Tag Archives: UC San Diego

New chip for neuromorphic computing runs at a fraction of the energy of today’s systems

An August 17, 2022 news item on Nanowerk announces big (so to speak) claims from a team researching neuromorphic (brainlike) computer chips,

An international team of researchers has designed and built a chip that runs computations directly in memory and can run a wide variety of artificial intelligence (AI) applications–all at a fraction of the energy consumed by computing platforms for general-purpose AI computing.

The NeuRRAM neuromorphic chip brings AI a step closer to running on a broad range of edge devices, disconnected from the cloud, where they can perform sophisticated cognitive tasks anywhere and anytime without relying on a network connection to a centralized server. Applications abound in every corner of the world and every facet of our lives, and range from smart watches, to VR headsets, smart earbuds, smart sensors in factories and rovers for space exploration.

The NeuRRAM chip is not only twice as energy efficient as the state-of-the-art “compute-in-memory” chips, an innovative class of hybrid chips that runs computations in memory, it also delivers results that are just as accurate as conventional digital chips. Conventional AI platforms are a lot bulkier and typically are constrained to using large data servers operating in the cloud.

In addition, the NeuRRAM chip is highly versatile and supports many different neural network models and architectures. As a result, the chip can be used for many different applications, including image recognition and reconstruction as well as voice recognition.

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An August 17, 2022 University of California at San Diego (UCSD) news release (also on EurekAlert), which originated the news item, provides more detail than usually found in a news release,

“The conventional wisdom is that the higher efficiency of compute-in-memory is at the cost of versatility, but our NeuRRAM chip obtains efficiency while not sacrificing versatility,” said Weier Wan, the paper’s first corresponding author and a recent Ph.D. graduate of Stanford University who worked on the chip while at UC San Diego, where he was co-advised by Gert Cauwenberghs in the Department of Bioengineering. 

The research team, co-led by bioengineers at the University of California San Diego, presents their results in the Aug. 17 [2022] issue of Nature.

Currently, AI computing is both power hungry and computationally expensive. Most AI applications on edge devices involve moving data from the devices to the cloud, where the AI processes and analyzes it. Then the results are moved back to the device. That’s because most edge devices are battery-powered and as a result only have a limited amount of power that can be dedicated to computing. 

By reducing power consumption needed for AI inference at the edge, this NeuRRAM chip could lead to more robust, smarter and accessible edge devices and smarter manufacturing. It could also lead to better data privacy as the transfer of data from devices to the cloud comes with increased security risks. 

On AI chips, moving data from memory to computing units is one major bottleneck. 

“It’s the equivalent of doing an eight-hour commute for a two-hour work day,” Wan said. 

To solve this data transfer issue, researchers used what is known as resistive random-access memory, a type of non-volatile memory that allows for computation directly within memory rather than in separate computing units. RRAM and other emerging memory technologies used as synapse arrays for neuromorphic computing were pioneered in the lab of Philip Wong, Wan’s advisor at Stanford and a main contributor to this work. Computation with RRAM chips is not necessarily new, but generally it leads to a decrease in the accuracy of the computations performed on the chip and a lack of flexibility in the chip’s architecture. 

“Compute-in-memory has been common practice in neuromorphic engineering since it was introduced more than 30 years ago,” Cauwenberghs said.  “What is new with NeuRRAM is that the extreme efficiency now goes together with great flexibility for diverse AI applications with almost no loss in accuracy over standard digital general-purpose compute platforms.”

A carefully crafted methodology was key to the work with multiple levels of “co-optimization” across the abstraction layers of hardware and software, from the design of the chip to its configuration to run various AI tasks. In addition, the team made sure to account for various constraints that span from memory device physics to circuits and network architecture. 

“This chip now provides us with a platform to address these problems across the stack from devices and circuits to algorithms,” said Siddharth Joshi, an assistant professor of computer science and engineering at the University of Notre Dame , who started working on the project as a Ph.D. student and postdoctoral researcher in Cauwenberghs lab at UC San Diego. 

Chip performance

Researchers measured the chip’s energy efficiency by a measure known as energy-delay product, or EDP. EDP combines both the amount of energy consumed for every operation and the amount of times it takes to complete the operation. By this measure, the NeuRRAM chip achieves 1.6 to 2.3 times lower EDP (lower is better) and 7 to 13 times higher computational density than state-of-the-art chips. 

Researchers ran various AI tasks on the chip. It achieved 99% accuracy on a handwritten digit recognition task; 85.7% on an image classification task; and 84.7% on a Google speech command recognition task. In addition, the chip also achieved a 70% reduction in image-reconstruction error on an image-recovery task. These results are comparable to existing digital chips that perform computation under the same bit-precision, but with drastic savings in energy. 

Researchers point out that one key contribution of the paper is that all the results featured are obtained directly on the hardware. In many previous works of compute-in-memory chips, AI benchmark results were often obtained partially by software simulation. 

Next steps include improving architectures and circuits and scaling the design to more advanced technology nodes. Researchers also plan to tackle other applications, such as spiking neural networks.

“We can do better at the device level, improve circuit design to implement additional features and address diverse applications with our dynamic NeuRRAM platform,” said Rajkumar Kubendran, an assistant professor for the University of Pittsburgh, who started work on the project while a Ph.D. student in Cauwenberghs’ research group at UC San Diego.

In addition, Wan is a founding member of a startup that works on productizing the compute-in-memory technology. “As a researcher and  an engineer, my ambition is to bring research innovations from labs into practical use,” Wan said. 

New architecture 

The key to NeuRRAM’s energy efficiency is an innovative method to sense output in memory. Conventional approaches use voltage as input and measure current as the result. But this leads to the need for more complex and more power hungry circuits. In NeuRRAM, the team engineered a neuron circuit that senses voltage and performs analog-to-digital conversion in an energy efficient manner. This voltage-mode sensing can activate all the rows and all the columns of an RRAM array in a single computing cycle, allowing higher parallelism. 

In the NeuRRAM architecture, CMOS neuron circuits are physically interleaved with RRAM weights. It differs from conventional designs where CMOS circuits are typically on the peripheral of RRAM weights.The neuron’s connections with the RRAM array can be configured to serve as either input or output of the neuron. This allows neural network inference in various data flow directions without incurring overheads in area or power consumption. This in turn makes the architecture easier to reconfigure. 

To make sure that accuracy of the AI computations can be preserved across various neural network architectures, researchers developed a set of hardware algorithm co-optimization techniques. The techniques were verified on various neural networks including convolutional neural networks, long short-term memory, and restricted Boltzmann machines. 

As a neuromorphic AI chip, NeuroRRAM performs parallel distributed processing across 48 neurosynaptic cores. To simultaneously achieve high versatility and high efficiency, NeuRRAM supports data-parallelism by mapping a layer in the neural network model onto multiple cores for parallel inference on multiple data. Also, NeuRRAM offers model-parallelism by mapping different layers of a model onto different cores and performing inference in a pipelined fashion.

An international research team

The work is the result of an international team of researchers. 

The UC San Diego team designed the CMOS circuits that implement the neural functions interfacing with the RRAM arrays to support the synaptic functions in the chip’s architecture, for high efficiency and versatility. Wan, working closely with the entire team, implemented the design; characterized the chip; trained the AI models; and executed the experiments. Wan also developed a software toolchain that maps AI applications onto the chip. 

The RRAM synapse array and its operating conditions were extensively characterized and optimized at Stanford University. 

The RRAM array was fabricated and integrated onto CMOS at Tsinghua University. 

The Team at Notre Dame contributed to both the design and architecture of the chip and the subsequent machine learning model design and training.

The research started as part of the National Science Foundation funded Expeditions in Computing project on Visual Cortex on Silicon at Penn State University, with continued funding support from the Office of Naval Research Science of AI program, the Semiconductor Research Corporation and DARPA [{US} Defense Advanced Research Projects Agency] JUMP program, and Western Digital Corporation. 

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

A compute-in-memory chip based on resistive random-access memory by Weier Wan, Rajkumar Kubendran, Clemens Schaefer, Sukru Burc Eryilmaz, Wenqiang Zhang, Dabin Wu, Stephen Deiss, Priyanka Raina, He Qian, Bin Gao, Siddharth Joshi, Huaqiang Wu, H.-S. Philip Wong & Gert Cauwenberghs. Nature volume 608, pages 504–512 (2022) DOI: https://doi.org/10.1038/s41586-022-04992-8 Published: 17 August 2022 Issue Date: 18 August 2022

This paper is open access.

Pandemic science breakthroughs: combining supercomputing materials with specialized oxides to mimic brain function

This breakthrough in neuromorphic (brainlike) computing is being attributed to the pandemic (COVID-19) according to a September 3, 2021 news item on phys.org,

Isaac Newton’s groundbreaking scientific productivity while isolated from the spread of bubonic plague is legendary. University of California San Diego physicists can now claim a stake in the annals of pandemic-driven science.

A team of UC San Diego [University of California San Diego] researchers and colleagues at Purdue University have now simulated the foundation of new types of artificial intelligence computing devices that mimic brain functions, an achievement that resulted from the COVID-19 pandemic lockdown. By combining new supercomputing materials with specialized oxides, the researchers successfully demonstrated the backbone of networks of circuits and devices that mirror the connectivity of neurons and synapses in biologically based neural networks.

A September 3, 2021 UC San Diego news release by Mario Aguilera, which originated the news item, delves further into the topic of neuromorphic computing,

As bandwidth demands on today’s computers and other devices reach their technological limit, scientists are working towards a future in which new materials can be orchestrated to mimic the speed and precision of animal-like nervous systems. Neuromorphic computing based on quantum materials, which display quantum-mechanics-based properties, allow scientists the ability to move beyond the limits of traditional semiconductor materials. This advanced versatility opens the door to new-age devices that are far more flexible with lower energy demands than today’s devices. Some of these efforts are being led by Department of Physics Assistant Professor Alex Frañó and other researchers in UC San Diego’s Quantum Materials for Energy Efficient Neuromorphic Computing (Q-MEEN-C), a Department of Energy-supported Energy Frontier Research Center.

“In the past 50 years we’ve seen incredible technological achievements that resulted in computers that were progressively smaller and faster—but even these devices have limits for data storage and energy consumption,” said Frañó, who served as one of the PNAS paper’s authors, along with former UC San Diego chancellor, UC president and physicist Robert Dynes. “Neuromorphic computing is inspired by the emergent processes of the millions of neurons, axons and dendrites that are connected all over our body in an extremely complex nervous system.”

As experimental physicists, Frañó and Dynes are typically busy in their laboratories using state-of-the-art instruments to explore new materials. But with the onset of the pandemic, Frañó and his colleagues were forced into isolation with concerns about how they would keep their research moving forward. They eventually came to the realization that they could advance their science from the perspective of simulations of quantum materials.

“This is a pandemic paper,” said Frañó. “My co-authors and I decided to study this issue from a more theoretical perspective so we sat down and started having weekly (Zoom-based) meetings. Eventually the idea developed and took off.”

The researchers’ innovation was based on joining two types of quantum substances—superconducting materials based on copper oxide and metal insulator transition materials that are based on nickel oxide. They created basic “loop devices” that could be precisely controlled at the nano-scale with helium and hydrogen, reflecting the way neurons and synapses are connected. Adding more of these devices that link and exchange information with each other, the simulations showed that eventually they would allow the creation of an array of networked devices that display emergent properties like an animal’s brain.

Like the brain, neuromorphic devices are being designed to enhance connections that are more important than others, similar to the way synapses weigh more important messages than others.

“It’s surprising that when you start to put in more loops, you start to see behavior that you did not expect,” said Frañó. “From this paper we can imagine doing this with six, 20 or a hundred of these devices—then it gets exponentially rich from there. Ultimately the goal is to create a very large and complex network of these devices that will have the ability to learn and adapt.”

With eased pandemic restrictions, Frañó and his colleagues are back in the laboratory, testing the theoretical simulations described in the PNAS [Proceedings of the National Academy of Sciences] paper with real-world instruments.

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

Low-temperature emergent neuromorphic networks with correlated oxide devices by Uday S. Goteti, Ivan A. Zaluzhnyy, Shriram Ramanathan, Robert C. Dynes, and Alex Frano. PNAS August 31, 2021 118 (35) e2103934118; DOI: https://doi.org/10.1073/pnas.2103934118

This paper is open access.

Fridge-free COVID-19 vaccines?

COVID-19 vaccines require cold storage conditions (in some cases, extraordinarily cold storage), which pose problems with both storage and distribution.

A September 7, 2021 news item on phys.org describes research that may make vaccine distribution and storage problems a thing of the past (Note: A link has been removed),

Nanoengineers at the University of California San Diego have developed COVID-19 vaccine candidates that can take the heat. Their key ingredients? Viruses from plants or bacteria.

The new fridge-free COVID-19 vaccines are still in the early stage of development. In mice, the vaccine candidates triggered high production of neutralizing antibodies against SARS-CoV-2, the virus that causes COVID-19. If they prove to be safe and effective in people, the vaccines could be a big game changer for global distribution efforts, including those in rural areas or resource-poor communities.

A September 7, 2021 University of California at San Diego (UCSD or UC San Diego) news release (also on EurekAlert), which originated the news item, delves further into the research,

“What’s exciting about our vaccine technology is that is thermally stable, so it could easily reach places where setting up ultra-low temperature freezers, or having trucks drive around with these freezers, is not going to be possible,” said Nicole Steinmetz, a professor of nanoengineering and the director of the Center for Nano-ImmunoEngineering at the UC San Diego Jacobs School of Engineering.

The vaccines are detailed in a paper published Sept. 7 [2021] in the Journal of the American Chemical Society.

The researchers created two COVID-19 vaccine candidates. One is made from a plant virus, called cowpea mosaic virus. The other is made from a bacterial virus, or bacteriophage, called Q beta.

Both vaccines were made using similar recipes. The researchers used cowpea plants and E. coli bacteria to grow millions of copies of the plant virus and bacteriophage, respectively, in the form of ball-shaped nanoparticles. The researchers harvested these nanoparticles and then attached a small piece of the SARS-CoV-2 spike protein to the surface. The finished products look like an infectious virus so the immune system can recognize them, but they are not infectious in animals and humans. The small piece of the spike protein attached to the surface is what stimulates the body to generate an immune response against the coronavirus.

The researchers note several advantages of using plant viruses and bacteriophages to make their vaccines. For one, they can be easy and inexpensive to produce at large scales. “Growing plants is relatively easy and involves infrastructure that’s not too sophisticated,” said Steinmetz. “And fermentation using bacteria is already an established process in the biopharmaceutical industry.”

Another big advantage is that the plant virus and bacteriophage nanoparticles are extremely stable at high temperatures. As a result, the vaccines can be stored and shipped without needing to be kept cold. They also can be put through fabrication processes that use heat. The team is using such processes to package their vaccines into polymer implants and microneedle patches. These processes involve mixing the vaccine candidates with polymers and melting them together in an oven at temperatures close to 100 degrees Celsius. Being able to directly mix the plant virus and bacteriophage nanoparticles with the polymers from the start makes it easy and straightforward to create vaccine implants and patches. 

The goal is to give people more options for getting a COVID-19 vaccine and making it more accessible. The implants, which are injected underneath the skin and slowly release vaccine over the course of a month, would only need to be administered once. And the microneedle patches, which can be worn on the arm without pain or discomfort, would allow people to self-administer the vaccine.

“Imagine if vaccine patches could be sent to the mailboxes of our most vulnerable people, rather than having them leave their homes and risk exposure,” said Jon Pokorski, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, whose team developed the technology to make the implants and microneedle patches.

“If clinics could offer a one-dose implant to those who would have a really hard time making it out for their second shot, that would offer protection for more of the population and we could have a better chance at stemming transmission,” added Pokorski, who is also a founding faculty member of the university’s Institute for Materials Discovery and Design.

In tests, the team’s COVID-19 vaccine candidates were administered to mice either via implants, microneedle patches, or as a series of two shots. All three methods produced high levels of neutralizing antibodies in the blood against SARS-CoV-2.

Potential Pan-Coronavirus Vaccine

These same antibodies also neutralized against the SARS virus, the researchers found.

It all comes down to the piece of the coronavirus spike protein that is attached to the surface of the nanoparticles. One of these pieces that Steinmetz’s team chose, called an epitope, is almost identical between SARS-CoV-2 and the original SARS virus.

“The fact that neutralization is so profound with an epitope that’s so well conserved among another deadly coronavirus is remarkable,” said co-author Matthew Shin, a nanoengineering Ph.D. student in Steinmetz’s lab. “This gives us hope for a potential pan-coronavirus vaccine that could offer protection against future pandemics.”

Another advantage of this particular epitope is that it is not affected by any of the SARS-CoV-2 mutations that have so far been reported. That’s because this epitope comes from a region of the spike protein that does not directly bind to cells. This is different from the epitopes in the currently administered COVID-19 vaccines, which come from the spike protein’s binding region. This is a region where a lot of the mutations have occurred. And some of these mutations have made the virus more contagious.

Epitopes from a nonbinding region are less likely to undergo these mutations, explained Oscar Ortega-Rivera, a postdoctoral researcher in Steinmetz’s lab and the study’s first author. “Based on our sequence analyses, the epitope that we chose is highly conserved amongst the SARS-CoV-2 variants.”

This means that the new COVID-19 vaccines could potentially be effective against the variants of concern, said Ortega-Rivera, and tests are currently underway to see what effect they have against the Delta variant, for example.

Plug and Play Vaccine

Another thing that gets Steinmetz really excited about this vaccine technology is the versatility it offers to make new vaccines. “Even if this technology does not make an impact for COVID-19, it can be quickly adapted for the next threat, the next virus X,” said Steinmetz.

Making these vaccines, she says, is “plug and play:” grow plant virus or bacteriophage nanoparticles from plants or bacteria, respectively, then attach a piece of the target virus, pathogen, or biomarker to the surface.

“We use the same nanoparticles, the same polymers, the same equipment, and the same chemistry to put everything together. The only variable really is the antigen that we stick to the surface,” said Steinmetz.

The resulting vaccines do not need to be kept cold. They can be packaged into implants or microneedle patches. Or, they can be directly administered in the traditional way via shots.

Steinmetz and Pokorski’s labs have used this recipe in previous studies to make vaccine candidates for diseases like HPV and cholesterol. And now they’ve shown that it works for making COVID-19 vaccine candidates as well.

Next Steps

The vaccines still have a long way to go before they make it into clinical trials. Moving forward, the team will test if the vaccines protect against infection from COVID-19, as well as its variants and other deadly coronaviruses, in vivo.

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

Trivalent Subunit Vaccine Candidates for COVID-19 and Their Delivery Devices by Oscar A. Ortega-Rivera, Matthew D. Shin, Angela Chen, Veronique Beiss, Miguel A. Moreno-Gonzalez, Miguel A. Lopez-Ramirez, Maria Reynoso, Hong Wang, Brett L. Hurst, Joseph Wang, Jonathan K. Pokorski, and Nicole F. Steinmetz. J. Am. Chem. Soc. 2021, XXXX, XXX, XXX-XXX DOI: https://doi.org/10.1021/jacs.1c06600 Publication Date:September 7, 2021 © 2021 American Chemical Society

This paper is behind a paywall.

Tiny sponges lure coronavirus away from lung cells

This research approach looks promising as three news releases trumpeting the possibilities indicate. First, there’s the June 17, 2020 American Chemical Society (ACS) news release,

Scientists are working overtime to find an effective treatment for COVID-19, the illness caused by the new coronavirus, SARS-CoV-2. Many of these efforts target a specific part of the virus, such as the spike protein. Now, researchers reporting in Nano Letters have taken a different approach, using nanosponges coated with human cell membranes –– the natural targets of the virus –– to soak up SARS-CoV-2 and keep it from infecting cells in a petri dish.

To gain entry, SARS-CoV-2 uses its spike protein to bind to two known proteins on human cells, called ACE2 and CD147. Blocking these interactions would keep the virus from infecting cells, so many researchers are trying to identify drugs directed against the spike protein. Anthony Griffiths, Liangfang Zhang and colleagues had a different idea: making a nanoparticle decoy with the virus’ natural targets, including ACE2 and CD147, to lure SARS-CoV-2 away from cells. And to test this idea, they conducted experiments with the actual SARS-CoV-2 virus in a biosafety level 4 lab.

The researchers coated a nanoparticle polymer core with cell membranes from either human lung epithelial cells or macrophages –– two cell types infected by SARS-CoV-2. They showed that the nanosponges had ACE2 and CD147, as well as other cell membrane proteins, projecting outward from the polymer core. When administered to mice, the nanosponges did not show any short-term toxicity. Then, the researchers treated cells in a dish with SARS-CoV-2 and the lung epithelial or macrophage nanosponges. Both decoys neutralized SARS-CoV-2 and prevented it from infecting cells to a similar extent. The researchers plan to next test the nanosponges in animals before moving to human clinical trials. In theory, the nanosponge approach would work even if SARS-CoV-2 mutates to resist other therapies, and it could be used against other viruses, as well, the researchers say.

In this illustration, a nanosponge coated with a human cell membrane acts as a decoy to prevent a virus from entering cells. Credit: Adapted from Nano Letters 2020, DOI: 10.1021/acs.nanolett.0c02278

There are two research teams involved, one at Boston University and the other at the University of California at San Diego (UC San Diego or UCSD). The June 18, 2020 Boston University news release (also on EurekAlert) by Kat J. McAlpine adds more details about the research, provides some insights from the researchers, and is a little redundant if you’ve already seen the ACS news release,

Imagine if scientists could stop the coronavirus infection in its tracks simply by diverting its attention away from living lung cells? A new therapeutic countermeasure, announced in a Nano Letters study by researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the University of California San Diego, appears to do just that in experiments that were carried out at the NEIDL in Boston.

The breakthrough technology could have major implications for fighting the SARS-CoV-2 virus responsible for the global pandemic that’s already claimed nearly 450,000 lives and infected more than 8 million people. But, perhaps even more significantly, it has the potential to be adapted to combat virtually any virus, such as influenza or even Ebola.

“I was skeptical at the beginning because it seemed too good to be true,” says NEIDL microbiologist Anna Honko, one of the co-first authors on the study. “But when I saw the first set of results in the lab, I was just astonished.”

The technology consists of very small, nanosized drops of polymers–essentially, soft biofriendly plastics–covered in fragments of living lung cell and immune cell membranes.

“It looks like a nanoparticle coated in pieces of cell membrane,” Honko says. “The small polymer [droplet] mimics a cell having a membrane around it.”

The SARS-CoV-2 virus seeks out unique signatures of lung cell membranes and latches onto them. When that happens inside the human body, the coronavirus infection takes hold, with the SARS-CoV-2 viruses hijacking lung cells to replicate their own genetic material. But in experiments at the NEIDL, BU researchers observed that polymer droplets laden with pieces of lung cell membrane did a better job of attracting the SARS-CoV-2 virus than living lung cells. [emphasis mine]

By fusing with the SARS-CoV-2 virus better than living cells can, the nanotechnology appears to be an effective countermeasure to coronavirus infection, preventing SARS-CoV-2 from attacking cells.

“Our guess is that it acts like a decoy, it competes with cells for the virus,” says NEIDL microbiologist Anthony Griffiths, co-corresponding author on the study. “They are little bits of plastic, just containing the outer pieces of cells with none of the internal cellular machinery contained inside living cells. Conceptually, it’s such a simple idea. It mops up the virus like a sponge.”

That attribute is why the UC San Diego and BU research team call the technology “nanosponges.” Once SARS-CoV-2 binds with the cell fragments inside a nanosponge droplet–each one a thousand times smaller than the width of a human hair–the coronavirus dies. Although the initial results are based on experiments conducted in cell culture dishes, the researchers believe that inside a human body, the biodegradable nanosponges and the SARS-CoV-2 virus trapped inside them could then be disposed of by the body’s immune system. The immune system routinely breaks down and gets rid of dead cell fragments caused by infection or normal cell life cycles.

There is also another important effect that the nanosponges have in the context of coronavirus infection. Honko says nanosponges containing fragments of immune cells can soak up cellular signals that increase inflammation [emphases mine]. Acute respiratory distress, caused by an inflammatory cascade inside the lungs, is the most deadly aspect of the coronavirus infection, sending patients into the intensive care unit for oxygen or ventilator support to help them breathe.

But the nanosponges, which can attract the inflammatory molecules that send the immune system into dangerous overdrive, can help tamp down that response, Honko says. By using both kinds of nanosponges, some containing lung cell fragments and some containing pieces of immune cells, she says it’s possible to “attack the coronavirus and the [body’s] response” responsible for disease and eventual lung failure.

At the NEIDL, Honko and Griffiths are now planning additional experiments to see how well the nanosponges can prevent coronavirus infection in animal models of the disease. They plan to work closely with the team of engineers at UC San Diego, who first developed the nanosponges more than a decade ago, to tailor the technology for eventual safe and effective use in humans.

“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets,” said Liangfang Zhang, a UC San Diego nanoengineer and leader of the California-based team, according to a UC San Diego press release. “Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys.”

When the novel coronavirus first appeared, the idea of using the nanosponges to combat the infection came to Zhang almost immediately. He reached out to the NEIDL for help. Looking ahead, the BU and UC San Diego collaborators believe the nanosponges can easily be converted into a noninvasive treatment.

“We should be able to drop it right into the nose,” Griffiths says. “In humans, it could be something like a nasal spray.”

Honko agrees: “That would be an easy and safe administration method that should target the appropriate [respiratory] tissues. And if you wanted to treat patients that are already intubated, you could deliver it straight into the lung.”

Griffiths and Honko are especially intrigued by the nanosponges as a new platform for treating all types of viral infections. “The broad spectrum aspect of this is exceptionally appealing,” Griffiths says. The researchers say the nanosponge could be easily adapted to house other types of cell membranes preferred by other viruses, creating many new opportunities to use the technology against other tough-to-treat infections like the flu and even deadly hemorrhagic fevers caused by Ebola, Marburg, or Lassa viruses.

“I’m interested in seeing how far we can push this technology,” Honko says.

The University of California at* San Diego has released a video illustrating the nanosponges work,

There’s also this June 17, 2020 University of California at San Diego (UC San Diego) news release (also on EurekAlert) by Ioana Patringenaru, which offers extensive new detail along with, if you’ve read one or both of the news releases in the above, a few redundant bits,

Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce.

The first data describing this new direction for fighting COVID-19 were published on June 17 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego and tested by researchers at Boston University.

The UC San Diego researchers call their nano-scale particles “nanosponges” because they soak up harmful pathogens and toxins.

In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.

“Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.

His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since [emphasis mine]. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.

In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.

Making and testing COVID-19 nanosponges

Each COVID-19 nanosponge–a thousand times smaller than the width of a human hair–consists of a polymer core coated in cell membranes extracted from either lung epithelial type II cells or macrophage cells. The membranes cover the sponges with all the same protein receptors as the cells they impersonate–and this inherently includes whatever receptors SARS-CoV-2 uses to enter cells in the body.

The researchers prepared several different concentrations of nanosponges in solution to test against the novel coronavirus. To test the ability of the nanosponges to block SARS-CoV-2 infectivity, the UC San Diego researchers turned to a team at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) to perform independent tests. In this BSL-4 lab–the highest biosafety level for a research facility–the researchers, led by Anthony Griffiths, associate professor of microbiology at Boston University School of Medicine, tested the ability of various concentrations of each nanosponge type to reduce the infectivity of live SARS-CoV-2 virus–the same strains that are being tested in other COVID-19 therapeutic and vaccine research.

At a concentration of 5 milligrams per milliliter, the lung cell membrane-cloaked sponges inhibited 93% of the viral infectivity of SARS-CoV-2. The macrophage-cloaked sponges inhibited 88% of the viral infectivity of SARS-CoV-2. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

“From the perspective of an immunologist and virologist, the nanosponge platform was immediately appealing as a potential antiviral because of its ability to work against viruses of any kind. This means that as opposed to a drug or antibody that might very specifically block SARS-CoV-2 infection or replication, these cell membrane nanosponges might function in a more holistic manner in treating a broad spectrum of viral infectious diseases. I was optimistically skeptical initially that it would work, and then thrilled once I saw the results and it sunk in what this could mean for therapeutic development as a whole,” said Anna Honko, a co-first author on the paper and a Research Associate Professor, Microbiology at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL).

In the next few months, the UC San Diego researchers and collaborators will evaluate the nanosponges’ efficacy in animal models. The UC San Diego team has already shown short-term safety in the respiratory tracts and lungs of mice. If and when these COVID-19 nanosponges will be tested in humans depends on a variety of factors, but the researchers are moving as fast as possible.

“Another interesting aspect of our approach is that even as SARS-CoV-2 mutates, as long as the virus can still invade the cells we are mimicking, our nanosponge approach should still work. I’m not sure this can be said for some of the vaccines and therapeutics that are currently being developed,” said Zhang.

The researchers also expect these nanosponges would work against any new coronavirus or even other respiratory viruses, including whatever virus might trigger the next respiratory pandemic.

Mimicking lung epithelial cells and immune cells

Since the novel coronavirus often infects lung epithelial cells as the first step in COVID-19 infection, Zhang and his colleagues reasoned that it would make sense to cloak a nanoparticle in fragments of the outer membranes of lung epithelial cells to see if the virus could be tricked into latching on it instead of a lung cell.

Macrophages, which are white blood cells that play a major role in inflammation, also are very active in the lung during the course of a COVID-19 illness, so Zhang and colleagues created a second sponge cloaked in macrophage membrane.

The research team plans to study whether the macrophage sponges also have the ability to quiet cytokine storms in COVID-19 patients.

“We will see if the macrophage nanosponges can neutralize the excessive amount of these cytokines as well as neutralize the virus,” said Zhang.

Using macrophage cell fragments as cloaks builds on years of work to develop therapies for sepsis using macrophage nanosponges.

In a paper published in 2017 in Proceedings of the National Academy of Sciences, Zhang and a team of researchers at UC San Diego showed that macrophage nanosponges can safely neutralize both endotoxins and pro-inflammatory cytokines in the bloodstream of mice. A San Diego biotechnology company co-founded by Zhang called Cellics Therapeutics is working to translate this macrophage nanosponge work into the clinic.

A potential COVID-19 therapeutic The COVID-19 nanosponge platform has significant testing ahead of it before scientists know whether it would be a safe and effective therapy against the virus in humans, Zhang cautioned [emphasis mine]. But if the sponges reach the clinical trial stage, there are multiple potential ways of delivering the therapy that include direct delivery into the lung for intubated patients, via an inhaler like for asthmatic patients, or intravenously, especially to treat the complication of cytokine storm.

A therapeutic dose of nanosponges might flood the lung with a trillion or more tiny nanosponges that could draw the virus away from healthy cells. Once the virus binds with a sponge, “it loses its viability and is not infective anymore, and will be taken up by our own immune cells and digested,” said Zhang.

“I see potential for a preventive treatment, for a therapeutic that could be given early because once the nanosponges get in the lung, they can stay in the lung for some time,” Zhang said. “If a virus comes, it could be blocked if there are nanosponges waiting for it.”

Growing momentum for nanosponges

Zhang’s lab at UC San Diego created the first membrane-cloaked nanoparticles over a decade ago. The first of these nanosponges were cloaked with fragments of red blood cell membranes. These nanosponges are being developed to treat bacterial pneumonia and have undergone all stages of pre-clinical testing by Cellics Therapeutics, the San Diego startup cofounded by Zhang. The company is currently in the process of submitting the investigational new drug (IND) application to the FDA for their lead candidate: red blood cell nanosponges for the treatment of methicillin-resistant staphylococcus aureus (MRSA) pneumonia. The company estimates the first patients in a clinical trial will be dosed next year.

The UC San Diego researchers have also shown that nanosponges can deliver drugs to a wound site; sop up bacterial toxins that trigger sepsis; and intercept HIV before it can infect human T cells.

The basic construction for each of these nanosponges is the same: a biodegradable, FDA-approved polymer core is coated in a specific type of cell membrane, so that it might be disguised as a red blood cell, or an immune T cell or a platelet cell. The cloaking keeps the immune system from spotting and attacking the particles as dangerous invaders.

“I think of the cell membrane fragments as the active ingredients. This is a different way of looking at drug development,” said Zhang. “For COVID-19, I hope other teams come up with safe and effective therapies and vaccines as soon as possible. At the same time, we are working and planning as if the world is counting on us.”

I wish the researchers good luck. For the curious, here’s a link to and a citation for the paper,

Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity by Qiangzhe Zhang, Anna Honko, Jiarong Zhou, Hua Gong, Sierra N. Downs, Jhonatan Henao Vasquez, Ronnie H. Fang, Weiwei Gao, Anthony Griffiths, and Liangfang Zhang. Nano Lett. 2020, XXXX, XXX, XXX-XXX DOI: https://doi.org/10.1021/acs.nanolett.0c02278 Publication Date:June 17, 2020 Copyright © 2020 American Chemical Society

This paper appears to be open access.

Here, too, is the Cellics Therapeutics website.

*University of California as San Diego corrected to University of California at San Diego on Dec. 30, 2020.

Controlling agricultural pests with CRISPR-based technology

CRISPR (clustered regularly interspaced short palindromic repeats) technology is often touted as being ‘precise’, which as far as I can tell, is not exactly the case (see my Nov. 28, 2018 posting about the CRISPR babies [scroll down about 30% of the way for the first hint that CRISPR isn’t]). So, it’s a bit odd to see the word ‘precise’ used as part of a new CRISPR-based technology’s name (from a January 8, 2019 news item on ScienceDaily,

Using the CRISPR gene editing tool, Nikolay Kandul, Omar Akbari and their colleagues at UC San Diego [UC is University of California] and UC Berkeley devised a method of altering key genes that control insect sex determination and fertility.

A description of the new “precision-guided sterile insect technique,” [emphasis mine] or pgSIT, is published Jan. 8 [2019] in the journal Nature Communications.

A January 8, 209 UCSD press release (also on EurekAlert) by Mario Aguilera, which originated the news item, delves further into the research,

When pgSIT-derived eggs are introduced into targeted populations, the researchers report, only adult sterile males emerge, resulting in a novel, environmentally friendly and relatively low-cost method of controlling pest populations in the future.

“CRISPR technology has empowered our team to innovate a new, effective, species-specific, self-limiting, safe and scalable genetic population control technology with remarkable potential to be developed and utilized in a plethora of insect pests and disease vectors,” said Akbari, an assistant professor in UC San Diego’s Division of Biological Sciences. “In the future, we strongly believe this technology will be safely used in the field to suppress and even eradicate target species locally, thereby revolutionizing how insects are managed and controlled going forward.”

Since the 1930s, agricultural researchers have used select methods to release sterile male insects into the wild to control and eradicate pest populations. In the 1950s, a method using irradiated males was implemented in the United States to eliminate the pest species known as the New World Screwworm fly, which consumes animal flesh and causes extensive damage to livestock. Such radiation-based methods were later used in Mexico and parts of Central America and continue today.

Instead of radiation, the new pgSIT (precision-guided sterile insect technique), developed over the past year-and-a-half by Kandul and Akbari in the fruit fly Drosophila, uses CRISPR to simultaneously disrupt key genes that control female viability and male fertility in pest species. pgSIT, the researchers say, results in sterile male progeny with 100 percent efficiency. Because the targeted genes are common to a vast cross-section of insects, the researchers are confident the technology can be applied to a range of insects, including disease-spreading mosquitoes.

The researchers envision a system in which scientists genetically alter and produce eggs of a targeted pest species. The eggs are then shipped to a pest location virtually anywhere in the world, circumventing the need for a production facility on-site. Once the eggs are deployed at the pest location, the researchers say, the newly born sterile males will mate with females in the wild and be incapable of producing offspring, driving down the population.

“This is a novel twist of a very old technology,” said Kandul, an assistant project scientist in UC San Diego’s Division of Biological Sciences. “That novel twist makes it extremely portable from one species to another species to suppress populations of mosquitoes or agricultural pests, for example those that feed on valuable wine grapes.”

The new technology is distinct from continuously self-propagating “gene drive” systems that propagate genetic alterations from generation to generation. Instead, pgSIT is considered a “dead end” since male sterility effectively closes the door on future generations.

“The sterile insect technique is an environmentally safe and proven technology,” [emphasis mine] the researchers note in the paper. “We aimed to develop a novel, safe, controllable, non-invasive genetic CRISPR-based technology that could be transferred across species and implemented worldwide in the short-term to combat wild populations.”

With pgSIT proven in fruit flies, the scientists are hoping to develop the technology in Aedes aegypti, the mosquito species responsible for transmitting dengue fever, Zika, yellow fever and other diseases to millions of people.

“The extension of this work to other insect pests could prove to be a general and very useful strategy to deal with many vector-borne diseases that plague humanity and wreak havoc an agriculture globally,” said Suresh Subramani, global director of the Tata Institute for Genetics and Society.

I have one comment about the ‘safety’ of the sterile insect technique. It’s been safe up until now but, assuming this technique works as described: What happens as this new and more powerful technique is more widely deployed possibly eliminating whole species of insects? Might these ‘pests’ have a heretofore unknown beneficial effect somewhere in the food chain or in an ecosystem? Or, there may be other unintended consequences.

Moving on, here’s a link to and a citation for the paper,

Transforming insect population control with precision guided sterile males with demonstration in flies by Nikolay P. Kandul, Junru Liu, Hector M. Sanchez C., Sean L. Wu, John M. Marshall, & Omar S. Akbari. Nature Communications volume 10, Article number: 84 (2019) DOI: https://doi.org/10.1038/s41467-018-07964-7 Published 08 January 2019

This paper is open access.

The researchers have made this illustrative image available,

Caption: This is a schematic of the new precision-guided sterile insect technique (pgSIT), which uses components of the CRISPR/Cas9 system to disrupt key genes that control female viability and male fertility, resulting in sterile male progeny. Credit: Nikolay Kandul, Akbari Lab, UC San Diego

Australian peacock spiders, photonic nanostructures, and making money

Researcher Bor-Kai Hsiung’s work has graced this blog before but the topic was tarantulas and their structural colour. This time, it’s all about Australian peacock spiders and their structural colour according to a December 22, 2017 news item on ScienceDaily,

Even if you are arachnophobic, you probably have seen pictures or videos of Australian peacock spiders (Maratus spp.). These tiny spiders are only 1-5 mm long but are famous for their flamboyant courtship displays featuring diverse and intricate body colorations, patterns, and movements.

The spiders extremely large anterior median eyes have excellent color vision and combine with their bright colors to make peacock spiders cute enough to cure most people of their arachnophobia. But these displays aren’t just pretty to look at, they also inspire new ways for humans to produce color in technology.

One species of peacock spider — the rainbow peacock spider (Maratus robinsoni) is particularly neat, because it showcases an intense rainbow iridescent signal in males’ courtship displays to the females. This is the first known instance in nature of males using an entire rainbow of colors to entice females. Dr. Bor-Kai Hsiung led an international team of researchers from the US (UAkron, Cal Tech, UC San Diego, UNL [University of Nebraska-Lincoln]), Belgium (Ghent University), Netherlands (UGroningen), and Australia to discover how rainbow peacock spiders produce this unique multi-color iridescent signal.

A December 22, 2017 Ghent University (Belgium) press release on Alpha Galileo, which originated the news item, provides more technical detail,

Using a diverse array of research techniques, including light and electron microscopy, hyperspectral imaging, imaging scatterometry, nano 3D printing and optical modeling, the team found the origin of this intense rainbow iridescence emerged from specialized abdominal scales of the spiders. These scales have an airfoil-like microscopic 3D contour with nanoscale diffraction grating structures on the surface.

The interaction between the surface nano-diffraction grating and the microscopic curvature of the scales enables separation and isolation of light into its component wavelengths at finer angles and smaller distances than are possible with current manmade engineering technologies.

Inspiration from these super iridescent scales can be used to overcome current limitations in spectral manipulation, and to further reduce the size of optical spectrometers for applications where fine-scale spectral resolution is required in a very small package, notably instruments on space missions, or wearable chemical detection systems. And it could have a wide array of implications to fields ranging from life sciences and biotechnologies to material sciences and engineering.

Here’s a video of an Australian rainbow peacock spider,

Here’s more from the YouTube description published on April 13, 2017 by Peacockspiderman,

Scenes of Maratus robinsoni, a spider Peter Robinson discovered and David Hill and I named it after him in 2012. You can read our description on pages 36-41 in Peckhamia 103.2, which can be downloaded from the Peckhamia website http://peckhamia.com/peckhamia_number…. This is one of the two smallest species of peacock spider (2.5 mm long) and the only spider we know of in which colour changes occur every time it moves, this video was created to document this. Music: ‘Be Still’ by Johannes Bornlöf licensed through my MCN ‘Brave Bison’ from ‘Epidemic Sound’ For licensing inquiries please contact Brave Bison licensing@bravebison.io

The University of California at San Diego also published a December 22, 2017 news release about this work, which covers some of the same ground while providing a few new tidbits of information,

Brightly colored Australian peacock spiders (Maratus spp.) captivate even the most arachnophobic viewers with their flamboyant courtship displays featuring diverse and intricate body colorations, patterns, and movements – all packed into miniature bodies measuring less than five millimeters in size for many species. However, these displays are not just pretty to look at. They also inspire new ways for humans to produce color in technology.

One species of peacock spider – the rainbow peacock spider (Maratus robinsoni) – is particularly impressive, because it showcases an intense rainbow iridescent signal in males’ courtship displays to females. This is the first known instance in nature of males using an entire rainbow of colors to entice females to mate. But how do males make their rainbows? A new study published in Nature Communications looked to answer that question.

Figuring out the answers was inherently interdisciplinary so Bor-Kai Hsiung, a postdoctoral scholar at Scripps Institution of Oceanography at the University of California San Diego, assembled an international team that included biologists, physicists and engineers. Starting while he was a Ph.D. student at The University of Akron under the mentorship of Todd Blackledge and Matthew Shawkey, the team included researchers from UA, Scripps Oceanography, California Institute of Technology, and University of Nebraska-Lincoln, the University of Ghent in Belgium, University of Groningen in Netherlands, and Australia to discover how rainbow peacock spiders produce this unique iridescent signal.

The team investigated the spider’s photonic structures using techniques that included light and electron microscopy, hyperspectral imaging, imaging scatterometry and optical modeling to generate hypotheses about how the spider’s scale generate such intense rainbows. The team then used cutting-edge nano 3D printing to fabricate different prototypes to test and validate their hypotheses. In the end, they found that the intense rainbow iridescence emerged from specialized abdominal scales on the spiders. These scales combine an airfoil-like microscopic 3D contour with nanoscale diffraction grating structures on the surface. It is the interaction between the surface nano-diffraction grating and the microscopic curvature of the scales that enables separation and isolation of light into its component wavelengths at finer angles and smaller distances than are possible with current engineering technologies.

“Who knew that such a small critter would create such an intense iridescence using extremely sophisticated mechanisms that will inspire optical engineers,” said Dimitri Deheyn, Hsuing’s advisor at Scripps Oceanography and a coauthor of the study.

For Hsiung, the finding wasn’t quite so unexpected.

“One of the main questions that I wanted to address in my Ph.D. dissertation was ‘how does nature modulate iridescence?’ From a biomimicry perspective, to fully understand and address a question, one has to take extremes from both ends into consideration. I purposefully chose to study these tiny spiders with intense iridescence after having investigated the non-iridescent blue tarantulas,” said Hsiung.

The mechanism behind these tiny rainbows may inspire new color technology, but would not have been discovered without research combining basic natural history with physics and engineering, the researchers said.

“Nanoscale 3D printing allowed us to experimentally validate our models, which was really exciting,” said Shawkey. “We hope that these techniques will become common in the future.”

“As an engineer, what I found fascinating about these spider structural colors is how these long evolved complex structures can still outperform human engineering,” said Radwanul Hasan Siddique, a postdoctoral scholar at Caltech and study coauthor. “Even with high-end fabrication techniques, we could not replicate the exact structures. I wonder how the spiders assemble these fancy structural patterns in the first place!”

Inspiration from these super iridescent spider scales can be used to overcome current limitations in spectral manipulation, and to reduce the size of optical spectrometers for applications where fine-scale spectral resolution is required in a very small package, notably instruments on space missions, or wearable chemical detection systems.

In the end, peacock spiders don’t just produce nature’s smallest rainbows.They could also have implications for a wide array of fields ranging from life sciences and biotechnologies to material sciences and engineering.

Before citing the paper and providing a link, here’s a story by Robert F. Service for Science magazine about attempts to capitalize on ‘spider technology’, in this case spider silk,

The hype over spider silk has been building since 1710. That was the year François Xavier Bon de Saint Hilaire, president of the Royal Society of Sciences in Montpellier, France, wrote to his colleagues, “You will be surpriz’d to hear, that Spiders make a Silk, as beautiful, strong and glossy, as common Silk.” Modern pitches boast that spider silk is five times stronger than steel yet more flexible than rubber. If it could be made into ropes, a macroscale web would be able to snare a jetliner.

The key word is “if.” Researchers first cloned a spider silk gene in 1990, in hopes of incorporating it into other organisms to produce the silk. (Spiders can’t be farmed like silkworms because they are territorial and cannibalistic.) Today, Escherichia coli bacteria, yeasts, plants, silkworms, and even goats have been genetically engineered to churn out spider silk proteins, though the proteins are often shorter and simpler than the spiders’ own. Companies have managed to spin those proteins into enough high-strength thread to produce a few prototype garments, including a running shoe by Adidas and a lightweight parka by The North Face. But so far, companies have struggled to mass produce these supersilks.

Some executives say that may finally be about to change. One Emeryville, California-based startup, Bolt Threads, says it has perfected growing spider silk proteins in yeast and is poised to turn out tons of spider silk thread per year. In Lansing, Michigan, Kraig Biocraft Laboratories says it needs only to finalize negotiations with silkworm farms in Vietnam to produce mass quantities of a combination spider/silkworm silk, which the U.S. Army is now testing for ballistics protection. …

I encourage you to read Service’s article in its entirety if the commercialization prospects for spider silk interest you as it includes gems such as this,

Spider silk proteins are already making their retail debut—but in cosmetics and medical devices, not high-strength fibers. AMSilk grows spider silk proteins in E. coli and dries the purified protein into powders or mixes it into gels, for use as additives for personal care products, such as moisture-retaining skin lotions. The silk proteins supposedly help the lotions form a very smooth, but breathable, layer over the skin. Römer says the company now sells tons of its purified silk protein ingredients every year.

Finally, here’s a citation for and a link to the paper about Australian peacock spiders and nanophotonics,

Rainbow peacock spiders inspire miniature super-iridescent optics by Bor-Kai Hsiung, Radwanul Hasan Siddique, Doekele G. Stavenga, Jürgen C. Otto, Michael C. Allen, Ying Liu, Yong-Feng Lu, Dimitri D. Deheyn, Matthew D. Shawkey, & Todd A. Blackledge. Nature Communications 8, Article number: 2278 (2017) doi:10.1038/s41467-017-02451-x Published online: 22 December 2017

This paper is open access.

As for Bor-Kai Hsiung’s other mentions here:

How tarantulas get blue (December 7, 2015 posting)

Noniridescent photonics inspired by tarantulas (October 19, 2016 posting)

More on the blue tarantula noniridescent photonics (December 28, 2016 posting)

Humans can distinguish molecular differences by touch

Yesterday, in my December 18, 2017 post about medieval textiles, I posed the question, “How did medieval artisans create nanoscale and microscale gilding when they couldn’t see it?” I realized afterwards that an answer to that question might be in this December 13, 2017 news item on ScienceDaily,

How sensitive is the human sense of touch? Sensitive enough to feel the difference between surfaces that differ by just a single layer of molecules, a team of researchers at the University of California San Diego has shown.

“This is the greatest tactile sensitivity that has ever been shown in humans,” said Darren Lipomi, a professor of nanoengineering and member of the Center for Wearable Sensors at the UC San Diego Jacobs School of Engineering, who led the interdisciplinary project with V. S. Ramachandran, director of the Center for Brain and Cognition and distinguished professor in the Department of Psychology at UC San Diego.

So perhaps those medieval artisans were able to feel the difference before it could be seen in the textiles they were producing?

Getting back to the matter at hand, a December 13, 2017 University of California at San Diego (UCSD) news release (also on EurekAlert) by Liezel Labios offers more detail about the work,

Humans can easily feel the difference between many everyday surfaces such as glass, metal, wood and plastic. That’s because these surfaces have different textures or draw heat away from the finger at different rates. But UC San Diego researchers wondered, if they kept all these large-scale effects equal and changed only the topmost layer of molecules, could humans still detect the difference using their sense of touch? And if so, how?

Researchers say this fundamental knowledge will be useful for developing electronic skin, prosthetics that can feel, advanced haptic technology for virtual and augmented reality and more.

Unsophisticated haptic technologies exist in the form of rumble packs in video game controllers or smartphones that shake, Lipomi added. “But reproducing realistic tactile sensations is difficult because we don’t yet fully understand the basic ways in which materials interact with the sense of touch.”

“Today’s technologies allow us to see and hear what’s happening, but we can’t feel it,” said Cody Carpenter, a nanoengineering Ph.D. student at UC San Diego and co-first author of the study. “We have state-of-the-art speakers, phones and high-resolution screens that are visually and aurally engaging, but what’s missing is the sense of touch. Adding that ingredient is a driving force behind this work.”

This study is the first to combine materials science and psychophysics to understand how humans perceive touch. “Receptors processing sensations from our skin are phylogenetically the most ancient, but far from being primitive they have had time to evolve extraordinarily subtle strategies for discerning surfaces—whether a lover’s caress or a tickle or the raw tactile feel of metal, wood, paper, etc. This study is one of the first to demonstrate the range of sophistication and exquisite sensitivity of tactile sensations. It paves the way, perhaps, for a whole new approach to tactile psychophysics,” Ramachandran said.

Super-Sensitive Touch

In a paper published in Materials Horizons, UC San Diego researchers tested whether human subjects could distinguish—by dragging or tapping a finger across the surface—between smooth silicon wafers that differed only in their single topmost layer of molecules. One surface was a single oxidized layer made mostly of oxygen atoms. The other was a single Teflon-like layer made of fluorine and carbon atoms. Both surfaces looked identical and felt similar enough that some subjects could not differentiate between them at all.

According to the researchers, human subjects can feel these differences because of a phenomenon known as stick-slip friction, which is the jerking motion that occurs when two objects at rest start to slide against each other. This phenomenon is responsible for the musical notes played by running a wet finger along the rim of a wine glass, the sound of a squeaky door hinge or the noise of a stopping train. In this case, each surface has a different stick-slip frequency due to the identity of the molecules in the topmost layer.

In one test, 15 subjects were tasked with feeling three surfaces and identifying the one surface that differed from the other two. Subjects correctly identified the differences 71 percent of the time.

In another test, subjects were given three different strips of silicon wafer, each strip containing a different sequence of 8 patches of oxidized and Teflon-like surfaces. Each sequence represented an 8-digit string of 0s and 1s, which encoded for a particular letter in the ASCII alphabet. Subjects were asked to “read” these sequences by dragging a finger from one end of the strip to the other and noting which patches in the sequence were the oxidized surfaces and which were the Teflon-like surfaces. In this experiment, 10 out of 11 subjects decoded the bits needed to spell the word “Lab” (with the correct upper and lowercase letters) more than 50 percent of the time. Subjects spent an average of 4.5 minutes to decode each letter.

“A human may be slower than a nanobit per second in terms of reading digital information, but this experiment shows a potentially neat way to do chemical communications using our sense of touch instead of sight,” Lipomi said.

Basic Model of Touch

The researchers also found that these surfaces can be differentiated depending on how fast the finger drags and how much force it applies across the surface. The researchers modeled the touch experiments using a “mock finger,” a finger-like device made of an organic polymer that’s connected by a spring to a force sensor. The mock finger was dragged across the different surfaces using multiple combinations of force and swiping velocity. The researchers plotted the data and found that the surfaces could be distinguished given certain combinations of velocity and force. Meanwhile, other combinations made the surfaces indistinguishable from each other.

“Our results reveal a remarkable human ability to quickly home in on the right combinations of forces and swiping velocities required to feel the difference between these surfaces. They don’t need to reconstruct an entire matrix of data points one by one as we did in our experiments,” Lipomi said.

“It’s also interesting that the mock finger device, which doesn’t have anything resembling the hundreds of nerves in our skin, has just one force sensor and is still able to get the information needed to feel the difference in these surfaces. This tells us it’s not just the mechanoreceptors in the skin, but receptors in the ligaments, knuckles, wrist, elbow and shoulder that could be enabling humans to sense minute differences using touch,” he added.

This work was supported by member companies of the Center for Wearable Sensors at UC San Diego: Samsung, Dexcom, Sabic, Cubic, Qualcomm and Honda.

For those who prefer their news by video,

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

Human ability to discriminate surface chemistry by touch by Cody W. Carpenter, Charles Dhong, Nicholas B. Root, Daniel Rodriquez, Emily E. Abdo, Kyle Skelil, Mohammad A. Alkhadra, Julian Ramírez, Vilayanur S. Ramachandran and Darren J. Lipomi. Mater. Horiz., 2018, Advance Article DOI: 10.1039/C7MH00800G

This paper is open access but you do need to have opened a free account on the website.

The ultimate natural sunscreen

For those of us in the northern hemisphere, sunscreen season is on the horizon. While the “ultimate natural sunscreen” researchers from the University of California at San Diego (UCSD) have developed is a long way from the marketplace, this is encouraging news (from a May 17, 2017 news item on Nanowerk),

Chemists, materials scientists and nanoengineers at UC San Diego have created what may be the ultimate natural sunscreen.

In a paper published in the American Chemical Society journal ACS Central Science, they report the development of nanoparticles that mimic the behavior of natural melanosomes, melanin-producing cell structures that protect our skin, eyes and other tissues from the harmful effects of ultraviolet radiation.

“Basically, we succeeded in making a synthetic version of the nanoparticles that our skin uses to produce and store melanin and demonstrated in experiments in skin cells that they mimic the behavior of natural melanosomes,” said Nathan Gianneschi, a professor of chemistry and biochemistry, materials science and engineering and nanoengineering at UC San Diego, who headed the team of researchers. The achievement has practical applications.

A May 17, 2017 UCSD news release, which originated the news item, delves into the research,

“Defects in melanin production in humans can cause diseases such as vitiligo and albinism that lack effective treatments,” Gianneschi added.

Vitiligo develops when the immune system wrongly attempts to clear normal melanocytes from the skin, effectively stopping the production of melanocytes. Albinism is due to genetic defects that lead to either the absence or a chemical defect in tyrosinase, a copper-containing enzyme involved in the production of melanin. Both of these diseases lack effective treatments and result in a significant risk of skin cancer for patients.

“The widespread prevalence of these melanin-related diseases and an increasing interest in the performance of various polymeric materials related to melanin prompted us to look for novel synthetic routes for preparing melanin-like materials,” Gianneschi said.

UC San Diego Ultimate natural sunscreenThe scientists found that the synthetic nanoparticles were taken up in tissue culture by keratinocytes, the predominant cell type found in the epidermis, the outer layer of skin. Photo by Yuran Huang and Ying Jones/UC San Diego

Melanin particles are produced naturally in many different sizes and shapes by animals—for iridescent feathers in birds or the pigmented eyes and skin of some reptiles. But scientists have discovered that extracting melanins from natural sources is a difficult and potentially more complex process than producing them synthetically.

Gianneschi and his team discovered two years ago that synthetic melanin-like nanoparticles could be developed in a precisely controllable manner to mimic the performance of natural melanins used in bird feathers.

“We hypothesized that synthetic melanin-like nanoparticles would mimic naturally occurring melanosomes and be taken up by keratinocytes, the predominant cell type found in the epidermis, the outer layer of skin,” said Gianneschi.

In healthy humans, melanin is delivered to keratinocytes in the skin after being excreted as melanosomes from melanocytes.

The UC San Diego scientists prepared melanin-like nanoparticles through the spontaneous oxidation of dopamine—developing biocompatible, synthetic analogues of naturally occurring melanosomes. Then they studied their update, transport, distribution and ultraviolet radiation-protective capabilities in human keratinocytes in tissue culture.

The researchers found that these synthetic nanoparticles were not only taken up and distributed normally, like natural melanosomes, within the keratinocytes, they protected the skin cells from DNA damage due to ultraviolet radiation.

“Considering limitations in the treatment of melanin-defective related diseases and the biocompatibility of these synthetic melanin-like nanoparticles in terms of uptake and degradation, these systems have potential as artificial melanosomes for the development of novel therapies, possibly supplementing the biological functions of natural melanins,” the researchers said in their paper.

The other co-authors of the study were Yuran Huang and Ziying Hu of UC San Diego’s Materials Science and Engineering Program, Yiwen Li and Maria Proetto of the Department of Chemistry and Biochemistry; Xiujun Yue of the Department of Nanoengineering; and Ying Jones of the Electron Microscopy Core Facility.

The UC San Diego Office of Innovation and Commercialization has filed a patent application on the use of polydopamine-based artificial melanins as an intracellular UV-shield. Companies interested in commercializing this invention should contact Skip Cynar at invent@ucsd.edu

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

Mimicking Melanosomes: Polydopamine Nanoparticles as Artificial Microparasols by
Yuran Huang, Yiwen Li, Ziying Hu, Xiujun Yue, Maria T. Proetto, Ying Jones, and Nathan C. Gianneschi. ACS Cent. Sci., Article ASAP DOI: 10.1021/acscentsci.6b00230 Publication Date (Web): May 18, 2017

Copyright © 2017 American Chemical Society

This is an open access paper,

Using CRISPR to reverse retinosa pigmentosa (eye disease)

Years ago I worked as a publicist for the BC (British Columbia) Motorcycle Federation’s Ride for Sight; they were raising funds for research into retinitis pigmentosa (RP). I hadn’t thought about that in years but it all came back when I saw this April 21, 2017 news item on ScienceDaily,

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego [UCSD] School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa.

Caption: This is a confocal micrograph of mouse retina depicting optic fiber layer. Credit: Image courtesy of National Center for Microscopy and Imaging Research, UC San Diego.

An April 21, 2017 UCSD news release by Scott LaFee (also on EurekAlert), which originated the news item, delves further into retinitis pigmentosa and this CRISPR research,

Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes’ photoreceptors, specialized cells in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells.

In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness.

In their published research, a team led by senior author Kang Zhang, MD, PhD, chief of ophthalmic genetics, founding director of the Institute for Genomic Medicine and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine, used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3.

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, allows researchers to target specific stretches of genetic code and edit DNA at precise locations, modifying select gene functions. Deactivating either Nrl or Nr2e3 reprogrammed rod cells to become cone cells.

“Cone cells are less vulnerable to the genetic mutations that cause RP,” said Zhang. “Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision.”

The scientists tested their approach in two different mouse models of RP. In both cases, they found an abundance of reprogrammed cone cells and preserved cellular architecture in the retinas. Electroretinography testing of rod and cone receptors in live mice show improved function.

Zhang said a recent independent study led by Zhijian Wu, PhD, at National Eye Institute, part of the National Institutes of Health, also reached similar conclusions.

The researchers used adeno-associated virus (AAV) to perform the gene therapy, which they said should help advance their work to human clinical trials quicker. “AAV is a common cold virus and has been used in many successful gene therapy treatments with a relatively good safely profile,” said Zhang. “Human clinical trials could be planned soon after completion of preclinical study. There is no treatment for RP so the need is great and pressing. In addition, our approach of reprogramming mutation-sensitive cells to mutation-resistant cells may have broader application to other human diseases, including cancer.”

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

Gene and mutation independent therapy via CRISPR-Cas9 mediated cellular reprogramming in rod photoreceptors by Jie Zhu, Chang Ming, Xin Fu, Yaou Duan, Duc Anh Hoang, Jeffrey Rutgard, Runze Zhang, Wenqiu Wang, Rui Hou, Daniel Zhang, Edward Zhang, Charlotte Zhang, Xiaoke Hao, Wenjun Xiong, and Kang Zhang. Cell Research advance online publication 21 April 2017; doi: 10.1038/cr.2017.57

This paper (it’s in the form of a letter to the editor) is open access.