Tag Archives: Massachusetts Institute of Technology (MIT)

Precision targeting of the liver for gene editing

Apparently the magic is in the lipid nanoparticles. A March 1, 2021 news item on Nanowerk announced research into lipid nanoparticles as a means to deliver CRISPR (clustered regularly interspaced short palindromic repeats) to specific organs (Note: A link has been removed),

The genome editing technology CRISPR has emerged as a powerful new tool that can change the way we treat disease. The challenge when altering the genetics of our cells, however, is how to do it safely, effectively, and specifically targeted to the gene, tissue and organ that needs treatment.

Scientists at Tufts University and the Broad Institute of Harvard [University] and MIT [Massachusetts Institute of Technology] have developed unique nanoparticles comprised of lipids — fat molecules — that can package and deliver gene editing machinery specifically to the liver.

In a study published in the Proceedings of the National Academy of Sciences [PNAS] (“Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3”), they have shown that they can use the lipid nanoparticles (LNPs) to efficiently deliver the CRISPR machinery into the liver of mice, resulting in specific genome editing and the reduction of blood cholesterol levels by as much as 57% — a reduction that can last for at least several months with just one shot.

A March 2, 2021 Tufts University news release (also on EurekAlert but published March 1, 2021), which originated the news item, provides greater insight into and technical detail about the research,

The problem of high cholesterol plagues more than 29 million Americans, according to the Centers for Disease Control and Prevention. The condition is complex and can originate from multiple genes as well as nutritional and lifestyle choices, so it is not easy to treat. The Tufts and Broad researchers, however, have modified one gene that could provide a protective effect against elevated cholesterol if it can be shut down by gene editing.

The gene that the researchers focused on codes for the angiopoietin-like 3 enzyme (Angptl3). That enzyme tamps down the activity of other enzymes – lipases – that help break down cholesterol. If researchers can knock out the Angptl3 gene, they can let the lipases do their work and reduce levels of cholesterol in the blood. It turns out that some lucky people have a natural mutation in their Angptl3 gene, leading to consistently low levels of triglycerides and low-density lipoprotein (LDL) cholesterol, commonly called “bad” cholesterol, in their bloodstream without any known clinical downsides.

“If we can replicate that condition by knocking out the angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” said Qiaobing Xu, associate professor of biomedical engineering at Tufts’ School of Engineering and corresponding author of the study. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.”

Xu’s team was able to do precisely that in mouse models. After a single injection of lipid nanoparticles packed with mRNA coding for CRISPR-Cas9 and a single-guide RNA targeting Angptl3, they observed a profound reduction in LDL cholesterol by as much as 57% and triglyceride levels by about 29 %, both of which remained at those lowered levels for at least 100 days. The researchers speculate that the effect may last much longer than that, perhaps limited only by the slow turnover of cells in the liver, which can occur over a period of about a year. The reduction of cholesterol and triglycerides is dose dependent, so their levels could be adjusted by injecting fewer or more LNPs in the single shot, the researchers said.

By comparison, an existing, FDA [US Food and Drug Administration]-approved version of CRISPR mRNA-loaded LNPs could only reduce LDL cholesterol by at most 15.7% and triglycerides by 16.3% when it was tested in mice, according to the researchers.

The trick to making a better LNP was in customizing the components – the molecules that come together to form bubbles around the mRNA. The LNPs are made up of long chain lipids that have a charged or polar head that is attracted to water, a carbon chain tail that points toward the middle of the bubble containing the payload, and a chemical linker between them. Also present are polyethylene glycol, and yes, even some cholesterol – which has a normal role in lipid membranes to make them less leaky – to hold their contents better.

The researchers found that the nature and relative ratio of these components appeared to have profound effects on the delivery of mRNA into the liver, so they tested LNPs with many combinations of heads, tails, linkers and ratios among all components for their ability to target liver cells. Because the in vitro potency of an LNP formulation rarely reflects its in vivo performance, they directly evaluated the delivery specificity and efficacy in mice that have a reporter gene in their cells that lights up red when genome editing occurs. Ultimately, they found a CRISPR mRNA-loaded LNP that lit up just the liver in mice, showing that it could specifically and efficiently deliver gene-editing tools into the liver to do their work.

The LNPs were built upon earlier work at Tufts, where Xu and his team developed LNPs with as much as 90% efficiency in delivering mRNA into cells. A unique feature of those nanoparticles was the presence of disulfide bonds between the long lipid chains. Outside the cells, the LNPs form a stable spherical structure that locks in their contents. When they are inside a cell, the environment within breaks the disulfide bonds to disassemble the nanoparticles. The contents are then quickly and efficiently released into the cell. By preventing loss outside the cell, the LNPs can have a much higher yield in delivering their contents.

“CRISPR is one of the most powerful therapeutic tools for the treatment of diseases with a genetic etiology. We have recently seen the first human clinical trail for CRISPR therapy enabled by LNP delivery to be administered systemically to edit genes inside the human body. Our LNP platform developed here holds great potential for clinical translation,” said Min Qiu, post-doctoral researcher in Xu’s lab at Tufts.  “We envision that with this LNP platform in hand, we could now make CRISPR a practical and safe approach to treat a broad spectrum of liver diseases or disorders,” said Zachary Glass, graduate student in the Xu lab. Qiu and Glass are co-first authors of the study.

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

Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3 by Min Qiu, Zachary Glass, Jinjin Chen, Mary Haas, Xin Jin, Xuewei Zhao, Xuehui Rui, Zhongfeng Ye, Yamin Li, Feng Zhang, and Qiaobing Xu. PNAS March 9, 2021 118 (10) e2020401118 DOI: https://doi.org/10.1073/pnas.2020401118

This paper appears to be behind a paywall.

A 3D spider web, a VR (virtual reality) setup, and sonification (music)

Markus Buehler and his musical spider webs are making news again.

Caption: Cross-sectional images (shown in different colors) of a spider web were combined into this 3D image and translated into music. Credit: Isabelle Su and Markus Buehler

The image (so pretty) you see in the above comes from a Markus Buehler presentation that was made at the American Chemical Society (ACS) meeting. ACS Spring 2021 being held online April 5-30, 2021. The image was also shown during a press conference which the ACS has made available for public viewing. More about that later in this posting.

The ACS issued an April 12, 2021 news release (also on EurekAlert), which provides details about Buehler’s latest work on spider webs and music,

Spiders are master builders, expertly weaving strands of silk into intricate 3D webs that serve as the spider’s home and hunting ground. If humans could enter the spider’s world, they could learn about web construction, arachnid behavior and more. Today, scientists report that they have translated the structure of a web into music, which could have applications ranging from better 3D printers to cross-species communication and otherworldly musical compositions.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30 [2021]. Live sessions will be hosted April 5-16, and on-demand and networking content will continue through April 30 [2021]. The meeting features nearly 9,000 presentations on a wide range of science topics.

“The spider lives in an environment of vibrating strings,” says Markus Buehler, Ph.D., the project’s principal investigator, who is presenting the work. “They don’t see very well, so they sense their world through vibrations, which have different frequencies.” Such vibrations occur, for example, when the spider stretches a silk strand during construction, or when the wind or a trapped fly moves the web.

Buehler, who has long been interested in music, wondered if he could extract rhythms and melodies of non-human origin from natural materials, such as spider webs. “Webs could be a new source for musical inspiration that is very different from the usual human experience,” he says. In addition, by experiencing a web through hearing as well as vision, Buehler and colleagues at the Massachusetts Institute of Technology (MIT), together with collaborator Tomás Saraceno at Studio Tomás Saraceno, hoped to gain new insights into the 3D architecture and construction of webs.

With these goals in mind, the researchers scanned a natural spider web with a laser to capture 2D cross-sections and then used computer algorithms to reconstruct the web’s 3D network. The team assigned different frequencies of sound to strands of the web, creating “notes” that they combined in patterns based on the web’s 3D structure to generate melodies. The researchers then created a harp-like instrument and played the spider web music in several live performances around the world.

The team also made a virtual reality setup that allowed people to visually and audibly “enter” the web. “The virtual reality environment is really intriguing because your ears are going to pick up structural features that you might see but not immediately recognize,” Buehler says. “By hearing it and seeing it at the same time, you can really start to understand the environment the spider lives in.”

To gain insights into how spiders build webs, the researchers scanned a web during the construction process, transforming each stage into music with different sounds. “The sounds our harp-like instrument makes change during the process, reflecting the way the spider builds the web,” Buehler says. “So, we can explore the temporal sequence of how the web is being constructed in audible form.” This step-by-step knowledge of how a spider builds a web could help in devising “spider-mimicking” 3D printers that build complex microelectronics. “The spider’s way of ‘printing’ the web is remarkable because no support material is used, as is often needed in current 3D printing methods,” he says.

In other experiments, the researchers explored how the sound of a web changes as it’s exposed to different mechanical forces, such as stretching. “In the virtual reality environment, we can begin to pull the web apart, and when we do that, the tension of the strings and the sound they produce change. At some point, the strands break, and they make a snapping sound,” Buehler says.

The team is also interested in learning how to communicate with spiders in their own language. They recorded web vibrations produced when spiders performed different activities, such as building a web, communicating with other spiders or sending courtship signals. Although the frequencies sounded similar to the human ear, a machine learning algorithm correctly classified the sounds into the different activities. “Now we’re trying to generate synthetic signals to basically speak the language of the spider,” Buehler says. “If we expose them to certain patterns of rhythms or vibrations, can we affect what they do, and can we begin to communicate with them? Those are really exciting ideas.”

You can go here for the April 12, 2021 ‘Making music from spider webs’ ACS press conference’ it runs about 30 mins. and you will hear some ‘spider music’ played.

Getting back to the image and spider webs in general, we are most familiar with orb webs (in the part of Canada where I from if nowhere else), which look like spirals and are 2D. There are several other types of webs some of which are 3D, like tangle webs, also known as cobwebs, funnel webs and more. See this March 18, 2020 article “9 Types of Spider Webs: Identification + Pictures & Spiders” by Zach David on Beyond the Treat for more about spiders and their webs. If you have the time, I recommend reading it.

I’ve been following Buehler’s spider web/music work for close to ten years now; the latest previous posting is an October 23, 2019 posting where you’ll find a link to an application that makes music from proteins (spider webs are made up of proteins; scroll down about 30% of the way; it’s in the 2nd to last line of the quoted text about the embedded video).

Here is a video (2 mins. 17 secs.) of a spider web music performance that Buehler placed on YouTube,

Feb 3, 2021

Markus J. Buehler

Spider’s Canvas/Arachonodrone show excerpt at Palais de Tokyo, Paris, on November 2018. Video by MIT CAST. More videos can be found on www.arachnodrone.com. The performance was commissioned by Studio Tomás Saraceno (STS), in the context of Saraceno’s carte blanche exhibition, ON AIR. Spider’s Canvas/Arachnodrone was performed by Isabelle Su and Ian Hattwick on the spider web instrument, Evan Ziporyn on the EWI (Electronic Wind Instrument), and Christine Southworth on the guitar and EBow (Electronic Bow)

You can find more about the spider web music and Buehler’s collaborators on http://www.arachnodrone.com/,

Spider’s Canvas / Arachnodrone is inspired by the multifaceted work of artist Tomas Saraceno, specifically his work using multiple species of spiders to make sculptural webs. Different species make very different types of webs, ranging not just in size but in design and functionality. Tomas’ own web sculptures are in essence collaborations with the spiders themselves, placing them sequentially over time in the same space, so that the complex, 3-dimensional sculptural web that results is in fact built by several spiders, working together.

Meanwhile, back among the humans at MIT, Isabelle Su, a Course 1 doctoral student in civil engineering, has been focusing on analyzing the structure of single-species spider webs, specifically the ‘tent webs’ of the cyrtophora citricola, a tropical spider of particular interest to her, Tomas, and Professor Markus Buehler. Tomas gave the department a cyrtophora spider, the department gave the spider a space (a small terrarium without glass), and she in turn built a beautiful and complex web. Isabelle then scanned it in 3D and made a virtual model. At the suggestion of Evan Ziporyn and Eran Egozy, she then ported the model into Unity, a VR/game making program, where a ‘player’ can move through it in numerous ways. Evan & Christine Southworth then worked with her on ‘sonifying’ the web and turning it into an interactive virtual instrument, effectively turning the web into a 1700-string resonating instrument, based on the proportional length of each individual piece of silk and their proximity to one another. As we move through the web (currently just with a computer trackpad, but eventually in a VR environment), we create a ‘sonic biome’: complex ‘just intonation’ chords that come in and out of earshot according to which of her strings we are closest to. That part was all done in MAX/MSP, a very flexible high level audio programming environment, which was connected with the virtual environment in Unity. Our new colleague Ian Hattwick joined the team focusing on sound design and spatialization, building an interface that allowed him the sonically ‘sculpt’ the sculpture in real time, changing amplitude, resonance, and other factors. During this performance at Palais de Tokyo, Isabelle toured the web – that’s what the viewer sees – while Ian adjusted sounds, so in essence they were together “playing the web.” Isabelle provides a space (the virtual web) and a specific location within it (by driving through), which is what the viewer sees, from multiple angles, on the 3 scrims. The location has certain acoustic potentialities, and Ian occupies them sonically, just as a real human performer does in a real acoustic space. A rough analogy might be something like wandering through a gothic cathedral or a resonant cave, using your voice or an instrument at different volumes and on different pitches to find sonorous resonances, echoes, etc. Meanwhile, Evan and Christine are improvising with the web instrument, building on Ian’s sound, with Evan on EWI (Electronic Wind Instrument) and Christine on electric guitar with EBow.

For the visuals, Southworth wanted to create the illusion that the performers were actually inside the web. We built a structure covered in sharkstooth scrim, with 3 projectors projecting in and through from 3 sides. Southworth created images using her photographs of local Lexington, MA spider webs mixed with slides of the scan of the web at MIT, and then mixed those images with the projection of the game, creating an interactive replica of Saraceno’s multi-species webs.

If you listen to the press conference, you will hear Buehler talk about practical applications for this work in materials science.

Use kombucha to produce bacterial cellulose

The combination of the US Army, bacterial cellulose, and kombucha seems a little unusual. However, this January 26, 2021 U.S. Army Research Laboratory news release (also on EurekAlert) provides some clues as to how this combination makes sense,

Kombucha tea, a trendy fermented beverage, inspired researchers to develop a new way to generate tough, functional materials using a mixture of bacteria and yeast similar to the kombucha mother used to ferment tea.

With Army funding, using this mixture, also called a SCOBY, or symbiotic culture of bacteria and yeast, engineers at MIT [Massachusetts Institute of Technology] and Imperial College London produced cellulose embedded with enzymes that can perform a variety of functions, such as sensing environmental pollutants and self-healing materials.

The team also showed that they could incorporate yeast directly into the cellulose, creating living materials that could be used to purify water for Soldiers in the field or make smart packaging materials that can detect damage.

“This work provides insights into how synthetic biology approaches can harness the design of biotic-abiotic interfaces with biological organization over multiple length scales,” said Dr. Dawanne Poree, program manager, Army Research Office, an element of the U.S. Army Combat Capabilities Development Command, now known as DEVCOM, Army Research Laboratory. “This is important to the Army as this can lead to new materials with potential applications in microbial fuel cells, sense and respond systems, and self-reporting and self-repairing materials.”

The research, published in Nature Materials was funded by ARO [Army Research Office] and the Army’s Institute for Soldier Nanotechnologies [ISN] at the Massachusetts Institute of Technology. The U.S. Army established the ISN in 2002 as an interdisciplinary research center devoted to dramatically improving the protection, survivability, and mission capabilities of the Soldier and Soldier-supporting platforms and systems.

“We foresee a future where diverse materials could be grown at home or in local production facilities, using biology rather than resource-intensive centralized manufacturing,” said Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering.

Researchers produced cellulose embedded with enzymes, creating living materials that could be used to purify water for Soldiers in the field or make smart packaging materials that can detect damage. These fermentation factories, which usually contain one species of bacteria and one or more yeast species, produce ethanol, cellulose, and acetic acid that gives kombucha tea its distinctive flavor.

Most of the wild yeast strains used for fermentation are difficult to genetically modify, so the researchers replaced them with a strain of laboratory yeast called Saccharomyces cerevisiae. They combined the yeast with a type of bacteria called Komagataeibacter rhaeticus that their collaborators at Imperial College London had previously isolated from a kombucha mother. This species can produce large quantities of cellulose.

Because the researchers used a laboratory strain of yeast, they could engineer the cells to do any of the things that lab yeast can do, such as producing enzymes that glow in the dark, or sensing pollutants or pathogens in the environment. The yeast can also be programmed so that they can break down pollutants/pathogens after detecting them, which is highly relevant to Army for chem/bio defense applications.

“Our community believes that living materials could provide the most effective sensing of chem/bio warfare agents, especially those of unknown genetics and chemistry,” said Dr. Jim Burgess ISN program manager for ARO.

The bacteria in the culture produced large-scale quantities of tough cellulose that served as a scaffold. The researchers designed their system so that they can control whether the yeast themselves, or just the enzymes that they produce, are incorporated into the cellulose structure. It takes only a few days to grow the material, and if left long enough, it can thicken to occupy a space as large as a bathtub.

“We think this is a good system that is very cheap and very easy to make in very large quantities,” said MIT graduate student and the paper’s lead author, Tzu-Chieh Tang. To demonstrate the potential of their microbe culture, which they call Syn-SCOBY, the researchers created a material incorporating yeast that senses estradiol, which is sometimes found as an environmental pollutant. In another version, they used a strain of yeast that produces a glowing protein called luciferase when exposed to blue light. These yeasts could be swapped out for other strains that detect other pollutants, metals, or pathogens.

The researchers are now looking into using the Syn-SCOBY system for biomedical or food applications. For example, engineering the yeast cells to produce antimicrobials or proteins that could benefit human health.

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

Living materials with programmable functionalities grown from engineered microbial co-cultures by Charlie Gilbert, Tzu-Chieh Tang, Wolfgang Ott, Brandon A. Dorr, William M. Shaw, George L. Sun, Timothy K. Lu & Tom Ellis. Nature Materials (2021) DOI: https://doi.org/10.1038/s41563-020-00857-5 Published: 11 January 2021

This paper is behind a paywall.

Self-assembled molecular nanofibers that are stronger than steel

A January 26, 2021 news item on Nanowerk announces a promising discovery in ‘self-assembly research’ (Note: A link has been removed,

Self-assembly is ubiquitous in the natural world, serving as a route to form organized structures in every living organism. This phenomenon can be seen, for instance, when two strands of DNA — without any external prodding or guidance — join to form a double helix, or when large numbers of molecules combine to create membranes or other vital cellular structures. Everything goes to its rightful place without an unseen builder having to put all the pieces together, one at a time.

For the past couple of decades, scientists and engineers have been following nature’s lead, designing molecules that assemble themselves in water, with the goal of making nanostructures, primarily for biomedical applications such as drug delivery or tissue engineering.

“These small-molecule-based materials tend to degrade rather quickly,” explains Julia Ortony, assistant professor in [Massachusetts Institute of Technology] MIT’s Department of Materials Science and Engineering (DMSE), “and they’re chemically unstable, too. The whole structure falls apart when you remove the water, particularly when any kind of external force is applied.”

She and her team, however, have designed a new class of small molecules that spontaneously assemble into nanoribbons with unprecedented strength, retaining their structure outside of water. The results of this multi-year effort, which could inspire a broad range of applications, were described in Nature Nanotechnology (“Self-assembly of aramid amphiphiles into ultra-stable nanoribbons and aligned nanoribbon threads”) by Ortony and coauthors.

“This seminal work — which yielded anomalous mechanical properties through highly controlled self-assembly — should have a big impact on the field,” asserts Professor Tazuko Aida, deputy director for the RIKEN Center for Emergent Matter Science and professor of chemistry and biotechnology at the University of Tokyo, who was not involved in the research.

A January 26, 2021 MIT news release, which originated the news item, describe the work in more detail,

The material the MIT group constructed — or rather, allowed to construct itself — is modeled after a cell membrane. Its outer part is “hydrophilic,” which means it likes to be in water, whereas its inner part is “hydrophobic,” meaning it tries to avoid water. This configuration, Ortony comments, “provides a driving force for self-assembly,” as the molecules orient themselves to minimize interactions between the hydrophobic regions and water, consequently taking on a nanoscale shape.

The shape, in this case, is conferred by water, and ordinarily the whole structure would collapse when dried. But Ortony and her colleagues came up with a plan to keep that from happening. When molecules are loosely bound together, they move around quickly, analogous to a fluid; as the strength of intermolecular forces increases, motion slows and molecules assume a solid-like state. The idea, Ortony explains, “is to slow molecular motion through small modifications to the individual molecules, which can lead to a collective, and hopefully dramatic, change in the nanostructure’s properties.”

One way of slowing down molecules, notes Ty Christoff-Tempesta, a PhD student and first author of the paper, “is to have them cling to each other more strongly than in biological systems.” That can be accomplished when a dense network of strong hydrogen bonds join the molecules together. “That’s what gives a material like Kevlar — constructed of so-called ‘aramids’ — its chemical stability and strength,” states Christoff-Tempesta.

Ortony’s team incorporated that capability into their design of a molecule that has three main components: an outer portion that likes to interact with water, aramids in the middle for binding, and an inner part that has a strong aversion to water. The researchers tested dozens of molecules meeting these criteria before finding the design that led to long ribbons with nanometer-scale thickness. The authors then measured the nanoribbons’ strength and stiffness to understand the impact of including Kevlar-like interactions between molecules. They discovered that the nanoribbons were unexpectedly sturdy — stronger than steel, in fact. 

This finding led the authors to wonder if the nanoribbons could be bundled to produce stable macroscopic materials. Ortony’s group devised a strategy whereby aligned nanoribbons were pulled into long threads that could be dried and handled. Notably, Ortony’s team showed that the threads could hold 200 times their own weight and have extraordinarily high surface areas — 200 square meters per gram of material. “This high surface-to-mass ratio offers promise for miniaturizing technologies by performing more chemistry with less material,” explains Christoff-Tempesta. To this end, they have already developed nanoribbons whose surfaces are coated with molecules that can pull heavy metals, like lead or arsenic, out of contaminated water. Other efforts in the research group are aimed at using bundled nanoribbons in electronic devices and batteries.

Ortony, for her part, is still amazed that they’ve been able to achieve their original research goal of “tuning the internal state of matter to create exceptionally strong molecular nanostructures.” Things could easily have gone the other way; these materials might have proved to be disorganized, or their structures fragile, like their predecessors, only holding up in water. But, she says, “we were excited to see that our modifications to the molecular structure were indeed amplified by the collective behavior of molecules, creating nanostructures with extremely robust mechanical properties. The next step, figuring out the most important applications, will be exciting.”

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

Self-assembly of aramid amphiphiles into ultra-stable nanoribbons and aligned nanoribbon threads by Ty Christoff-Tempesta, Yukio Cho, Dae-Yoon Kim, Michela Geri, Guillaume Lamour, Andrew J. Lew, Xiaobing Zuo, William R. Lindemann & Julia H. Ortony. Nature Nanotechnology (2021) DOI: https://doi.org/10.1038/s41565-020-00840-w Published: 18 January 2021

This paper is behind a paywall.

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?.

Stretching diamonds to improve electronic devices

On the last day of 2020, City University of Hong Kong (CityU) announced a technique for stretching diamonds that could result in a new generation of electronic devices. A December 31, 2020 news item on ScienceDaily makes the announcement,

Diamond is the hardest material in nature. It also has great potential as an excellent electronic material. A research team has demonstrated for the first time the large, uniform tensile elastic straining of microfabricated diamond arrays through the nanomechanical approach. Their findings have shown the potential of strained diamonds as prime candidates for advanced functional devices in microelectronics, photonics, and quantum information technologies.

A December 31, 2020 CityU press release on EurekAlert , which originated the news item, delves further into the research,

The research was co-led by Dr Lu Yang, Associate Professor in the Department of Mechanical Engineering (MNE) at CityU and researchers from Massachusetts Institute of Technology (MIT) and Harbin Institute of Technology (HIT). Their findings have been recently published in the prestigious scientific journal Science, titled “Achieving large uniform tensile elasticity in microfabricated diamond“.

“This is the first time showing the extremely large, uniform elasticity of diamond by tensile experiments. Our findings demonstrate the possibility of developing electronic devices through ‘deep elastic strain engineering’ of microfabricated diamond structures,” said Dr Lu.

Diamond: “Mount Everest” of electronic materials

Well known for its hardness, industrial applications of diamonds are usually cutting, drilling, or grinding. But diamond is also considered as a high-performance electronic and photonic material due to its ultra-high thermal conductivity, exceptional electric charge carrier mobility, high breakdown strength and ultra-wide bandgap. Bandgap is a key property in semi-conductor, and wide bandgap allows operation of high-power or high-frequency devices. “That’s why diamond can be considered as ‘Mount Everest’ of electronic materials, possessing all these excellent properties,” Dr Lu said.

However, the large bandgap and tight crystal structure of diamond make it difficult to “dope”, a common way to modulate the semi-conductors’ electronic properties during production, hence hampering the diamond’s industrial application in electronic and optoelectronic devices. A potential alternative is by “strain engineering”, that is to apply very large lattice strain, to change the electronic band structure and associated functional properties. But it was considered as “impossible” for diamond due to its extremely high hardness.

Then in 2018, Dr Lu and his collaborators discovered that, surprisingly, nanoscale diamond can be elastically bent with unexpected large local strain. This discovery suggests the change of physical properties in diamond through elastic strain engineering can be possible. Based on this, the latest study showed how this phenomenon can be utilized for developing functional diamond devices.

Uniform tensile straining across the sample

The team firstly microfabricated single-crystalline diamond samples from a solid diamond single crystals. The samples were in bridge-like shape – about one micrometre long and 300 nanometres wide, with both ends wider for gripping (See image: Tensile straining of diamond bridges). The diamond bridges were then uniaxially stretched in a well-controlled manner within an electron microscope. Under cycles of continuous and controllable loading-unloading of quantitative tensile tests, the diamond bridges demonstrated a highly uniform, large elastic deformation of about 7.5% strain across the whole gauge section of the specimen, rather than deforming at a localized area in bending. And they recovered their original shape after unloading.

By further optimizing the sample geometry using the American Society for Testing and Materials (ASTM) standard, they achieved a maximum uniform tensile strain of up to 9.7%, which even surpassed the maximum local value in the 2018 study, and was close to the theoretical elastic limit of diamond. More importantly, to demonstrate the strained diamond device concept, the team also realized elastic straining of microfabricated diamond arrays.

Tuning the bandgap by elastic strains

The team then performed density functional theory (DFT) calculations to estimate the impact of elastic straining from 0 to 12% on the diamond’s electronic properties. The simulation results indicated that the bandgap of diamond generally decreased as the tensile strain increased, with the largest bandgap reduction rate down from about 5 eV to 3 eV at around 9% strain along a specific crystalline orientation. The team performed an electron energy-loss spectroscopy analysis on a pre-strained diamond sample and verified this bandgap decreasing trend.

Their calculation results also showed that, interestingly, the bandgap could change from indirect to direct with the tensile strains larger than 9% along another crystalline orientation. Direct bandgap in semi-conductor means an electron can directly emit a photon, allowing many optoelectronic applications with higher efficiency.

These findings are an early step in achieving deep elastic strain engineering of microfabricated diamonds. By nanomechanical approach, the team demonstrated that the diamond’s band structure can be changed, and more importantly, these changes can be continuous and reversible, allowing different applications, from micro/nanoelectromechanical systems (MEMS/NEMS), strain-engineered transistors, to novel optoelectronic and quantum technologies. “I believe a new era for diamond is ahead of us,” said Dr Lu.

Here’s an illustration provided by the researchers,

Caption: Stretching of microfabricated diamonds pave ways for applications in next-generation microelectronics.. Credit: Dang Chaoqun / City University of Hong Kong

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

Achieving large uniform tensile elasticity in microfabricated diamond by Chaoqun Dang, Jyh-Pin Chou, Bing Dai, Chang-Ti Chou, Yang Yang, Rong Fan, Weitong Lin, Fanling Meng, Alice Hu, Jiaqi Zhu, Jiecai Han, Andrew M. Minor, Ju Li, Yang Lu. Science 01 Jan 2021: Vol. 371, Issue 6524, pp. 76-78 DOI: 10.1126/science.abc4174

This paper is behind a paywall.

Reading a virus like a book

Teaching grammar and syntax to artificial intelligence (AI) algorithms (specifically natural language processing (NLP) algorithms) has helped researchers understand and predict viral mutations more speedily. This facility is especially useful at a time when the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus seems to be mutating into more easily transmissible variants.

Will Douglas Heaven’s Jan. 14, 2021 article for the Massachusetts Institute of Technology’s MIT Technology Review describes the work that links AI, grammar, and mutating viruses (Note: Links have been removed),

Galileo once observed that nature is written in math. Biology might be written in words. Natural-language processing (NLP) algorithms are now able to generate protein sequences and predict virus mutations, including key changes that help the coronavirus evade the immune system.

The key insight making this possible is that many properties of biological systems can be interpreted in terms of words and sentences. “We’re learning the language of evolution,” says Bonnie Berger, a computational biologist at the Massachusetts Institute of Technology [MIT].

In the last few years, a handful of researchers—including teams from geneticist George Church’s [Professor of Health Sciences and Technology at Harvard University and MIT, etc.] lab and Salesforce [emphasis mine]—have shown that protein sequences and genetic codes can be modeled using NLP techniques.

In a study published in Science today, Berger and her colleagues pull several of these strands together and use NLP to predict mutations that allow viruses to avoid being detected by antibodies in the human immune system, a process known as viral immune escape. The basic idea is that the interpretation of a virus by an immune system is analogous to the interpretation of a sentence by a human.

Berger’s team uses two different linguistic concepts: grammar and semantics (or meaning). The genetic or evolutionary fitness of a virus—characteristics such as how good it is at infecting a host—can be interpreted in terms of grammatical correctness. A successful, infectious virus is grammatically correct; an unsuccessful one is not.

Similarly, mutations of a virus can be interpreted in terms of semantics. Mutations that make a virus appear different to things in its environment—such as changes in its surface proteins that make it invisible to certain antibodies—have altered its meaning. Viruses with different mutations can have different meanings, and a virus with a different meaning may need different antibodies to read it.

Instead of millions of sentences, they trained the NLP model on thousands of genetic sequences taken from three different viruses: 45,000 unique sequences for a strain of influenza, 60,000 for a strain of HIV, and between 3,000 and 4,000 for a strain of Sars-Cov-2, the virus that causes covid-19. “There’s less data for the coronavirus because there’s been less surveillance,” says Brian Hie, a graduate student at MIT, who built the models.

The overall aim of the approach is to identify mutations that might let a virus escape an immune system without making it less infectious—that is, mutations that change a virus’s meaning without making it grammatically incorrect.

But it’s also just the beginning. Treating genetic mutations as changes in meaning could be applied in different ways across biology. “A good analogy can go a long way,” says Bryson [Bryan Bryson, a biologist at MIT].

If you have time, I recommend reading Heaven’s Jan. 14, 2021 article in its entirety as it’s well written with clear explanations. As for the article’s mentions of George Church and Salesforce, the former could be expected while the latter is not (by me, I speak for no one else).

I find it fascinating that a company which describes itself (from What is Salesforce?) as providing “… customer relationship management, or CRM. It gives all your departments — including marketing, sales, commerce, and service — a shared view of your customers … ” seems to be conducting investigations into one (or more?) areas of biology.

For those who’d like to dive into the science as described in Heaven’s article, here’s a link to and a citation for the paper,

Learning the language of viral evolution and escape by Brian Hie, Ellen D. Zhong, Bonnie Berger, Bryan Bryson. Science 15 Jan 2021: Vol. 371, Issue 6526, pp. 284-288 DOI: 10.1126/science.abd7331

This paper appears to be open access (or it is, at least for now).

There is also a preprint version available on bioRxiv, which is an open access repository.

Technical University of Munich: embedded ethics approach for AI (artificial intelligence) and storing a tv series in synthetic DNA

I stumbled across two news bits of interest from the Technical University of Munich in one day (Sept. 1, 2020, I think). The topics: artificial intelligence (AI) and synthetic DNA (deoxyribonucleic acid).

Embedded ethics and artificial intelligence (AI)

An August 27, 2020 Technical University of Munich (TUM) press release (also on EurekAlert but published Sept. 1, 2020) features information about a proposal to embed ethicists in with AI development teams,

The increasing use of AI (artificial intelligence) in the development of new medical technologies demands greater attention to ethical aspects. An interdisciplinary team at the Technical University of Munich (TUM) advocates the integration of ethics from the very beginning of the development process of new technologies. Alena Buyx, Professor of Ethics in Medicine and Health Technologies, explains the embedded ethics approach.

Professor Buyx, the discussions surrounding a greater emphasis on ethics in AI research have greatly intensified in recent years, to the point where one might speak of “ethics hype” …

Prof. Buyx: … and many committees in Germany and around the world such as the German Ethics Council or the EU Commission High-Level Expert Group on Artificial Intelligence have responded. They are all in agreement: We need more ethics in the development of AI-based health technologies. But how do things look in practice for engineers and designers? Concrete solutions are still few and far between. In a joint pilot project with two Integrative Research Centers at TUM, the Munich School of Robotics and Machine Intelligence (MSRM) with its director, Prof. Sami Haddadin, and the Munich Center for Technology in Society (MCTS), with Prof. Ruth Müller, we want to try out the embedded ethics approach. We published the proposal in Nature Machine Intelligence at the end of July [2020].

What exactly is meant by the “embedded ethics approach”?

Prof.Buyx: The idea is to make ethics an integral part of the research process by integrating ethicists into the AI development team from day one. For example, they attend team meetings on a regular basis and create a sort of “ethical awareness” for certain issues. They also raise and analyze specific ethical and social issues.

Is there an example of this concept in practice?

Prof. Buyx: The Geriatronics Research Center, a flagship project of the MSRM in Garmisch-Partenkirchen, is developing robot assistants to enable people to live independently in old age. The center’s initiatives will include the construction of model apartments designed to try out residential concepts where seniors share their living space with robots. At a joint meeting with the participating engineers, it was noted that the idea of using an open concept layout everywhere in the units – with few doors or individual rooms – would give the robots considerable range of motion. With the seniors, however, this living concept could prove upsetting because they are used to having private spaces. At the outset, the engineers had not given explicit consideration to this aspect.

Prof.Buyx: The approach sounds promising. But how can we avoid “embedded ethics” from turning into an “ethics washing” exercise, offering companies a comforting sense of “being on the safe side” when developing new AI technologies?

That’s not something we can be certain of avoiding. The key is mutual openness and a willingness to listen, with the goal of finding a common language – and subsequently being prepared to effectively implement the ethical aspects. At TUM we are ideally positioned to achieve this. Prof. Sami Haddadin, the director of the MSRM, is also a member of the EU High-Level Group of Artificial Intelligence. In his research, he is guided by the concept of human centered engineering. Consequently, he has supported the idea of embedded ethics from the very beginning. But one thing is certain: Embedded ethics alone will not suddenly make AI “turn ethical”. Ultimately, that will require laws, codes of conduct and possibly state incentives.

Here’s a link to and a citation for the paper espousing the embedded ethics for AI development approach,

An embedded ethics approach for AI development by Stuart McLennan, Amelia Fiske, Leo Anthony Celi, Ruth Müller, Jan Harder, Konstantin Ritt, Sami Haddadin & Alena Buyx. Nature Machine Intelligence (2020) DOI: https://doi.org/10.1038/s42256-020-0214-1 Published 31 July 2020

This paper is behind a paywall.

Religion, ethics and and AI

For some reason embedded ethics and AI got me to thinking about Pope Francis and other religious leaders.

The Roman Catholic Church and AI

There was a recent announcement that the Roman Catholic Church will be working with MicroSoft and IBM on AI and ethics (from a February 28, 2020 article by Jen Copestake for British Broadcasting Corporation (BBC) news online (Note: A link has been removed),

Leaders from the two tech giants met senior church officials in Rome, and agreed to collaborate on “human-centred” ways of designing AI.

Microsoft president Brad Smith admitted some people may “think of us as strange bedfellows” at the signing event.

“But I think the world needs people from different places to come together,” he said.

The call was supported by Pope Francis, in his first detailed remarks about the impact of artificial intelligence on humanity.

The Rome Call for Ethics [sic] was co-signed by Mr Smith, IBM executive vice-president John Kelly and president of the Pontifical Academy for Life Archbishop Vincenzo Paglia.

It puts humans at the centre of new technologies, asking for AI to be designed with a focus on the good of the environment and “our common and shared home and of its human inhabitants”.

Framing the current era as a “renAIssance”, the speakers said the invention of artificial intelligence would be as significant to human development as the invention of the printing press or combustion engine.

UN Food and Agricultural Organization director Qu Dongyu and Italy’s technology minister Paola Pisano were also co-signatories.

Hannah Brockhaus’s February 28, 2020 article for the Catholic News Agency provides some details missing from the BBC report and I found it quite helpful when trying to understand the various pieces that make up this initiative,

The Pontifical Academy for Life signed Friday [February 28, 2020], alongside presidents of IBM and Microsoft, a call for ethical and responsible use of artificial intelligence technologies.

According to the document, “the sponsors of the call express their desire to work together, in this context and at a national and international level, to promote ‘algor-ethics.’”

“Algor-ethics,” according to the text, is the ethical use of artificial intelligence according to the principles of transparency, inclusion, responsibility, impartiality, reliability, security, and privacy.

The signing of the “Rome Call for AI Ethics [PDF]” took place as part of the 2020 assembly of the Pontifical Academy for Life, which was held Feb. 26-28 [2020] on the theme of artificial intelligence.

One part of the assembly was dedicated to private meetings of the academics of the Pontifical Academy for Life. The second was a workshop on AI and ethics that drew 356 participants from 41 countries.

On the morning of Feb. 28 [2020], a public event took place called “renAIssance. For a Humanistic Artificial Intelligence” and included the signing of the AI document by Microsoft President Brad Smith, and IBM Executive Vice-president John Kelly III.

The Director General of FAO, Dongyu Qu, and politician Paola Pisano, representing the Italian government, also signed.

The president of the European Parliament, David Sassoli, was also present Feb. 28.

Pope Francis canceled his scheduled appearance at the event due to feeling unwell. His prepared remarks were read by Archbishop Vincenzo Paglia, president of the Academy for Life.

You can find Pope Francis’s comments about the document here (if you’re not comfortable reading Italian, hopefully, the English translation which follows directly afterward will be helpful). The Pope’s AI initiative has a dedicated website, Rome Call for AI ethics, and while most of the material dates from the February 2020 announcement, they are keeping up a blog. It has two entries, one dated in May 2020 and another in September 2020.

Buddhism and AI

The Dalai Lama is well known for having an interest in science and having hosted scientists for various dialogues. So, I was able to track down a November 10, 2016 article by Ariel Conn for the futureoflife.org website, which features his insights on the matter,

The question of what it means and what it takes to feel needed is an important problem for ethicists and philosophers, but it may be just as important for AI researchers to consider. The Dalai Lama argues that lack of meaning and purpose in one’s work increases frustration and dissatisfaction among even those who are gainfully employed.

“The problem,” says the Dalai Lama, “is … the growing number of people who feel they are no longer useful, no longer needed, no longer one with their societies. … Feeling superfluous is a blow to the human spirit. It leads to social isolation and emotional pain, and creates the conditions for negative emotions to take root.”

If feeling needed and feeling useful are necessary for happiness, then AI researchers may face a conundrum. Many researchers hope that job loss due to artificial intelligence and automation could, in the end, provide people with more leisure time to pursue enjoyable activities. But if the key to happiness is feeling useful and needed, then a society without work could be just as emotionally challenging as today’s career-based societies, and possibly worse.

I also found a talk on the topic by The Venerable Tenzin Priyadarshi, first here’s a description from his bio at the Dalai Lama Center for Ethics and Transformative Values webspace on the Massachusetts Institute of Technology (MIT) website,

… an innovative thinker, philosopher, educator and a polymath monk. He is Director of the Ethics Initiative at the MIT Media Lab and President & CEO of The Dalai Lama Center for Ethics and Transformative Values at the Massachusetts Institute of Technology. Venerable Tenzin’s unusual background encompasses entering a Buddhist monastery at the age of ten and receiving graduate education at Harvard University with degrees ranging from Philosophy to Physics to International Relations. He is a Tribeca Disruptive Fellow and a Fellow at the Center for Advanced Study in Behavioral Sciences at Stanford University. Venerable Tenzin serves on the boards of a number of academic, humanitarian, and religious organizations. He is the recipient of several recognitions and awards and received Harvard’s Distinguished Alumni Honors for his visionary contributions to humanity.

He gave the 2018 Roger W. Heyns Lecture in Religion and Society at Stanford University on the topic, “Religious and Ethical Dimensions of Artificial Intelligence.” The video runs over one hour but he is a sprightly speaker (in comparison to other Buddhist speakers I’ve listened to over the years).

Judaism, Islam, and other Abrahamic faiths examine AI and ethics

I was delighted to find this January 30, 2020 Artificial Intelligence: Implications for Ethics and Religion event as it brought together a range of thinkers from various faiths and disciplines,

New technologies are transforming our world every day, and the pace of change is only accelerating.  In coming years, human beings will create machines capable of out-thinking us and potentially taking on such uniquely-human traits as empathy, ethical reasoning, perhaps even consciousness.  This will have profound implications for virtually every human activity, as well as the meaning we impart to life and creation themselves.  This conference will provide an introduction for non-specialists to Artificial Intelligence (AI):

What is it?  What can it do and be used for?  And what will be its implications for choice and free will; economics and worklife; surveillance economies and surveillance states; the changing nature of facts and truth; and the comparative intelligence and capabilities of humans and machines in the future? 

Leading practitioners, ethicists and theologians will provide cross-disciplinary and cross-denominational perspectives on such challenges as technology addiction, inherent biases and resulting inequalities, the ethics of creating destructive technologies and of turning decision-making over to machines from self-driving cars to “autonomous weapons” systems in warfare, and how we should treat the suffering of “feeling” machines.  The conference ultimately will address how we think about our place in the universe and what this means for both religious thought and theological institutions themselves.

UTS [Union Theological Seminary] is the oldest independent seminary in the United States and has long been known as a bastion of progressive Christian scholarship.  JTS [Jewish Theological Seminary] is one of the academic and spiritual centers of Conservative Judaism and a major center for academic scholarship in Jewish studies. The Riverside Church is an interdenominational, interracial, international, open, welcoming, and affirming church and congregation that has served as a focal point of global and national activism for peace and social justice since its inception and continues to serve God through word and public witness. The annual Greater Good Gathering, the following week at Columbia University’s School of International & Public Affairs, focuses on how technology is changing society, politics and the economy – part of a growing nationwide effort to advance conversations promoting the “greater good.”

They have embedded a video of the event (it runs a little over seven hours) on the January 30, 2020 Artificial Intelligence: Implications for Ethics and Religion event page. For anyone who finds that a daunting amount of information, you may want to check out the speaker list for ideas about who might be writing and thinking on this topic.

As for Islam, I did track down this November 29, 2018 article by Shahino Mah Abdullah, a fellow at the Institute of Advanced Islamic Studies (IAIS) Malaysia,

As the global community continues to work together on the ethics of AI, there are still vast opportunities to offer ethical inputs, including the ethical principles based on Islamic teachings.

This is in line with Islam’s encouragement for its believers to convey beneficial messages, including to share its ethical principles with society.

In Islam, ethics or akhlak (virtuous character traits) in Arabic, is sometimes employed interchangeably in the Arabic language with adab, which means the manner, attitude, behaviour, and etiquette of putting things in their proper places. Islamic ethics cover all the legal concepts ranging from syariah (Islamic law), fiqh ( jurisprudence), qanun (ordinance), and ‘urf (customary practices).

Adopting and applying moral values based on the Islamic ethical concept or applied Islamic ethics could be a way to address various issues in today’s societies.

At the same time, this approach is in line with the higher objectives of syariah (maqasid alsyariah) that is aimed at conserving human benefit by the protection of human values, including faith (hifz al-din), life (hifz alnafs), lineage (hifz al-nasl), intellect (hifz al-‘aql), and property (hifz al-mal). This approach could be very helpful to address contemporary issues, including those related to the rise of AI and intelligent robots.

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Part of the difficulty with tracking down more about AI, ethics, and various religions is linguistic. I simply don’t have the language skills to search for the commentaries and, even in English, I may not have the best or most appropriate search terms.

Television (TV) episodes stored on DNA?

According to a Sept. 1, 2020 news item on Nanowerk, the first episode of a tv series, ‘Biohackers’ has been stored on synthetic DNA (deoxyribonucleic acid) by a researcher at TUM and colleagues at another institution,

The first episode of the newly released series “Biohackers” was stored in the form of synthetic DNA. This was made possible by the research of Prof. Reinhard Heckel of the Technical University of Munich (TUM) and his colleague Prof. Robert Grass of ETH Zürich.

They have developed a method that permits the stable storage of large quantities of data on DNA for over 1000 years.

A Sept. 1, 2020 TUM press release, which originated the news item, proceeds with more detail in an interview format,

Prof. Heckel, Biohackers is about a medical student seeking revenge on a professor with a dark past – and the manipulation of DNA with biotechnology tools. You were commissioned to store the series on DNA. How does that work?

First, I should mention that what we’re talking about is artificially generated – in other words, synthetic – DNA. DNA consists of four building blocks: the nucleotides adenine (A), thymine (T), guanine (G) and cytosine (C). Computer data, meanwhile, are coded as zeros and ones. The first episode of Biohackers consists of a sequence of around 600 million zeros and ones. To code the sequence 01 01 11 00 in DNA, for example, we decide which number combinations will correspond to which letters. For example: 00 is A, 01 is C, 10 is G and 11 is T. Our example then produces the DNA sequence CCTA. Using this principle of DNA data storage, we have stored the first episode of the series on DNA.

And to view the series – is it just a matter of “reverse translation” of the letters?

In a very simplified sense, you can visualize it like that. When writing, storing and reading the DNA, however, errors occur. If these errors are not corrected, the data stored on the DNA will be lost. To solve the problem, I have developed an algorithm based on channel coding. This method involves correcting errors that take place during information transfers. The underlying idea is to add redundancy to the data. Think of language: When we read or hear a word with missing or incorrect letters, the computing power of our brain is still capable of understanding the word. The algorithm follows the same principle: It encodes the data with sufficient redundancy to ensure that even highly inaccurate data can be restored later.

Channel coding is used in many fields, including in telecommunications. What challenges did you face when developing your solution?

The first challenge was to create an algorithm specifically geared to the errors that occur in DNA. The second one was to make the algorithm so efficient that the largest possible quantities of data can be stored on the smallest possible quantity of DNA, so that only the absolutely necessary amount of redundancy is added. We demonstrated that our algorithm is optimized in that sense.

DNA data storage is very expensive because of the complexity of DNA production as well as the reading process. What makes DNA an attractive storage medium despite these challenges?

First, DNA has a very high information density. This permits the storage of enormous data volumes in a minimal space. In the case of the TV series, we stored “only” 100 megabytes on a picogram – or a billionth of a gram of DNA. Theoretically, however, it would be possible to store up to 200 exabytes on one gram of DNA. And DNA lasts a long time. By comparison: If you never turned on your PC or wrote data to the hard disk it contains, the data would disappear after a couple of years. By contrast, DNA can remain stable for many thousands of years if it is packed right.

And the method you have developed also makes the DNA strands durable – practically indestructible.

My colleague Robert Grass was the first to develop a process for the “stable packing” of DNA strands by encapsulating them in nanometer-scale spheres made of silica glass. This ensures that the DNA is protected against mechanical influences. In a joint paper in 2015, we presented the first robust DNA data storage concept with our algorithm and the encapsulation process developed by Prof. Grass. Since then we have continuously improved our method. In our most recent publication in Nature Protocols of January 2020, we passed on what we have learned.

What are your next steps? Does data storage on DNA have a future?

We’re working on a way to make DNA data storage cheaper and faster. “Biohackers” was a milestone en route to commercialization. But we still have a long way to go. If this technology proves successful, big things will be possible. Entire libraries, all movies, photos, music and knowledge of every kind – provided it can be represented in the form of data – could be stored on DNA and would thus be available to humanity for eternity.

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

Reading and writing digital data in DNA by Linda C. Meiser, Philipp L. Antkowiak, Julian Koch, Weida D. Chen, A. Xavier Kohll, Wendelin J. Stark, Reinhard Heckel & Robert N. Grass. Nature Protocols volume 15, pages86–101(2020) Issue Date: January 2020 DOI: https://doi.org/10.1038/s41596-019-0244-5 Published [online] 29 November 2019

This paper is behind a paywall.

As for ‘Biohackers’, it’s a German science fiction television series and you can find out more about it here on the Internet Movie Database.

New capacitor for better wearable electronics?

Supercapacitors are a predictable source of scientific interest and excitement. The latest entry in the ‘supercapacitor stakes’ is from a Russian/Finnish/US team according to a June 11, 2020 Skoltech (Skolkovo Institute of Science and Technology) press release (also on EurekAlert),

Researchers from Skoltech [Russia], Aalto University [Finland] and Massachusetts Institute of Technology [MIT; US] have designed a high-performance, low-cost, environmentally friendly, and stretchable supercapacitor that can potentially be used in wearable electronics. The paper was published in the Journal of Energy Storage.

Supercapacitors, with their high power density, fast charge-discharge rates, long cycle life, and cost-effectiveness, are a promising power source for everything from mobile and wearable electronics to electric vehicles. However, combining high energy density, safety, and eco-friendliness in one supercapacitor suitable for small devices has been rather challenging.

“Usually, organic solvents are used to increase the energy density. These are hazardous, not environmentally friendly, and they reduce the power density compared to aqueous electrolytes with higher conductivity,” says Professor Tanja Kallio from Aalto University, a co-author of the paper.

The researchers proposed a new design for a “green” and simple-to-fabricate supercapacitor. It consists of a solid-state material based on nitrogen-doped graphene flake electrodes distributed in the NaCl-containing hydrogel electrolyte. This structure is sandwiched between two single-walled carbon nanotube film current collectors, which provides stretchability. Hydrogel in the supercapacitor design enables compact packing and high energy density and allows them to use the environmentally friendly electrolyte.

The scientists managed to improve the volumetric capacitive performance, high energy density and power density for the prototype over analogous supercapacitors described in previous research. “We fabricated a prototype with unchanged performance under the 50% strain after a thousand stretching cycles. To ensure lower cost and better environmental performance, we used a NaCl-based electrolyte. Still the fabrication cost can be lowered down by implementation of 3D printing or other advanced fabrication techniques,” concluded Skoltech professor Albert Nasibulin.

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

Superior environmentally friendly stretchable supercapacitor based on nitrogen-doped graphene/hydrogel and single-walled carbon nanotubes by Evgeniia Gilshtein, Cristina Flox, Farhan S.M. Ali, Bahareh Mehrabimatin, Fedor S.Fedorov, Shaoting Lin, Xuanhe Zhao, Albert G. Nasibulin, Tanja Kallio. Journal of Energy Storage Volume 30, August 2020, 101505 DOI: https://doi.org/10.1016/j.est.2020.101505

This paper is behind a paywall.

I’m trying to remember if I’ve ever before seen a material that combines graphene and single-walled carbon nanotubes (SWCNTs). Anyway, here’s an image the researchers are using illustrate their work,

Caption: This is an outline of the new supercapacitor. Credit: Pavel Odinev / Skoltech