Tag Archives: Northwestern University

Nanorods as multistate switches

This research goes beyond the binary (0 or 1) and to an analog state that resembles quantum states. Fascinating, yes? An Oct. 10, 2016 news item on phys.org tells more,

Rice University scientists have discovered how to subtly change the interior structure of semi-hollow nanorods in a way that alters how they interact with light, and because the changes are reversible, the method could form the basis of a nanoscale switch with enormous potential.

“It’s not 0-1, it’s 1-2-3-4-5-6-7-8-9-10,” said Rice materials scientist Emilie Ringe, lead scientist on the project, which is detailed in the American Chemical Society journal Nano Letters. “You can differentiate between multiple plasmonic states in a single particle. That gives you a kind of analog version of quantum states, but on a larger, more accessible scale.”

Ringe and colleagues used an electron beam to move silver from one location to another inside gold-and-silver nanoparticles, something like a nanoscale Etch A Sketch. The result is a reconfigurable optical switch that may form the basis for a new type of multiple-state computer memory, sensor or catalyst.

An Oct. 10, 2016 Rice University news release, which originated the news item, describes the work in additional detail,

At about 200 nanometers long, 500 of the metal rods placed end-to-end would span the width of a human hair. However, they are large in comparison with modern integrated circuits. Their multistate capabilities make them more like reprogrammable bar codes than simple memory bits, she said.

“No one has been able to reversibly change the shape of a single particle with the level of control we have, so we’re really excited about this,” Ringe said.

Altering a nanoparticle’s internal structure also alters its external plasmonic response. Plasmons are the electrical ripples that propagate across the surface of metallic materials when excited by light, and their oscillations can be easily read with a spectrometer — or even the human eye — as they interact with visible light.

The Rice researchers found they could reconfigure nanoparticle cores with pinpoint precision. That means memories made of nanorods need not be merely on-off, Ringe said, because a particle can be programmed to emit many distinct plasmonic patterns.

The discovery came about when Ringe and her team, which manages Rice’s advanced electron microscopy lab, were asked by her colleague and co-author Denis Boudreau, a professor at Laval University in Quebec, to characterize hollow nanorods made primarily of gold but containing silver.

“Most nanoshells are leaky,” Ringe said. “They have pinholes. But we realized these nanorods were defect-free and contained pockets of water that were trapped inside when the particles were synthesized. We thought: We have something here.”

Ringe and the study’s lead author, Rice research scientist Sadegh Yazdi, quickly realized how they might manipulate the water. “Obviously, it’s difficult to do chemistry there, because you can’t put molecules into a sealed nanoshell. But we could put electrons in,” she said.

Focusing a subnanometer electron beam on the interior cavity split the water and inserted solvated electrons – free electrons that can exist in a solution. “The electrons reacted directly with silver ions in the water, drawing them to the beam to form silver,” Ringe said. The now-silver-poor liquid moved away from the beam, and its silver ions were replenished by a reaction of water-splitting byproducts with the solid silver in other parts of the rod.

“We actually were moving silver in the solution, reconfiguring it,” she said. “Because it’s a closed system, we weren’t losing anything and we weren’t gaining anything. We were just moving it around, and could do so as many times as we wished.”

The researchers were then able to map the plasmon-induced near-field properties without disturbing the internal structure — and that’s when they realized the implications of their discovery.

“We made different shapes inside the nanorods, and because we specialize in plasmonics, we mapped the plasmons and it turned out to have a very nice effect,” Ringe said. “We basically saw different electric-field distributions at different energies for different shapes.” Numerical results provided by collaborators Nicolas Large of the University of Texas at San Antonio and George Schatz of Northwestern University helped explain the origin of the modes and how the presence of a water-filled pocket created a multitude of plasmons, she said.

The next challenge is to test nanoshells of other shapes and sizes, and to see if there are other ways to activate their switching potentials. Ringe suspects electron beams may remain the best and perhaps only way to catalyze reactions inside particles, and she is hopeful.

“Using an electron beam is actually not as technologically irrelevant as you might think,” she said. “Electron beams are very easy to generate. And yes, things need to be in vacuum, but other than that, people have generated electron beams for nearly 100 years. I’m sure 40 years ago people were saying, ‘You’re going to put a laser in a disk reader? That’s crazy!’ But they managed to do it.

“I don’t think it’s unfeasible to miniaturize electron-beam technology. Humans are good at moving electrons and electricity around. We figured that out a long time ago,” Ringe said.

The research should trigger the imaginations of scientists working to create nanoscale machines and processes, she said.

“This is a reconfigurable unit that you can access with light,” she said. “Reading something with light is much faster than reading with electrons, so I think this is going to get attention from people who think about dynamic systems and people who think about how to go beyond current nanotechnology. This really opens up a new field.”

Here’s a link to and a citation for the paper,

Reversible Shape and Plasmon Tuning in Hollow AgAu Nanorods by Sadegh Yazdi, Josée R. Daniel, Nicolas Large, George C. Schatz, Denis Boudreau, and Emilie Ringe. Nano Lett., Article ASAP DOI: 10.1021/acs.nanolett.6b02946 Publication Date (Web): October 5, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

The researchers have made this video available for the public,

2016 Nobel Chemistry Prize for molecular machines

Wednesday, Oct. 5, 2016 was the day three scientists received the Nobel Prize in Chemistry for their work on molecular machines, according to an Oct. 5, 2016 news item on phys.org,

Three scientists won the Nobel Prize in chemistry on Wednesday [Oct. 5, 2016] for developing the world’s smallest machines, 1,000 times thinner than a human hair but with the potential to revolutionize computer and energy systems.

Frenchman Jean-Pierre Sauvage, Scottish-born Fraser Stoddart and Dutch scientist Bernard “Ben” Feringa share the 8 million kronor ($930,000) prize for the “design and synthesis of molecular machines,” the Royal Swedish Academy of Sciences said.

Machines at the molecular level have taken chemistry to a new dimension and “will most likely be used in the development of things such as new materials, sensors and energy storage systems,” the academy said.

Practical applications are still far away—the academy said molecular motors are at the same stage that electrical motors were in the first half of the 19th century—but the potential is huge.

Dexter Johnson in an Oct. 5, 2016 posting on his Nanoclast blog (on the IEEE [Institute of Electrical and Electronics Engineers] website) provides some insight into the matter (Note: A link has been removed),

In what seems to have come both as a shock to some of the recipients and a confirmation to all those who envision molecular nanotechnology as the true future of nanotechnology, Bernard Feringa, Jean-Pierre Sauvage, and Sir J. Fraser Stoddart have been awarded the 2016 Nobel Prize in Chemistry for their development of molecular machines.

The Nobel Prize was awarded to all three of the scientists based on their complementary work over nearly three decades. First, in 1983, Sauvage (currently at Strasbourg University in France) was able to link two ring-shaped molecules to form a chain. Then, eight years later, Stoddart, a professor at Northwestern University in Evanston, Ill., demonstrated that a molecular ring could turn on a thin molecular axle. Then, eight years after that, Feringa, a professor at the University of Groningen, in the Netherlands, built on Stoddardt’s work and fabricated a molecular rotor blade that could spin continually in the same direction.

Speaking of the Nobel committee’s selection, Donna Nelson, a chemist and president of the American Chemical Society told Scientific American: “I think this topic is going to be fabulous for science. When the Nobel Prize is given, it inspires a lot of interest in the topic by other researchers. It will also increase funding.” Nelson added that this line of research will be fascinating for kids. “They can visualize it, and imagine a nanocar. This comes at a great time, when we need to inspire the next generation of scientists.”

The Economist, which appears to be previewing an article about the 2016 Nobel prizes ahead of the print version, has this to say in its Oct. 8, 2016 article,

BIGGER is not always better. Anyone who doubts that has only to look at the explosion of computing power which has marked the past half-century. This was made possible by continual shrinkage of the components computers are made from. That success has, in turn, inspired a search for other areas where shrinkage might also yield dividends.

One such, which has been poised delicately between hype and hope since the 1990s, is nanotechnology. What people mean by this term has varied over the years—to the extent that cynics might be forgiven for wondering if it is more than just a fancy rebranding of the word “chemistry”—but nanotechnology did originally have a fairly clear definition. It was the idea that machines with moving parts could be made on a molecular scale. And in recognition of this goal Sweden’s Royal Academy of Science this week decided to award this year’s Nobel prize for chemistry to three researchers, Jean-Pierre Sauvage, Sir Fraser Stoddart and Bernard Feringa, who have never lost sight of nanotechnology’s original objective.

Optimists talk of manufacturing molecule-sized machines ranging from drug-delivery devices to miniature computers. Pessimists recall that nanotechnology is a field that has been puffed up repeatedly by both researchers and investors, only to deflate in the face of practical difficulties.

There is, though, reason to hope it will work in the end. This is because, as is often the case with human inventions, Mother Nature has got there first. One way to think of living cells is as assemblies of nanotechnological machines. For example, the enzyme that produces adenosine triphosphate (ATP)—a molecule used in almost all living cells to fuel biochemical reactions—includes a spinning molecular machine rather like Dr Feringa’s invention. This works well. The ATP generators in a human body turn out so much of the stuff that over the course of a day they create almost a body-weight’s-worth of it. Do something equivalent commercially, and the hype around nanotechnology might prove itself justified.

Congratulations to the three winners!

Not exactly ‘Prey’: self-organizing materials that can mimic swarm behaviour

Prey, a 2002 novel by Michael Crichton, focused on nanotechnology and other emerging technologies and how their development could lead to unleashing swarms of nanobots with agendas of their own. Crichton’s swarms had collective artificial intelligence, and could massive themselves together to take on different macroscale shapes to achieve their own ends. This latest development has nowhere near that potential—not yet and probably never. From a July 21, 2016 news item on ScienceDaily,

A new study by an international team of researchers, affiliated with Ulsan National Institute of Science and Technology (UNIST) [Korea] has announced that they have succeeded in demonstarting control over the interactions occurring among microscopic spheres, which cause them to self-propel into swarms, chains, and clusters.

The research published in the current online edition of Nature Materials takes lessons from cooperation in nature, including that observed in honey bee swarms and bacterial clusters. In the study, the team has successfully demonstrated the self-organizing pattern formation in active materials at microscale by modifying only one parameter.

A July 21, 2016 UNIST press release, which originated the news item, expands on the theme,

This breakthrough comes from a research, conducted by Dr. Steve Granick (School of Natural Science, UNIST) of IBS Center for Soft and Living Matter in collaboration with Dr. Erik Luijten from Northwestern University. Ming Han, a PhD student in Luijten’s laboratory, and Jing Yan, a former graduate student at the University of Illinois, served as co-first authors of the paper.

Researchers expect that such active particles could open a new class of technologies with applications in medicine, chemistry, and engineering as well as advance scientists’ fundamental understanding of collective, dynamic behavior in systems.

According to the research team, the significance of team work was stressed by both Dr. Luijten and Dr. Granick as this current breakthrough is part of a longtime partnership using a new class of soft-matter particles known as Janus colloids, which Dr. Granick had earlier created in his laboratory. The theoretical computer simulations were completed by the team, led by Dr. Luijten and Dr. Granick used these colloids to experimentally test the collective, dynamic behavior in the laboratory.

The micron-sized spheres, typically suspended in solution, were named after the Roman god with two faces as they have attractive interactions on one side and negative charges on the other side.

The electrostatic interactions between the two sides of the self-propelled spheres could be manipulated by subjecting the colloids to an electric field. Some experienced stronger repulsions between their forward-facing sides, while others went through the opposite. Along with them, another set remained completely neutral. This imbalance caused the self-propelled particles to swim and self-organize into one of the following patterns, which are swarms, chains, clusters and isotropic gases.

To avoid head-to-head collisions, head-repulsive particles swam side-by-side, forming into swarms. Depending on the electric-field frequency, tail-repulsive particles positioned their tails apart, thus encouraging them to face each other to form jammed clusters of high local density. Also, swimmers with equal-and-opposite charges attracted one another into connected chains.

Dr. Granick states, “This truly is a joint work of the technological know-how by the Korean IBS and the University of Illinois, as well as the computer simulations technology by Northwestern University.” He expects that this breakthrough has probable application in sensing, drug delivery, or even microrobotics.

With this discovery, a drug could be placed within particles, for instance, that cluster into the delivery spot. Moreover, alterations in the environment could be perceived if the system unexpectedly switches from swarming to forming chains.

Here’s a link to and a citation for the paper,

Reconfiguring active particles by electrostatic imbalance by Jing Yan, Ming Han, Jie Zhang, Cong Xu, Erik Luijten, & Steve Granick. Nature Materials (2016)  doi:10.1038/nmat4696 Published online 11 July 2016

This paper is behind a paywall.

Ultimate discovery tool?

For anyone familiar with the US nanomedicine scene, Chad Mirkin’s appearance in this announcement from Northwestern University isn’t much of a surprise.  From a June 23, 2016 news item on ScienceDaily,

The discovery power of the gene chip is coming to nanotechnology. A Northwestern University research team is developing a tool to rapidly test millions and perhaps even billions or more different nanoparticles at one time to zero in on the best particle for a specific use.

When materials are miniaturized, their properties—optical, structural, electrical, mechanical and chemical—change, offering new possibilities. But determining what nanoparticle size and composition are best for a given application, such as catalysts, biodiagnostic labels, pharmaceuticals and electronic devices, is a daunting task.

“As scientists, we’ve only just begun to investigate what materials can be made on the nanoscale,” said Northwestern’s Chad A. Mirkin, a world leader in nanotechnology research and its application, who led the study. “Screening a million potentially useful nanoparticles, for example, could take several lifetimes. Once optimized, our tool will enable researchers to pick the winner much faster than conventional methods. We have the ultimate discovery tool.”

A June 23, 2016 Northwestern University news release (also on EurekAlert), which originated the news item, describes the work in more detail,

Using a Northwestern technique that deposits materials on a surface, Mirkin and his team figured out how to make combinatorial libraries of nanoparticles in a very controlled way. (A combinatorial library is a collection of systematically varied structures encoded at specific sites on a surface.) Their study will be published June 24 by the journal Science.

The nanoparticle libraries are much like a gene chip, Mirkin says, where thousands of different spots of DNA are used to identify the presence of a disease or toxin. Thousands of reactions can be done simultaneously, providing results in just a few hours. Similarly, Mirkin and his team’s libraries will enable scientists to rapidly make and screen millions to billions of nanoparticles of different compositions and sizes for desirable physical and chemical properties.

“The ability to make libraries of nanoparticles will open a new field of nanocombinatorics, where size — on a scale that matters — and composition become tunable parameters,” Mirkin said. “This is a powerful approach to discovery science.”

“I liken our combinatorial nanopatterning approach to providing a broad palette of bold colors to an artist who previously had been working with a handful of dull and pale black, white and grey pastels,” said co-author Vinayak P. Dravid, the Abraham Harris Professor of Materials Science and Engineering in the McCormick School of Engineering.

Using five metallic elements — gold, silver, cobalt, copper and nickel — Mirkin and his team developed an array of unique structures by varying every elemental combination. In previous work, the researchers had shown that particle diameter also can be varied deliberately on the 1- to 100-nanometer length scale.

Some of the compositions can be found in nature, but more than half of them have never existed before on Earth. And when pictured using high-powered imaging techniques, the nanoparticles appear like an array of colorful Easter eggs, each compositional element contributing to the palette.

To build the combinatorial libraries, Mirkin and his team used Dip-Pen Nanolithography, a technique developed at Northwestern in 1999, to deposit onto a surface individual polymer “dots,” each loaded with different metal salts of interest. The researchers then heated the polymer dots, reducing the salts to metal atoms and forming a single nanoparticle. The size of the polymer dot can be varied to change the size of the final nanoparticle.

This control of both size and composition of nanoparticles is very important, Mirkin stressed. Having demonstrated control, the researchers used the tool to systematically generate a library of 31 nanostructures using the five different metals.

To help analyze the complex elemental compositions and size/shape of the nanoparticles down to the sub-nanometer scale, the team turned to Dravid, Mirkin’s longtime friend and collaborator. Dravid, founding director of Northwestern’s NUANCE Center, contributed his expertise and the advanced electron microscopes of NUANCE to spatially map the compositional trajectories of the combinatorial nanoparticles.

Now, scientists can begin to study these nanoparticles as well as build other useful combinatorial libraries consisting of billions of structures that subtly differ in size and composition. These structures may become the next materials that power fuel cells, efficiently harvest solar energy and convert it into useful fuels, and catalyze reactions that take low-value feedstocks from the petroleum industry and turn them into high-value products useful in the chemical and pharmaceutical industries.

Here’s a diagram illustrating the work,

 Caption: A combinatorial library of polyelemental nanoparticles was developed using Dip-Pen Nanolithography. This novel nanoparticle library opens up a new field of nanocombinatorics for rapid screening of nanomaterials for a multitude of properties. Credit: Peng-Cheng Chen/James Hedrick

Caption: A combinatorial library of polyelemental nanoparticles was developed using Dip-Pen Nanolithography. This novel nanoparticle library opens up a new field of nanocombinatorics for rapid screening of nanomaterials for a multitude of properties. Credit: Peng-Cheng Chen/James Hedrick

Here’s a link to and a citation for the paper,

Polyelemental nanoparticle libraries by Peng-Cheng Chen, Xiaolong Liu, James L. Hedrick, Zhuang Xie, Shunzhi Wang, Qing-Yuan Lin, Mark C. Hersam, Vinayak P. Dravid, Chad A. Mirkin. Science  24 Jun 2016: Vol. 352, Issue 6293, pp. 1565-1569 DOI: 10.1126/science.aaf8402

This paper is behind a paywall.

Congratulations to Markus Buehler on his Foresight Institute Feynman Prize for advances in nanotechnology

A May 24, 2016 Massachusetts Institute of Technology (MIT) news release celebrates Markus Buehler’s latest award,

On May 21 [2016], Department of Civil and Environmental Engineering head and McAfee Professor of Engineering Markus J. Buehler received the 2015 Foresight Institute Feynman Prize in Theoretical Molecular Nanotechnology. Buehler’s award was one of three prizes presented by the Foresight Institute, a leading think tank and public interest organization, at its annual conference in Palo Alto, California. …

The Foresight Institute recognized Buehler for his important contributions to making nanotechnology scalable for large-scale materials applications, enabled by bottom-up multiscale computational methods, and linking new manufacturing and characterization methods.

Focusing on mechanical properties — especially deformation and failure — and translation from biological materials and structures to bio-inspired synthetic materials, his work has led to the development and application of new modeling, design, and manufacturing approaches for advanced materials that offer greater resilience and a wide range of controllable properties from the nano- to the macroscale.

Buehler’s signature achievement, according to the Institute, is the application of molecular and chemical principles in the analysis of mechanical systems, with the aim to design devices and materials that provide a defined set of functions.

“It’s an incredible honor to receive such an esteemed award. I owe this to the outstanding students and postdocs whom I had a pleasure to work with over the years, my colleagues, as well my own mentors,” Buehler said. “Richard Feynman was a revolutionary scientist of his generation. It’s a privilege to share his goals of researching molecular technology at very small scale to create new, more efficient, and better lasting materials at much larger scale that will help transform lives and industries.”

The two other award winners are Professor Michelle Y. Simmons of the University of New South Wales [Australia], who won the Feynman Prize for Experimental Molecular Nanotechnology, and Northwestern University graduate student Chuyang Cheng, who won the Distinguished Student Award.

I have featured Buehler’s work here a number of times. The most recent appearance was in  a May 29, 2015 posting about synthesizing spider’s silk.

“One minus one equals zero” has been disproved

Two mirror-image molecules can be optically active according to an April 27, 2016 news item on ScienceDaily,

In 1848, Louis Pasteur showed that molecules that are mirror images of each other had exactly opposite rotations of light. When mixed in solution, they cancel the effects of the other, and no rotation of light is observed. Now, a research team has demonstrated that a mixture of mirror-image molecules crystallized in the solid state can be optically active.

An April 26, 2016 Northwestern University news release (also on EurekAlert), which originated the news item, expands on the theme,

In the world of chemistry, one minus one almost always equals zero.

But new research from Northwestern University and the Centre National de la Recherche Scientifique (CNRS) in France shows that is not always the case. And the discovery will change scientists’ understanding of mirror-image molecules and their optical activity.

Now, Northwestern’s Kenneth R. Poeppelmeier and his research team are the first to demonstrate that a mixture of mirror-image molecules crystallized in the solid state can be optically active. The scientists first designed and made the materials and then measured their optical properties.

“In our case, one minus one does not always equal zero,” said first author Romain Gautier of CNRS. “This discovery will change scientists’ understanding of these molecules, and new applications could emerge from this observation.”

The property of rotating light, which has been known for more than two centuries to exist in many molecules, already has many applications in medicine, electronics, lasers and display devices.

“The phenomenon of optical activity can occur in a mixture of mirror-image molecules, and now we’ve measured it,” said Poeppelmeier, a Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences. “This is an important experiment.”

Although this phenomenon has been predicted for a long time, no one — until now — had created such a racemic mixture (a combination of equal amounts of mirror-image molecules) and measured the optical activity.

“How do you deliberately create these materials?” Poeppelmeier said. “That’s what excites me as a chemist.” He and Gautier painstakingly designed the material, using one of four possible solid-state arrangements known to exhibit circular dichroism (the ability to absorb differently the “rotated” light).

Next, Richard P. Van Duyne, a Morrison Professor of Chemistry at Northwestern, and graduate student Jordan M. Klingsporn measured the material’s optical activity, finding that mirror-image molecules are active when arranged in specific orientations in the solid state.

Here’s a link to and a citation for the paper,

Optical activity from racemates by Romain Gautier, Jordan M. Klingsporn, Richard P. Van Duyne, & Kenneth R. Poeppelmeier. Nature Materials (2016) doi:10.1038/nmat4628 Published online 18 April 2016

This paper is behind a paywall.

Trojan horse nanoparticle for asthma

A brand new technique for dealing with asthma is being proposed by researchers at Northwestern University (US), according to an April 18, 2016 news item on ScienceDaily,

In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell, to convince the immune system not to attack it, according to new Northwestern Medicine research. As a result, the allergic reaction in the airways is shut down long- term and an asthma attack prevented.

The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.

“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said senior author Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “This may eliminate the need for life-long use of medications to treat lung allergy.”

An April 18, 2016 Northwestern University news release (also on EurekAlert) by Marla Paul, which originated the news item, expands on the theme,

It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical Northwestern research.

The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co., which is working with Miller to bring this new approach to patients. A clinical trial using the nanoparticles to treat celiac disease is in development.

“It’s a universal treatment,” Miller said. “Depending on what allergy you want to eliminate, you can load up the nanoparticle with ragweed pollen or a peanut protein.”

The nanoparticles are composed of an FDA-approved biopolymer called PLGA that includes lactic acid and glycolic acid.

Also a senior author is Lonnie Shea, adjunct professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and of obstetrics and gynecology at Feinberg, and chair of biomedical engineering at the University of Michigan.

When the allergen-loaded nanoparticle is injected into the bloodstream of mice, the immune system isn’t concerned with it because it sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.

“The vacuum-cleaner cell presents the allergen or antigen to the immune system in a way that says, ‘No worries, this belongs here,’” Miller said. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.

The allergen, in this case egg protein, was administered into the lungs of mice who have been pretreated to be allergic to the protein and already had antibodies in their blood against it. So when they were re-exposed to it, they responded with an allergic response like asthma. After being treated with the nanoparticle, they no longer had an allergic response to the allergen.

The approach also has a second benefit. It creates a more normal, balanced immune system by increasing the number of regulatory T cells, immune cells important for recognizing the airway allergens as normal. This method turns off the dangerous Th2 T cell that causes the allergy and expands the good, calming regulatory T cells.

If I understand this rightly, they’re rebalancing the immune system so it doesn’t treat innocuous material (dust, mould, etc.) as an allergen.

Here’s a link to and a citation for the paper,

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization by Charles B. Smarr, Woon Teck Yap, Tobias P. Neef, Ryan M. Pearson, Zoe N. Hunter, Igal Ifergan, Daniel R. Getts, Paul J. Bryce, Lonnie D. Shea, and Stephen D. Miller. PNAS 2016 doi: 10.1073/pnas.1505782113 Published ahead of print April 18, 2016,

This paper is behind a paywall.

Babies have more general physics knowledge than experts realized

A Feb. 10, 2016 news item on ScienceDaily sheds some light on babies and their knowledge of physics,

We are born with a basic grasp of physics, just enough not to be surprised when we interact with objects. Scientists discovered this in the past two decades. What they did not know yet was that, as early as five months of age, this ‘naive’ physics also extends to liquids and materials that do not behave like solids (for example, sand), as demonstrated by a new study.

A Feb. 10, 2016 SISSA (International School of Advanced Studies) press release (also on EurekAlert), which originated the news item, describes the conclusions and the research in more detail,

If we hold a ball and then let go of it and the ball remains suspended in mid-air, even a baby a few months old will be surprised. Just like an adult, the baby expects the ball to fall to the floor. Even at such a young age humans already have some rudimentary knowledge of the behaviour of solids. Now a new study extends this knowledge to add liquids and other non-solids to the “naïve physics” of infants.

“This new study developed out of previous experiments”, explains Alissa Ferry, SISSA research scientist and among the authors of the paper, “in which we observed that infants were surprised when a liquid failed to behave as a liquid (in those experiments we “cheated” by disguising solids as liquids)”. Their surprise, explains Ferry, demonstrates that their expectations for a liquid had not been met. “However, what we couldn’t establish was whether the infants knew how a liquid should behave or whether they just expected it to be different from a solid”.

Ferry and colleagues (the first author is Susan Hespos of Northwestern University in Illinois, USA, where the experiments were conducted) therefore devised a new set of tests with a greater range of materials and “interactions”. In a first “habituation” phase, the infants were shown the contents of a glass by tilting the glass in front of them. The glass either contained a solid (which, when not moving, had identical appearance to water) or some water. When the glass was tilted back and forth, the two materials behaved differently: the solid remained perfectly still whereas the water moved. This phase served to teach the infants whether they were looking at a solid or a liquid.

Next, the infants were shown an identical glass to the one seen in the previous phase (making them believe that it was the same glass) which contained either the material they had already seen or the other material. At this point, the infants watched the experimenter either pour the contents (liquid or solid) of the glass into another glass containing a grid or submerge the grid in the liquid (or rest it on top of the solid) inside the glass.

“In the previous experiments we merely poured the contents of the glass. This time we added a grid to find out whether the infants really understood the loose cohesiveness of liquids, which can pass through a perforated surface and recompose in the vessel unlike solids which, being highly cohesive, cannot pass through a grid” explains Ferry.

In the habituation phase, in fact, the infants could know how liquids change shape with movement, but it was unknown if they could use this knowledge to understand other properties of liquids, like loose cohesiveness. “If infants understand the properties of liquids, then they should be surprised when, what they think is a liquid gets trapped on a grid”.

And the analysis of the infants’ behaviour shows that when they expected a liquid they were surprised to see it blocked by the grid (or see the grid unable to penetrate the material). Conversely, if they thought they were looking at a solid, then they were surprised when they saw it pass through the grid.

The investigators also used other materials like sand and small glass spheres. “Even in these cases the infants showed that they knew the behaviour of substances”, concludes Ferry. “This is especially interesting because, while we can imagine that 5-month-old infants already have had extensive direct experience with liquids and especially water through meals, baths and 9 months in the amniotic liquid, it’s unlikely that they’ve had many encounters with sand or glass balls, suggesting that infants have a naïve understanding of the physics of nonsolid substances”.

Here’s a link to and a citation for the paper,

Five-Month-Old Infants Have General Knowledge of How Nonsolid Substances Behave and Interact by Susan J. Hespos, Alissa L. Ferry, Erin M. Anderson, Emily N. Hollenbeck, anb Lance J. Rips. Psychological Science February 2016 vol. 27 no. 2 244-256 doi: 10.1177/0956797615617897 Published online: January 7, 2016

This paper is behind a paywall.

A view to controversies about nanoparticle drug delivery, sticky-flares, and a PNAS surprise

Despite all the excitement and claims for nanoparticles as vehicles for drug delivery to ‘sick’ cells there is at least one substantive problem, the drug-laden nanoparticles don’t actually enter the interior of the cell. They are held in a kind of cellular ‘waiting room’.

Leonid Schneider in a Nov. 20, 2015 posting on his For Better Science blog describes the process in more detail,

A large body of scientific nanotechnology literature is dedicated to the biomedical aspect of nanoparticle delivery into cells and tissues. The functionalization of the nanoparticle surface is designed to insure their specificity at targeting only a certain type of cells, such as cancers cells. Other technological approaches aim at the cargo design, in order to ensure the targeted release of various biologically active agents: small pharmacological substances, peptides or entire enzymes, or nucleotides such as regulatory small RNAs or even genes. There is however a main limitation to this approach: though cells do readily take up nanoparticles through specific membrane-bound receptor interaction (endocytosis) or randomly (pinocytosis), these nanoparticles hardly ever truly reach the inside of the cell, namely its nucleocytoplasmic space. Solid nanoparticles are namely continuously surrounded by the very same membrane barrier they first interacted with when entering the cell. These outer-cell membrane compartments mature into endosomal and then lysosomal vesicles, where their cargo is subjected to low pH and enzymatic digestion. The nanoparticles, though seemingly inside the cell, remain actually outside. …

What follows is a stellar piece featuring counterclaims about and including Schneider’s own journalistic research into scientific claims that the problem of gaining entry to a cell’s true interior has been addressed by technologies developed in two different labs.

Having featured one of the technologies here in a July 24, 2015 posting titled: Sticky-flares nanotechnology to track and observe RNA (ribonucleic acid) regulation and having been contacted a couple of times by one of the scientists, Raphaël Lévy from the University of Liverpool (UK), challenging the claims made (Lévy’s responses can be found in the comments section of the July 2015 posting), I thought a followup of sorts was in order.

Scientific debates (then and now)

Scientific debates and controversies are part and parcel of the scientific process and what most outsiders, such as myself, don’t realize is how fraught it is. For a good example from the past, there’s Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (from its Wikipedia entry), Note: Links have been removed),

Leviathan and the Air-Pump: Hobbes, Boyle, and the Experimental Life (published 1985) is a book by Steven Shapin and Simon Schaffer. It examines the debate between Robert Boyle and Thomas Hobbes over Boyle’s air-pump experiments in the 1660s.

The style seems more genteel than what a contemporary Canadian or US audience is accustomed to but Hobbes and Boyle (and proponents of both sides) engaged in bruising communication.

There was a lot at stake then and now. It’s not just the power, prestige, and money, as powerfully motivating as they are, it’s the research itself. Scientists work for years to achieve breakthroughs or to add more to our common store of knowledge. It’s painstaking and if you work at something for a long time, you tend to be invested in it. Saying you’ve wasted ten years of your life looking at the problem the wrong way or have misunderstood your data is not easy.

As for the current debate, Schneider’s description gives no indication that there is rancour between any of the parties but it does provide a fascinating view of two scientists challenging one of the US’s nanomedicine rockstars, Chad Mirkin. The following excerpt follows the latest technical breakthroughs to the interior portion of the cell through three phases of the naming conventions (Nano-Flares, also known by its trade name, SmartFlares, which is a precursor technology to Sticky-Flares), Note: Links have been removed,

The next family of allegedly nucleocytoplasmic nanoparticles which Lévy turned his attention to, was that of the so called “spherical nucleic acids”, developed in the lab of Chad Mirkin, multiple professor and director of the International Institute for Nanotechnology at the Northwestern University, USA. These so called “Nano-Flares” are gold nanoparticles, functionalized with fluorophore-coupled oligonucleotides matching the messenger RNA (mRNA) of interest (Prigodich et al., ACS Nano 3:2147-2152, 2009; Seferos et al., J Am. Chem.Soc. 129:15477-15479, 2007). The mRNA detection method is such that the fluorescence is initially quenched by the gold nanoparticle proximity. Yet when the oligonucleotide is displaced by the specific binding of the mRNA molecules present inside the cell, the fluorescence becomes detectable and serves thus as quantitative read-out for the intracellular mRNA abundance. Exactly this is where concerns arise. To find and bind mRNA, spherical nucleic acids must leave the endosomal compartments. Is there any evidence that Nano-Flares ever achieve this and reach intact the nucleocytoplasmatic space, where their target mRNA is?

Lévy’s lab has focused its research on the commercially available analogue of the Nano-Flares, based on the patent to Mirkin and Northwestern University and sold by Merck Millipore under the trade name of SmartFlares. These were described by Mirkin as “a powerful and prolific tool in biology and medical diagnostics, with ∼ 1,600 unique forms commercially available today”. The work, led by Lévy’s postdoctoral scientist David Mason, now available in post-publication process at ScienceOpen and on Figshare, found no experimental evidence for SmartFlares to be ever found outside the endosomal membrane vesicles. On the contrary, the analysis by several complementary approaches, i.e., electron, fluorescence and photothermal microscopy, revealed that the probes are retained exclusively within the endosomal compartments.

In fact, even Merck Millipore was apparently well aware of this problem when the product was developed for the market. As I learned, Merck performed a number of assays to address the specificity issue. Multiple hundred-fold induction of mRNA by biological cell stimulation (confirmed by quantitative RT-PCR) led to no significant changes in the corresponding SmartFlare signal. Similarly, biological gene downregulation or experimental siRNA knock-down had no effect on the corresponding SmartFlare fluorescence. Cell lines confirmed as negative for a certain biomarker proved highly positive in a SmartFlare assay.  Live cell imaging showed the SmartFlare signal to be almost entirely mitochondrial, inconsistent with reported patterns of the respective mRNA distributions.  Elsewhere however, cyanine dye-labelled oligonucleotides were found to unspecifically localise to mitochondria   (Orio et al., J. RNAi Gene Silencing 9:479-485, 2013), which might account to the often observed punctate Smart Flare signal.

More recently, Mirkin lab has developed a novel version of spherical nucleic acids, named Sticky-Flares (Briley et al., PNAS 112:9591-9595, 2015), which has also been patented for commercial use. The claim is that “the Sticky-flare is capable of entering live cells without the need for transfection agents and recognizing target RNA transcripts in a sequence-specific manner”. To confirm this, Lévy used the same approach as for the striped nanoparticles [not excerpted here]: he approached Mirkin by email and in person, requesting the original microscopy data from this publication. As Mirkin appeared reluctant, Lévy invoked the rules for data sharing by the journal PNAS, the funder NSF as well as the Northwestern University. After finally receiving Mirkin’s thin-optical microscopy data by air mail, Lévy and Mason re-analyzed it and determined the absence of any evidence for endosomal escape, while all Sticky-Flare particles appeared to be localized exclusively inside vesicular membrane compartments, i.e., endosomes (Mason & Levy, bioRxiv 2015).

I encourage you to read Schneider’s Nov. 20, 2015 posting in its entirety as these excerpts can’t do justice to it.

The PNAS surprise

PNAS (Proceedings of the National Academy of Science) published one of Mirkin’s papers on ‘Sticky-flares’ and is where scientists, Raphaël Lévy and David Mason, submitted a letter outlining their concerns with the ‘Sticky-flares’ research. Here’s the response as reproduced in Lévy’s Nov. 16, 2015 posting on his Rapha-Z-Lab blog

Dear Dr. Levy,

I regret to inform you that the PNAS Editorial Board has declined to publish your Letter to the Editor. After careful consideration, the Board has decided that your letter does not contribute significantly to the discussion of this paper.

Thank you for submitting your comments to PNAS.

Sincerely yours,
Inder Verma
Editor-in-Chief

Judge for yourself, Lévy’s and Mason’s letter can be found here (pdf) and here.

Conclusions

My primary interest in this story is in the view it provides of the scientific process and the importance of and difficulty associated with the debates.

I can’t venture an opinion about the research or the counterarguments other than to say that Lévy’s and Mason’s thoughtful challenge bears more examination than PNAS is inclined to accord. If their conclusions or Chad Mirkin’s are wrong, let that be determined in an open process.

I’ll leave the very last comment to Schneider who is both writer and cartoonist, from his Nov. 20, 2015 posting,

LeonidSchneiderImagination

A perovskite memristor with three stable resistive states

Thanks to Dexter Johnson’s Oct. 22, 2015 posting on his Nanoclast blog (on the IEEE [Institute of Electrical and Electronics Engineers]) website, I’ve found information about a second memristor with three terminals, aka, three stable resistive states,  (the first is mentioned in my April 10, 2015 posting). From Dexter’s posting (Note: Links have been removed),

Now researchers at ETH Zurich have designed a memristor device out of perovskite just 5 nanometres thick that has three stable resistive states, which means it can encode data as 0,1 and 2, or a “trit” as opposed to a “bit.”

The research, which was published in the journal ACS Nano, developed model devices that have two competing nonvolatile resistive switching processes. These switching processes can be alternatively triggered by the effective switching voltage and time applied to the device.

“Our component could therefore also be useful for a new type of IT (Information Technology) that is not based on binary logic, but on a logic that provides for information located ‘between’ the 0 and 1,” said Jennifer Rupp, professor in the Department of Materials at ETH Zurich, in a press release. “This has interesting implications for what is referred to as fuzzy logic, which seeks to incorporate a form of uncertainty into the processing of digital information. You could describe it as less rigid computing.”

An Oct. 19, 2015 Swiss National Science Foundation press release provides context for the research,

Two IT giants, Intel and HP, have entered a race to produce a commercial version of memristors, a new electronics component that could one day replace flash memory (DRAM) used in USB memory sticks, SD cards and SSD hard drives. “Basically, memristors require less energy since they work at lower voltages,” explains Jennifer Rupp, professor in the Department of Materials at ETH Zurich and holder of a SNSF professorship grant. “They can be made much smaller than today’s memory modules, and therefore offer much greater density. This means they can store more megabytes of information per square millimetre.” But currently memristors are only at the prototype stage. [emphasis mine]

There is a memristor-based product on the market as I noted in a Sept. 10, 2015 posting, although that may not be the type of memristive device that Rupp seems to be discussing. (Should you have problems accessing the Swiss National Science Foundation press release, you can find a lightly edited version (a brief [two sentences] history of the memristor has been left out) here on Azonano.

Jacopo Prisco wrote for CNN online in a March 2, 2015 article about memristors and Rupp’s work (Note: A link has been removed),

Simply put, the memristor could mean the end of electronics as we know it and the beginning of a new era called “ionics”.

The transistor, developed in 1947, is the main component of computer chips. It functions using a flow of electrons, whereas the memristor couples the electrons with ions, or electrically charged atoms.

In a transistor, once the flow of electrons is interrupted by, say, cutting the power, all information is lost. But a memristor can remember the amount of charge that was flowing through it, and much like a memory stick it will retain the data even when the power is turned off.

This can pave the way for computers that will instantly turn on and off like a light bulb and never lose data: the RAM, or memory, will no longer be erased when the machine is turned off, without the need to save anything to hard drives as with current technology.

Jennifer Rupp is a Professor of electrochemical materials at ETH Zurich, and she’s working with IBM to build a memristor-based machine.

Memristors, she points out, function in a way that is similar to a human brain: “Unlike a transistor, which is based on binary codes, a memristor can have multi-levels. You could have several states, let’s say zero, one half, one quarter, one third, and so on, and that gives us a very powerful new perspective on how our computers may develop in the future,” she told CNN’s Nick Glass.

This is the CNN interview with Rupp,

Prisco also provides an update about HP’s memristor-based product,

After manufacturing the first ever memristor, Hewlett Packard has been working for years on a new type of computer based on the technology. According to plans, it will launch by 2020.

Simply called “The Machine”, it uses “electrons for processing, photons for communication, and ions for storage.”

I first wrote about HP’s The Machine in a June 25, 2014 posting (scroll down about 40% of the way).

There are many academic teams researching memristors including a team at Northwestern University. I highlighted their announcement of a three-terminal version in an April 10, 2015 posting. While Rupp’s team achieved its effect with a perovskite substrate, the Northwestern team used a molybdenum disulfide (MoS2) substrate.

For anyone wanting to read the latest research from ETH, here’s a link to and a citation for the paper,

Uncovering Two Competing Switching Mechanisms for Epitaxial and Ultrathin Strontium Titanate-Based Resistive Switching Bits by Markus Kubicek, Rafael Schmitt, Felix Messerschmitt, and Jennifer L. M. Rupp. ACS Nano, Article ASAP DOI: 10.1021/acsnano.5b02752 Publication Date (Web): October 8, 2015

Copyright © 2015 American Chemical Society

This paper is behind a paywall.

Finally, should you find the commercialization aspects of the memristor story interesting, there’s a June 6, 2015 posting by Knowm CEO (chief executive officer) Alex Nugent waxes eloquent on HP Labs’ ‘memristor problem’ (Note: A link has been removed),

Today I read something that did not surprise me. HP has said that their memristor technology will be replaced by traditional DRAM memory for use in “The Machine”. This is not surprising for those of us who have been in the field since before HP’s memristor marketing engine first revved up in 2008. While I have to admit the miscommunication between HP’s research and business development departments is starting to get really old, I do understand the problem, or at least part of it.

There are two ways to develop memristors. The first way is to force them to behave as you want them to behave. Most memristors that I have seen do not behave like fast, binary, non-volatile, deterministic switches. This is a problem because this is how HP wants them to behave. Consequently a perception has been created that memristors are for non-volatile fast memory. HP wants a drop-in replacement for standard memory because this is a large and established market. Makes sense of course, but its not the whole story on memristors.

Memristors exhibit a huge range of amazing phenomena. Some are very fast to switch but operate probabilistically. Others can be changed a little bit at a time and are ideal for learning. Still others have capacitance (with memory), or act as batteries. I’ve even seen some devices that can be programmed to be a capacitor or a resistor or a memristor. (Seriously).

Nugent, whether you agree with him or not provides, some fascinating insight. In the excerpt I’ve included here, he seems to provide confirmation that it’s possible to state ‘there are no memristors on the market’ and ‘there are memristors on the market’ because different devices are being called memristors.