Category Archives: medicine

mRNA, COVID-19 vaccines, treating genetic diseases before birth, and the scientist who started it all

This post was going to be about new research into fetal therapeutics and mRNA.But, since I’ve been very intrigued by the therapeutic agent, mRNA, which has been a big part of the COVID-19 vaccine story; this seemed like a good opportunity to dive a little more deeply into that topic at the same time.

It’s called messenger ribonucleic acid (mRNA) and until seeing this video I had only the foggiest idea of how it works, which is troubling since at least two COVID-19 vaccines are based on this ‘new’ technology. From a November 10, 2020 article by Damian Garde for STAT,

Garde’s article offers detail about mRNA along with fascinating insight into how science and entreneurship works.

mRNA—it’s in the details, plus, the loneliness of pioneer researchers, a demotion, and squabbles

Garde’s November 10, 2020 article provides some explanation about how mRNA vaccines work and it takes a look at what can happen to pioneering scientists (Note: A link has been removed),

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the body’s trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory. [emphasis mine]

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval [until 2021].

Whether mRNA vaccines succeed or not, their path from a gleam in a scientist’s eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations — and an unprecedented flow of cash into the biotech industry.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire — antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karikó wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karikó was convinced it was one she could work around. Few shared her confidence.

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

There’s no opportune time for demotion, but 1995 had already been uncommonly difficult. Karikó had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which she’d devoted countless hours was slipping through her fingers.

“I thought of going somewhere else, or doing something else,” Karikó said. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”

In time, those better experiments came together. After a decade of trial and error, Karikó and her longtime collaborator at Penn — Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University — discovered a remedy for mRNA’s Achilles’ heel.

The stumbling block, as Karikó’s many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karikó and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikó and Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses.

“That was a key discovery,” said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. “Karikó and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.”

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technology’s lean years. And it was the starter pistol for the vaccine sprint to come.

Entrepreneurs rush in

Garde’s November 10, 2020 article shifts focus from Karikó, Weissman, and specifics about mRNA to the beginnings of what might be called an entrepreneurial gold rush although it starts sedately,

Derrick Rossi [emphasis mine], a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karikó and Weissman deserve the Nobel Prize in chemistry.

“If anyone asks me whom to vote for some day down the line, I would put them front and center,” he said. “That fundamental discovery is going to go into medicines that help the world.”

But Rossi didn’t have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells [emphasis mine].

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinson’s disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend — and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

“I think you can do a lot better than that,” Langer recalled telling Rossi, referring to stem cells. “I think you could make new drugs, new vaccines — everything.”

Within several months, Rossi, Langer, Afeyan [Noubar Afeyan, venture capitalist, founded and runs Flagship Ventures], and another physician-researcher at Harvard formed the firm Moderna — a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firm’s “promise rivals that of the earliest biotechnology companies over 30 years ago — adding an entirely new drug category to the pharmaceutical arsenal.”

But although Moderna has made each of the founders hundreds of millions of dollars — even before the company had produced a single product — Rossi’s account is marked by bitterness. In interviews with the [Boston] Globe in October [2020], he accused Langer and Afeyan of propagating a condescending myth that he didn’t understand his discovery’s full potential until they pointed it out to him.

Garde goes on to explain how BioNTech came into the mRNA picture and contrasts the two companies’ approaches to biotechnology as a business. It seems BioNTech has not cashed in the same way as has Moderna. (For some insight into who’s making money from COVID-19 check out Giacomo Tognini’s December 23, 2020 article (Meet The 50 Doctors, Scientists And Healthcare Entrepreneurs Who Became Pandemic Billionaires In 2020) for Forbes.)

Garde ends his November 10, 2020 article on a mildly cautionary note,

“You have all these odd clinical and pathological changes caused by this novel bat coronavirus [emphasis mine], and you’re about to meet it with all of these vaccines with which you have no experience,” said Paul Offit, an infectious disease expert at Children’s Hospital of Philadelphia and an authority on vaccines.

What happened to Katalin Karikó?

Matthew Rosza’s January 25, 2021 article about Karikó and her pioneering work features an answer to my question and some advice,

“I want young people to feel — if my example, because I was demoted, rejected, terminated, I was even subject for deportation one point — [that] if they just pursue their thing, my example helps them to wear rejection as a badge,” Karikó, who today is a senior vice president at BioNTech RNA Pharmaceuticals, told Salon last month when discussing her story. “‘Okay, well, I was rejected. I know. Katalin was rejected and still [succeeded] at the end.’ So if it helps them, then it helps them.”

Despite her demotion, Karikó continued with her work and, along with a fellow immunologist named Dr. Drew Weissman, penned a series of influential articles starting in 2005. These articles argued that mRNA vaccines would not be neutralized by the human immune system as long as there were specific modifications to nucleosides, a compound commonly found in RNA.

By 2013, Karikó’s work had sufficiently impressed experts that she left the University of Pennsylvania for BioNTech RNA Pharmaceuticals.

Karikó tells Salon that the experience taught her one important lesson: In life there will be people who, for various reasons, will try to hold you back, and you can’t let them get you down.

“People that are in power, they can help you or block you,” Karikó told Salon. “And sometimes people select to make your life miserable. And now they cannot be happy with me because now they know that, ‘Oh, you know, we had the confrontation and…’ But I don’t spend too much time on these things.”

Before moving onto the genetic research which prompted this posting, I have an answer to the following questions:

Could an mRNA vaccine affect your DNA (deoxyribonucleic acid) and how do mRNA vaccines differ from the traditional ones?

No, DNA is not affected by the COVID-19 mRNA vaccines, according to a January 5, 2021 article by Jason Murdock for Newsweek,

The type of vaccines used against COVID-19 do not interact with or alter human genetic code, also known as DNA, scientists say.

In traditional vaccines, a piece of a virus, known as an “antigen,” would be injected into the body to force the immune system to make antibodies to fight off future infection. But mRNA-based methods do not use a live virus, and cannot give someone COVID.

Instead, mRNA vaccines give cells the instructions to make a “spike” protein also found on the surface of the virus that causes COVID. The body kickstarts its immune response by creating the antibodies needed to combat those specific virus proteins.

Once the spike protein is created, the cell breaks down the instructions provided by the mRNA molecule, leaving the human immune system prepared to combat infection. The mRNA vaccines are not a medicine—nor a cure—but a preventative measure.

Gavi, a vaccine alliance partnered with the World Health Organization (WHO), has said that mRNA instructions will become degraded in approximately 72 hours.

It says mRNA strands are “chemical intermediaries” between DNA in our chromosomes and the “cellular machinery that produces the proteins we need to function.”

But crucially, while mRNA vaccines will give the human body the blueprints on how to assemble proteins, the alliance said in a fact-sheet last month that “mRNA isn’t the same as DNA, and it can’t combine with our DNA to change our genetic code.”

It explained: “Some viruses like HIV can integrate their genetic material into the DNA of their hosts, but this isn’t true of all viruses… mRNA vaccines don’t carry these enzymes, so there is no risk of the genetic material they contain altering our DNA.”

The [US] Centers for Disease Control and Prevention (CDC) says on its website that mRNA vaccines that are rolling out don’t “interact with our DNA in any way,” and “mRNA never enters the nucleus of the cell, which is where our DNA (genetic material) is kept.”

Therapeutic fetal mRNA treatment

Rossi’s work on mRNA and embryonic stem cells bears a relationship of sorts to this work focusing on prebirth therapeutics. (From a January 13, 2021 news item on Nanowerk), Note: A link has been removed,

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy.

The proof-of-concept study, published in Science Advances (“Ionizable Lipid Nanoparticles for In Utero mRNA Delivery”), engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

A January 13, 2021 Children’s Hospital of Philadelphia (CHOP) news release (also on EurekAlert), which originated the news item, delves further into the research,

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Of the potential vehicles for introducing therapeutic protein replacement, mRNA is distinct from other nucleic acids, such as DNA, because it does not need to enter the nucleus and can use the body’s own machinery to produce the desired proteins. Currently, the common methods of nucleic acid delivery include viral vectors and nonviral approaches. Although viral vectors may be well-suited to gene therapy, they come with the potential risk of unwanted integration of the transgene or parts of the viral vector in the recipient genome. Thus, there is an important need to develop safe and effective nonviral nucleic acid delivery technologies to treat prenatal diseases.

In order to identify potential nonviral delivery systems for therapeutic mRNA, the researchers engineered a library of lipid nanoparticles, small particles less than 100 nanometers in size that effectively enter cells in mouse fetal recipients. Each lipid nanoparticle formulation was used to encapsulate mRNA, which was administered to mouse fetuses. The researchers found that several of the lipid nanoparticles enabled functional mRNA delivery to fetal livers and that some of those lipid nanoparticles also delivered mRNA to the fetal lungs and intestines. They also assessed the lipid nanoparticles for toxicity and found them to be as safe or safer than existing formulations.

Having identified the lipid nanoparticles that were able to accumulate within fetal livers, lungs, and intestines with the highest efficiency and safety, the researchers also tested therapeutic potential of those designs by using them to deliver erythropoietin (EPO) mRNA, as the EPO protein is easily trackable. They found that EPO mRNA delivery to liver cells in mouse fetuses resulted in elevated levels of EPO protein in the fetal circulation, providing a model for protein replacement therapy via the liver using these lipid nanoparticles.

“A central challenge in the field of gene therapy is the delivery of nucleic acids to target cells and tissues, without causing side effects in healthy tissue. This is difficult to achieve in adult animals and humans, which have been studied extensively. Much less is known in terms of what is required to achieve in utero nucleic acid delivery,” said Mitchell. “We are very excited by the initial results of our lipid nanoparticle technology to deliver mRNA in utero in safe and effective manner, which could open new avenues for lipid nanoparticles and mRNA therapeutics to treat diseases before birth.”

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

Ionizable lipid nanoparticles for in utero mRNA delivery by Rachel S. Riley, Meghana V. Kashyap, Margaret M. Billingsley, Brandon White, Mohamad-Gabriel Alameh, Sourav K. Bose, Philip W. Zoltick, Hiaying Li, Rui Zhang, Andrew Y. Cheng, Drew Weissman, William H. Peranteau, Michael J. Mitchell. Science Advances 13 Jan 2021: Vol. 7, no. 3, eaba1028 DOI: 10.1126/sciadv.aba1028

This paper appears to be open access. BTW, I noticed Drew Weissman’s name as one of the paper’s authors and remembered him as one of the first to recognize Karikó’s pioneering work. I imagine that when he co-authored papers with Karikó he was risking his reputation.

Funny how a despised field of research has sparked a ‘gold rush’ for research and for riches, yes?.

CRISPR technology is like a pair of scissors and a dimmer switch?

The ‘pair of scissors’ analogy is probably the most well known of the attempts to describe how the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene editing system works. It seems a new analogy is about to be added according to a January 19 2021 news item on ScienceDaily (Note: This October 30, 2019 posting features more CRISPR analogies),

In a series of experiments with laboratory-cultured bacteria, Johns Hopkins scientists have found evidence that there is a second role for the widely used gene-cutting system CRISPR-Cas9 — as a genetic dimmer switch for CRISPR-Cas9 genes. Its role of dialing down or dimming CRISPR-Cas9 activity may help scientists develop new ways to genetically engineer cells for research purposes.

Here’s an image illustrating the long form of the tracrRNA or ‘dimmer switch’ alongside the more commonly used short form,

Caption: Left – a schematic of the long form of the tracrRNA used by the CRISPR-Cas9 system in bacteria; Right – the standard guide RNA used by many scientists as part of the gene-cutting CRISPR-Cas9 system. Credit: Joshua Modell, Rachael Workman and Johns Hopkins Medicine

A January 19 ,2021 Johns Hopkins Medicine news release (also on EurekAlert), which originated the news item, explains about CRISPR and what the acronym stands for, as well as, giving more details about the discovery,

First identified in the genome of gut bacteria in 1987, CRISPR-Cas9 is a naturally occurring but unusual group of genes with a potential for cutting DNA sequences in other types of cells that was realized 25 years later. Its value in genetic engineering — programmable gene alteration in living cells, including human cells — was rapidly appreciated, and its widespread use as a genome “editor” in thousands of laboratories worldwide was recognized in the awarding of the Nobel Prize in Chemistry last year to its American and French co-developers.

CRISPR stands for clustered, regularly interspaced short palindromic repeats. Cas9, which refers to CRISPR-associated protein 9, is the name of the enzyme that makes the DNA slice. Bacteria naturally use CRISPR-Cas9 to cut viral or other potentially harmful DNA and disable the threat, says Joshua Modell, Ph.D., assistant professor of molecular biology and genetics at the Johns Hopkins University School of Medicine. In this role, Modell says, “CRISPR is not only an immune system, it’s an adaptive immune system — one that can remember threats it has previously encountered by holding onto a short piece of their DNA, which is akin to a mug shot.” These mug shots are then copied into “guide RNAs” that tell Cas9 what to cut.

Scientists have long worked to unravel the precise steps of CRISPR-Cas9’s mechanism and how its activity in bacteria is dialed up or down. Looking for genes that ignite or inhibit the CRISPR-Cas9 gene-cutting system for the common, strep-throat causing bacterium Streptococcus pyogenes, the Johns Hopkins scientists found a clue regarding how that aspect of the system works.

Specifically, the scientists found a gene in the CRISPR-Cas9 system that, when deactivated, led to a dramatic increase in the activity of the system in bacteria. The product of this gene appeared to re-program Cas9 to act as a brake, rather than as a “scissor,” to dial down the CRISPR system.

“From an immunity perspective, bacteria need to ramp up CRISPR-Cas9 activity to identify and rid the cell of threats, but they also need to dial it down to avoid autoimmunity — when the immune system mistakenly attacks components of the bacteria themselves,” says graduate student Rachael Workman, a bacteriologist working in Modell’s laboratory.

To further nail down the particulars of the “brake,” the team’s next step was to better understand the product of the deactivated gene (tracrRNA). RNA is a genetic cousin to DNA and is vital to carrying out DNA “instructions” for making proteins. TracrRNAs belong to a unique family of RNAs that do not make proteins. Instead, they act as a kind of scaffold that allows the Cas9 enzyme to carry the guide RNA that contains the mug shot and cut matching DNA sequences in invading viruses.

TracrRNA comes in two sizes: long and short. Most of the modern gene-cutting CRISPR-Cas9 tools use the short form. However, the research team found that the deactivated gene product was the long form of tracrRNA, the function of which has been entirely unknown.

The long and short forms of tracrRNA are similar in structure and have in common the ability to bind to Cas9. The short form tracrRNA also binds to the guide RNA. However, the long form tracrRNA doesn’t need to bind to the guide RNA, because it contains a segment that mimics the guide RNA. “Essentially, long form tracrRNAs have combined the function of the short form tracrRNA and guide RNA,” says Modell.

In addition, the researchers found that while guide RNAs normally seek out viral DNA sequences, long form tracrRNAs target the CRISPR-Cas9 system itself. The long form tracrRNA tends to sit on DNA, rather than cut it. When this happens in a particular area of a gene, it prevents that gene from expressing, — or becoming functional.

To confirm this, the researchers used genetic engineering to alter the length of a certain region in long form tracrRNA to make the tracrRNA appear more like a guide RNA. They found that with the altered long form tracrRNA, Cas9 once again behaved more like a scissor.

Other experiments showed that in lab-grown bacteria with a plentiful amount of long form tracrRNA, levels of all CRISPR-related genes were very low. When the long form tracrRNA was removed from bacteria, however, expression of CRISPR-Cas9 genes increased a hundredfold.

Bacterial cells lacking the long form tracrRNA were cultured in the laboratory for three days and compared with similarly cultured cells containing the long form tracrRNA. By the end of the experiment, bacteria without the long form tracrRNA had completely died off, suggesting that long form tracrRNA normally protects cells from the sickness and death that happen when CRISPR-Cas9 activity is very high.

“We started to get the idea that the long form was repressing but not eliminating its own CRISPR-related activity,” says Workman.

To see if the long form tracrRNA could be re-programmed to repress other bacterial genes, the research team altered the long form tracrRNA’s spacer region to let it sit on a gene that produces green fluorescence. Bacteria with this mutated version of long form tracrRNA glowed less green than bacteria containing the normal long form tracrRNA, suggesting that the long form tracrRNA can be genetically engineered to dial down other bacterial genes.

Another research team, from Emory University, found that in the parasitic bacteria Francisella novicida, Cas9 behaves as a dimmer switch for a gene outside the CRISPR-Cas9 region. The CRISPR-Cas9 system in the Johns Hopkins study is more widely used by scientists as a gene-cutting tool, and the Johns Hopkins team’s findings provide evidence that the dimmer action controls the CRISPR-Cas9 system in addition to other genes.

The researchers also found the genetic components of long form tracrRNA in about 40% of the Streptococcus group of bacteria. Further study of bacterial strains that don’t have the long form tracrRNA, says Workman, will potentially reveal whether their CRISPR-Cas9 systems are intact, and other ways that bacteria may dial back the CRISPR-Cas9 system.

The dimmer capability that the experiments uncovered, says Modell, offers opportunities to design new or better CRISPR-Cas9 tools aimed at regulating gene activity for research purposes. “In a gene editing scenario, a researcher may want to cut a specific gene, in addition to using the long form tracrRNA to inhibit gene activity,” he says.

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

A natural single-guide RNA repurposes Cas9 to autoregulate CRISPR-Cas expression by Rachael E. Workman, Teja Pammi, Binh T.K. Nguyen, Leonardo W. Graeff, Erika Smith, Suzanne M. Sebald, Marie J. Stoltzfus, Chad W. Euler, Joshua W. Modell. Cell DOI:https://doi.org/10.1016/j.cell.2020.12.017 Published Online:J anuary 08, 2021

This paper is behind a paywall.

Put a ring on it: preventing clumps of gold nanoparticles

Caption: A comparison of how linear PEG (left) and cyclic PEG (right) attach to a gold nanoparticle Credit: Yubo Wang, Takuya Yamamoto

A January 20, 2021 news item on phys.org focuses on work designed to stop gold nanoparticles from clumping together (Note: A link has been removed),

Hokkaido University scientists have found a way to prevent gold nanoparticles from clumping, which could help towards their use as an anti-cancer therapy.

Attaching ring-shaped synthetic compounds to gold nanoparticles helps them retain their essential light-absorbing properties, Hokkaido University researchers report in the journal Nature Communications.

A January 20, 2021 Hokkaido University press release (also on EurekAlert but published Jan. 21, 2020), which originated the news item, elaborates on the work,

Metal nanoparticles have unique light-absorbing properties, making them interesting for a wide range of optical, electronic and biomedical applications. For example, if delivered to a tumour, they could react with applied light to kill cancerous tissue. A problem with this approach, though, is that they easily clump together in solution, losing their ability to absorb light. This clumping happens in response to a variety of factors, including temperature, salt concentration and acidity.

Scientists have been trying to find ways to ensure nanoparticles stay dispersed in their target environments. Covering them with polyethylene glycol, otherwise known as PEG, has been relatively successful at this in the case of gold nanoparticles. PEG is biocompatible and can prevent gold surfaces from clumping together in the laboratory and in living organisms, but improvements are still needed.

Applied chemist Takuya Yamamoto and colleagues at Hokkaido University, The University of Tokyo, and Tokyo Institute of Technology found that mixing gold nanoparticles with ring-shaped PEG, rather than the normally linear PEG, significantly improved dispersion. The ‘cyclic-PEG’ (c-PEG) attaches to the surfaces of the nanoparticles without forming chemical bonds with them, a process called physisorption. The coated nanoparticles remained dispersed when frozen, freeze-dried and heated.

The team tested the c-PEG-covered gold nanoparticles in mice and found that they cleared slowly from the blood and accumulated better in tumours compared to gold nanoparticles coated with linear PEG. However, accumulation was lower than desired levels, so the researchers recommend further investigations to fine-tune the nanoparticles for this purpose.

Associate Professor Takuya Yamamoto is part of the Laboratory of Chemistry of Molecular Assemblies at Hokkaido University, where he studies the properties and applications of various cyclic chemical compounds.

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

Enhanced dispersion stability of gold nanoparticles by the physisorption of cyclic poly(ethylene glycol) by Yubo Wang, Jose Enrico Q. Quinsaat, Tomoko Ono, Masatoshi Maeki, Manabu Tokeshi, Takuya Isono, Kenji Tajima, Toshifumi Satoh, Shin-ichiro Sato, Yutaka Miura & Takuya Yamamoto. Nature Communications volume 11, Article number: 6089 (2020) DOI: https://doi.org/10.1038/s41467-020-19947-8 Published: 30 November 2020

This paper is open access.

A lotus root-inspired hydrogel fiber for surgical sutures

By FotoosRobin – originally posted to Flickr as Lotus root, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=4826529

The lotus (Nelumbo nucifera) rhizome (mass of roots) is not the prettiest part of the lotus but its fibers (and presumably fiber from other parts of the lotus plant) served as inspiration for a hydrogel that might be used as a surgical suture according to a Jan. 14, 2021 news item on phys.org (Note: Links have been removed),

“The lotus roots may break, but the fiber remains joined”—an old Chinese saying that reflects the unique structure and mechanical properties of the lotus fiber. The outstanding mechanical properties of lotus fibers can be attributed to their unique spiral structure, which provides an attractive model for biomimetic design of artificial fibers.

In a new study published in Nano Letters, a team led by Prof. Yu Shuhong from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS) reported a bio-inspired lotus-fiber-mimetic spiral structure bacterial cellulose (BC) hydrogel fiber with high strength, high toughness, excellent biocompatibility, good stretchability, and high energy dissipation.

A Jan. 14, 2021 University of Science and Technology of China press release on the Chinese Academy of Sciences website (also on EurekAlert), which originated the news item, describes the new hydrogel in more detail,

Unlike polymer-based hydrogel, the newly designed biomimetic hydrogel fiber (BHF) is based on the BC hydrogel with 3D cellulose nanofiber networks produced by bacteria. The cellulose nanofibers provide the reversible hydrogen bonding network that results in unique mechanical properties.

The researchers applied a constant tangential force to the pretreated BC hydrogel along the cross-sectional direction. Then, the two sides of the hydrogel were subjected to opposite tangential forces, and local plastic deformation occurred.

The hydrogen bonds in the 3D network of cellulose nanofibers were broken by the tangential force, causing the hydrogel strip to twist spirally and the network to slip and deform. When the tangential force was removed, the hydrogen bonds reformed between the nanofibers, and the spiral structure of the fiber was fixed.

Benefited from lotus-fiber-mimetic spiral structure, the toughness of BHF can reach ?116.3 MJ m-3, which is more than nine times higher than those of non-spiralized BC hydrogel fiber. Besides, once the BHF is stretched, it is nearly non-resilient.

Combining outstanding mechanical properties with excellent biocompatibility derived from BC, BHF is a promising hydrogel fiber for biomedical material, especially for surgical suture, a commonly used structural biomedical material for wound repair.

Compared with commercial surgical suture with higher modulus, the BHF has similar modulus and strength to soft tissue, like skin. The outstanding stretchability and energy dissipation of BHF allow it to absorb energy from the tissue deformation around a wound and effectively protect the wound from rupture, which makes BHF an ideal surgical suture.

What’s more, the porous structure of BHF also allows it to adsorb functional small molecules, such as antibiotics or anti-inflammatory compounds, and sustainably release them on wounds. With an appropriate design, BHF would be a powerful platform for many medical applications.

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

Bio-Inspired Lotus-Fiber-like Spiral Hydrogel Bacterial Cellulose Fibers by Qing-Fang Guan, Zi-Meng Han, YinBo Zhu, Wen-Long Xu, Huai-Bin Yang, Zhang-Chi Ling, Bei-Bei Yan, Kun-Peng Yang, Chong-Han Yin, HengAn Wu, and Shu-Hong Yu. Nano Lett. 2021, XXXX, XXX, XXX-XXX DOI: https://doi.org/10.1021/acs.nanolett.0c03707 Publication Date:January 5, 2021 Copyright © 2021 American Chemical Society

This paper is behind a paywall.

Eradicating bacteria biofilm with nanocrystals

A January 8, 2021 news item on ScienceDaily announces new work from South Korea’s Pohang University of Science & Technology (POSTECH),

The COVID-19 pandemic is raising fears of new pathogens such as new viruses or drug-resistant bacteria. To this, a Korean research team has recently drawn attention for developing the technology for removing antibiotic-resistant bacteria by controlling the surface texture of nanomaterials.

A joint research team from POSTECH and UNIST [Ulsan National Institute of Science and Technology] has introduced mixed-FeCo-oxide-based surface-textured nanostructures (MTex) as highly efficient magneto-catalytic platform in the international journal Nano Letters. The team consisted of professors In Su Lee and Amit Kumar with Dr. Nitee Kumari of POSTECH’s Department of Chemistry and Professor Yoon-Kyung Cho and Dr. Sumit Kumar of UNIST’s Department of Biomedical Engineering.

Caption: Schematic diagram showing removal of bacterial biofilm via Mtex Credit: POSTECH

A January 8, 2021 POSTECH press release (also on EurkeAlert), which originated the news item, delves further,

First, the researchers synthesized smooth surface nanocrystals in which various metal ions were wrapped in an organic polymer shell and heated them at a very high temperature. While annealing the polymer shell, a high-temperature solid-state chemical reaction induced mixing of other metal ions on the nanocrystal surface, creating a number of few-nm-sized branches and holes on it. This unique surface texture was found to catalyze a chemical reaction that produced reactive oxygen species (ROS) that kills the bacteria. It was also confirmed to be highly magnetic and easily attracted toward the external magnetic field. The team had discovered a synthetic strategy for converting normal nanocrystals without surface features into highly functional mixed-metal-oxide nanocrystals.

The research team named this surface topography – with branches and holes that resembles that of a ploughed field – “MTex.” This unique surface texture has been verified to increase the mobility of nanoparticles to allow efficient penetration into biofilm matrix while showing high activity in generating reactive oxygen species (ROS) that are lethal to bacteria.

This system produces ROS over a broad pH range and can effectively diffuse into the biofilm and kill the embedded bacteria resistant to antibiotics. And since the nanostructures are magnetic, biofilm debris can be scraped out even from the hard-to-reach microchannels.

“This newly developed MTex shows high catalytic activity, distinct from the stable smooth-surface of the conventional spinel forms,” explained Dr. Amit Kumar, one of the corresponding authors of the paper. “This characteristic is very useful in infiltrating biofilms even in small spaces and is effective in killing the bacteria and removing biofilms.”

“This research allows to regulate the surface nanotexturization, which opens up possibilities to augment and control the exposure of active sites,” remarked Professor In Su Lee who led the research. “We anticipate the nanoscale-textured surfaces to contribute significantly in developing a broad array of new enzyme-like properties at the nano-bio interface.”

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

Surface-Textured Mixed-Metal-Oxide Nanocrystals as Efficient Catalysts for ROS Production and Biofilm Eradication by Nitee Kumari, Sumit Kumar, Mamata Karmacharya, Sateesh Dubbu, Taewan Kwon, Varsha Singh, Keun Hwa Chae, Amit Kumar, Yoon-Kyoung Cho, and In Su Lee. Nano Lett. 2021, 21, 1, 279–287 DOI: https://doi.org/10.1021/acs.nanolett.0c03639 Publication Date: December 11, 2020 Copyright © 2020 American Chemical Society

This paper is behind a paywall.

CRISPR/Cas9 used successfully to edit SIV (simian immunodeficiency virus, which is similar to HIV) out of monkey genome

Before reading further please note, the research discussed in this posting is based on animal testing, which many people find highly disturbing.

CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), or more familiarly CRISPR/Cas9, has been been used to edit simian immunodeficiency virus from infected monkeys’ cells according to a December 2, 2020 article by Matthew Rozsa for Salon.com (Note: Links have been removed),

With multiple coronavirus vaccines being produced as we speak, the COVID-19 pandemic appears to have an end in sight, though the HIV pandemic continues after more than 40 years. That might seem like a head-scratcher: why is HIV, a virus we’ve known about for decades, so much harder to cure than a virus discovered just last year? Part of the reason is that HIV, as a retrovirus, is a more complex virus to vaccinate against than SARS-CoV-2 — hence why a vaccine or other cure has eluded scientists for decades. 

Now, a surprising new study on a related retrovirus shows incredible promise for the potential to develop a cure for HIV, or human immunodeficiency virus. In an article published in the scientific journal Nature Communications, scientists revealed that they had used CRISPR – a genetic technology that can alter DNA and whose developers won the 2020 Nobel Prize in Chemistry [specifically, Jennifer Doudna and Emanuelle Charpentier received the Nobel for developing CRISPR-cas9 or CRISPR/Cas9 not CRISPR alone) — to successfully edit SIV (simian immunodeficiency virus), a virus similar to HIV, out of the genomes of non-human primates.  Specifically, the scientists were able to edit out the SIV genome from rhesus macaque monkeys’ infected cells.

For anyone who’s interested in how CRISPR was developed and the many contributions which have led to the current state-of-the-art for CRISPR gene editing, see the History subsection of Wikipedia’s CRISPR entry.

Getting back to Rozsa’s December 2, 2020 article,

“This study used the CRISPR CaS9 system, which has been described as molecular scissors,” Andrew G. MacLean, PhD, wrote to Salon. MacLean is an associate professor at the Tulane National Primate Research Center and the Department of Microbiology and Immunology at Tulane University School of Medicine and was a senior co-investigator of the study. “It uses a highly specific targeting system to cut out a specific portion of DNA that is necessary for HIV to be able to produce more virus.”

He added, “Our collaborators at in the Khalili Lab at Temple University have developed a method of ‘packaging’ this within a single so-called vector. A vector is a non-disease causing virus that is used as a carrier for the CRISPR CaS9 scissors to get it into the tissues of interest.”

The experiments with SIV are considered to be a gateway to understanding HIV, as HIV is believed to have evolved from SIV, and is genetically similar.

“The rhesus macaque model of HIV/AIDS is the most valuable model to test efficacy of new interventions or approaches for preventing or treating HIV infection, prior to human clinical trials,” Binhua Ling, PhD, associate professor at the Southwest National Primate Research Center, Texas Biomedical Research Institute, wrote to Salon. “This first proof-of-principal [emphasis mine] study on the rhesus macaque model indicates that this virus-vehicle-delivered-CRISPR system can reach many tissue sites of the body, and is able to effectively delete virus DNA in infected cells. This paves the way for applying the same technology to the human body, which could lead to a cure for HIV infection.”

Tricia H. Burdo, PhD, another senior co-investigator on the new study who works at the Lewis Katz School of Medicine at Temple University, explained to Salon by email that “HIV is in a class of viruses (retroviruses) that inserts itself into the DNA of the host, so you can really think of this now as a genetic disease” — in other words, the kind of thing that would be ripe for CRISPR’s scissors-like ability to remove errant or unwanted genetic material. Burdo notes that the CRISPR technology discussed in the article “cuts out this foreign viral gene.”

The study was conducted on eight Rhesus macaque monkeys. That is a very small number to start with and not all of the monkeys received the CRISPR/Cas9 treatment. From the ‘Animals used in the study and ethical statement‘ subsection of the study, “Animals were sacrificed for tissue collection 3 weeks after … .” Leaving aside how anyone may feel about ‘sacrificing …’, three weeks is not a long time for observation.

Should you be interested, there is a November 30, 2020 Tulane University news release announcing the research.

If you want to read the whole study, here’s a link and a citation,

CRISPR based editing of SIV proviral DNA in ART treated non-human primates by Pietro Mancuso, Chen Chen, Rafal Kaminski, Jennifer Gordon, Shuren Liao, Jake A. Robinson, Mandy D. Smith, Hong Liu, Ilker K. Sariyer, Rahsan Sariyer, Tiffany A. Peterson, Martina Donadoni, Jaclyn B. Williams, Summer Siddiqui, Bruce A. Bunnell, Binhua Ling, Andrew G. MacLean, Tricia H. Burdo & Kamel Khalili. Nature Communications volume 11, Article number: 6065 (2020) DOI: https://doi.org/10.1038/s41467-020-19821-7 Published: 27 November 2020

This paper is open access.

As Rozsa notes in his December 2, 2020 article, the Joint United Nations Programme on HIV/AIDS estimates that 32.7 million [24.8 million–42.2 million] people have died from AIDS-related illnesses since the start (1981?) of the epidemic to the end of 2019.

Water and minerals have a nanoscale effect on bones

Courtesy: University of Arkansas

What a great image of bones! This December 3, 2020 University of Arkansas news release (also on EurekAlert) by Matt McGowan features research focused on bone material looks exciting. The date for the second study citation and link that I have listed (at the end of this posting) suggests the more recent study may have been initially overlooked in the deluge of COVID-19 research we are experiencing,

University of Arkansas researchers Marco Fielder and Arun Nair have conducted the first study of the combined nanoscale effects of water and mineral content on the deformation mechanisms and thermal properties of collagen, the essence of bone material.

The researchers also compared the results to the same properties of non-mineralized collagen reinforced with carbon nanotubes, which have shown promise as a reinforcing material for bio-composites. This research aids in the development of synthetic materials to mimic bone.

Using molecular dynamics — in this case a computer simulation of the physical movements of atoms and molecules — Nair and Fielder examined the mechanics and thermal properties of collagen-based bio-composites containing different weight percentages of minerals, water and carbon nanotubes when subjected to external loads.

They found that variations of water and mineral content had a strong impact on the mechanical behavior and properties of the bio-composites, the structure of which mimics nanoscale bone composition. With increased hydration, the bio-composites became more vulnerable to stress. Additionally, Nair and Fielder found that the presence of carbon nanotubes in non-mineralized collagen reduced the deformation of the gap regions.

The researchers also tested stiffness, which is the standard measurement of a material’s resistance to deformation. Both mineralized and non-mineralized collagen bio-composites demonstrated less stability with greater water content. Composites with 40% mineralization were twice as strong as those without minerals, regardless of the amount of water content. Stiffness of composites with carbon nanotubes was comparable to that of the mineralized collagen.

“As the degree of mineralization or carbon nanotube content of the collagenous bio-composites increased, the effect of water to change the magnitude of deformation decreased,” Fielder said.

The bio-composites made of collagen and carbon nanotubes were also found to have a higher specific heat than the studied mineralized collagen bio-composites, making them more likely to be resistant to thermal damage that could occur during implantation or functional use of the composite. Like most biological materials, bone is a hierarchical – with different structures at different length scales. At the microscale level, bone is made of collagen fibers, composed of smaller nanofibers called fibrils, which are a composite of collagen proteins, mineralized crystals called apatite and water. Collagen fibrils overlap each other in some areas and are separated by gaps in other areas.

“Though several studies have characterized the mechanics of fibrils, the effects of variation and distribution of water and mineral content in fibril gap and overlap regions are unexplored,” said Nair, who is an associate professor of mechanical engineering. “Exploring these regions builds an understanding of the structure of bone, which is important for uncovering its material properties. If we understand these properties, we can design and build better bio-inspired materials and bio-composites.”

Here are links and citations for both papers mentioned in the news release,

Effects of hydration and mineralization on the deformation mechanisms of collagen fibrils in bone at the nanoscale by Marco Fielder & Arun K. Nair. Biomechanics and Modeling in Mechanobiology volume 18, pages57–68 (2019) Biomech Model Mechanobiol 18, 57–68 (2019). DOI: https://doi.org/10.1007/s10237-018-1067-y First published: 07 August 2018 Issue Date: 15 February 2019

This paper is behind a paywall.

A computational study of mechanical properties of collagen-based bio-composites by Marco Fielder & Arun K. Nair. International Biomechanics Volume 7, 2020 – Issue 1 Pages 76-87 DOI: https://doi.org/10.1080/23335432.2020.1812428 Published online: 02 Sep 2020

This paper is open access.

Detecting COVID-19 in under five minutes with paper-based sensor made of graphene

A Dec. 7, 2020 news item on Nanowerk announced a new technology for rapid COVID-19 testing (Note: A link has been removed),

As the COVID-19 pandemic continues to spread across the world, testing remains a key strategy for tracking and containing the virus. Bioengineering graduate student, Maha Alafeef, has co-developed a rapid, ultrasensitive test using a paper-based electrochemical sensor that can detect the presence of the virus in less than five minutes.

The team led by professor Dipanjan Pan reported their findings in ACS Nano (“Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip”).

“Currently, we are experiencing a once-in-a-century life-changing event,” said Alafeef. “We are responding to this global need from a holistic approach by developing multidisciplinary tools for early detection and diagnosis and treatment for SARS-CoV-2.”

I wonder why they didn’t think to provide a caption for the graphene substrate (the square surface) underlying the gold electrode (the round thing) or provide a caption for the electrode. Maybe they assumed anyone knowledgeable about graphene would be able to identify it?

Caption: COVID-19 electrochemical sensing platform. Credit: University of Illinois

A Dec. 7, 2020 University of Illinois Grainger College of Engineering news release (also on EurekAlert) by Huan Song, which originated the news item, provides more technical detail including a description of the graphene substrate and the gold electrode, which make up the cheaper, faster COVID-19 sensing platform,

There are two broad categories of COVID-19 tests on the market. The first category uses reverse transcriptase real-time polymerase chain reaction (RT-PCR) and nucleic acid hybridization strategies to identify viral RNA. Current FDA [US Food and Drug Administration]-approved diagnostic tests use this technique. Some drawbacks include the amount of time it takes to complete the test, the need for specialized personnel and the availability of equipment and reagents.

The second category of tests focuses on the detection of antibodies. However, there could be a delay of a few days to a few weeks after a person has been exposed to the virus for them to produce detectable antibodies.

In recent years, researchers have had some success with creating point-of-care biosensors using 2D nanomaterials such as graphene to detect diseases. The main advantages of graphene-based biosensors are their sensitivity, low cost of production and rapid detection turnaround. “The discovery of graphene opened up a new era of sensor development due to its properties. Graphene exhibits unique mechanical and electrochemical properties that make it ideal for the development of sensitive electrochemical sensors,” said Alafeef. The team created a graphene-based electrochemical biosensor with an electrical read-out setup to selectively detect the presence of SARS-CoV-2 genetic material.

There are two components [emphasis mine] to this biosensor: a platform to measure an electrical read-out and probes to detect the presence of viral RNA. To create the platform, researchers first coated filter paper with a layer of graphene nanoplatelets to create a conductive film [emphasis mine]. Then, they placed a gold electrode with a predefined design on top of the graphene [emphasis mine] as a contact pad for electrical readout. Both gold and graphene have high sensitivity and conductivity which makes this platform ultrasensitive to detect changes in electrical signals.

Current RNA-based COVID-19 tests screen for the presence of the N-gene (nucleocapsid phosphoprotein) on the SARS-CoV-2 virus. In this research, the team designed antisense oligonucleotide (ASOs) probes to target two regions of the N-gene. Targeting two regions ensures the reliability of the senor in case one region undergoes gene mutation. Furthermore, gold nanoparticles (AuNP) are capped with these single-stranded nucleic acids (ssDNA), which represents an ultra-sensitive sensing probe for the SARS-CoV-2 RNA.

The researchers previously showed the sensitivity of the developed sensing probes in their earlier work published in ACS Nano. The hybridization of the viral RNA with these probes causes a change in the sensor electrical response. The AuNP caps accelerate the electron transfer and when broadcasted over the sensing platform, results in an increase in the output signal and indicates the presence of the virus.

The team tested the performance of this sensor by using COVID-19 positive and negative samples. The sensor showed a significant increase in the voltage of positive samples compared to the negative ones and confirmed the presence of viral genetic material in less than five minutes. Furthermore, the sensor was able to differentiate viral RNA loads in these samples. Viral load is an important quantitative indicator of the progress of infection and a challenge to measure using existing diagnostic methods.

This platform has far-reaching applications due to its portability and low cost. The sensor, when integrated with microcontrollers and LED screens or with a smartphone via Bluetooth or wifi, could be used at the point-of-care in a doctor’s office or even at home. Beyond COVID-19, the research team also foresees the system to be adaptable for the detection of many different diseases.

“The unlimited potential of bioengineering has always sparked my utmost interest with its innovative translational applications,” Alafeef said. “I am happy to see my research project has an impact on solving a real-world problem. Finally, I would like to thank my Ph.D. advisor professor Dipanjan Pan for his endless support, research scientist Dr. Parikshit Moitra, and research assistant Ketan Dighe for their help and contribution toward the success of this study.”

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

Rapid, Ultrasensitive, and Quantitative Detection of SARS-CoV-2 Using Antisense Oligonucleotides Directed Electrochemical Biosensor Chip by Maha Alafeef, Ketan Dighe, Parikshit Moitra, and Dipanjan Pan. ACS Nano 2020, 14, 12, 17028–17045 DOI: https://doi.org/10.1021/acsnano.0c06392 Publication Date:October 20, 2020 Copyright © 2020 American Chemical Society

I’m not sure where I found this notice but it is most definitely from the American Chemical Society: “This paper is freely accessible, at this time, for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.”

Mite silk as the basis for a new nanobiomaterial

For the record, this is spider mite silk (I have many posts about spider silk and its possible applications on this blog; just search ‘spider silk’)..

The international collaborative team includes a Canadian university in combination with a Spanish university and a Serbian university. The composition of the team is one I haven’t seen here before. From a December 17, 2020 news item on phys.org (Note: A link has been removed),

An international team of researchers has developed a new nanomaterial from the silk produced by the Tetranychus lintearius mite. This nanomaterial has the ability to penetrate human cells without damaging them and, therefore, has “promising biomedical properties”.

The Nature Scientific Reports journal has published an article by an international scientific team led by Miodrag Grbiç, a researcher from the universities of La Rioja (Spain), Western Ontario (Canada) and Belgrade (Serbia), in its latest issue entitled “The silk of gorse spider mite Tetranychus lintearius represents a novel natural source of nanoparticles and biomaterials.”

In it, researchers from the Murcian Institute for Agricultural and Food Research and Development (IMIDA), the Barcelona Institute of Photonic Sciences, the University of Western Ontario (Canada), the University of Belgrade (Serbia) and the University of La Rioja describe the discovery and characterisation of this mite silk. They also demonstrate its great potential as a source of nanoparticles and biomaterials for medical and technological uses.

A December 17, 2020 Universidad de La Rioja press release (also on EurekAlert), which originated the news item, further explains the research,

The interest of this new material, which is more resistant than steel, ultra flexible, nano-sized, biodegradable, biocompatible and has an excellent ability to penetrate human cells without damaging them, lies in its natural character and its size (a thousand times smaller than human hair), which facilitates cell penetration.

These characteristics are ideal for use in pharmacology and biomedicine since it is biocompatible with organic tissues (stimulates cell proliferation without producing toxicity) and, in principle, biodegradable due to its protein structure (it does not produce residues).

Researcher Miodrag Grbi?, who heads the international group that has researched this mite silk, highlights “its enormous potential for biomedical applications, as thanks to its size it is able to easily penetrate both healthy and cancerous human cells”, which makes it ideal for transporting drugs in cancer therapies, as well as for the development of biosensors to detect pathogens and viruses.

THE ‘RIOJANO BUG’

Tetranychus lintearius is an endemic mite from the European Atlantic coast that feeds exclusively on gorse (Ulex europaeus). It is around 0.3 mm in size, making it smaller than the comma on a keyboard, while the strength of its silk is twice as high as standard spider silk.

It is a very rare species that has only been found so far in the municipality of Valgañón (La Rioja, Spain), in Sierra de la Demanda. It was located thanks to the collaboration of Rosario García, a botanist and former dean of the Faculty of Science and Technology at the University of La Rioja, which is why researchers call it “the Rioja bug” (“El Bicho Riojano”).

The resistance of the silk produced by Tetranychus lintearius is twice that of spider silk, a standard material used for this type of research, and stronger than steel. It also has advantages over the fibres secreted by the silkworm due to its higher Young’s modulus, its electrical charge and its smaller size. These characteristics, along with its lightness, make it a promising natural nanomaterial for technological uses.

This finding is the result of work carried out by the international group of researchers led by Miodrag Grbi?, who sequenced the genome of the red spider Tetranychus urticae in 2011, publishing the results in Nature: https://www.nature.com/articles/nature10640.

Unlike the red spider (Tetranychus urticae), the gorse mite (Tetranychus lintearius) produces a large amount of silk. It has been reared in the laboratories of the Department of Agriculture and Food of the University of La Rioja, under the care of Professor Ignacio Pérez Moreno, allowing research to continue. Red spider silk is difficult to handle and has a lower production rate.

Here’s a link to and a citation for the 2020 paper,

The silk of gorse spider mite Tetranychus lintearius represents a novel natural source of nanoparticles and biomaterials by Antonio Abel Lozano-Pérez, Ana Pagán, Vladimir Zhurov, Stephen D. Hudson, Jeffrey L. Hutter, Valerio Pruneri, Ignacio Pérez-Moreno, Vojislava Grbic’, José Luis Cenis, Miodrag Grbic’ & Salvador Aznar-Cervantes. Scientific Reports volume 10, Article number: 18471 (2020) DOI: https://doi.org/10.1038/s41598-020-74766-7 Published: 28 October 2020

This paper is open access.

Why is Precision Nanosystems Inc. in the local (Vancouver, Canada) newspaper?

Usually when a company is featured in a news item, there’s some reason why it’s considered newsworthy. Even after reading the article twice, I still don’t see what makes the Precision Nanosystems Inc. (PNI) newsworthy.

Kevin Griffin’s Jan. 17, 2021 article about Vancouver area Precision Nanosystems Inc. (PNI) for The Province is interesting for anyone who’s looking for information about members of the local biotechnology and/or nanomedicine community (Note: Links have been removed),

A Vancouver nanomedicine company is part of a team using new genetic technology to develop a COVID-19 vaccine.

Precision NanoSystems Incorporated is working on a vaccine in the same class the ones made by Pfizer-BioNTech and Moderna, the only two COVID-19 vaccines approved by Health Canada.

PNI’s vaccine is based on a new kind of technology called mRNA which stands for messenger ribonucleic acid. The mRNA class of vaccines carry genetic instructions to make proteins that trigger the body’s immune system. Once a body has antibodies, it can fight off a real infection when it comes in contact with SARS-CoV-2, the name of the virus that causes COVID-19.

James Taylor, CEO of Precision NanoSystems, said the “revolutionary technology is having an impact not only on COVID-19 pandemic but also the treatment of other diseases.

The federal government has invested $18.2 million in PNI to carry its vaccine candidate through pre-clinical studies and clinical trails.

Ottawa has also invested another $173 million in Medicago, a Quebec-city based company which is developing a virus-like particle vaccine on a plant-based platform and building a large-scale vaccine and antibody production facility. The federal government has an agreement with Medicago to buy up to 76 million doses (enough for 38 million people) of its COVID-19 vaccine.

PNI’s vaccine, which the company is developing with other collaborators, is still at an early, pre-clinical stage.

Taylor is one of the co-founders of PNI along with Euan Ramsay, the company’s chief commercial officer.

The scientific co-founders of PNI are physicist Carl Hansen [emphasis mine] and Pieter Cullis. Cullis is also board chairman and scientific adviser at Acuitas Therapeutics [emphasis mine], the UBC biotechnology company that developed the delivery system for the Pfizer-BioNTech COVID-19 vaccine.

PNI, founded in 2010 as a spin-off from UBC [University of British Columbia], focuses on developing technology and expertise in genetic medicine to treat a wide range of infectious and rare diseases and cancers.

What has been described as PNI’s flagship product is a NanoAssemblr Benchtop Instrument, which allows scientists to develop nanomedicines for testing.

It’s informational but none of this is new, if you’ve been following developments in the COVID-19 vaccine story or local biotechnology scene. The $18.2 million federal government investment was announced in the company’s latest press release dated October 23, 2020. Not exactly fresh news.

One possibility is that the company is trying to generate publicity prior to a big announcement. As to why a reporter would produce this profile, perhaps he was promised an exclusive?

Acuitas Therapeutics, which I highlighted in the excerpt from Griffin’s story, has been featured here before in a November 12, 2020 posting about lipid nanoparticles and their role in the development of the Pfizer-BioNTech COVID-19 vaccine.

Curiously (or not), Griffin didn’t mention Vancouver’s biggest ‘COVID-19 star’, AbCellera. You can find out more about that company in my December 30, 2020 posting titled, Avo Media, Science Telephone, and a Canadian COVID-19 billionaire scientist, which features a link to a video about AbCellera’s work (scroll down about 60% of the way to the subsection titled: Avo Media, The Tyee, and Science Telephone, second paragraph).

The Canadian COVID-19 billionaire scientist? That would be Carl Hansen, Chief Executive Officer and co-founder of AbCellera and co-founder of PNI. it’s such a small world sometimes.