Category Archives: science

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?.

A quantum phenomenon (Kondo effect) and nanomaterials

This is a little outside my comfort zone but here goes anyway. From a December 23, 2020 news item on phys.org (Note: Links have been removed),

Osaka City University scientists have developed mathematical formulas to describe the current and fluctuations of strongly correlated electrons in quantum dots. Their theoretical predictions could soon be tested experimentally.

Theoretical physicists Yoshimichi Teratani and Akira Oguri of Osaka City University, and Rui Sakano of the University of Tokyo have developed mathematical formulas that describe a physical phenomenon happening within quantum dots and other nanosized materials. The formulas, published in the journal Physical Review Letters, could be applied to further theoretical research about the physics of quantum dots, ultra-cold atomic gasses, and quarks.

At issue is the Kondo effect. This effect was first described in 1964 by Japanese theoretical physicist Jun Kondo in some magnetic materials, but now appears to happen in many other systems, including quantum dots and other nanoscale materials.

A December 23, 2020 Osaka City University press release (also on EurekAlert), which originated the news item, provides more detail,

Normally, electrical resistance drops in metals as the temperature drops. But in metals containing magnetic impurities, this only happens down to a critical temperature, beyond which resistance rises with dropping temperatures.

Scientists were eventually able to show that, at very low temperatures near absolute zero, electron spins become entangled with the magnetic impurities, forming a cloud that screens their magnetism. The cloud’s shape changes with further temperature drops, leading to a rise in resistance. This same effect happens when other external ‘perturbations’, such as a voltage or magnetic field, are applied to the metal. 

Teratani, Sakano and Oguri wanted to develop mathematical formulas to describe the evolution of this cloud in quantum dots and other nanoscale materials, which is not an easy task. 

To describe such a complex quantum system, they started with a system at absolute zero where a well-established theoretical model, namely Fermi liquid theory, for interacting electrons is applicable. They then added a ‘correction’ that describes another aspect of the system against external perturbations. Using this technique, they wrote formulas describing electrical current and its fluctuation through quantum dots. 

Their formulas indicate electrons interact within these systems in two different ways that contribute to the Kondo effect. First, two electrons collide with each other, forming well-defined quasiparticles that propagate within the Kondo cloud. More significantly, an interaction called a three-body contribution occurs. This is when two electrons combine in the presence of a third electron, causing an energy shift of quasiparticles. 

“The formulas’ predictions could soon be investigated experimentally”, Oguri says. “Studies along the lines of this research have only just begun,” he adds. 

The formulas could also be extended to understand other quantum phenomena, such as quantum particle movement through quantum dots connected to superconductors. Quantum dots could be a key for realizing quantum information technologies, such as quantum computers and quantum communication.

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

Fermi Liquid Theory for Nonlinear Transport through a Multilevel Anderson Impurity by Yoshimichi Teratani, Rui Sakano, and Akira Oguri. Phys. Rev. Lett. 125, 216801 (Issue Vol. 125, Iss. 21 — 20 November 2020) DOI: https://doi.org/10.1103/PhysRevLett.125.216801 Published Online: 17 November 2020

This paper is behind a paywall.

A better quality of cultivated meat from McMaster University?

This could be a bit stomach-churning for some folks.

Researchers at Canada’s McMaster University have developed and are commercializing a technique for cultivated meat (the first experiment involved mouse meat). (You could call it vat-grown meat.) A January 19, 2021 news item on phys.org makes the announcement (Note: Links have been removed),

McMaster researchers have developed a new form of cultivated meat using a method that promises more natural flavor and texture than other alternatives to traditional meat from animals.

Researchers Ravi Selvaganapathy and Alireza Shahin-Shamsabadi, both of the university’s School of Biomedical Engineering, have devised a way to make meat by stacking thin sheets of cultivated muscle and fat cells grown together in a lab setting. The technique is adapted from a method used to grow tissue for human transplants.

A January 19, 2021 McMaster University news release (also on EurekAlert) by Wade Hemsworth, which originated the news item, offers more details,

The sheets of living cells, each about the thickness of a sheet of printer paper, are first grown in culture and then concentrated on growth plates before being peeled off and stacked or folded together. The sheets naturally bond to one another before the cells die.

The layers can be stacked into a solid piece of any thickness, Selvaganapathy says, and “tuned” to replicate the fat content and marbling of any cut of meat – an advantage over other alternatives.

“We are creating slabs of meat,” he says. “Consumers will be able to buy meat with whatever percentage of fat they like – just like they do with milk.”

As they describe in the journal Cells Tissues Organs, the researchers proved the concept by making meat from available lines of mouse cells. Though they did not eat the mouse meat described in the research paper, they later made and cooked a sample of meat they created from rabbit cells.

“It felt and tasted just like meat,” says Selvaganapathy.

There is no reason to think the same technology would not work for growing beef, pork or chicken, and the model would lend itself well to large-scale production, Selvaganapathy says.

The researchers were inspired by the meat-supply crisis in which worldwide demand is growing while current meat consumption is straining land and water resources and generating troubling levels of greenhouse gases.

“Meat production right now is not sustainable,” Selvaganapathy says. “There has to be an alternative way of creating meat.”

Producing viable meat without raising and harvesting animals would be far more sustainable, more sanitary and far less wasteful, the researchers point out. While other forms of cultured meat have previously been developed, the McMaster researchers believe theirs has the best potential for creating products consumers will accept, enjoy and afford.

The researchers have formed a start-up company to begin commercializing the technology.

The researchers have included a picture of the ‘meat’,

Caption: A sample of meat cultivated by researchers at Canada’s McMaster University, using cells from mice. Credit: McMaster University

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

Engineering Murine Adipocytes and Skeletal Muscle Cells in Meat-like Constructs Using Self-Assembled Layer-by-Layer Biofabrication: A Platform for Development of Cultivated Meat by Alireza Shahin-Shamsabadi and P. R. (Ravi) Selvaganapathy. Cells Tissues Organs (2021). DOI: 10.1159/000511764

This paper is behind a paywall.

1st biohybrid artificial retina built with silk fibroin & retinal cells

A December 12, 2020 news item on Nanowerk announces a step forward in the development of artificial retinas,

“The biohybrid retina is a cell therapy for the reconstruction of the damaged retina by implanting healthy cells in the patient’s eye,” says Fivos Panetsos, director of the Neuro-computation and Neuro-robotics Group of the UCM and member of the Institute of Health Research of the Hospital Clínico San Carlos de Madrid (IdISSC).

A December 11, 2020 Universidad Complutense de Madrid (UCM) press release on EurekAlert, which originated the news item, delves further,

The cells of the artificial retina adhere to very thin silk fibroin biofilms – a biomaterial 100% biocompatible with human tissue – and covered by a gel which protects them during eye surgery and allows them to survive during the time they need to get integrated with the surrounding tissue after transplantation.

“The transplanted retina also contains mesenchymal cells that function as producers of neuroprotective and neuroreparative molecules and facilitate functional integration between implanted and patient cells”, adds UCM’s researcher and director of the study, published in the Journal of Neural Engineering .

One more step in a problem with more than 196 million affected

To build this artificial retina, researchers have developed silk fibroin films with mechanical characteristics similar to Bruch’s membrane – the layer of cells that supports the neural retina. Then, they have biofunctionalized them so that retinal cells could adhere, and on them they have grown epithelial and neural cells. Finally, they have carried out an in vitro study of the structural and functional characteristics of the biohybrid.

Age-Related Macular Degeneration (AMD) is a neurodegenerative disease that causes a progressive loss of central vision and even blindness in its most advanced stage. Triggered by heterogeneous, complex and still poorly understood mechanisms, it is the leading cause of irreversible vision loss in people over 65 years of age and affects more than 196 million people worldwide.

AMD is an incurable disease, and current treatments can only alleviate symptoms and slow down the progression of the disease. “This research is an important step towards solving the problem of blindness faced by AMD patients”, concludes Panetsos.

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

First steps for the development of silk fibroin-based 3D biohybrid retina for age-related macular degeneration (AMD) by Nahla Jemni-Damer, Atocha Guedan-Duran, Jasmin Cichy, Paloma Lozano-Picazo, Daniel Gonzalez-Nieto, José Perez-Rigueiro, Francisco Rojo, Gustavo V. Guinea, Assunta Virtuoso, Giovanni Cirillo, Michele Papa, Félix Armada-Maresca, Carlota Largo-Aramburu, Salvador D Aznar-Cervantes, José L Cenis, and Fivos Panetsos.Journal of Neural Engineering, Volume 17, Number 5 (or 2020 Neural Eng. 17 055003) DOI: doi: 10.1088/1741-2552/abb9c0 Published 28 October 2020 • © 2020 IOP Publishing Ltd

This paper is behind a paywall.

Digital aromas? And a potpourri of ‘scents and sensibility’

Mmm… smelly books. Illustration by Dorothy Woodend.[downloaded from https://thetyee.ca/Culture/2020/11/19/Smell-More-Important-Than-Ever/]

I don’t get to post about scent as often as I would like, although I have some pretty interesting items here, those links to follow towards of this post).

Digital aromas

This Nov. 11, 2020 Weizmann Institute of Science press release (also on EurekAlert published on Nov. 19, 2020) from Israel gladdened me,

Fragrances – promising mystery, intrigue and forbidden thrills – are blended by master perfumers, their recipes kept secret. In a new study on the sense of smell, Weizmann Institute of Science researchers have managed to strip much of the mystery from even complex blends of odorants, not by uncovering their secret ingredients, but by recording and mapping how they are perceived. The scientists can now predict how any complex odorant will smell from its molecular structure alone. This study may not only revolutionize the closed world of perfumery, but eventually lead to the ability to digitize and reproduce smells on command. The proposed framework for odors, created by neurobiologists, computer scientists, and a master-perfumer, and funded by a European initiative [NanoSmell] for Future Emerging Technologies (FET-OPEN), was published in Nature.

“The challenge of plotting smells in an organized and logical manner was first proposed by Alexander Graham Bell [emphasis mine] over 100 years ago,” says Prof. Noam Sobel of the Institute’s Neurobiology Department. Bell threw down the gauntlet: “We have very many different kinds of smells, all the way from the odor of violets [emphasis mine] and roses up to asafoetida. But until you can measure their likenesses and differences you can have no science of odor.” This challenge had remained unresolved until now.

This century-old challenge indeed highlighted the difficulty in fitting odors into a logical system: There are millions of odor receptors in our noses, consisting hundreds of different subtypes, each shaped to detect particular molecular features. Our brains potentially perceive millions of smells in which these single molecules are mixed and blended at varying intensities. Thus, mapping this information has been a challenge. But Sobel and his colleagues, led by graduate student Aharon Ravia and Dr. Kobi Snitz, found there is an underlying order to odors. They reached this conclusion by adopting Bell’s concept – namely to describe not the smells themselves, but rather the relationships between smells as they are perceived.

In a series of experiments, the team presented volunteer participants with pairs of smells and asked them to rate these smells on how similar the two seemed to one another, ranking the pairs on a similarity scale ranging from “identical” to “extremely different.” In the initial experiment, the team created 14 aromatic blends, each made of about 10 molecular components, and presented them two at a time to nearly 200 volunteers, so that by the end of the experiment each volunteer had evaluated 95 pairs.

To translate the resulting database of thousands of reported perceptual similarity ratings into a useful layout, the team refined a physicochemical measure they had previously developed. In this calculation, each odorant is represented by a single vector that combines 21 physical measures (polarity, molecular weight, etc.). To compare two odorants, each represented by a vector, the angle between the vectors is taken to reflect the perceptual similarity between them. A pair of odorants with a low angle distance between them are predicted similar, those with high angle distance between them are predicted different.

To test this model, the team first applied it to data collected by others, primarily a large study in odor discrimination by Bushdid [C. Bushdid] and colleagues from the lab of Prof. Leslie Vosshall at the Rockefeller Institute in New York. The Weizmann team found that their model and measurements accurately predicted the Bushdid results: Odorants with low angle distance between them were hard to discriminate; odors with high angle distance between them were easy to discriminate. Encouraged by the model accurately predicting data collected by others, the team continued to test for themselves.

The team concocted new scents and invited a fresh group of volunteers to smell them, again using their method to predict how this set of participants would rate the pairs – at first 14 new blends and then, in the next experiment, 100 blends. The model performed exceptionally well. In fact, the results were in the same ballpark as those for color perception – sensory information that is grounded in well-defined parameters. This was especially surprising considering each individual likely has a unique complement of smell receptor subtypes, which can vary by as much as 30% across individuals.

Because the “smell map,” [emphasis mine] or “metric” predicts the similarity of any two odorants, it can also be used to predict how an odorant will ultimately smell. For example, any novel odorant that is within 0.05 radians or less from banana will smell exactly like banana. As the novel odorant gains distance from banana, it will smell banana-ish, and beyond a certain distance, it will stop resembling banana.

The team is now developing a web-based tool. This set of tools not only predicts how a novel odorant will smell, but can also synthesize odorants by design. For example, one can take any perfume with a known set of ingredients, and using the map and metric, generate a new perfume with no components in common with the original perfume, but with exactly the same smell. Such creations in color vision, namely non-overlapping spectral compositions that generate the same perceived color, are called color metamers, and here the team generated olfactory metamers.

The study’s findings are a significant step toward realizing a vision of Prof. David Harel of the Computer and Applied Mathematics Department, who also serves as Vice President of the Israel Academy of Sciences and Humanities and who was a co-author of the study: Enabling computers to digitize and reproduce smells. In addition, of course, to being able to add realistic flower or sea aromas to your vacation pictures on social media, giving computers the ability to interpret odors in the way that humans do could have an impact on environmental monitoring and the biomedical and food industries, to name a few. Still, master perfumer Christophe Laudamiel, who is also a co-author of the study, remarks that he is not concerned for his profession just yet.

Sobel concludes: “100 years ago, Alexander Graham Bell posed a challenge. We have now answered it: The distance between rose and violet is 0.202 radians (they are remotely similar), the distance between violet and asafoetida is 0.5 radians (they are very different), and the difference between rose and asafoetida is 0.565 radians (they are even more different). We have converted odor percepts into numbers, and this should indeed advance the science of odor.”

I emphasized Alexander Graham Bell and the ‘smell map’ because I thought they were interesting and violets because they will be mentioned again later in this post.

Meanwhile, here’s a link to and a citation for the paper (the proposed framework for odors),

A measure of smell enables the creation of olfactory metamers by Aharon Ravia, Kobi Snitz, Danielle Honigstein, Maya Finkel, Rotem Zirler, Ofer Perl, Lavi Secundo, Christophe Laudamiel, David Harel & Noam Sobel. Nature volume 588, pages 118–123 (2020) DOI: https://doi.org/10.1038/s41586-020-2891-7 Published online: 11 November 2020 Journal Issue Date: 03 December 2020

This paper is behind a paywall.

Smelling like an old book

Some folks are missing the smell of bookstores and according to Dorothy Woodend’s Nov. 19, 2020 article for The Tyee, that longing has resulted in a perfume (Note: Links have been removed),

The news that Powell’s Books, Portland’s (Oregon, US) beloved bookstore, had released a signature scent was greeted with bemusement by some, confusion by others. But to me it made perfect scents. (Err, sense.) If you love something, I mean really love it, you love the way it smells.

Old books have a distinctive peppery aroma that draws bibliophiles like bears to honey. Some people are very specific about their book smells, preferring vintage Penguin paperbacks from the mid to late 1960s. Those orange spines aged like fine wine.

Powell’s created the scent after people complained about missing the smell of the store during lockdown. It got me thinking about how identity is often bound up with smell and, more widely, how smells belong to cultural, even historic moments.

Olfactory obsolescence can have weird side effects … . Memories of one’s grandfather smelling like pipe tobacco are pretty much now only a literary conceit. But pipe smoke isn’t the only dinosaur smell that is going extinct. Even in my lifetime, I remember the particular aroma of baseball cards and chalk dust.

Remember violets? Here’s more about Powell’s Unisex Fragrance (from Powell’s purchase webpage),

Notes:
• Wood
• Violet
• Biblichor

Description:
Like the crimson rhododendrons in Rebecca, the heady fragrance of old paper creates an atmosphere ripe with mood and possibility. Invoking a labyrinth of books; secret libraries; ancient scrolls; and cognac swilled by philosopher-kings, Powell’s by Powell’s delivers the wearer to a place of wonder, discovery, and magic heretofore only known in literature.

How to wear:
This scent contains the lives of countless heroes and heroines. Apply to the pulse points when seeking sensory succor or a brush with immortality.

Details:
• 1 ounce
• Glass bottle
• Limited-edition item available while supplies last

Shipping details:
Powell’s Unisex Fragrance ships separately and only in the contiguous United States [emphasis mine]. Special shipping rates apply.

Links: oPhone and heritage smells

Some years I was quite intrigued by the oPhone (scent by telephone) and wrote these: For the smell of it, a Feb. 14, 2014 posting, and Smelling Paris in New York (update on the oPhone), a June 18, 2014 posting. I haven’t found any updates about oPhone in my brief searches on the web.

There was a previous NANOSMELL (sigh, these projects have various approaches to capitalization) posting: Scented video games: a nanotechnology project in Europe published here in a May 27, 2016 posting.

More recently on the smell front, there was this May 22, 2017 posting, Preserving heritage smells (scents). FYI, the authors of the 2017 paper are part of the Odeuropa project described in the next subsection.

Context: NanoSmell and Odeuropa

Science funding is intimately linked to science policy. Examination of science funding can be useful for understanding some of the contrasts between how science is conducted in different jurisdictions, e.g., Europe and Canada.

Before launching into the two ‘scent’ projects, NanoSmell and Odeuropa, I’m offering a brief description of one of the European Union’s (EU) most comprehensive and substantive (many, many Euros) science funding initiatives.The latest iteration of this initiative has funded and is funding both NanoSmell and Odeuropa.

Horizon Europe

The initiative has gone under different names: Framework Programmes 1-7, then in 2014, it was called Horizon 2020 with its end date part of its name. The latest initiative, Horizon Europe is destined to start in 2021 and end in 2027.

The most recent Horizon Europe budget information I’ve been able to find is in this Nov. 10, 2020 article by Éanna Kelly and Goda Naujokaitytė for ScienceBusiness.net,

EU governments and the European Parliament on Tuesday [Nov. 10, 2020] afternoon announced an extra €4 billion will be added to the EU’s 2021-2027 research budget, following one-and-a-half days of intense negotiations in Brussels.

The deal, which still requires a final nod from parliament and member states, puts Brussels closer to implementing its gigantic €1.8 trillion budget and COVID-19 recovery package. [emphasis mine]

In all, a series of EU programmes gained an additional €15 billion. Among them, the student exchange programme Erasmus+ went up by €2.2 billion, health spending in EU4Health by €3.4 billion, and the InvestEU programme got an additional €1 billion.

Parliamentarians have been fighting to reverse cuts [emphasis mine] made to science and other investment programmes since July [2020], when EU leaders settled on €80.9 billion (at 2018 prices) for Horizon Europe, significantly less than €94.4 billion proposed by the European Commission.

“I am really proud that we fought – all six of us as a team,” said van Overtveldt [Johan Van Overtveldt, Belgian MEP {member of European Parliament} on the budget committee], pointing to the other budget MEPs who headed talks with the German Presidency of the Council. “You can take the term ‘fight’ literally. We had to fight for what we got.”

“We are all very proud of what we achieved, not for the parliament’s pride but in the interest of European citizens short-term and long-term,” van Overveldt said.

One of the most visible campaigners for science in the Parliament, MEP Christian Ehler, spokesman on Horizon Europe for the European Peoples’ Party, called the deal “a victory for researchers, scientists and citizens alike.” [emphasis mine]

The challenge now for negotiators will be to figure out how to divide extra funds [emphasis mine] within Horizon Europe fairly, with officials attached to public-private partnerships, the European Research Council, the new research missions, and the European Innovation Council all baying for more cash.

To sum up, in July 2020, legislators settled on the figure of €80.9 billion for science funding over the seven year period of 2021 – 2027 to administered by Horizon Europe. After fighting €4 billion was added for a total of €84.9 billion in research funding over the next seven years.

This is fascinating to me; I don’t recall ever seeing any mention of Canadian legislators arguing over how much money should be allocated to research in articles about the Canadian budget. The usual approach is treat the announcement as a fait accompli and a matter for celebration or intense criticism.

Smell of money?

All this talk of budgets and heritage smells has me thinking about the ‘smell of money’. What happens as money or currency becomes virtual rather than actual? And, what happened to the smell of Canadian money which is now made of plastic?

I haven’t found any answers to those questions but I did find an interesting June 14, 2012 article by Sarah Gardner for Marketplace.org titled, Sniffing out what money smells like. The focus is on money made of cotton and linen. One other note, this is not the Canadian Broadcasting Corporation’s Marketplace television programme. This is a US programme from American Public Media (from the Markeplace.org FAQs webpage).

Now onto the funding for European smell research.

NanoSmell

The Israeli researchers’ work was funded by Horizon 2020’s NanoSmell project which ran from Sept. 1, 2015 – August 31, 2019 and this was their objective (from the CORDIS NanoSmell project page),

“Despite years of promise, an odor-emitting component in devices such as televisions, phones, computers and more has yet to be developed. Two major obstacles in the way of such development are poor understanding of the olfactory code (the link between odorant structure, neural activity, and odor perception), and technical inability to emit odors in a reversible manner. Here we propose a novel multidisciplinary path to solving this basic scientific question (the code), and in doing so generate a solution to the technical limitation (controlled odor emission). The Bachelet lab will design DNA strands that assume a 3D structure that will specifically bind to a single type of olfactory receptor and induce signal transduction. These DNA-based “”artificial odorants”” will be tagged with a nanoparticle that changes their conformation in response to an external electromagnetic field. Thus, we will have in hand an artificial odorant that is remotely switchable. The Hansson lab will use tissue culture cells expressing insect olfactory receptors, functional imaging, and behavioral tests to validate the function and selectivity of these switchable odorants in insects. The Carleton lab will use imaging in order to investigate the patterns of neural activity induced by these artificial odorants in rodents. The Sobel lab will apply these artificial odorants to the human olfactory system, [emphasis mine] and measure perception and neural activity following switching the artificial smell on and off. Finally, given a potential role for olfactory receptors in skin, the Del Rio lab will test the efficacy of these artificial odorants in promoting wound healing. At the basic science level, this approach may allow solving the combinatorial code of olfaction. At the technology level, beyond novel pharmacology, we will provide proof-of-concept for countless novel applications ranging from insect pest-control to odor-controlled environments and odor-emitting devices such as televisions, phones, and computers.” [emphasis mine]

Unfortunately, I can’t find anything on the NanoSmell Project Results page with links to any proof-of-concept publications or pilot projects for the applications mentioned. Mind you, I wouldn’t have recognized the Israeli team’s A measure of smell enables the creation of olfactory metamers as a ‘smell map’.

Odeuropa

Remember the ‘heritage smells’ 2017 posting? The research paper listed there has two authors, both of whom form one of the groups (University College London; scroll down) associated with Odeuropa’s Horizon 2020 project announced in a Nov. 17, 2020 posting by the project lead, Inger Leemans on the Odeuropa website (Note: A link has been removed),

The Odeuropa consortium is very proud to announce that it has been awarded a €2.8M grant from the EU Horizon 2020 programme for the project, “ODEUROPA: Negotiating Olfactory and Sensory Experiences in Cultural Heritage Practice and Research”.Smell is an urgent topic which is fast gaining attention in different communities. Amongst the questions the Odeuropa project will focus on are: what are the key scents, fragrant spaces, and olfactory practices that have shaped our cultures? How can we extract sensory data from large-scale digital text and image collections? How can we represent smell in all its facets in a database? How should we safeguard our olfactory heritage? And — why should we? …

The project bundles an array of academic expertise from across many disciplines—history, art history, computational linguistics, computer vision, semantic web, museology, heritage science, and chemistry, with further expertise from cultural heritage institutes, intangible heritage organisations, policy makers, and the creative and fragrance industries.

I’m glad to see this interest in scent, heritage, communication, and more. Perhaps one day we’ll see similar interest here in Canada. Subtle does not mean unimportant, eh?

Gene therapy in Canada; a November 2020 report and two events in December 2020

There’s a lot of action, albeit quiet and understated, in the Canadian gene therapy ‘discussion’. One major boost to the discussion was the Nov. 3, 2020 release of a report by the Canadian Council of Academies (CCA), “From Research to Reality; The Expert Panel on the Approval and Use of Somatic Gene Therapies in Canada.”

Dec. 2 – 3, 2020 Breaking Through

Another boost is the the free and virtual, upcoming 2020 Gairdner Ontario International Symposium “Breaking Through: Delivering on the Promise of Gene Therapy“; an international symposium on gene therapy research and practice, which will feature a presentation on the CCA’s report,

Breaking Through brings together Canadian and international leaders to explore the past, present, and future of somatic gene therapy research and practice. This two-day virtual event will examine the successes, challenges and opportunities from the bench to the bedside. It will also feature:

  • Speaker sessions from Canadian and international researchers at the forefront of gene therapy research.
  • A panel discussion exploring the opportunities and challenges facing Canadian scientists, regulators, clinicians, decision-makers, and patients (Presented by NRC).
  • A presentation and Expert Panel discussion on the Council of Canadian Academies’ latest report, From Research to Reality, and a closing panel discussion about the future of gene therapies and gene editing (Presented by Genome Canada).

The title for the CCA report bears an uncanny resemblance to the name for a Canadian initiative highlighting science research, Research2Reality (R2R). (If you’re curious, you can check out my past postings on R2R by using ‘Research2Reality’ as the term for the blog’s search engine.

Glybera

This name stood out: Michael Hayden (scroll down to his name and click), one of the featured speakers for this Dec. 2 – 3, 2020 event, reminded me of the disturbing Glybera story,

Dr. Hayden identified the first mutations underlying lipoprotein lipase (LPL) deficiency and developed gene therapy approaches to treat this condition, the first approved gene therapy (Glybera) in the western world.

Kelly Crowe’s Nov. 17, 2018 story for the Canadian Broadcasting Corporation (CBC) lays it out,

It is one of this country’s great scientific achievements.

The first drug ever approved that can fix a faulty gene.

It’s called Glybera, and it can treat a painful and potentially deadly genetic disorder with a single dose — a genuine made-in-Canada medical breakthrough.

But most Canadians have never heard of it.

A team of researchers at the University of British Columbia spent decades developing the treatment for people born with a genetic mutation that causes lipoprotein lipase defficiency (LPLD).

If you have the time, do read Crowe’s Nov. 17, 2018 story but as I warned in another post, it’s heartbreaking.

Fora brief summary, the company which eventually emerged with the licensing rights to Glybera, charged $1m per dose and a single dose is good for 10 years. It seems governments are reluctant to approve the cost and for many individuals, it’s an impossible price to meet, every 10 years. So, the drug is dead. Or perhaps not? Take a look at the symposium’s agenda (scroll down) for description,

GLYBERA REINVENTED: A WINDING STORY OF COMMITMENT, CREATIVITY, AND INNOVATION

Michael Hayden, MB, ChB, PhD, FRCP(C), FRSC, C.M., O.B.C University Killam Professor, Senior Scientist, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics,

University of British Columbia (Vancouver, BC)

Money issues

One theme from the agenda jumped out at me: money. The focus seems to be largely on accessibility and costs. The Nov. 3, 2020 CCA news release (also on EurekAlert) about the report also prominently featured costs,

Gene therapies are being approved for use in Canada, but could strain healthcare budgets and exacerbate existing treatment inequities [emphasis mine] across the country. However, there are opportunities to control spending, streamline approvals and support fair access through innovation, coordination and collaboration, according to a new expert panel report from the Council of Canadian Academies (CCA).

“Rapid scientific advances mean potentially life-changing treatments are approaching the clinic at an accelerated pace,” said Janet Rossant, PhD, C.C., FRSC, and Chair of the Expert Panel. “These new therapies, however, pose a number of challenges in terms of their introduction into the Canadian healthcare system and ensuring access to those who would most benefit.”

Gene therapies and gene editing

Before moving on, you might find it useful to know (if you don’t already) that gene therapy can be roughly divided into somatic cell gene therapy and germline gene therapy as per the Gene Therapy entry in Wikipedia.

Two other items on the symposium’s agenda (scroll down) drew my attention,

Genome editing and the promise for future therapies

Ronald Cohn, MD, FACMG, FCAHS President and CEO,
The Hospital for Sick Children (SickKids) (Toronto, ON)

COMING SOON: THE FUTURE OF GENE EDITING AND GENE THERAPIES

Presented by: Genome Canada

Rob Annan, PhD President and CEO,
Genome Canada (Ottawa, ON)

R. Alta Charo, J.D. Warren P. Knowles Professor of Law & Bioethics,
University of Wisconsin Law School (Madison, USA)

Jay Ingram, C.M. Science broadcaster and writer, Former Co-Host, Discovery Channel’s “Daily Planet” (Calgary, AB)

Vardit Ravitsky, PhD, FCAHS Full Professor, Bioethics Program, Department of Social and Preventative Medicine, School of Public Health, Université de Montréal; President, International Association of Bioethics (Montréal, QC)

Janet Rossant, PhD, C.C., FRSC President,
Gairdner Foundation (Toronto, ON) [also a member of the CCA expert panel for report on somatic cell therapies ‘From research to reality …’)

Genome editing, by the way and if you don’t know, is also known as gene editing. The presence of the word ‘future’ in both the presentations has my antennae quivering. Could they be hinting at germline editing possibilities? At this time, the research is illegal in Canada.

If you don’t happen to know, somatic gene editing, covered in the CCA report, does not affect future generations as opposed to germline gene editing, which does. Should you be curious about the germline gene editing discussion in Canada, I covered as much information as I could uncover in an April 26, 2019 posting on topic.

Jay Ingram’s presence on the panel sponsored by Genome Canada is a bit of a surprise.

I saw him years ago as the moderator for a panel presentation sponsored by Genome British Columbia. The discussion was about genetics and ethics, which was illustrated by clips from the television programme, ReGenesis (from its IMDB entry),

[Fictional] Geneticist David Sandstrom is the chief scientist at the prestigious virology/micro-biology NORBAC laboratory, a joint enterprise between the USA, Canada and Mexico for countering bio-terrorism.

Ingram (BA in microbiology and an MA that’s not identified in his Wikipedia entry) was a television science presenter for a number of years and has continued to work in the field of science communication. He didn’t seem all that knowledgeable about genetics when he moderated the ReGenesis panel but perhaps his focus will be about the communication element?

For anyone interested in attending the free and virtual “Breaking Through” event, you can register here.

CAR-T cell therapies (a type of somatic cell therapy)

One final note, the first week of December seems to be gene therapy week in Canada. There is another free and virtual event, the second session of the Summit for Cancer Immunotherapy: 2020 Speaker Series (Hosted by BioCanRx, Canada’s Immunotherapy Network), Note: I made a few changes to make this excerpt a bit easier to read,

Session Two: Developing better CAR T-Cell Therapies by engaging patients, performing systematic reviews and assessing real-world and economic evidence
Wednesday, December 9, 1:30 pm – 3:15pm EST [emphasis mine]

Chimeric Antigen Receptor T-cell (CAR-T) therapy is a personalized immunotherapy, currently being assessed in a Canadian Phase I/II clinical trial to test safety and feasibility for relapsed/refractory blood cancer (CD19+ Acute Lymphoblastic Leukemia and non-Hodgkin’s Lymphoma).

This virtual seminar will provide an overview of a multidisciplinary team’s collaborative efforts to synthesize evidence for the development of this clinical trial protocol, using a novel approach (the ‘Excelerator’ model). This approach involved the completion of a systematic review (objective review of existing trial data), engagement of patients and clinicians, and drawing from real world and economic evidence.

Dr. Fergusson will provide a brief introduction. Dr. Kednapa Thavorn will discuss the team’s use of economic modelling to select trial factors to maximize economic feasibility of the therapy, and Mackenzie Wilson (HQP) will discuss the current efforts and future directions to engage diverse stakeholders to inform this work. Gisell Castillo (HQP) will speak about the interviews that were conducted with patients and hematologists to identify potential barriers and enablers to participation and recruitment to the trial.

The team will also discuss two ongoing projects which build on this work. Dr. Lalu will provide an overview on the team’s patient engagement program throughout development of the trial protocol and plans to expand this program to other immunotherapy trials. Joshua Montroy (HQP) will also discuss ongoing work building on the initial systematic review, to use individual participant data meta-analysis to identify factors that may impact the efficacy of CAR-T cell therapy.

Dr. Justin Presseau will moderate the question and answer period.

And there’s this,

Who should attend?

Scientific and health care community including researchers, clinicians and HQP along with patients and caregivers. Note: There will be a plain language overview before the session begins and an opportunity to ask questions after the discussion.

If you want to know more about CAR T-cell therapy, sometimes called gene or cell therapy or immune effect cell therapy, prior to the Dec., 9, 2020 event, this page on the cancer.org website should prove helpful.

Congratulations to Molly Shoichet (her hydrogels are used in regenerative medicine and more) for winning the $1 million Gerhard Herzberg Canada Gold Medal

I imagine that most anyone who’s been in contact with Ms. Shoichet is experiencing a thrill on hearing this morning’s (November 10, 2020) news about winning Canada’s highest honour for science and engineering research. (Confession: she, very kindly, once gave me a brief interview for a posting on this blog, more about that later).

Why Molly Shoichet won the Gerhard Herzberg Canada Gold Medal

Emily Chung’s Nov. 10, 2020 news item on the Canadian Broadcasting Corporation (CBC) website announces the exciting news (Note: Links have been removed),

A Toronto chemical engineering professor has won the $1 million Gerhard Herzberg Canada Gold Medal, the country’s top science prize, for her work designing gels that mimic human tissues.

The Natural Sciences and Engineering Research Council of Canada (NSERC) announced Tuesday [Nov. 10, 2020] that Molly Shoichet, professor of chemical engineering and applied chemistry and Canada Research Chair in Tissue Engineering at the University of Toronto is this year’s recipient of the award, which recognizes “sustained excellence” and “overall influence” of research conducted in Canada in the natural sciences or engineering.

Shoichet’s hydrogels are used for drug development and  delivery and regenerative medicine to heal injuries and treat diseases.

NSERC said Shoichet’s work has led to the development of several “game-changing” applications of such materials. They “delivered a crucial breakthrough” by allowing cells to be grown in three dimensions as they do in the body, rather than the two dimensions they typically do in a petri dish.

Hydrogels are polymer materials — materials such as plastics, made of repeating units — that become swollen with water.

“If you’ve ever eaten Jell-o, that’s a hydrogel,” Shoichet said. Slime and the absorbent material inside disposable diapers are also hydrogels.

Shoichet was born in Toronto, and studied science and engineering at the Massachusetts Institute of Technology and the University of Massachusetts Amherst. After graduating, she worked in the biotech industry alongside “brilliant biologists,” she said. She noticed that the biologists’ research was limited by what types of materials were available.

As an engineer, she realized she could help by custom designing materials for biologists. She could make materials specifically suit their needs, to answer their specific questions by designing hydrogels to mimic particular tissues.

Her collaborations with biologists have also generated three spinoff companies, including AmacaThera, which was recently approved to run human trials of a long-acting anesthetic delivered with an injectable hydrogel to deal with post-surgical pain.

Shoichet noted that drugs given to deal with that kind of pain lead to a quarter of opioid addictions, which have been a deadly problem in Canada and around the world.

“What we’re really excited about is not only meeting that critical need of providing people with greater pain relief for a sustained period of time, but also possibly putting a dent in the operation,” she said. 

Liz Do’s Nov. 10, 2020 University of Toronto news release provides more details (Note: Links have been removed),

The  Herzberg Gold Medal is awarded by the Natural Sciences and Engineering Research Council (NSERC) in recognition of research contributions characterized by both excellence and influence.

“I was completely overwhelmed when I was told the good news,” says Shoichet. “There are so many exceptional people who’ve won this award and I admire them. To think of my peers putting me in that same category is really incredible.”

A pioneer in regenerative medicine, tissue engineering and drug delivery, Shoichet and her team are internationally known for their discovery and innovative use of 3D hydrogels.

“One of the challenges facing drug screening is that many of the drugs discovered work well in the lab, but not in people, and a possible explanation for this discrepancy is that these drugs are discovered in environments that do not reflect that of the body,” explains Shoichet.

Shoichet’s team has invented a series of biomaterials that provide a soft, three-dimensional environment in which to grow cells. These hydrogels — water-swollen materials — better mimic human tissue than hard two-dimensional plastic dishes that are typically used. “Now we can do more predictive drug screening,” says Shoichet.

Her lab is using these biomaterials to discover drugs for breast and brain cancer and a rare lung disease. Shoichet’s lab has been equally innovative in regenerative medicine strategies to promote repair of the brain after stroke and overcome blindness.

“Everything that we do is motivated by answering a question in biology, using our engineering and chemistry tools to answer those questions,” says Shoichet.

“The hope is that our contributions will ultimately make a positive impact in the cancer community and in treating diseases for which we can only slow the progression rather than stop and reverse, such as with blindness.”

Shoichet is also an advocate for and advisor on the fields of science and engineering. She has advised both federal and provincial governments through her service on Canada’s Science, Technology and Innovation Council and the Ontario Research Innovation Council. From 2014 to 2018, she was the Senior Advisor to the President on Science & Engineering Engagement at the University of Toronto. She is the co-founder of Research2Reality [emphasis mine], which uses social media to promote innovative research across the country. She also served as Ontario’s first Chief Scientist [emphasis mine], with a mandate to advance science and innovation in the province.

Shoichet is the only person to be elected a fellow of all three of Canada’s National Academies and is a foreign member of the U.S. National Academy of Engineering, and fellow of the Royal Society (UK) — the oldest and most prestigious academic society.

Doug Ford (premier of Ontario) and Molly Shoichet

She did serve as Ontario’s first Chief Scientist—for about six months (Nov. 2017 – July 2018). Molly Shoichet was fired when a new provincial government was elected in the summer of 2018. Here’s more about the incident from a July 4, 2018 article by Ryan Maloney for huffingtonpost.ca (Note: Links have been removed),

New Ontario Premier Doug Ford has fired the province’s first chief scientist.

Dr. Molly Shoichet, a renowned biomedical engineer who teaches at the University of Toronto, was appointed in November [2017] to advise the government and ensure science and research were at the forefront of decision-making.

Shoichet told HuffPost Canada in an email that the she does not believe the decision was about her, and “I don’t even know whether it was about this role.” She said she is disappointed but honoured to have served Ontarians, even for a short time.

Ford’s spokesman, Simon Jefferies told The Canadian Press Wednesday that the government is starting the process of “finding a suitable and qualified replacement.” [emphasis mine]

The move comes just days after Ford’s Progressive Conservatives officially took power in Canada’s largest province with a majority government.

Almost a year later, there was no replacement in sight according to a June 24, 2019 opinion piece by Kimberly Girling (then the Research and Policy Director of the Evidence for Democracy not-for-profit) for the star.com,

Premier Doug Ford, I’m concerned for your government.

I know you feel it too. Last week, one year into your mandate and faced with sharply declining polls after your first provincial budget, you conducted a major cabinet shuffle. This shuffle is clearly an attempt to “put the right people in the right place at the right time” and improve the outcomes of your cabinet. But I’m still concerned.

Since your election, your caucus has made many bold decisions. Unfortunately, it seems many are Ontarians unhappy with most of these decisions, and I’m not sure the current shuffle is enough to fix this.

[] I think you’re missing someone.

What about a Chief Scientist?

It isn’t a radical idea. Actually, you used to have one. Ontario’s first Chief Scientist, Dr. Molly Shoichet, was appointed to advise the government on science policy and champion science and innovation for Ontario. However, when your government was elected, you fired Dr. Shoichet within the first week.

It’s been a year, and so far we haven’t seen any attempts to fill this vacant position. [emphasis mine]

I wonder if Doug Ford and his crew regret the decision to fire Shoichet especially now that the province is suffering from a new peak in rising COVID-19 case numbers. These days government could do with a little bit of good news.

The only way we might ever know is if Doug Ford writes a memoir (in about 20 or 30 years from now).

Molly Shoichet, Research2Reality, and FrogHeart

A May 11, 2015 posting announced the launch of Research2Reality and it’s in this posting that I have a few comments from Molly Shoichet about co-founding a national science communication project. Given how busy she was at the time, I was amazed she took a few minutes to speak to me and took more time to make it possible for me to interview Raymond Laflamme (then director of the Institute for Quantum Computing at the University of Waterloo [Ontario]) and a prominent physicist.

Here are the comments Molly Shoichet offered (from the May 11, 2015 posting),

“I’m very excited about this and really hope that other people will be too,” says Shoichet. The audience for the Research2Reality endeavour is for people who like to know more and have questions when they see news items about science discoveries that can’t be answered by investigating mainstream media programmes or trying to read complex research papers.

This is a big undertaking. ” Mike [Mike MacMillan, co-founder] and I thought about this for about two years.” Building on the support they received from the University of Toronto, “We reached out to the vice-presidents of research at the top fifteen universities in the country.” In the end, six universities accepted the invitation to invest in this project,

Five years later, it’s still going.

Finally: Congratulations Molly Shoichet!

How do viruses and physics go together? Find out at a Nov. 4, 2020 Perimeter Institute (PI) virtual lecture

I got this announcement from an Oct. 29, 2020 Perimeter Institute (PI) Emmy Noether newsletter (received via email),

Catherne Beauchemin

A Physicist’s Adventures in Virology WEDNESDAY, NOVEMBER 4 at 7 pm ET [4 pm PT]

In recent years, there has been a rise in cynicism about many traditionally well-respected institutions – science, academia, news reporting, and even the concepts of experts and expertise more generally. Many people’s primary – or only – exposure to science is through biological or health science, especially during the COVID-19 pandemic.

In health research, rising cynicism has spawned the anti-vaccine movement, and a growing reliance on advice from peer networks rather than experts. In part, such movements are fuelled by several examples of provably false, so-called “scientific results,” coming about either through fraud or incompetence. While skepticism is crucial to science, cynicism rooted in a lack of trust can devalue scientific contributions.

In her lecture webcast, physicist Catherine Beauchemin will explore the erosion of trust in health research, presenting examples from influenza and COVID-19. …

I went to the A Physicist’s Adventures in Virology event and livestrream page to find this,

Two essential ingredients of the scientific method are skepticism and independent confirmation – the ability to glean for oneself whether an established theory or a new hypothesis is true or false. But not everyone has the capacity to perform the experiments to obtain such a confirmation.

Consider, for example, the costs of constructing your own Large Hadron Collider, or your ability as a non-expert to critically read and understand a scientific publication. In practice, acceptance of scientific theories is more often based on trust than on independent confirmation. When that trust is eroded, issues emerge.

Catherine Beauchemin is a Professor of Physics at Ryerson University and a Deputy Program Director in the RIKEN Interdisciplinary Theoretical and Mathematical Sciences Program in Japan. For the last 18 years, she has been developing mathematical and computational descriptions of how viruses spread from cell to cell, a field she calls “virophysics.”

In her November 4 [2020] Perimeter Public Lecture webcast, Beauchemin will highlight some of the issues that have eroded trust in health research, presenting examples from influenza and COVID-19. She will show why she believes many of these issues have their root in the fact that hypotheses in health research are formulated as words rather than mathematical expressions – and why a dose of physics may be just the prescription we need.

Enjoy!

CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 in the forest

It seems lignin is a bit of a problem. Its presence in a tree makes processing the wood into various products more difficult. (Of course, some people appreciate trees for other reasons both practical [carbon sequestration?] and/or aesthetic.)

In any event, scientists have been working on ways to reduce the amount of lignin in poplar trees since at least 2014 (see my April 7, 2014 posting titled ‘Good lignin, bad lignin: Florida researchers use plant waste to create lignin nanotubes while researchers in British Columbia develop trees with less lignin’; scroll down about 40% of the way for the ‘less lignin’ story).

(I don’t believe the 2014 research was accomplished with the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 technique as it had only been developed in 2012.)

The latest in the quest to reduce the amount of lignin of poplar trees comes from a Belgian/US team, from an Oct. 6, 2020 news item on ScienceDaily,

Researchers led by prof. Wout Boerjan (VIB-UGent [Ghent University] Center for Plant Systems Biology) have discovered a way to stably finetune the amount of lignin in poplar by applying CRISPR/Cas9 technology. Lignin is one of the main structural substances in plants and it makes processing wood into, for example, paper difficult. This study is an important breakthrough in the development of wood resources for the production of paper with a lower carbon footprint, biofuels, and other bio-based materials. Their work, in collaboration with VIVES University College (Roeselare, Belgium) and University of Wisconsin (USA) appears in Nature Communications.

Picture Tailoring lignin and growth by creating CCR2 allelic variants (From left to right: wild type, CCR2(-/-), CCR2(-/*) line 206, CCR2(-/*) line 12) Courtesy: VIB (Flanders Institute of Biotechnology)

An Oct. 6, 2020 VIB (Vlaams Instituut voor Biotechnologie; Flanders Institute of Biotechnology) press release (also on EurekAlert), which originated the news item, explains the reason for this research and how CRISPR (clustered regularly interspaced short palindromic repeats) technology could help realize it,

Towards a bio-based economy

Today’s fossil-based economy results in a net increase of CO2 in the Earth’s atmosphere and is a major cause of global climate change. To counter this, a shift towards a circular and bio-based economy is essential. Woody biomass can play a crucial role in such a bio-based economy by serving as a renewable and carbon-neutral resource for the production of many chemicals. Unfortunately, the presence of lignin hinders the processing of wood into bio-based products.

Prof. Wout Boerjan (VIB-UGent): “A few years ago, we performed a field trial with poplars that were engineered to make wood containing less lignin. Most plants showed large improvements in processing efficiency for many possible applications. The downside, however, was that the reduction in lignin accomplished with the technology we used then – RNA interference – was unstable and the trees grew less tall.”

New tools

Undeterred, the researchers went looking for a solution. They employed the recent CRISPR/Cas9 technology in poplar to lower the lignin amount in a stable way, without causing a biomass yield penalty. In other words, the trees grew just as well and as tall as those without genetic changes.

Dr. Barbara De Meester (VIB-UGent): “Poplar is a diploid species, meaning every gene is present in two copies. Using CRISPR/Cas9, we introduced specific changes in both copies of a gene that is crucial for the biosynthesis of lignin. We inactivated one copy of the gene, and only partially inactivated the other. The resulting poplar line had a stable 10% reduction in lignin amount while it grew normally in the greenhouse. Wood from the engineered trees had an up to 41% increase in processing efficiency”.

Dr. Ruben Vanholme (VIB-UGent): “The mutations that we have introduced through CRISPR/Cas9 are similar to those that spontaneously arise in nature. The advantage of the CRISPR/Cas9 method is that the beneficial mutations can be directly introduced into the DNA of highly productive tree varieties in only a fraction of the time it would take by a classical breeding strategy.”

The applications of this method are not only restricted to lignin but might also be useful to engineer other traits in crops, providing a versatile new breeding tool to improve agricultural productivity.

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

Tailoring poplar lignin without yield penalty by combining a null and haploinsufficient CINNAMOYL-CoA REDUCTASE2 allele by Barbara De Meester, Barbara Madariaga Calderón, Lisanne de Vries, Jacob Pollier, Geert Goeminne, Jan Van Doorsselaere, Mingjie Chen, John Ralph, Ruben Vanholme & Wout Boerjan. Nature Communications volume 11, Article number: 5020 (2020) DOI: https://doi.org/10.1038/s41467-020-18822-w Published 06 October 2020

This paper is open access.