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Nanotechnology provides sensors for liver-on-chip drug testing

Hebrew University liver-on-chip device. Photo credit: Yaakov Nahmias / Hebrew University

One of the indirect ways in which nanotechnology is impacting medical research, in synergy with biotechnology, is by enabling a “liver-on-chip” replacement for animal teting. A hat tip to Nanotechnology Now for reprinting this news release from Hebrew University “Israeli-German Partnership Aims To Replace Animal Experiments With Advanced Liver-On-Chip Devices“:

Safety evaluation is a critical part of drug and cosmetic development. In recent years there is a growing understanding that animal experiments fail to predict the human response. This necessitates the development of alternative models to predict drug toxicity.

The recent tightening of European regulations preventing the cosmetic industry from using animals in research and development, blocks companies like L’Oréal and Estée Lauder from developing new products, bringing massive investment into this field.

The main challenge in replacing animal experiments is that human cells seldom survive more than a few days outside the body. To address this challenge, scientists at The Hebrew University of Jerusalem and the Fraunhofer Institute for Cell Therapy and Immunology in Germany partnered to create a liver-on-chip device mimicking human physiology.

“The liver organs we created were less than a millimeter in diameter and survive for more than a month,” said Professor Yaakov Nahmias, the study’s lead author and Director of the Alexander Grass Center for Bioengineering at The Hebrew University.

While other groups showed similar results, the breakthrough came when the groups added nanotechnology-based sensors to the mix. “We realized that because we are building the organs ourselves, we are not limited to biology, and could introduce electronic and optical sensors to the tissue itself. Essentially we are building bionic organs on a chip,” said Nahmias.

The addition of nanotechnology-based optoelectronic sensors to the living tissues enabled the group to identify a new mechanism of acetaminophen (Tylenol) toxicity.

“Because we placed sensors inside the tissue, we could detect small and fast changes in cellular respiration that nobody else could,” said Nahmias. “Suddenly nothing we saw made sense”. The authors discovered that acetaminophen blocked respiration, much faster and at a much lower dose than previously believed. The current understanding was that acetaminophen was broken to a toxic compound, called NAPQI, before damaging the cells. As the liver could naturally deactivate NAPQI, damage was thought to occur only at high doses and in cases of diseased or compromised liver function.

The current study, released online in the leading journal Archives of Toxicology [abstract], turns 50 years of research on its head. The authors found that acetaminophen itself can stop cellular respiration in minutes, even in the absence of NAPQI, explaining much of the off target effects of the drugs.

“This is a fascinating study”, said Professor Oren Shibolet, Head of the Liver Unit at the Tel-Aviv Sourasky Medical Center, and one of the leading experts on drug-induced liver injury, who was not involved in the original study. “We knew that acetaminophen can cause nephrotoxicity as well as rare but serious skin reactions, but up until now, we didn’t really understand the mechanism of such an effect. This new technology provides exceptional insight into drug toxicity, and could in fact transform current practice.”

The results mark the first discovery of a new toxicity mechanism using the newly emerging human-on-a-chip technology, suggesting that the development of alternative models for animal testing is just around the corner. The global market of this technology is estimated to grow to $17 billion by 2018, showing a double-digit annual growth rate in the last three years.

Yissum, the Research and Development Company of The Hebrew University, together with the Fraunhofer Institute for Cell Therapy and Immunology (IZI-BB) in Germany submitted a joint provisional patent application earlier this year and are actively seeking industrial partners.

Testing drugs and cosmetics in animals was never really satisfactory; it was merely the only option available. With this combination of microfluidics, human cells, and an array of very sensitive sensors based on nanotechnology to monitor exactly what is happening at the molecular level in these cells, drug development and testing will become increasingly precise and reliable. One beauty of very powerful technologies, like nanotechnology, is that they can be applied in different ways at different stages of development to achieve a variety of goals. With better ways to test, it may one day no longer take an estimated $1.3 billion to develop a new drug.
—James Lewis, PhD

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Femtosecond imaging with near nanometer spatial resolution

Three-dimensional rendering of surface features imaged by ptychographic coherent diffractive imaging. (Source: University of Colorado). The surface shown is a portion of Fig. 4a. Judging from the scale bar in the scanning electron micrograph of this surface shown in Fig. 1b, the inner diameter of the circle is about 10 µm (10,000 nm).

As we noted back in April, Richard Feynman in his classic 1959 talk challenged his fellow physicists to make the electron microscope 100 times better. A “new super powerful electron microscope that can pinpoint the position of single atoms” had been unveiled at a facility in the UK. While that SuperSTEM is one of only three in the world, a recently demonstrated technology based upon “tabletop extreme-ultraviolet ptychography” brings complementary nanometer-scale resolution to a much smaller (and presumably less expensive) instrument. A hat tip to John Faith for bringing this EETimes article by R Colin Johnson to our attention “EUV Breaks Through to Angstrom“:

The wavelength of visible light — 400-to-700 nanometers — makes it impossible with today’s tools to take photographs of nanoscale objects with any sort of reasonable resolution. The answer has been to use scanning electron microscopy (SEM) and atomic force microscopy (ATM), which yield reasonable images. These tools, however, produce nothing close to the angstrom-level (tenth of a nanometer) resolution of a new type of microscope that uses femtosecond pulses of extreme ultraviolet light (EUV) — the same wavelength light to be used for sub-10 nanometer semiconductor lithography.] …

The claim made here of angstrom-level resolution appears to be a substantial overstatement of the published result (see below). Nevertheless, the technique does appear to offer substantial advantages, and may approach this resolution in the near future.

This amazing breakthrough … was made possible by a grant from the Semiconductor Research Corp. (SRC) to scientists at the University of Colorado (Boulder) who invented the EUV microscope, namely Margaret Murnane, professor of physics and electrical and computer engineering and Henry Kapteyn, professor of physics and electrical and computer engineering there.

“SRC is very happy with results of this experiment,” Kwok Ng, senior science director of Nanomanufacturing Materials and Processes at SRC told EE Times. “In general when you go to less than 10-nm features, it is a big problem to image them. The fact that the EUV microscope is a table-top device will be a big boon to the industry.” …

“The EUV laser-like beams can be used for defect detection either standalone or as an inline tool during manufacturing,” Kapteyn told EE Times. “The high-contrast, full-field, real-time images of functioning circuits and nano systems will advance the state-of-the-art in fabrication applications.”

The Open Access research report “High contrast 3D imaging of surfaces near the wavelength limit using tabletop EUV ptychography” is published in the journal Ultramicroscopy. Coherent diffractive imaging (CDI) is presented as a new full field imaging technique that can achieve very high spatial and temporal resolution simultaneously.

As explained in the research paper, the resolution approaches the angstrom scale only in the axial direction, where it is estimated at 0.6 nm. In the lateral directions it is only 40 nm. However, the temporal resolution is indeed near the femtosecond scale ( 1 fs = 10-15 s). A spatially coherent beam from fs pulses of a tabletop extreme ultraviolet laser illuminates an object, the intensity of the scattered light is collected on a pixel array detector, and the data is computationally interpreted to provide quantitative amplitude and phase contrast information about a surface or object. Pthychography CDI acquires diffraction patterns from several adjacent overlapping positions, making it possible to solve the phase retrieval problem. Including this information from the reflected complex exit surface wave provides additional information about the surface composition and contrast.

The other part of the process, as explained in the paper, is using the high harmonic generation process to produce bright spatially coherent beams from a tabletop laser, spanning the range from the vacuum ultraviolet (wavelengths less than 200 nm) to the soft X-ray region of the spectrum (wavelengths less than 10 nm)

This paper demonstrates “high contrast, high quality, full field 3D imaging of surfaces” by combining the tabletop laser source of coherent harmonics at a wavelength of 30 nm with ptychographic CDI. The current resolution is 0.6 nm axially and 40 nm laterally, combined with a long working distance of 3 to 10 cm. The authors claim that “this work will make it possible to image the fastest charge, spin and phonon dynamics in functioning nanosystems in real space and time”

It will be interesting to see if this technology improves to the point of resolving individual atoms and their movements, especially in the rapid dynamic processes that occur at the nanoscale.
—James Lewis, PhD

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Macroscopic mechanical manipulation controls molecular machine array

Pliers representing amphipathic binaphthyl (left), chemical formula of amphipathic binaphthyl (center), and three-dimensional conformation of amphipathic binaphthyl. Credit: NIMS MANA

Current nanotechnology is about nanomaterials, nanodevices, and simple molecular machines. Advanced nanotechnology will largely be about complex systems of artificial molecular machines, rather as life can be described as complex systems of biological molecular machines. So any new insight about molecular machines is of potential interest as a signpost toward advanced nanotechnology. A hat tip to AZO NANO for reprinting this press release from Japan’s National Institute for Materials Science “Motion of Supramolecular Machines Successfully Controlled through Simple Mechanical Manipulation“:

NIMS MANA researchers found that molecular machines can be easily manipulated using very small mechanical energy, taking advantage of the property that they aggregate on the surface of water. This study was published in the online version of the German Chemical Society’s journal “Angewandte Chemie International Edition” on June 12, 2015. (D. Ishikawa, T. Mori, Y. Yonamine, W. Nakanishi, D. L. Cheung, J. P. Hill, and K. Ariga “Mechanochemical tuning of binaphthyl conformation at the air-water interface” Angew. Chem. Int. Ed., DOI: 10.1002/anie.201503363)

MANA Scientist Waka Nakanishi and other researchers at the Supermolecules Unit (Katsuhiko Ariga, director) of the NIMS International Center for Materials Nanoarchitectonics (MANA), in collaboration with Dr. David Cheung at the University of Strathclyde (UK), found that molecular machines (molecules capable of mechanical movement) can be easily manipulated using very small mechanical energy, taking advantage of the property that they aggregate on the surface of water. Our findings are expected to contribute to the development of basic technology for the operation of various molecular machines that have been studied for their application as sensor and other types of devices.

The way mechanical energy works to run a machine has been well understood and put into application at a macro level. In contrast, due to limited quantitative methods available, it had been poorly understood at the nano level, as illustrated by molecular machines, how the whole mechanical force spreads and impacts the molecular conformation and function. In order to apply mechanical energy at the molecular level and to freely manipulate molecular-level machines, it is critical to understand operating principles that explain these questions.

We recently succeeded in taking detailed measurements on conformational change in molecules in relation to pressure exerted on them as we applied mechanical energy to molecular machines (supramolecular assembly) that aggregated at the air–water interface. In this study, we used plier-shaped binaphthyl molecules as molecular machines. At the air–water interface, binaphthyl molecules are arranged in the same orientation and aligned, forming a single-molecule-thick film. When we applied external mechanical energy to compress and expand this film by moving a partition on the surface of water, we were able to efficiently and repeatedly open and close the binaphthyl molecules. Thus, we concluded that the angle at which the molecules open and close can be controlled by applying a very small force.

To date, conformational change in molecular machines had been measured three-dimensionally. At the two-dimensional air–water interface, molecular arrangements are simpler. In addition, while a supramolecular assembly is very small with a thickness at only a molecular level, its area is large enough to be visible to the naked eye. As such, change in molecular conformation can be observed by precisely controlling the movement of the partition, which can be shifted manually, using machines. In this way, it is now feasible with comparative ease to understand these phenomena in detail. Moreover, based on the fact that the level of mechanical energy we applied in this study was much smaller than the levels of optical and thermal energies normally used to run molecular machines, there are high expectations on this technology for its potential to develop into a simple and energy-saving new nanotechnology. …

In the summary at the end of their paper, the authors state “We anticipate that the use of the air–water interface as a medium for mechanochemistry will open a new field involving molecular conformational control and consequent control of molecular function.” It is difficult for me to imagine how a collection of molecular machines floating on an air-liquid interface could be controlled to do useful complex work, but perhaps machines on a solid surface? It should be interesting to follow how these researchers apply their novel observation.
—James Lewis, PhD

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A tunable bandgap by doping a few atomic layers of black phosphorous

Phosphorene (with in-situ deposition of potassium (K) atoms to induce doping) – The natural successor to Graphene? Credit: Institute for Basic Science

The process of finding novel arrangements of atoms with interesting and useful properties does not appear to be slowing. A hat tip to ScienceDaily for reprinting this news release from the Institute for Basic Science, Korea “Black Phosphorus (BP) Surges Ahead of Graphene“:

A Korean team of scientists tune BP’s band gap to form a superior conductor, allowing for the application to be mass produced for electronic and optoelectronics devices

The research team operating out of Pohang University of Science and Technology (POSTECH), affiliated with the Institute for Basic Science’s (IBS) Center for Artificial Low Dimensional Electronic Systems (CALDES), reported a tunable band gap in BP, effectively modifying the semiconducting material into a unique state of matter with anisotropic dispersion. This research outcome potentially allows for great flexibility in the design and optimization of electronic and optoelectronic devices like solar panels and telecommunication lasers.

To truly understand the significance of the team’s findings, it’s instrumental to understand the nature of two-dimensional (2-D) materials, and for that one must go back to 2010 when the world of 2-D materials was dominated by a simple thin sheet of carbon, a layered form of carbon atoms constructed to resemble honeycomb, called graphene. Graphene was globally heralded as a wonder-material thanks to the work of two British scientists who won the Nobel Prize for Physics for their research on it.

Graphene is extremely thin and has remarkable attributes. It is stronger than steel yet many times lighter, more conductive than copper and more flexible than rubber. All these properties combined make it a tremendous conductor of heat and electricity. A defect–free layer is also impermeable to all atoms and molecules. This amalgamation makes it a terrifically attractive material to apply to scientific developments in a wide variety of fields, such as electronics, aerospace and sports. For all its dazzling promise there is however a disadvantage; graphene has no band gap.

Stepping Stones to a Unique State

A material’s band gap is fundamental to determining its electrical conductivity. Imagine two river crossings, one with tightly-packed stepping-stones, and the other with large gaps between stones. The former is far easier to traverse because a jump between two tightly-packed stones requires less energy. A band gap is much the same; the smaller the gap the more efficiently the current can move across the material and the stronger the current.

Graphene has a band gap of zero in its natural state, however, and so acts like a conductor; the semiconductor potential can’t be realized because the conductivity can’t be shut off, even at low temperatures. This obviously dilutes its appeal as a semiconductor, as shutting off conductivity is a vital part of a semiconductor’s function.

Birth of a Revolution

Phosphorus is the fifteenth element in the periodic table and lends its name to an entire class of compounds. Indeed it could be considered an archetype of chemistry itself. Black phosphorus is the stable form of white phosphorus and gets its name from its distinctive color. Like graphene, BP is a semiconductor and also cheap to mass produce. The one big difference between the two is BP’s natural band gap, allowing the material to switch its electrical current on and off. The research team tested on few layers of BP called phosphorene which is an allotrope of phosphorus.

Keun Su Kim, an amiable professor stationed at POSTECH speaks in rapid bursts when detailing the experiment, “We transferred electrons from the dopant – potassium – to the surface of the black phosphorus, which confined the electrons and allowed us to manipulate this state. Potassium produces a strong electrical field which is what we required to tune the size of the band gap.”

This process of transferring electrons is known as doping and induced a giant Stark effect, which tuned the band gap allowing the valence and conductive bands to move closer together, effectively lowering the band gap and drastically altering it to a value between 0.0 ~ 0.6 electron Volt (eV) from its original intrinsic value of 0.35 eV. Professor Kim explained, “Graphene is a Dirac semimetal. It’s more efficient in its natural state than black phosphorus but it’s difficult to open its band gap; therefore we tuned BP’s band gap to resemble the natural state of graphene, a unique state of matter that is different from conventional semiconductors.”

The potential for this new improved form of black phosphorus is beyond anything the Korean team hoped for, and very soon it could potentially be applied to several sectors including engineering where electrical engineers can adjust the band gap and create devises with the exact behavior desired. The 2-D revolution, it seems, has arrived and is here for the long run.

The research was published in Science [abstract]. A full text e-print is available.
—James Lewis, PhD

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Novel wireframe nanostructures from new DNA origami design process

The versatility of the 3D wireframe design technique was demonstrated with the construction of the snub cube, an Archimedean solid with 60 edges, 24 vertices and 38 faces including 6 squares and 32 equilateral triangles. Credit: TED-43 GFDL ( or CC BY 3.0 (, via Wikimedia Commons

The scaffolded DNA origami technique has been extended to build complex, programmable wireframe structures exhibitng precise control of branching and curvature. A hat tip to KurzweilAI for reporting this Arizona State University Biodesign Institute news release “Rare form: novel structures built from DNA emerge“:

… Hao Yan, a researcher at Arizona State University’s Biodesign Institute, has worked for many years to refine [DNA origami]. His aim is to compose new sets of design rules, vastly expanding the range of nanoscale architectures generated by the method. In new research, a variety of innovative nanoforms are described, each displaying unprecedented design control. …

In the current study, complex nano-forms displaying arbitrary wireframe architectures have been created, using a new set of design rules. “Earlier design methods used strategies including parallel arrangement of DNA helices to approximate arbitrary shapes, but precise fine-tuning of DNA wireframe architectures that connect vertices in 3D space has required a new approach,” Yan says.

Yan has long been fascinated with Nature’s seemingly boundless capacity for design innovation. The new study describes wireframe structures of high complexity and programmability, fabricated through the precise control of branching and curvature, using novel organizational principles for the designs. (Wireframes are skeletal three-dimensional models represented purely through lines and vertices.)

The resulting nanoforms include symmetrical lattice arrays, quasicrystalline structures, curvilinear arrays, and a simple wire art sketch in the 100-nm scale, as well as 3D objects including a snub cube with 60 edges and 24 vertices and a reconfigurable Archimedean solid that can be controlled to make the unfolding and refolding transitions between 3D and 2D.

The research appears in the advanced online edition of the journal Nature Nanotechnology [abstract]. …

The new design rules were next tested with the assembly of increasingly complex nanostructures, involving vertices ranging from 2 to 10 arms, with many different angles and curvatures involved, including a complex pattern of birds and flowers.

The accuracy of the design was subsequently confirmed by AFM imaging, proving that the method could successfully yield highly sophisticated wireframe DNA nanostructures. …

The authors stress that the new design innovations described can be used to compose and construct any imaginable wireframe nanostructure— a significant advancement for the burgeoning field. On the horizon, nanoscale structures may one day be marshaled to hunt cancer cells in the body or act as robot assembly lines for the design of new drugs.

This new design approach has clearly produced a variety of intricate nanostructures. It will be interesting to see what new functional devices and nanomachines arise from this increased structural repertoire.
—James Lewis, PhD

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Conference video: Artificial Biochemistry with DNA

DNA as a Universal Substrate for Chemical Kinetics- embedded control circuit to direct molecular events. Credit: David Soloveichik

A select set of videos from the 2013 Foresight Technical Conference: Illuminating Atomic Precision, held January 11-13, 2013 in Palo Alto, have been made available on vimeo. Videos have been posted of those presentations for which the speakers have consented. Other presentations contained confidential information and will not be posted.

The fourth speaker at the Commercial Scale Devices – Part 2 session, the winner of the 2012 Feynman Prize for Theoretical work, David Soloveichik, presented his prize-winning work “Artificial Biochemistry with DNA” – video length 29:14. Dr. Soloveichik began his talk by asking if we could recapitulate the feats of biology, specifically computation with networks of molecular interactions, with de novo engineering. After the basic technology is developed, possible applications could include artificial control modules that could be inserted into cells to create “smart drugs”, or as control modules for completely artificial systems (“wet robots”). Dr. Soloveichik has made the slides from his talk available here.

Dr. Soloveichik noted that living cells are controlled by regulatory networks that are complex not only because of their size, but also because of their dynamic properties and kinetic behavior. As an example, he cited the cyanobacterial circadian clock oscillator, in which limit cycle oscillations can continue for 10 days in vitro due to mutual binding and phosphorylation-dephosphorylation reactions. In these control networks, the chemical interactions are for the purpose of processing information so that network structure is more important than the chemical identity of the interacting species.

To create a technology from scratch capable of producing complex molecular systems, perhaps exceeding the results of biology, Dr. Soloveichik pointed to the need for a material whose interactions can be programmed. Nucleic acids are an ideal choice because to make two single strands bind to each other, it is only necessary to make one the Watson-Crick complement of the other. 3-D structure and sequence are not important; only what parts are complementary and can bind other parts is important. He calls sequences that effectively act as units “domains” and gives them numbers, indicating W-C complement by a star (*). Two identical strands competing for the same binding partner can cause strand displacement, or branch migration, which occurs readily without the help of enzymes. Bernie Yurke was the first to realize that strand displacement can be used to rationally engineer molecular scale changes in structure. What was missing was a flexible strategy to chain or cascade such changes together to create functional networks.

The system, Dr. Soloveichik explained, obeys three rules obeyed in all possible ways: the bind rule, the release rule, and the displace rule. There are two kinds of domains: long and short. The short domain is short enough that its binding is readily reversible. The bind rule says that two single strand domains that are W-C complements of each other can bind. THe release rule says that any strand bound by a short domain can unbind. The key displace rule says that you can displace a domain by an identical domain, but only if an adjacent domain is already bound. the physical basis of this rule is that there is a large kinetic barrier to beginning strand displacement, but co0localization can overcome it by increasing the effective local concentration. The rate of displacements can be controlled over six orders of magnitude by changing the length or the binding strength of the short domain. Dr. Soloveichik illustrated these rules with an AND logic gate constructed from a small number of domains. Ne noted a 2011 Science paper (“Scaling Up Digital Circuit Computation with DNA Strand Displacement Cascades” by Qian and Winfree) in which the square-root of a 4-bit number was calculated by a circuit that comprised 130 DNA strands. He also mentioned Microsoft’s Visual DNA Strand Displacement formal language (DSD) for describing and modeling strand displacement cascades, and a flash game developed by David Baker’s group

To demonstrate what strand displacement cascades can do, Dr. Soloveichik presented a theoretical argument that strand displacement cascades can in principle mimic the temporal dynamics of any other chemical system, implying they can exhibit any complex computational or regulatory function possible in a chemical system. He illustrated this claim with the strand displacement implementation of a bimolecular reaction X + Y –> Z at rate k. X, Y, and Z correspond to certain DNA strands; production and consumption correspond to these strands being free or bound, etc. Several examples were presented.
—James Lewis, PhD

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Ribosome subunits tethered to make versatile artificial molecular machine

An engineered ribosome with a permanent connection between its subunits (red) can operate side-by-side with a cell’s own protein production machinery. Credit: Erik Carlson

Engineering Nature’s primordial molecular machine—the ribosome—promises a path to unnatural polymers that may expand the set of properties provided by proteins and biomimetic polymers to engineer artificial molecular machine systems. A hat tip to ScienceDaily for reprinting this University of Illinois at Chicago news release written by Sam Hostettler “Researchers design first artificial ribosome“:

Researchers at the University of Illinois at Chicago and Northwestern University have engineered a tethered ribosome that works nearly as well as the authentic cellular component, or organelle, that produces all the proteins and enzymes within the cell.

The engineered ribosome may enable the production of new drugs and next-generation biomaterials and lead to a better understanding of how ribosomes function.

The artificial ribosome, called Ribo-T, was created in the laboratories of Alexander Mankin, director of the UIC College of Pharmacy’s Center for Biomolecular Sciences, and Northwestern’s Michael Jewett, assistant professor of chemical and biological engineering.

The human-made ribosome may be able to be manipulated in the laboratory to do things natural ribosomes cannot do.

When the cell makes a protein, mRNA (messenger RNA) is copied from DNA. The ribosomes’ two subunits, one large and one small, unite on mRNA to form the functional unit that assembles the protein in a process called translation. Once the protein molecule is complete, the ribosome subunits — both of which are themselves made up of RNA and protein — separate from each other.

In a new study in the journal Nature [abstract], the researchers describe the design and properties of Ribo-T, a ribosome with subunits that will not separate. Ribo-T may be able to be tuned to produce unique and functional polymers for exploring ribosome functions or producing designer therapeutics — and perhaps one day even non-biological polymers.

No one has ever developed something of this nature.

“We felt like there was a small — very small — chance Ribo-T could work, but we did not really know,” Mankin said.

Mankin, Jewett and their colleagues were frustrated in their investigations by the ribosomes’ subunits falling apart and coming together in every cycle of protein synthesis. Could the subunits be permanently linked together? The researchers devised a novel designer ribosome with tethered subunits — Ribo-T.

“What we were ultimately able to do was show that by creating an engineered ribosome where the ribosomal RNA is shared between the two subunits and linked by these small tethers, we could actually create a dual translation system,” Jewett said.

“It was surprising that our hybrid chimeric RNA could support assembly of a functional ribosome in the cell. It was also surprising that this tethered ribosome could support growth in the absence of wild-type ribosomes,” he said.

Ribo-T worked even better than Mankin and Jewett believed it could. Not only did Ribo-T make proteins in a test-tube, it was able to make enough protein in bacterial cells that lacked natural ribosomes to keep the bacteria alive.

Jewett and Mankin were surprised by this. Scientists had previously believed that the ability of the two ribosomal subunits to separate was required for protein synthesis.

“Obviously this assumption was incorrect,” Jewett said.

“Our new protein-making factory holds promise to expand the genetic code in a unique and transformative way, providing exciting opportunities for synthetic biology and biomolecular engineering,” Jewett said.

“This is an exciting tool to explore ribosomal functions by experimenting with the most critical parts of the protein synthesis machine, which previously were ‘untouchable,’” Mankin added.

The researchers’ abstract succinctly describes the possibilities of their artificial ribosome and the orthogonal translational systems it makes possible:

The ribosome is a ribonucleoprotein machine responsible for protein synthesis. In all kingdoms of life it is composed of two subunits, each built on its own ribosomal RNA (rRNA) scaffold. The independent but coordinated functions of the subunits, including their ability to associate at initiation, rotate during elongation, and dissociate after protein release, are an established model of protein synthesis. Furthermore, the bipartite nature of the ribosome is presumed to be essential for biogenesis, since dedicated assembly factors keep immature ribosomal subunits apart and prevent them from translation initiation1. Free exchange of the subunits limits the development of specialized orthogonal genetic systems that could be evolved for novel functions without interfering with native translation. Here we show that ribosomes with tethered and thus inseparable subunits (termed Ribo-T) are capable of successfully carrying out protein synthesis. By engineering a hybrid rRNA composed of both small and large subunit rRNA sequences, we produced a functional ribosome in which the subunits are covalently linked into a single entity by short RNA linkers. Notably, Ribo-T was not only functional in vitro, but was also able to support the growth of Escherichia coli cells even in the absence of wild-type ribosomes. We used Ribo-T to create the first fully orthogonal ribosome–messenger RNA system, and demonstrate its evolvability by selecting otherwise dominantly lethal rRNA mutations in the peptidyl transferase centre that facilitate the translation of a problematic protein sequence. Ribo-T can be used for exploring poorly understood functions of the ribosome, enabling orthogonal genetic systems, and engineering ribosomes with new functions.

Additional comments were provided by Heidi Ledford in an article published by Nature and republished by Scientific American.
—James Lewis, PhD

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Another nanotechnology computer memory breakthrough from Feynman Prize winner

A schematic shows the layered structure of tantalum oxide, multilayer graphene and platinum used for a new type of memory developed at Rice University. The memory device overcomes crosstalk problems that cause read errors in other devices. (Credit: Tour Group/Rice University)

One prominent area in which nanoscale science and technology is providing a rich pipeline feeding current and near-term improvements in technology is computer hardware, and in particular, solid-state computer memories. One year ago, we cited a breakthrough nanoporous silicon oxide technology for resistive random-access memory (RRAM) developed by the research group of James Tour, winner of the 2008 Foresight Institute Feynman Prize in the Experimental category. Now he appears to have topped this memory architecture with another memory breakthrough. A hat tip to KurzweilAI for reporting this Rice University news release “Tantalizing discovery may boost memory technology“:

Scientists at Rice University have created a solid-state memory technology that allows for high-density storage with a minimum incidence of computer errors.

The memories are based on tantalum oxide, a common insulator in electronics. Applying voltage to a 250-nanometer-thick sandwich of graphene, tantalum, nanoporous tantalum oxide and platinum creates addressable bits where the layers meet. Control voltages that shift oxygen ions and vacancies switch the bits between ones and zeroes.

The discovery by the Rice lab of chemist James Tour could allow for crossbar array memories that store up to 162 gigabits, much higher than other oxide-based memory systems under investigation by scientists. (Eight bits equal one byte; a 162-gigabit unit would store about 20 gigabytes of information.)

Details appear online in the American Chemical Society journal Nano Letters [abstract].

Like the Tour lab’s previous discovery of silicon oxide memories, the new devices require only two electrodes per circuit, making them simpler than present-day flash memories that use three. “But this is a new way to make ultradense, nonvolatile computer memory,” Tour said.

Nonvolatile memories hold their data even when the power is off, unlike volatile random-access computer memories that lose their contents when the machine is shut down.

Modern memory chips have many requirements: They have to read and write data at high speed and hold as much as possible. They must also be durable and show good retention of that data while using minimal power.

Tour said Rice’s new design, which requires 100 times less energy than present devices, has the potential to hit all the marks.

“This tantalum memory is based on two-terminal systems, so it’s all set for 3-D memory stacks,” he said. “And it doesn’t even need diodes or selectors, making it one of the easiest ultradense memories to construct. This will be a real competitor for the growing memory demands in high-definition video storage and server arrays.”

The layered structure consists of tantalum, nanoporous tantalum oxide and multilayer graphene between two platinum electrodes. In making the material, the researchers found the tantalum oxide gradually loses oxygen ions, changing from an oxygen-rich, nanoporous semiconductor at the top to oxygen-poor at the bottom. Where the oxygen disappears completely, it becomes pure tantalum, a metal.

The researchers determined three related factors give the memories their unique switching ability.

First, the control voltage mediates how electrons pass through a boundary that can flip from an ohmic (current flows in both directions) to a Schottky (current flows one way) contact and back.

Second, the boundary’s location can change based on oxygen vacancies. These are “holes” in atomic arrays where oxygen ions should exist, but don’t. The voltage-controlled movement of oxygen vacancies shifts the boundary from the tantalum/tantalum oxide interface to the tantalum oxide/graphene interface. “The exchange of contact barriers causes the bipolar switching,” said Gunuk Wang, lead author of the study and a former postdoctoral researcher at Rice.

Third, the flow of current draws oxygen ions from the tantalum oxide nanopores and stabilizes them. These negatively charged ions produce an electric field that effectively serves as a diode to hinder error-causing crosstalk. While researchers already knew the potential value of tantalum oxide for memories, such arrays have been limited to about a kilobyte because denser memories suffer from crosstalk that allows bits to be misread.

The graphene does double duty as a barrier that keeps platinum from migrating into the tantalum oxide and causing a short circuit.

Tour said tantalum oxide memories can be fabricated at room temperature. He noted the control voltage that writes and rewrites the bits is adjustable, which allows a wide range of switching characteristics.

Wang said the remaining hurdles to commercialization include the fabrication of a dense enough crossbar device to address individual bits and a way to control the size of the nanopores.

Improvements in computer memory can be expected to have far-reaching effects on all areas of science and technology, especially by facilitating and extending the application of big data and data science in areas from genomic research to clinical medicine to increasingly general artificial intelligence applications. As incremental advances in nanotechnology provide increasingly fine control over the structure of matter at the nanometer scale, they point toward the even greater advances that will occur once high-throughput atomically precise manufacturing becomes available.
—James Lewis, PhD

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Automated design of polyhedral meshes for DNA origami

Björn Högberg and Erik Benson with models of their origami 3D meshes. Credit: Ulf Sirborn

Scaffolded DNA origami, one of the mainstays of structural DNA nanotechnology since its invention in 2006, continues to undergo improvement. A press release from Sweden’s Karolinska Institutet “3D ‘printouts’ at the nanoscale using self-assembling DNA structures“:

A novel way of making 3D nanostructures from DNA is described in a study published in the renowned journal Nature [abstract]. The study was led by researchers at Sweden’s Karolinska Institutet who collaborated with a group at Finland’s Aalto University. The new technique makes it possible to synthesize 3D DNA origami structures that are also able to tolerate the low salt concentrations inside the body, which opens the way for completely new biological applications of DNA nanotechnology. The design process is also highly automated, which enables the creation of synthetic DNA nanostructures of remarkable complexity.

The team behind the study likens the new approach to a 3D printer for nanoscale structures. The user draws the desired structure, in the form of a polygon object, in 3D software normally used for computer-aided design or animation. Graph-theoretic algorithms and optimization techniques are then used to calculate the DNA sequences needed to produce the structure.

When the synthesized DNA sequences are combined in a salt solution, they assemble themselves into the correct structure. One of the big advantages of building nanostructures out of DNA is that the bases bind to each other through base-paring in a predictable fashion.

“This new method makes it very easy to design DNA nanostructures and gives more design freedom,” says study leader Björn Högberg from the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “We can now make structures that were impossible to design previously and we can do it in the same way as one might draw a 3D structure for printing out in macroscopic scale, but instead of making it out of plastic, we print it in DNA at the nanoscale.”

Using this technique, the team has built a ball, spiral, rod and bottle-shaped structure, and a DNA printout of the so-called Stanford Bunny, which is a common test model for 3D modelling. Apart from being simpler compared to former ways of making DNA origami, the method – importantly – does not require high concentrations of magnesium salt.

“For biological applications, the most crucial difference is that we can now create structures that can be folded in, and remain viable in, physiological salt concentrations that are more suitable for biological applications of DNA nanostructures,” explains Dr Högberg.

“ An advantage of the automated design process is that one can now deal systematically with even quite complex structures. Advanced computing methods are likely to be a key enabler in the scaling of DNA nanotechnology from fundamental studies towards groundbreaking applications,” says Professor Pekka Orponen, who directed the team at the Aalto University Computer Science Department.

The possible applications are many. The team at Karolinska Institutet has previously made a DNA nano-caliper used for studying cell signalling. The new technique makes it possible to conduct similar biological experiments in a way that resembles conditions within cells even more closely. DNA nanostructures have also been used to make targeted capsules able to deliver cancer drugs direct to tumour cells, which can reduce the amount of drugs needed. …

Taking this research together with yesterday’s post, it is gratifying to see that both DNA bricks and scaffolded DNA origami, two alternative implementations of structural DNA nanotechnology, are advancing rapidly. These parallel advances lay a robust foundation for the modular molecular composite nanosystems strategy formulated as part of the 2007 Foresight and Battelle Technology Roadmap for Productive Nanosystems. It might turn out to be especially important that this new research produces novel structures stable under salt conditions compatible with biological systems. To date, many of the most complex and functional applications of DNA nanotechnology (for example) are focused on medical needs. Facilitating the development of DNA nanotechnology to meet medical needs might synergistically facilitate the development of DNA nanotechnology for other uses, such as computation or molecular manufacturing/atomically precise manufacturing.
—James Lewis, PhD

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Arranging molecular chromophores on DNA brick nanobreadboards

ON-OFF cycling of AND logic gate formed by arrangement of four single-molecule chromophores on a DNA brick nanobreadboard. Credit: Canon et al. ACS Photonics.

The idea of using a DNA framework as a “nanobreadboard” to prototype various nanoscale circuits and device arrays goes back at least to Paul Rothemund’s 2006 invention of scaffolded DNA origami technology. The idea played a central role in the development of the concept of modular molecular composite nanosystems formulated as part of the 2007 Foresight and Battelle Technology Roadmap for Productive Nanosystems. Earlier this year researchers at Boise State University in Idaho published an open access article in the journal ACS PhotonicsExcitonic AND Logic Gates on DNA Brick Nanobreadboards“. However, instead of scaffolded DNA origami, these researchers built their nanobreadboards using an alternate form of structural DNA nanotechnology (see “Arbitrarily complex 3D DNA nanostructures built from DNA bricks“) that has been extended to fabricate micrometer-scale structures that offer unique opportunities as molecular “breadboards”.

To make single-molecule optical devices for computing and other applications, which exploit the interactions between light and matter at much smaller length scales than the free-space wavelength of light, these molecular chromophores must be precisely arranged to enhance non-radiative dipole-dipole coupling between neighboring chromophores. subnanometer resolution. This coupling facilitates an energy transfer process (FRET – Förster Resonance Energy Transfer) that occurs over a distance that is typically 5 nm or less. Molecular orientation also plays a role. Previous studies of multi-chromophore excitonic circuits have positioned the chromophores using single DNA duplexes or multiarm DNA junctions, or DNA origami. With DNA origami, however, it is only practical to conjugate chromophores to selected staple strands; the long scaffold strand can only play a role in the overall structure since conjugation to the scaffold strand is impractical. This restricted role of the scaffold strand limits the feasibility of using DNA origami for the rapid prototyping of excitonic circuits that is essential to achieve complex functionality.

DNA brick-based nanobreadboards, however, can be assembled by selecting components from a master DNA library. Different complex shapes can be obtained merely by selecting different subsets of the master library, while DNA origami would require re-designing all the staple strands for each new breadboard. The authors also claim that because of the absence of a scaffold strand and because any DNA brick can carry covalently attached chromophores, packing density and position control is twice what it would be with DNA origami. Capitalizing on these advantages:

… In this work, we show (1) four-chromophore systems with two dynamically controlled inputs permitting bilevel switches that can be coupled to demonstrate fully excitonic AND logic, and (2) dynamic excitonic switching and logic operations controlled by isothermal DNA reactions in stoichiometric quantities. …

Although two AND gates are described (each using four chromophores in different spatial arrangements), the authors claim that any and all logic gate operations can be implemented. Further, the coupling of multiple excitonic devices on a nanobreadboard promotes achieving greater circuit complexity. In each design, two chromophores are permanently attached to the nanobreadboard, while the other two are added to or removed from DNA tethers by strand displacement. When both of these are attached to the nanobreadboard, they complete a FRET transmission, and the gates are in the ON-state. Both AND gate designs showed successful switching, and the procedure clearly leaves room for further optimization. This paper provides another indication that we are still in early days for determining the functional potential of DNA nanotechnology and modular molecular composite nanosystems.
—James Lewis, PhD

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