencing has better than doubled every two years since 2003 — back at a time when it cost $3.8 billion (i.e. the Human Genome Project). Today, thanks to advances in such things as nucleic acid chemistry and detection, a company like Life Technologiescan process DNA on a semiconductor chip at a cost of $1,000 per genome. Other companies can sequence an entire genome in one single day. And the implications are significant, including the advent of highly personalized medicine in which drugs can be developed to treat your specific genome. Say goodbye to one-size-fits-all medicine.

2. Digital currency

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The idea of digital currency is slowing starting to make the rounds, including the potential for Bitcoin, but what many of us don’t realize is that’s it’s here to stay. Sure,it’s had a rough start, but once established and disseminated, electronic cash will allow for efficient and convenient online exchanges — and all without the need for those pesky banks. Despite the obvious need for a distributed digital currency protocol, the adoption rate has been relatively slow. Barriers to entry include availability (it’s in limited supply), the cryptography problem (the public still needs to be assured that it’s secure), the establishment of a recognized and trustworthy dispute system (sensing some opportunities here), and user confidence (a problem similar to the one that emerged when paper money first emerged).

3. Memristors

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Back in 1971, University of California at Berkeley professor Leon Chua predicted a revolution in electrical circuits — and his vision has finally come true. Traditionally, circuits are constructed with capacitors, resistors, and inductors. But Chua speculated that there could be a fourth component, what he called the memristor (short for memory resistor). What sets this technological innovation apart is that, unlike a resistor, it can “remember” charges even after power is lost. As a result, this would allow the memristor to store information. This has given rise to the suggestion that it could eventually become a part of computer memory — including non-volatile solid-state memory with significantly greater densities than traditional hard drives (as much as one petabit per cm3). The first memristor was developed in May 2008 by HP, who plan on having a commercial version available by the end of 2014. And aside from memory storage, memristors could prove useful in signal processing, neural networks, and brain-computer interfaces.

4. Robots that can do crazy futuristic stuff

Today we have robots that can self-replicatere-assemble after being kicked apartshape-shift,swarmcreate emergent effectsbuild other robotsslither like a snakejump to the tops of buildingswalk like a pack mule, and run faster than a human. They even have their own internet. Put it all together and you realize that we’re in the midst of a robotic revolution that’s poised to change virtually everything.

5. Waste to biofuels

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Imagine being able to turn all our garbage into something useful like fuel. Oh wait, we can do that. It’s called “energy recovery from waste” — a process that typically involves the production of electricity or biofuels (like methane, methanol, ethanol or synthetic fuels) by burning it. Cities like Edmonton, Alberta are already doing it — and they’re scaling up. By next year, Edmonton’s Waste-to-Biofuels Facility will convert more than 100,000 tons of municipal solid waste into 38 million litres of biofuels annually. Moreover, their waste-based biofuels can reduce greenhouse gas emissions by more than 60% compared to gasoline. This largely overlooked revolution is turning garbage (including plastic) into a precious resource. Already today, Sweden is importing waste from its European neighbors to fuel its garbage-to-energy program.

6. Gene therapy

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Though we’re in the midst of the biotechnology revolution, our attention tends to get focused on such things as stem cells, tissue engineering, genome mapping, and new pharmaceuticals. What’s often lost in the discussion is the fact that we already have the ability to go directly into our DNA and swap genes at will. We can essentially trade bad genes for good, allowing us to treat or prevent diseases (such as muscular dystrophy and cystic fibrosis) — interventions that don’t require drugs or surgery. And just as significantly, gene therapy could eventually give rise genetic enhancements (like increased memory or intelligence) and life extension therapies. Gattaca is already here, it just hasn’t been distributed yet.

7. RNA interference

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The discovery of RNA interference (RNAi) was considered so monumental that it won Andrew Fire and Craig C. Mello the Nobel Prize back in 2006. Similar to gene therapy, RNA interference allows biologists to manipulate the functions of genes. It works by using cells to shut-off or turn down the activity of specific genes, and it does this by destroying or disrupting messenger molecules (for example by preventing mRNA from producing a protein). Today, RNAi is being used in thousands of labs. It’s becoming an indispensable research tool (to create novel cell cultures), it has inspired the creation of algorithms in computational biology studies, and it holds tremendous potential for the treatment of diseases like cancer and Lou Gehrig’s disease.

8. Organic electronics

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Traditionally, our visions of cybernetics and the cyborg is one in which natural, organic parts have been replaced with mechanical devices or prostheses. The notion of a half-human, half-machine has very much become ingrained in our thinking — but it’s likely wrong. Thanks to the rise of the nascent field of organic electronics, it’s more likely that we’ll rework the body’s biological systems and introduce new organic components altogether. Already today, scientists have engineered cyborg tissue that can sense its environment. Other researchers have invented chemical circuits that can channel neurotransmitters instead of electric voltages. And as Mark Changizi has suggested, future humans will continue to harness the powers of their biological constitutions and engage in what Stanislas Dehaene calls neuronal recycling.

9. Concentrated solar power

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A recent innovation in solar power technology is starting to take the world by storm, though few talk about it. It’s called concentrated solar power (CSP), and it’s a massively distributed system for extracting solar energy with mirrors and lenses. It works by focusing the incoming sunlight into a highly concentrated area. The result is a highly scalable and efficient energy source that is allowing for gigawatt sized solar power plants. Another similar technology, what’s called concentrated photovoltaics, results in concentrated sunlight being converted to heat, which in turn gets converted to electricity. CPV plants will not only solve much of the world’s energy needs, it will also double as a desalination station.

Images: Alila Sao Mai/shutterstock [1], BitCoin [2], IEEE Spectrum/R. Stanley Williams [3], City of Edmonton [5], somersault18:24/Shutterstock [6], Medgadget [7], AlphaGalileo Foundation [8], Desertec [9].

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Rotaxane mimics ribosome to spin out peptides

Rotaxane mimics ribosome to spin out peptides

10 January 2013

Laura Howes

 

The field of molecular machines has taken a new bio-inspired turn to assemble another molecule, in this case linking up individual amino acids into a peptide. While this molecular peptide synthesiser isn’t going to rival a ribosome for speed any time soon, it does suggest a way to make multicomponent polymers.

 

robotic ribosomeIs the assembly of the peptide mechanical or chemical? © David Leigh

 

The project involved David Leigh’s groups at the University of Edinburgh and then at the University of Manchester, where he is now based. His group decided to mimic the ribosome, a cellular machine that can build proteins. ‘The ribosome uses a track where a machine moves along it processively,’ Leigh says. So when the group started thinking about how to build a synthetic version they naturally thought of the rotaxane architecture of a ring on a track. However, Leigh is keen to stress this is not intended as an artificial alternative for the ribosome, especially as his machine is much slower than its biological counterpart – it took 36 hours to synthesise a three amino acid peptide. Instead, Leigh says the work is a proof-of-concept for a molecular machine.

That’s something that Fraser Stoddart, father of rotaxane-based machines at Northwestern University in California, US, agrees with. Stoddart describes the work as ‘way out there in conception’, but that the idea of using molecules to build other molecules is ‘the direction that chemistry has got to go in’.

But while Leigh and Stoddart focus on the applications of the approach, Dean Astumian of the University of Maine, US, cautions against simple descriptions of molecular mechanical machines. ‘One of the big controversies is whether we should look for a mechanical description or whether it is predominantly a chemical phenomenon,’ he says.

For Astumian, the exciting thing about this work is the potential insights the molecule might bring to the workings of molecular machines. Does the ring move along the track smoothly, Astumian wonders, or is it a stochastic process with the ring moving back and forth until it overcomes an energy barrier and moves to the next amino acid on the track?

Whatever the answer, Leigh has a number of plans for the device, including increasing the number of amino acids that can be strung together. As the peptide sequence grows, says Leigh, ‘it will be very interesting to, at the single molecule level, see how these things fold as they are made’. There are also different chemistries and polymers to try, and Leigh also says he’d like to investigate keeping the information on the track so that it can be read again, just as RNA can be read more than once by a ribosome.


But Stoddart is clear that whilst molecular machines are starting to find applications this is just the beginning. ‘Chemistry is by far the youngest of the sciences and we haven’t scraped the surface yet. There’s so much we have to learn,’ he says.

REFERENCES

B Lewandowski et al, Science, 2013, DOI: 10.1126/science.1229753

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Researchers study formation of early cellular life

Researchers study formation of early cellular life

Shown are RNA strands (blue) and RNA enzymes (red) coming together within droplets of dextran. Scientists at Penn State have shown that this compartmentalization helps to catalyze chemical reactions.

UNIVERSITY PARK, Pa. — Researchers at Penn State University have developed a chemical model that mimics a possible step in the formation of cellular life on Earth 4 billion years ago. Using large “macromolecules” called polymers, the scientists created primitive cell-like structures that they infused with RNA — the genetic coding material that is thought to precede the appearance of DNA on Earth — and demonstrated how the molecules would react chemically under conditions that might have been present on the early Earth. The journal Nature Chemistry posted the research as an advance online publication Oct. 14.

In modern biology, all life, with the exception of some viruses, uses DNA as its genetic storage mechanism. According to the “RNA-world” hypothesis, RNA appeared on Earth first, serving as both the genetic-storage material and the functional molecules for catalyzing chemical reactions, then DNA and proteins evolved much later. Unlike DNA, RNA can adopt many different molecular conformations and so it is functionally interactive on the molecular level. In the research paper, two professors of chemistry, Christine Keating and Philip Bevilacqua, along with two graduate students, Christopher Strulson and Rosalynn Molden, probe one of the nagging mysteries of the RNA-world hypothesis.

“A missing piece of the RNA-world puzzle is compartmentalization,” Bevilacqua said. “It’s not enough to have the necessary molecules that make up RNA floating around; they need to be compartmentalized and they need to stay together without diffusing away. This packaging needs to happen in a small-enough space — something analogous to a modern cell — because a simple fact of chemistry is that molecules need to find each other for a chemical reaction to occur.”

To test how early cell-like structures could have formed and acted to compartmentalize RNA molecules even in the absence of lipid-like molecules that make up modern cellular membranes, Strulson and Molden generated simple, non-living model “cells” in the laboratory. “Our team prepared compartments using solutions of two polymers called polyethylene glycol (PEG) and dextran,” Keating explained. “These solutions form distinct polymer-rich aqueous compartments, into which molecules like RNA can become locally concentrated.”

The team members found that, once the RNA was packed into the dextran-rich compartments, the molecules were able to associate physically, resulting in chemical reactions. “Interestingly, the more densely the RNA was packed, the more quickly the reactions occurred,” Bevilacqua explained. “We noted an increase in the rate of chemical reactions of up to about 70-fold. Most importantly, we showed that for RNA to ‘do something’ — to react chemically — it has to be compartmentalized tightly into something like a cell. Our experiments with aqueous two-phase systems (ATPS) have shown that some compartmentalization mechanism may have provided catalysis in an early-Earth environment.”

Keating added that, although the team members do not suggest that PEG and dextran were the specific polymers present on the early Earth, they provide a clue to a plausible route to compartmentalization — phase separation. “Phase separation occurs when different types of polymers are present in solution at relatively high concentrations. Instead of mixing, the sample separates to form two distinct liquids, similar to how oil and water separate.” Keating explained. “The aqueous-phase compartments we manufactured using dextran and PEG can drive biochemical reactions by increasing local reactant concentrations. So, it’s possible that some other sorts of polymers might have been the molecules that drove compartmentalization on the early Earth.” Strulson added that, “In addition to the RNA-world hypothesis, these results may be relevant to RNA localization and function in non-membrane compartments in modern biology.”

The team members also found that the longer the string of RNA, the more densely it would be packed into the dextran compartment of the ATPS, while the shorter strings tended to be left out. “We hypothesize that this research result might indicate some kind of primitive sorting method,” Bevilacqua said. “As RNA gets shorter, it tends to have less enzyme activity. So, in an early-Earth system similar to our dextran-PEG model system, the full-length, functional RNA would have been sorted and concentrated into one phase, while the shorter RNA that is not only less functional, but also threatens to inhibit important chemical reactions, would not have been included.”

The scientists hope to continue their investigations by testing their model-cell method with other polymers. Keating added, “We are interested in looking at compartmentalization in polymer systems that are more closely related to those that may have been present on the early Earth, and also those that may be present in contemporary biological cells, where RNA compartmentalization remains important for a wide range of cellular processes.”

This research was funded by the National Science Foundation.

A high-resolution image associated with this research is available at http://science.psu.edu/news-and-events/2012-news/Bevilacqua10-2012.

Editors note: Full article can be found here.

Credit: http://live.psu.edu