Category Archives: medicine

Nanobiotics and a new machine learning model

A May 16, 2022 news item on phys.org announces work on a new machine learning model that could be useful in the research into engineered nanoparticles for medical purposes (Note: Links have been removed),

With antibiotic-resistant infections on the rise and a continually morphing pandemic virus, it’s easy to see why researchers want to be able to design engineered nanoparticles that can shut down these infections.

A new machine learning model that predicts interactions between nanoparticles and proteins, developed at the University of Michigan, brings us a step closer to that reality.

A May 16, 2022 University of Michigan news release by Kate McAlpine, which originated the news item, delves further into the work (Note: Links have been removed),

“We have reimagined nanoparticles to be more than mere drug delivery vehicles. We consider them to be active drugs in and of themselves,” said J. Scott VanEpps, an assistant professor of emergency medicine and an author of the study in Nature Computational Science.

Discovering drugs is a slow and unpredictable process, which is why so many antibiotics are variations on a previous drug. Drug developers would like to design medicines that can attack bacteria and viruses in ways that they choose, taking advantage of the “lock-and-key” mechanisms that dominate interactions between biological molecules. But it was unclear how to transition from the abstract idea of using nanoparticles to disrupt infections to practical implementation of the concept. 

“By applying mathematical methods to protein-protein interactions, we have streamlined the design of nanoparticles that mimic one of the proteins in these pairs,” said Nicholas Kotov, the Irving Langmuir Distinguished University Professor of Chemical Sciences and Engineering and corresponding author of the study. 

“Nanoparticles are more stable than biomolecules and can lead to entirely new classes of antibacterial and antiviral agents.”

The new machine learning algorithm compares nanoparticles to proteins using three different ways to describe them. While the first was a conventional chemical description, the two that concerned structure turned out to be most important for making predictions about whether a nanoparticle would be a lock-and-key match with a specific protein.

Between them, these two structural descriptions captured the protein’s complex surface and how it might reconfigure itself to enable lock-and-key fits. This includes pockets that a nanoparticle could fit into, along with the size such a nanoparticle would need to be. The descriptions also included chirality, a clockwise or counterclockwise twist that is important for predicting how a protein and nanoparticle will lock in.

“There are many proteins outside and inside bacteria that we can target. We can use this model as a first screening to discover which nanoparticles will bind with which proteins,” said Emine Sumeyra Turali Emre, a postdoctoral researcher in chemical engineering and co-first author of the paper, along with Minjeong Cha, a PhD student in materials science and engineering.

Emre and Cha explained that researchers could follow up on matches identified by their algorithm with more detailed simulations and experiments. One such match could stop the spread of MRSA, a common antibiotic-resistant strain, using zinc oxide nanopyramids that block metabolic enzymes in the bacteria.  

“Machine learning algorithms like ours will provide a design tool for nanoparticles that can be used in many biological processes. Inhibition of the virus that causes COVID-19 is one good example,” said Cha. “We can use this algorithm to efficiently design nanoparticles that have broad-spectrum antiviral activity against all variants.”

This breakthrough was enabled by the Blue Sky Initiative at the University of Michigan College of Engineering. It provided $1.5 million to support the interdisciplinary team carrying out the fundamental exploration of whether a machine learning approach could be effective when data on the biological activity of nanoparticles is so sparse.

“The core of the Blue Sky idea is exactly what this work covers: finding a way to represent proteins and nanoparticles in a unified approach to understand and design new classes of drugs that have multiple ways of working against bacteria,” said Angela Violi, an Arthur F. Thurnau Professor, a professor of mechanical engineering and leader of the nanobiotics Blue Sky project.

Emre led the building of a database of interactions between proteins that could help to predict nanoparticle and protein interaction. Cha then identified structural descriptors that would serve equally well for nanoparticles and proteins, working with collaborators at the University of Southern California, Los Angeles to develop a machine learning algorithm that combed through the database and used the patterns it found to predict how proteins and nanoparticles would interact with one another. Finally, the team compared these predictions for lock-and-key matches with the results from experiments and detailed simulations, finding that they closely matched.

Additional collaborators on the project include Ji-Young Kim, a postdoctoral researcher in chemical engineering at U-M, who helped calculate chirality in the proteins and nanoparticles. Paul Bogdan and Xiongye Xiao, a professor and PhD student, respectively, in electrical and computer engineering at USC [University of Southern California] contributed to the graph theory descriptors. Cha then worked with them to design and train the neural network, comparing different machine learning models. All authors helped analyze the data.

Here are links to and a citation for the research briefing and paper, respectively,

Universal descriptors to predict interactions of inorganic nanoparticles with proteins. Nature Computational Science (2022) [Research briefing] DOI: https://doi.org/10.1038/s43588-022-00230-3 Published: 28 April 2022

This paper is behind a paywall.

Unifying structural descriptors for biological and bioinspired nanoscale complexes by Minjeong Cha, Emine Sumeyra Turali Emre, Xiongye Xiao, Ji-Young Kim, Paul Bogdan, J. Scott VanEpps, Angela Violi & Nicholas A. Kotov. Nature Computational Science volume 2, pages 243–252 (2022) Issue Date: April 2022 DOI: https://doi.org/10.1038/s43588-022-00229-w Published: 28 April 2022

This paper appears to be open access.

Visualization of RNA structures at near-atomic resolution enabled by nanotechnology

The illustration that accompanies the research is both fascinating and baffling as its caption,

Caption: This illustration is inspired by the Paleolithic rock painting in the Lascaux cave, signifying the acronym of our method, ROCK. Figuratively, the patterns of the rock art in the background (brown) are the 2D projections of the engineered dimeric construct of the Tetrahymena group I intron, while the main object in the front (blue) is the reconstructed 3D cryo-EM map of the dimer, with one monomer in focus and refined to the high resolution that allowed the collaborators to build an atomic model of the RNA. Credit: Wyss Institute at Harvard University

This May 2, 2022 news item on ScienceDaily announces the research into RNA molecules made possible by ROCK (the technology being illustrated in the above),

We live in a world made and run by RNA [ribonucleic acid], the equally important sibling of the genetic molecule DNA. In fact, evolutionary biologists hypothesize that RNA existed and self-replicated even before the appearance of DNA and the proteins encoded by it. Fast forward to modern day humans: science has revealed that less than 3% of the human genome is transcribed into messenger RNA (mRNA) molecules that in turn are translated into proteins. In contrast, 82% of it is transcribed into RNA molecules with other functions many of which still remain enigmatic.

To understand what an individual RNA molecule does, its 3D structure needs to be deciphered at the level of its constituent atoms and molecular bonds. Researchers have routinely studied DNA and protein molecules by turning them into regularly packed crystals that can be examined with an X-ray beam (X-ray crystallography) or radio waves (nuclear magnetic resonance). However, these techniques cannot be applied to RNA molecules with nearly the same effectiveness because their molecular composition and structural flexibility prevent them from easily forming crystals.

Now, a research collaboration led by Wyss Core Faculty member Peng Yin, Ph.D. at the Wyss Institute for Biologically Inspired Engineering at Harvard University, and Maofu Liao, Ph.D. at Harvard Medical School (HMS), has reported a fundamentally new approach to the structural investigation of RNA molecules. ROCK, as it is called, uses an RNA nanotechnological technique that allows it to assemble multiple identical RNA molecules into a highly organized structure, which significantly reduces the flexibility of individual RNA molecules and multiplies their molecular weight. Applied to well-known model RNAs with different sizes and functions as benchmarks, the team showed that their method enables the structural analysis of the contained RNA subunits with a technique known as cryo-electron microscopy (cryo-EM). Their advance is reported in Nature Methods.

A May 2, 2022 Wyss Institute for Biologically Inspired Engineering at Harvard University news release (also on EurekAlert) by Benjamin Boettner, which originated the news item, delves further into the imaging technology, Note: Links have been removed,

“ROCK is breaking the current limits of RNA structural investigations and enables 3D structures of RNA molecules to be unlocked that are difficult or impossible to access with existing methods, and at near-atomic resolution,” said Yin, who together with Liao led the study. “We expect this advance to invigorate many areas of fundamental research and drug development, including the burgeoning field of RNA therapeutics.” Yin also is a leader of the Wyss Institute’s Molecular Robotics Initiative and Professor in the Department of Systems Biology at HMS.

Gaining control over RNA

Yin’s team at the Wyss Institute has pioneered various approaches that enable DNA and RNA molecules to self-assemble into large structures based on different principles and requirements, including DNA bricks and DNA origami. They hypothesized that such strategies could also be used to assemble naturally occurring RNA molecules into highly ordered circular complexes in which their freedom to flex and move is highly restricted by specifically linking them together. Many RNAs fold in complex yet predictable ways, with small segments base-pairing with each other. The result often is a stabilized “core” and “stem-loops” bulging out into the periphery. 

“In our approach we install ‘kissing loops’ that link different peripheral stem-loops belonging to two copies of an identical RNA in a way that allows a overall stabilized ring to be formed, containing multiple copies of the RNA of interest,” said Di Liu, Ph.D., one of two first-authors and a Postdoctoral Fellow in Yin’s group. “We speculated that these higher-order rings could be analyzed with high resolution by cryo-EM, which had been applied to RNA molecules with first success.”

Picturing stabilized RNA

In cryo-EM, many single particles are flash-frozen at cryogenic temperatures to prevent any further movements, and then visualized with an electron microscope and the help of computational algorithms that compare the various aspects of a particle’s 2D surface projections and reconstruct its 3D architecture. Peng and Liu teamed up with Liao and his former graduate student François Thélot, Ph.D., the other co-first author of the study. Liao with his group has made important contributions to the rapidly advancing cryo-EM field and the experimental and computational analysis of single particles formed by specific proteins.

“Cryo-EM has great advantages over traditional methods in seeing high-resolution details of biological molecules including proteins, DNAs and RNAs, but the small size and moving tendency of most RNAs prevent successful determination of RNA structures. Our novel method of assembling RNA multimers solves these two problems at the same time, by increasing the size of RNA and reducing its movement,” said Liao, who also is Associate Professor of Cell Biology at HMS. “Our approach has opened the door to rapid structure determination of many RNAs by cryo-EM.” The integration of RNA nanotechnology and cryo-EM approaches led the team to name their method “RNA oligomerization-enabled cryo-EM via installing kissing loops” (ROCK).

To provide proof-of-principle for ROCK, the team focused on a large intron RNA from Tetrahymena, a single-celled organism, and a small intron RNA from Azoarcus, a nitrogen-fixing bacterium, as well as the so-called FMN riboswitch. Intron RNAs are non-coding RNA sequences scattered throughout the sequences of freshly-transcribed RNAs and have to be “spliced” out in order for the mature RNA to be generated. The FMN riboswitch is found in bacterial RNAs involved in the biosynthesis of flavin metabolites derived from vitamin B2. Upon binding one of them, flavin mononucleotide (FMN), it switches its 3D conformation and suppresses the synthesis of its mother RNA.  

“The assembly of the Tetrahymena group I intron into a ring-like structure made the samples more homogenous, and enabled the use of computational tools leveraging the symmetry of the assembled structure. While our dataset is relatively modest in size, ROCK’s innate advantages allowed us to resolve the structure at an unprecedented resolution,” said Thélot. “The RNA’s core is resolved at 2.85 Å [one Ångström is one ten-billions (US) of a meter and the preferred metric used by structural biologists], revealing detailed features of the nucleotide bases and sugar backbone. I don’t think we could have gotten there without ROCK – or at least not without considerably more resources.” 

Cryo-EM also is able to capture molecules in different states if they, for example, change their 3D conformation as part of their function. Applying ROCK to the Azoarcus intron RNA and the FMN riboswitch, the team managed to identify the different conformations that the Azoarcus intron transitions through during its self-splicing process, and to reveal the relative conformational rigidity of the ligand-binding site of the FMN riboswitch.

“This study by Peng Yin and his collaborators elegantly shows how RNA nanotechnology can work as an accelerator to advance other disciplines. Being able to visualize and understand the structures of many naturally occurring RNA molecules could have tremendous impact on our understanding of many biological and pathological processes across different cell types, tissues, and organisms, and even enable new drug development approaches,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

The study was also authored by Joseph Piccirilli, Ph.D., an expert in RNA chemistry and biochemistry and Professor at The University of Chicago. It was supported by the National Science Foundation (NSF; grant# CMMI-1333215, CCMI-1344915, and CBET-1729397), Air Force Office of Scientific Research (AFOSR; grant MURI FATE, #FA9550-15-1-0514), National Institutes of Health (NIH; grant# 5DP1GM133052, R01GM122797, and R01GM102489), and the Wyss Institute’s Molecular Robotics Initiative.

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

Sub-3-Å cryo-EM structure of RNA enabled by engineered homomeric self-assembly by Di Liu, François A. Thélot, Joseph A. Piccirilli, Maofu Liao & Peng Yin. Nature Methods (2022) DOI: https://doi.org/10.1038/s41592-022-01455-w Published: 02 May 2022

This paper is behind a paywall.

Ionic skin for ‘smart’ skin

An April 28, 2022 University of British Columbia (UBC) news release (also on EurekAlert) announces a step forward in the attempt to create ‘smart’ skin, Note: Links have been removed,

In the quest to build smart skin that mimics the sensing capabilities of natural skin, ionic skins have shown significant advantages. They’re made of flexible, biocompatible hydrogels that use ions to carry an electrical charge. In contrast to smart skins made of plastics and metals, the hydrogels have the softness of natural skin. This offers a more natural feel to the prosthetic arm or robot hand they are mounted on, and makes them comfortable to wear.

These hydrogels can generate voltages when touched, but scientists did not clearly understand how — until a team of researchers at UBC devised a unique experiment, published today in Science.

“How hydrogel sensors work is they produce voltages and currents in reaction to stimuli, such as pressure or touch – what we are calling a piezoionic effect. But we didn’t know exactly how these voltages are produced,” said the study’s lead author Yuta Dobashi, who started the work as part of his master’s in biomedical engineering at UBC.

Working under the supervision of UBC researcher Dr. John Madden, Dobashi devised hydrogel sensors containing salts with positive and negative ions of different sizes. He and collaborators in UBC’s physics and chemistry departments applied magnetic fields to track precisely how the ions moved when pressure was applied to the sensor.

“When pressure is applied to the gel, that pressure spreads out the ions in the liquid at different speeds, creating an electrical signal. Positive ions, which tend to be smaller, move faster than larger, negative ions. This results in an uneven ion distribution which creates an electric field, which is what makes a piezoionic sensor work.”

The researchers say this new knowledge confirms that hydrogels work in a similar way to how humans detect pressure, which is also through moving ions in response to pressure, inspiring potential new applications for ionic skins.

“The obvious application is creating sensors that interact directly with cells and the nervous system, since the voltages, currents and response times are like those across cell membranes,” says Dr. Madden, an electrical and computer engineering professor in UBC’s faculty of applied science. “When we connect our sensor to a nerve, it produces a signal in the nerve. The nerve, in turn, activates muscle contraction.”

“You can imagine a prosthetic arm covered in an ionic skin. The skin senses an object through touch or pressure, conveys that information through the nerves to the brain, and the brain then activates the motors required to lift or hold the object. With further development of the sensor skin and interfaces with nerves, this bionic interface is conceivable.”

Another application is a soft hydrogel sensor worn on the skin that can monitor a patient’s vital signs while being totally unobtrusive and generating its own power.

Dobashi, who’s currently completing his PhD work at the University of Toronto, is keen to continue working on ionic technologies after he graduates.

“We can imagine a future where jelly-like ‘iontronics’ are used for body implants. Artificial joints can be implanted, without fear of rejection inside the human body. Ionic devices can be used as part of artificial knee cartilage, adding a smart sensing element.  A piezoionic gel implant might release drugs based on how much pressure it senses, for example.”

Dr. Madden added that the market for smart skins is estimated at $4.5 billion in 2019 and it continues to grow. “Smart skins can be integrated into clothing or placed directly on the skin, and ionic skins are one of the technologies that can further that growth.”

The research includes contributions from UBC chemistry PhD graduate Yael Petel and Carl Michal, UBC professor of physics, who used the interaction between strong magnetic fields and the nuclear spins of ions to track ion movements within the hydrogels. Cédric Plesse, Giao Nguyen and Frédéric Vidal at CY Cergy Paris University in France helped develop a new theory on how the charge and voltage are generated in the hydrogels.

Interview language(s): English (Dobashi, Madden), French (Plesse, Madden), Japanese (Dobashi)

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

Piezoionic mechanoreceptors: Force-induced current generation in hydrogels by
Yuta Dobashi, Dickson Yao, Yael Petel, Tan Ngoc Nguyen, Mirza Saquib Sarwar, Yacine Thabet, Cliff L. W. Ng, Ettore Scabeni Glitz, Giao Tran Minh Nguyen, Cédric Plesse, Frédéric Vidal, Carl A. Michal and John D. W. Madden. Science • 28 Apr 2022 • Vol 376, Issue 6592 • pp. 502-507 • DOI: 10.1126/science.aaw1974

This paper is behind a paywall.

Better recording with flexible backing on a brain-computer interface (BCI)

This work has already been patented, from a March 15, 2022 news item on ScienceDaily,

Engineering researchers have invented an advanced brain-computer interface with a flexible and moldable backing and penetrating microneedles. Adding a flexible backing to this kind of brain-computer interface allows the device to more evenly conform to the brain’s complex curved surface and to more uniformly distribute the microneedles that pierce the cortex. The microneedles, which are 10 times thinner than the human hair, protrude from the flexible backing, penetrate the surface of the brain tissue without piercing surface venules, and record signals from nearby nerve cells evenly across a wide area of the cortex.

This novel brain-computer interface has thus far been tested in rodents. The details were published online on February 25 [2022] in the journal Advanced Functional Materials. This work is led by a team in the lab of electrical engineering professor Shadi Dayeh at the University of California San Diego, together with researchers at Boston University led by biomedical engineering professor Anna Devor.

Caption: Artist rendition of the flexible, conformable, transparent backing of the new brain-computer interface with penetrating microneedles developed by a team led by engineers at the University of California San Diego in the laboratory of electrical engineering professor Shadi Dayeh. The smaller illustration at bottom left shows the current technology in experimental use called Utah Arrays. Credit: Shadi Dayeh / UC San Diego / SayoStudio

A March 14, 2022 University of California at San Diego news release (also on EurekAlert but published March 15, 2022), which originated the news item, delves further into the topic,

This new brain-computer interface is on par with and outperforms the “Utah Array,” which is the existing gold standard for brain-computer interfaces with penetrating microneedles. The Utah Array has been demonstrated to help stroke victims and people with spinal cord injury. People with implanted Utah Arrays are able to use their thoughts to control robotic limbs and other devices in order to restore some everyday activities such as moving objects.

The backing of the new brain-computer interface is flexible, conformable, and reconfigurable, while the Utah Array has a hard and inflexible backing. The flexibility and conformability of the backing of the novel microneedle-array favors closer contact between the brain and the electrodes, which allows for better and more uniform recording of the brain-activity signals. Working with rodents as model species, the researchers have demonstrated stable broadband recordings producing robust signals for the duration of the implant which lasted 196 days. 

In addition, the way the soft-backed brain-computer interfaces are manufactured allows for larger sensing surfaces, which means that a significantly larger area of the brain surface can be monitored simultaneously. In the Advanced Functional Materials paper, the researchers demonstrate that a penetrating microneedle array with 1,024 microneedles successfully recorded signals triggered by precise stimuli from the brains of rats. This represents ten times more microneedles and ten times the area of brain coverage, compared to current technologies.

Thinner and transparent backings

These soft-backed brain-computer interfaces are thinner and lighter than the traditional, glass backings of these kinds of brain-computer interfaces. The researchers note in their Advanced Functional Materials paper that light, flexible backings may reduce irritation of the brain tissue that contacts the arrays of sensors. 

The flexible backings are also transparent. In the new paper, the researchers demonstrate that this transparency can be leveraged to perform fundamental neuroscience research involving animal models that would not be possible otherwise. The team, for example, demonstrated simultaneous electrical recording from arrays of penetrating micro-needles as well as optogenetic photostimulation.

Two-sided lithographic manufacturing

The flexibility, larger microneedle array footprints, reconfigurability and transparency of the backings of the new brain sensors are all thanks to the double-sided lithography approach the researchers used. 

Conceptually, starting from a rigid silicon wafer, the team’s manufacturing process allows them to build microscopic circuits and devices on both sides of the rigid silicon wafer. On one side, a flexible, transparent film is added on top of the silicon wafer. Within this film, a bilayer of titanium and gold traces is embedded so that the traces line up with where the needles will be manufactured on the other side of the silicon wafer. 

Working from the other side, after the flexible film has been added, all the silicon is etched away, except for free-standing, thin, pointed columns of silicon. These pointed columns of silicon are, in fact, the microneedles, and their bases align with the titanium-gold traces within the flexible layer that remains after the silicon has been etched away. These titanium-gold traces are patterned via standard and scalable microfabrication techniques, allowing scalable production with minimal manual labor. The manufacturing process offers the possibility of flexible array design and scalability to tens of thousands of microneedles.  

Toward closed-loop systems

Looking to the future, penetrating microneedle arrays with large spatial coverage will be needed to improve brain-machine interfaces to the point that they can be used in “closed-loop systems” that can help individuals with severely limited mobility. For example, this kind of closed-loop system might offer a person using a robotic hand real-time tactical feedback on the objects the robotic hand is grasping.  

Tactile sensors on the robotic hand would sense the hardness, texture, and weight of an object. This information recorded by the sensors would be translated into electrical stimulation patterns which travel through wires outside the body to the brain-computer interface with penetrating microneedles. These electrical signals would provide information directly to the person’s brain about the hardness, texture, and weight of the object. In turn, the person would adjust their grasp strength based on sensed information directly from the robotic arm. 

This is just one example of the kind of closed-loop system that could be possible once penetrating microneedle arrays can be made larger to conform to the brain and coordinate activity across the “command” and “feedback” centers of the brain.

Previously, the Dayeh laboratory invented and demonstrated the kinds of tactile sensors that would be needed for this kind of application, as highlighted in this video.

Pathway to commercialization

The advanced dual-side lithographic microfabrication processes described in this paper are patented (US 10856764). Dayeh co-founded Precision Neurotek Inc. to translate technologies innovated in his laboratory to advance state of the art in clinical practice and to advance the fields of neuroscience and neurophysiology.

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

Scalable Thousand Channel Penetrating Microneedle Arrays on Flex for Multimodal and Large Area Coverage BrainMachine Interfaces by Sang Heon Lee, Martin Thunemann, Keundong Lee, Daniel R. Cleary, Karen J. Tonsfeldt, Hongseok Oh, Farid Azzazy, Youngbin Tchoe, Andrew M. Bourhis, Lorraine Hossain, Yun Goo Ro, Atsunori Tanaka, Kıvılcım Kılıç, Anna Devor, Shadi A. Dayeh. Advanced Functional Materials DOI: https://doi.org/10.1002/adfm.202112045 First published (online): 25 February 2022

This paper is open access.

Say goodbye to crunchy (ice crystal-laden) in ice cream thanks to cellulose nanocrystals (CNC)

The American Chemical Society (ACS) held its 2022 Spring Meeting from March 20 – 24, 2022 and it seems like a good excuse to feature ice cream.

Adding cellulose nanocrystals prevents the growth of small ice crystals (bottom left) into the large ones (top left) that can make ice cream (right) unpleasantly crunchy. Scale bar = 100 μm. Credit: Tao Wu

A March 20, 2022 news item on phys.org introduces an ice cream presentation given at the meeting on Monday, March 20, 2022,

Ice cream can be a culinary delight, except when it gets unpleasantly crunchy because ice crystals have grown in it. Today, scientists report that a form of cellulose obtained from plants can be added to the tasty treat to stop crystals cold—and the additive works better than currently used ice growth inhibitors in the face of temperature fluctuations. The findings could be extended to the preservation of other frozen foods and perhaps donated organs and tissues

A March 20, 2022 ACS press release, which originated the news item, provides more details about crunchy ice cream and how it might be avoided,

Freshly made ice cream contains tiny ice crystals. But during storage and transport, the ice melts and regrows. During this recrystallization process, smaller crystals melt, and the water diffuses to join larger ones, causing them to grow, says Tao Wu, Ph.D., the project’s principal investigator. If the ice crystals become bigger than 50 micrometers — or roughly the diameter of a hair — the dessert takes on a grainy, icy texture that reduces consumer appeal, Wu says. “Controlling the formation and growth of ice crystals is thus the key to obtaining high-quality frozen foods.”

One fix would be to copy nature’s solution: “Some fish, insects and plants can survive in sub-zero temperatures because they produce antifreeze proteins that fight the growth of ice crystals,” Wu says. But antifreeze proteins are costlier than gold and limited in supply, so they’re not practical to add to ice cream. Polysaccharides such as guar gum or locust bean gum are used instead. “But these stabilizers are not very effective,” Wu notes. “Their performance is influenced by many factors, including storage temperature and time, and the composition and concentration of other ingredients. This means they sometimes work in one product but not in another.” In addition, their mechanism of action is uncertain. Wu wanted to clarify how they work and develop better alternatives.

Although Wu didn’t use antifreeze proteins in the study, he drew inspiration from them. These proteins are amphiphilic, meaning they have a hydrophilic surface with an affinity for water, as well as a hydrophobic surface that repels water. Wu knew that nano-sized crystals of cellulose are also amphiphilic, so he figured it was worth checking if they could stop ice crystal growth in ice cream. These cellulose nanocrystals (CNCs) are extracted from the plant cell walls of agricultural and forestry byproducts, so they are inexpensive, abundant and renewable.

In a model ice cream — a 25% sucrose solution — the CNCs initially had no effect, says Min Li, a graduate student in Wu’s lab at the University of Tennessee. Though still small, ice crystals were the same size whether CNCs were present or not. But after the model ice cream was stored for a few hours, the researchers found that the CNCs completely shut down the growth of ice crystals, while the crystals continued to enlarge in the untreated model ice cream.

The team’s tests also revealed that the cellulose inhibits ice recrystallization through surface adsorption. CNCs, like antifreeze proteins, appear to stick to the surfaces of ice crystals, preventing them from drawing together and fusing. “This completely contradicted the existing belief that stabilizers inhibit ice recrystallization by increasing viscosity, which was thought to slow diffusion of water molecules,” adds Li, who will present the work at the meeting.

In their latest study, the scientists found that CNCs are more protective than current stabilizers when ice cream is exposed to fluctuating temperatures, such as when the treat is stored in the supermarket and then taken home. The team also discovered the additive can slow the melting of ice crystals, so it could be used to produce slow-melting ice cream. Other labs have shown the stabilizer is nontoxic at the levels needed in food, Wu notes, but the additive would require review by the U.S. Food and Drug Administration.

With further research, CNCs could be used to protect the quality of other foods — such as frozen dough and fish — or perhaps to preserve cells, tissues and organs in biomedicine, Wu says. “At present, a heart must be transplanted within a few hours after being removed from a donor,” he explains. “But this time limit could be eliminated if we could inhibit the growth of ice crystals when the heart is kept at low temperatures.”

Interesting to see that this research into ice cream crystals could lead to new techniques for organ transplants.

Maybe spray-on technology can be used for heart repair?

Courtesy: University of Ottawa

That is a pretty stunning image and this March 15, 2022 news item on phys.org provides an explanation of what you see (Note: A link has been removed),

Could a spritz of super-tiny particles of gold and peptides on a damaged heart potentially provide minimally invasive, on-the-spot repair?

Cutting-edge research led by University of Ottawa Faculty of Medicine Associate Professors Dr. Emilio Alarcon and Dr. Erik Suuronen suggests a spray-on technology using customized nanoparticles of one of the world’s most precious metals offers tremendous therapeutic potential and could eventually help save many lives. Cardiovascular diseases are the leading cause of death globally, claiming roughly 18 million lives each year.

In a paper recently published online in ACS Nano, a peer-reviewed journal that highlighted the new research on its supplementary cover, Dr. Alarcon and his team of fellow investigators suggest that this approach might one day be used in conjunction with coronary artery bypass surgeries. That’s the most common type of heart surgery.

A March 15, 2021 University of Ottawa news release (also on EurekAlert) by David McFadden, which originated the news item, describes the research in more detail (Note: A link has been removed),

The therapy tested by the researchers – which was sprayed on the hearts of lab mice – used very low concentrations of peptide-modified particles of gold created in the laboratory. From the nozzle of a miniaturized spraying apparatus, the material can be evenly painted on the surface of a heart within a few seconds.

Gold nanoparticles have been shown to have some unusual properties and are highly chemically reactive. For years, researchers have been employing gold nanoparticles – so tiny they are undetectable by the human eye – in such a wide range of technologies that it’s become an area of intense research interest.

In this case, the custom-made nanogold modified with peptides—a short chain of amino acids —was sprayed on the hearts of lab mice. The research found that the spray-on therapy not only resulted in an increase in cardiac function and heart electrical conductivity but that there was no off-target organ infiltration by the tiny gold particles.

“That’s the beauty of this approach. You spray, then you wait a couple of weeks, and the animals are doing just fine compared to the controls,” says Dr. Alarcon, who is part of the Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and also Director of the Bio-nanomaterials Chemistry and Engineering Laboratory at the University of the Ottawa Heart Institute.

Dr. Alarcon says that not only does the data suggest that the therapeutic action of the spray-on nanotherapeutic is highly effective, but its application is far simpler than other regenerative approaches for treating an infarcted heart.

At first, the observed improvement of cardiac function and electrical signal propagation in the hearts of tested mice was hard for the team to believe. But repeated experiments delivered the same positive results, according to Dr. Alarcon, who is part of the Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and Director of the Bio-nanomaterials Chemistry and Engineering Laboratory at the University of Ottawa Heart Institute.

To validate the exciting findings in mice, the team is now seeking to adapt this technology to minimally invasive procedures that will expedite testing in large animal models, such as rabbits and pigs.

Dr. Alarcon praised the research culture at uOttawa and the Heart Institute, saying that the freedom to explore is paramount. “When you have an environment where you are allowed to make mistakes and criticize, that really drives discoveries,” he says.

The team involved in the paper includes researchers from uOttawa and the University of Talca in Chile. Part of the work was funded by the Canadian government’s New Frontiers in Research Fund, which was launched in 2018 and supports transformative high risk/high reward research led by Canadian researchers working with local and international partners.

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

Nanoengineered Sprayable Therapy for Treating Myocardial Infarction by Marcelo Muñoz, Cagla Eren Cimenci, Keshav Goel, Maxime Comtois-Bona, Mahir Hossain, Christopher McTiernan, Matias Zuñiga-Bustos, Alex Ross, Brenda Truong, Darryl R. Davis, Wenbin Liang, Benjamin Rotstein, Marc Ruel, Horacio Poblete, Erik J. Suuronen, and Emilio I. Alarcon. ACS Nano 2022, 16, 3, 3522–3537 DOI: https://doi.org/10.1021/acsnano.1c08890 Publication Date: February 14, 2022 Copyright © 2022 The Authors. Published by American Chemical Society

This paper appears to be open access.

Biohybrid fish made from human cardiac cells could lead to artificial hearts

Biohybrid fish on a hook (Photo credit to Michael Rosnach, Keel Yong Lee, Sung-Jin Park, Kevin Kit Parker)

A February 10, 2022 news item on ScienceDaily announces research on a biohybrid fish,

Harvard University researchers, in collaboration with colleagues from Emory University, have developed the first fully autonomous biohybrid fish from human stem-cell derived cardiac muscle cells. The artificial fish swims by recreating the muscle contractions of a pumping heart, bringing researchers one step closer to developing a more complex artificial muscular pump and providing a platform to study heart disease like arrhythmia.

A February 10, 2022 Harvard University John A. Paulson School of Engineering and Applied Sciences news release (also on EurekAlert) by Leah Burrows explains how this research could lead to an artificial heart (Note: Links have been removed),

“Our ultimate goal is to build an artificial heart to replace a malformed heart in a child,” said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and senior author of the paper.  “Most of the work in building heart tissue or hearts, including some work we have done, is focused on replicating the anatomical features or replicating the simple beating of the heart in the engineered tissues. But here, we are drawing design inspiration from the biophysics of the heart, which is harder to do. Now, rather than using heart imaging as a blueprint, we are identifying the key biophysical principles that make the heart work, using them as design criteria, and replicating them in a system, a living, swimming fish, where it is much easier to see if we are successful.”

The research is published in Science

The biohybrid fish developed by the team builds off previous research from Parker’s Disease Biophysics Group. In 2012, the lab used cardiac muscle cells from rats to build a jellyfish-like biohybrid pump and in 2016 the researchers developed a swimming, artificial stingray also from rat heart muscle cells.

In this research, the team built the first autonomous biohybrid device made from human stem-cell derived cardiomyocytes. This device was inspired by the shape and swimming motion of a zebrafish. Unlike previous devices, the biohybrid zebrafish has two layers of muscle cells, one on each side of the tail fin. When one side contracts, the other stretches. That stretch triggers the opening of a mechanosensitive protein channel, which causes a contraction, which triggers a stretch and so on and so forth, leading to a closed loop system that can propel the fish for more than 100 days. 

“By leveraging cardiac mechano-electrical signaling between two layers of muscle, we recreated the cycle where each contraction results automatically as a response to the stretching on the opposite side,” said Keel Yong Lee, a postdoctoral fellow at SEAS and co-first author of the study. “The results highlight the role of feedback mechanisms in muscular pumps such as the heart.”

The researchers also engineered an autonomous pacing node, like a pacemaker, which controls the frequency and rhythm of these spontaneous contractions. Together, the two layers of muscle and the autonomous pacing node enabled the generation of continuous, spontaneous, and coordinated, back-and-forth fin movements.

“Because of the two internal pacing mechanisms, our fish can live longer, move faster and swim more efficiently than previous work,” said Sung-Jin Park, a former postdoctoral fellow in the Disease Biophysics Group at SEAS and co-first author of the study. “This new research provides a model to investigate mechano-electrical signaling as a therapeutic target of heart rhythm management and for understanding pathophysiology in sinoatrial node dysfunctions and cardiac arrhythmia.”

Park is currently an Assistant Professor at the Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine.

Unlike a fish in your refrigerator, this biohybrid fish improves with age. Its muscle contraction amplitude, maximum swimming speed, and muscle coordination all increased for the first month as the cardiomyocyte cells matured.  Eventually, the biohybrid fish reached speeds and swimming efficacy similar to zebrafish in the wild. 

Next, the team aims to build even more complex biohybrid devices from human heart cells. 

“I could build a model heart out of Play-Doh, it doesn’t mean I can build a heart,” said Parker. “You can grow some random tumor cells in a dish until they curdle into a throbbing lump and call it a cardiac organoid. Neither of those efforts is going to, by design, recapitulate the physics of a system that beats over a billion times during your lifetime while simultaneously rebuilding its cells on the fly. That is the challenge. That is where we go to work.”

The research was co-authored by David G. Matthews, Sean L. Kim, Carlos Antonio Marquez, John F. Zimmerman, Herdeline Ann M. Ardona, Andre G. Kleber and George V. Lauder. 

It was supported in part by National Institutes of Health National Center for Advancing Translational Sciences grant UH3TR000522, and National Science Foundation Materials Research Science and Engineering Center grant DMR-142057.

Before giving you a link and a citation for the paper, here’s a little more information about the work from a February 10, 2022 American Association for the Advancement of Science (AAAS) news release on EurekAlert announcing publication of the paper in their journal Science, Note: A link has been removed,

An autonomously swimming biohybrid fish, designed with a focus on two key regulatory features of the human heart, has revealed the importance of feedback mechanisms in muscular pumps (such as the heart). The findings could one day help inform the development of an artificial heart made from living muscle cells. Biohybrid systems – devices containing both biological and artificial components – are an effective way to investigate the physiological control mechanisms in biological organisms and to discover bio-inspired robotic solutions to a host of pressing concerns, including those related to human health. When it comes to natural fluid transport pumps, like those that circulate blood, the performance of biohybrid systems has been lacking, however.  Here, researchers considered whether two functional regulatory features of the heart — mechanoelectrical signaling and automaticity — could be transferred to a synthetic analog of another fluid transport system: a swimming fish. Lee et al. developed an autonomously swimming fish constructed from a bilayer of human cardiac cells; the muscular bilayer was integrated using tissue engineering techniques. Lee and team were able to control muscle contractions in the biohybrid fish using external optogenetic stimulation, allowing the fish analog to swim. In tests, the biohybrid fish outperformed the locomotory speed of previous biohybrid muscular systems, the authors say. It maintained spontaneous activity for 108 days. By contrast, say the authors, biohybrid fish equipped with single-layered muscle showed deteriorating activity within the first month. The data in this study demonstrate the potential of muscular bilayer systems and mechanoelectrical signaling as a means to promote maturation of in vitro muscle tissues, write Lee and colleagues. “Taken together,” the authors conclude, “the technology described here may represent foundational work toward the goal of creating autonomous systems capable of homeostatic regulation and adaptive behavioral control.”

For reporters interested in trends, this work builds upon previous work published in a July 2016 study in Science, in which Sung-jin Park et al. used cardiac cells from rats to develop a self-propelling ray fish analog.

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

An autonomously swimming biohybrid fish designed with human cardiac biophysics by Keel Yong Lee, Sung-Jin Park, David G. Matthews. Sean L. Kim, Carlos Antonio Marquez, John F. Zimmerman, Herdeline Ann M. Ardoña, Andre G. Kleber, George V. Lauder and Kevin Kit Parker. Science • 10 Feb 2022 • Vol 375, Issue 6581 • pp. 639-647 • DOI: 10.1126/science.abh0474

This paper is behind a paywall.

Spiky materials that can pop bacteria?

Bacteria interacting with four different topographies Courtesy: Imperial College London

A February 9, 2022 news item on phys.org describes some bioinspired research that could help cut down on the use of disinfectants,

Researchers have created intricately patterned materials that mimic antimicrobial, adhesive and drag reducing properties found in natural surfaces.

The team from Imperial College London found inspiration in the wavy and spiky surfaces found in insects, including on cicada and dragonfly wings, which ward off bacteria.

They hope the new materials could be used to create self-disinfecting surfaces and offer an alternative to chemically functionalized surfaces and cleaners, which can promote the growth of antibiotic-resistant bacteria.

A February 9, 2022 Imperial College London (ICL) press release by Caroline Brogan, which originated the news item, describes the work in more technical detail,

The tiny waves, which overlap at defined angles to create spikes and ripples, could also help to reduce drag on marine transport by mimicking shark skin, and to enhance the vibrancy of color without needing pigment, by mimicking insects.

Senior author Professor Joao Cabral, of Imperial’s Department of Chemical Engineering, said, “It’s inspiring to see in miniscule detail how the wings and skins of animals help them master their environments. Animals evolved wavy surfaces to kill bacteria, enhance color, and reduce drag while moving through water. We’re borrowing these natural tricks for the very same purposes, using a trick reminiscent of a Fourier wave superposition.”

Spiky structures

Researchers created the new materials by stretching and compressing a thin, soft, sustainable plastic resembling clingfilm to create three-dimensional nano- and microscale wavy patterns, compatible with sustainable and biodegradable polymers. 

The spiky structure was inspired by the way insects and fish have evolved to interact with their environments. The corrugated ripple effect is seen in the wings of cicadas and dragonflies, whose surfaces are made of tiny spikes which pop bacterial cells to keep the insects clean.  

The structure could also be applied to ships to reduce drag and boost efficiency – an application inspired by shark skin, which contains nanoscale horizontal ridges to reduce friction and drag.

Another application is in producing vibrant colours like those seen in the wings of morpho blue butterflies, whose cells are arranged to reflect and bend light into a brilliant blue without using pigment. Known as structural colour, other examples include the blue in peacock feathers, the shells of iridescent beetles, and blue human eyes.

Scaling up waves

To conduct the research, which is published in Physical Review Letters, the researchers studied specimens of cicadas and dragonflies from the Natural History Museum, and sedimentary deposits and rock formations documented by Trinity College Dublin.

They discovered that they could recreate these naturally occurring surface waves by stretching and then relaxing thin polymer skins in precise directions at the nanoscale.

While complex patterns can be fabricated by lithography and other methods, for instance in silicon microchip production, these are generally prohibitively expensive to use over large areas. This new technique, on the other hand, is ready to be scaled up relatively inexpensively if confirmed to be effective and robust. 

Potential applications include self-disinfecting surfaces in hospitals, schools, public transport, and food manufacturing. They could even help keep medical implants clean, which is important as these can host networks of bacterial matter known as biofilms that are notoriously difficult to kill. 

Naturally occurring wave patterns are also seen in the wrinkling of the human brain and fingertips as well as the ripples in sand beds. First author Dr Luca Pellegrino from the Department of Chemical Engineering, said: “The idea is compelling because it is simple: by mimicking the surface waves found in nature, we can create a palette of patterns with important applications. Through this work we can also learn more about the possible origins of these natural forms – a field called morphogenesis.” 

he next focus for the team is to test the effectiveness and robustness of the material in real-world settings, like on bus surfaces. The researchers hope it can contribute to solutions to surface cleanliness that are not reliant on chemical cleaners. To this end, they have been awarded a €5.4million EU HORIZON grant with collaborators ranging from geneticists at KU Leuven to a bus manufacturer to develop sustainable and robust antimicrobial surfaces for high traffic contexts. 

Here’s a link (the press release also has a link) to and a citation for the paper,

Ripple Patterns Spontaneously Emerge through Sequential Wrinkling Interference in Polymer Bilayers by Luca Pellegrino, Annabelle Tan, and João T. Cabral. Phys. Rev. Lett. 128, 058001 Vol. 128, Issue 5 — 4 February 2022 Published online 2 February 2022

This paper is behind a paywall.

This work reminds me of Sharklet, a company that was going to produce materials that mimicked the structure of sharkskin. Apparently, sharks have nanostructures on their skin which prevents bacteria and more from finding a home there.

Inhaled vaccine delivers broad protection against SARS-CoV-2

The results described in the news release are from a preclinical study, meaning they tested the vaccine on animals. The results were promising enough that there is a phase 1 clinical trial taking place now. On to the news.

A February 9, 2022 news item on ScienceDaily features some exciting research news,

Scientists at McMaster University who have developed an inhaled form of COVID vaccine have confirmed it can provide broad, long-lasting protection against the original strain of SARS-CoV-2 and variants of concern.

The research, recently published in the journal Cell, reveals the immune mechanisms and significant benefits of vaccines being delivered directly into the respiratory tract, rather than by traditional injection.

A February 9, 2022 McMaster University news release (also on EurekAlert) by Michelle Donovan, which originated the news item, provides more detail about the work,

Because inhaled vaccines target the lungs and upper airways where respiratory viruses first enter the body, they are far more effective at inducing a protective immune response, the researchers report.

The reported preclinical study, which was conducted on animal models, has provided the critical proof of concept to enable a Phase 1 clinical trial that is currently under way to evaluate inhaled aerosol vaccines in healthy adults who had already received two doses of a COVID mRNA vaccine.

The tested COVID vaccine strategy was built upon a robust tuberculosis vaccine research program established by Zhou Xing, a co-lead author of the new study and a professor at the McMaster Immunology Research Centre and Department of Medicine. 

“What we’ve discovered from many years’ research is that the vaccine delivered into the lung induces all-around protective respiratory mucosal immunity, a property that the injected vaccine is lacking,” Xing says.

Currently authorized COVID vaccines are all injected.   

“We wanted, first and foremost, to design a vaccine that would work well against any variant,” explains the study’s co-lead author Matthew Miller, an associate professor at McMaster’s Michael G. DeGroote Institute for Infectious Disease Research.

The McMaster COVID vaccine represents one of only a handful developed in Canada. The urgent work is a critical mission of Canada’s Global Nexus for Pandemics and Biological Threats, which is based at McMaster.

Researchers compared two types of adenovirus platforms for the vaccine. The viruses serve as vectors that can deliver vaccine directly to the lungs without causing illness themselves.

“We can remain ahead of the virus with our vaccine strategy,” says Miller. “Current vaccines are limited because they will need to be updated and will always be chasing the virus.”

Both types of the new McMaster vaccine are effective against highly transmissible variants because they are designed to target three parts of the virus, including two that are highly conserved among coronaviruses and do not mutate as quickly as spike. All COVID vaccines currently approved in Canada target only the spike protein, which has shown a remarkable ability to mutate.

“This vaccine might also provide pre-emptive protection against a future pandemic, and that’s really important because as we’ve seen during this pandemic – and as we saw in 2009 with the swine flu – even when we are able to rapidly make a vaccine for a pandemic virus, it’s already way too late. Millions of people died, even though we were able to make a vaccine in record time,” says Miller.

“We have revealed in our report that besides neutralizing antibodies and T cell immunity, the vaccine delivered into the lungs stimulates a unique form of immunity known as trained innate immunity, which is able to provide very broad protection against many lung pathogens besides SARS-CoV-2,” Xing adds. 

In additional to being needle and pain-free, an inhaled vaccine is so efficient at targeting the lungs and upper airways that it can achieve maximum protection with a small fraction of the dose of current vaccines – possibly as little as 1 per cent – meaning a single batch of vaccine could go 100 times further, the researchers say.

“This pandemic has shown us that vaccine supply can be a huge challenge.  Demonstrating that this alternative delivery method can significantly extend vaccine supply could be a game changer, particularly in a pandemic setting,” says Brian Lichty, an associate professor in the Department of Medicine who co-led the preclinical study along with Miller, Xing and the senior trainees Sam Afkhami and Michael D’Agostino, who are the joint first authors of the study.

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

Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2 by Sam Afkhami, Michael R. D’Agostino, Ali Zhang, Hannah D. Stacey, Art Marzok, Alisha Kang, Ramandeep Singh, Jegarubee Bavananthasivam, Gluke Ye, Xiangqian Luo, Fuan Wang, Jann C. Ang, Anna Zganiacz, Uma Sankar, Natallia Kazhdan, Joshua F.E. Koenig, Allyssa Phelps, Steven F. Gameiro, Shangguo Tang, Manel Jordana, Yonghong Wan, Karen L. Mossman, Mangalakumari Jeyanathan, Amy Gillgrass, Maria Fe C. Medina, Fiona Smaill, Brian D. Lichty, Matthew S. Miller, Zhou Xing. Cell, 2022; DOI: 10.1016/j.cell.2022.02.005

This is a ‘pre-proof’ journal paper. It is open access. However, from the PDF of the article, there is this statement from the journal publishers,

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2022 The Author(s). Published by Elsevier Inc.

In short, reader beware!

Xenobots (living robots) that can reproduce

Xenobots (living robots made from African frog (Xenopus laevis) frog cells) can now self-replicate. First mentioned here in a June 21, 2021 posting, xenobots have captured the imagination of various media outlets including the Canadian Broadcasting Corporation’s (CBC) Quirks and Quarks radio programme and blog where Amanda Buckiewicz posted a December 3, 2021 article about the latest xenobot development (Note: Links have been removed),

In a new study, Bongard [Joshua Bongard, a computer scientist at the University of Vermont] and his colleagues from Tufts University and Harvard’s Wyss Institute for Biologically Inspired Engineering found that the xenobots would autonomously collect loose single cells in their environment, gathering hundreds of cells together until new xenobots had formed.

“This took a little bit for us to wrap our minds around,” he said. “There’s no programming here. Instead, we’re designing or shaping these xenobots, and what they do, the way they behave, is based on shape.”

“We take a couple of thousand of those frog cells and we squish them together into a ball and put that in the bottom of a petri dish,” Bongard told Quirks & Quarks host Bob McDonald. 

“If you were to look into the dish, you would see some very small, what look like specks of pepper, moving about in the bottom of the petri dish.”

The xenobots initially received no instruction from humans on how to replicate. But when researchers added extra cells to the dish containing xenobots, they observed that the xenobots would assemble them into piles.

“Cells early in development are sticky,” said Bongard. “If the pile is large enough and the cells stick together, the outer ones on the surface will grow very small hairs, which are called cilia. And eventually, after four days, those cilia will start to beat back and forth like flexible oars, and the pile will start moving.”

“And that’s a child xenobot.” 

A November 29, 2021 Wyss Institute news release by Joshua Brown describes the process a little differently,

To persist, life must reproduce. Over billions of years, organisms have evolved many ways of replicating, from budding plants to sexual animals to invading viruses.

Now scientists at the University of Vermont, Tufts University, and the Wyss Institute for Biologically Inspired Engineering at Harvard University have discovered an entirely new form of biological reproduction—and applied their discovery to create the first-ever, self-replicating living robots.

The same team that built the first living robots (“Xenobots,” assembled from frog cells—reported in 2020) has discovered that these computer-designed and hand-assembled organisms can swim out into their tiny dish, find single cells, gather hundreds of them together, and assemble “baby” Xenobots inside their Pac-Man-shaped “mouth”—that, a few days later, become new Xenobots that look and move just like themselves.

And then these new Xenobots can go out, find cells, and build copies of themselves. Again and again.

In a Xenopus laevis frog, these embryonic cells would develop into skin. “They would be sitting on the outside of a tadpole, keeping out pathogens and redistributing mucus,” says Michael Levin, Ph.D., a professor of biology and director of the Allen Discovery Center at Tufts University and co-leader of the new research. “But we’re putting them into a novel context. We’re giving them a chance to reimagine their multicellularity.” Levin is also an Associate Faculty member at the Wyss Institute.

And what they imagine is something far different than skin. “People have thought for quite a long time that we’ve worked out all the ways that life can reproduce or replicate. But this is something that’s never been observed before,” says co-author Douglas Blackiston, Ph.D., the senior scientist at Tufts University and the Wyss Institute who assembled the Xenobot “parents” and developed the biological portion of the new study.

“This is profound,” says Levin. “These cells have the genome of a frog, but, freed from becoming tadpoles, they use their collective intelligence, a plasticity, to do something astounding.” In earlier experiments, the scientists were amazed that Xenobots could be designed to achieve simple tasks. Now they are stunned that these biological objects—a computer-designed collection of cells—will spontaneously replicate. “We have the full, unaltered frog genome,” says Levin, “but it gave no hint that these cells can work together on this new task,” of gathering and then compressing separated cells into working self-copies.

“These are frog cells replicating in a way that is very different from how frogs do it. No animal or plant known to science replicates in this way,” says Sam Kriegman, Ph.D.,  the lead author on the new study, who completed his Ph.D. in Bongard’s lab at UVM and is now a post-doctoral researcher at Tuft’s Allen Center and Harvard University’s Wyss Institute for Biologically Inspired Engineering.

Both Buckiewicz’s December 3, 2021 article and Brown’s November 29, 2021 Wyss Institute news release are good reads with liberal used of embedded images. If you have time, start with Buckiewicz as she provides a good introduction and follow up with Brown who gives more detail and has an embedded video of a December 1, 2021 panel discussion with the scientists behind the xenobots.

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

Kinematic self-replication in reconfigurable organisms by Sam Kriegman, Douglas Blackiston, Michael Levin, and Josh Bongard. PNAS [Proceedings of the National Academy of Sciences] December 7, 2021 118 (49) e2112672118; https://doi.org/10.1073/pnas.2112672118

This paper appears to be open access.