Topological Phases In Biological Systems (Physics)

LMU physicists have shown that topological phases could exist in biology, and in so doing they have identified a link between solid-state physics and biophysics.

Interaction chain. Source: C. Hohmann

The concept of topological phase transitions has become an important topic in theoretical physics, and was first applied to the characterization of unusual states of matter in the 1980s. The quantum Hall effect (QHE) is one example where ideas drawn from topology have yielded new insights into initially puzzling phenomena. The QHE is observed in atomically thin films. When these, effectively two-dimensional, materials are subjected to a smoothly varying magnetic field, their electrical resistance changes in discrete steps. The significance of such topological states in condensed-matter physics was acknowledged by the award of the 2016 Nobel Prize for Physics to its discoverers.

Now LMU physicists led by Professor Erwin Frey have used this same topological concept to elucidate the dynamics of a biological model system. “We asked whether the kinds of stepwise topological phase transitions discovered in solid-state physics could be found in biological systems,” says Philipp Geiger, a doctoral student in Frey’s team and joint first author of the new study together with Johannes Knebel. The model system chosen for investigation was one that Frey’s group had previously employed to investigate the population dynamics of ecosystems in which diverse mobile species compete with each other.

The basic elements used to model this system are rock-paper-scissors (RPS) cycles, which are a classical element of game theory. Each of these elements (or strategies) defeats one of the others, but succumbs to the third. “From this basic model, we built an interaction chain by connecting many such RPS cycles to one another,” Geiger explains. “In addition, we made the original model much more abstract in character.”

In their abstract version of the model, in which species compete for with their nearest neighbors in dominance relationships that are governed by RPS rules, the authors observed the emergence of a strong degree of polarization on one side or other of the interaction lattice. In other words, species in these positions came to dominate the whole system. Whether the evolutionary dynamics of the model led to peak polarization on the left or the right side of the interaction chain was shown to depend solely on the quantitative relationship between just two interaction rates, and the dynamics was otherwise robust against small perturbations in strengths of interactions.

With the aid of methods drawn from solid-state physics, Frey and his colleagues were able to account for the polarization of the evolutionary dynamics in terms of topological phases, such that changes in polarization could be treated in the same way as phase transitions. “The model shows for the first time that such effects can occur in biology,” says Frey. “This study can be viewed as the first step toward the application of the concept of topological phases in biological systems. It is even conceivable that one could make use of topological phases in the context of the analysis of genetic regulatory networks. How such phases can be realized experimentally is an interesting question and a challenging task for future research.”

References: Johannes Knebel, Philipp M. Geiger, and Erwin Frey, “Topological Phase Transition in Coupled Rock-Paper-Scissors Cycles”, Phys. Rev. Lett. 125, 258301 – Published 17 December 2020. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.125.258301 https://doi.org/10.1103/PhysRevLett.125.258301

Provided by LMU Munich

AI Could Lead To Faster, Better Analysis Of Donated Blood (Medicine)

Researchers develop new tool capable of precision diagnosis and better classification of blood products, opening the door to better matches for transfusions.

Machine learning could change the way donated blood is evaluated for quality and selected for transfusion to patients, thanks to an international study that analyzed changes in the shape of red blood cells from stored samples. The study, published in the journal Proceedings of the National Academy of Sciences, was a collaboration of experts in five countries and 12 academic institutions, including the University of Alberta.

Jason Acker was a lead author of a new international study showing that machine learning can be used to analyze samples of red blood cells faster and more precisely than human experts—a finding that could change how donated blood is assessed, stored and selected for transfusion into patients. (Photo: Faculty of Medicine & Dentistry, August 2020)

“This project is an excellent example of how we are using our world-class expertise in precision health to contribute to the interdisciplinary work required to make fundamental changes in blood diagnostics,” said Jason Acker, professor in the Department of Laboratory Medicine & Pathology and one of the lead authors of the study. 

Acker, also a senior scientist at Canadian Blood Services’ Centre for Innovation and a member of the Women and Children’s Health Research Institute, has decades of experience in the assessment of donated blood products.

“Canadian Blood Services is responsible for managing the blood supply in all provinces and territories except Quebec, and we’re chiefly concerned about the quality of the products. One of the things we routinely evaluate is the form of the cells, which we’ve been monitoring for 20 years using very traditional methods,” he explained.

The shape of things to come

When blood is taken outside the body and separated to be stored, red blood cells start changing their shape as they age, which eventually affects their ability to function and carry oxygen through the body’s tissues when they’re transfused. The red cell products can only be stored for 42 days, so they need to be monitored closely. Currently, donated red blood cells are evaluated by placing a drop of blood on a glass slide and looking at the cells, classifying them based on their shape from a sample of 100 cells. A morphology index is calculated, which is a “score” of the average shape of the sample cells.

“It’s very time-consuming. We’re only looking at 100 cells, and it’s very subjective. One technician may give a score of 70, while another may give a score of 80,” said Acker. “It’s really important that we get it right, because we’re trying to monitor the progress of a product that will actually be transfused into Canadians.”

Looking to develop a faster and more accurate procedure to monitor the donated blood, Acker and his colleagues tapped into the potential of artificial intelligence. They used imaging flow cytometry—technology available at a few of the academic institutions involved, including the U of A—to capture images of tens of thousands of cells from a droplet of blood and create a large database for analysis. With these images, the team was able to automate the traditional expert assessment by training a computer with example images of healthy and unhealthy red blood cell shapes. The automated process analyzed more than 100 blood samples—which usually takes months for a team of technicians—in just one day.

In addition to successfully replicating the traditional process, the researchers wanted to address the discrepancies between experts’ evaluations of the shapes of the cells. “We said, ‘What happens if we don’t tell the computer what a sphere is?’ And we basically let it look at a variety of different parameters. That’s the nice thing about machine learning—it looks at things that we as humans would not even think about, and it generates data on that,” said Acker.

“The computer actually did a better job than we could, and it was able to pick up subtle differences in a way that we can’t as humans. It’s not surprising that the red cells don’t just go from one shape to another. This computer showed that there’s actually a gradual progression of shape in samples from blood products, and it’s able to better classify these changes. It radically changes the speed at which we can make these assessments of blood product quality.”

“This will help us identify donor factors such as age and gender, blood product manufacturing processes and storage conditions that we can focus on to make sure that we’re getting safe products to patients.”, said Jason Acker.

The successful outcome of the experiment provided the research team with algorithms that help show how machine learning can be used to classify the quality of red cells faster and more precisely. These algorithms are now used to study other factors that can affect the quality of donated blood products.

“This will help us identify donor factors such as age and gender, blood product manufacturing processes and storage conditions that we can focus on to make sure that we’re getting safe products to patients,” said Acker.

Opening doors to personalized transfusions

Among the other factors being identified, the technology was able to distinguish subpopulations of cells within the same blood product, which could help health professionals spot potential health issues faster and discover risk factors of certain products going to a specific patient. Acker’s current research is focused on learning whether there are potential risks of a patient receiving blood from a donor of the opposite sex, one example that would help categorize products and apply transfusions beyond the traditional classifications.

“We already match for different blood groups. We also select specific blood products for treatment of babies or for other patient groups,” explained Acker. “But what this research is leading us to is the fact that we have the ability to be much more precise in how we match blood donors and recipients based on specific characteristics of blood cells. Through this study we have developed machine learning tools that are going to help inform how this change in clinical practice evolves.”

The study was funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research, the U.S. National Science Foundation, the UK Biotechnology and Biological Sciences Research Council and Carigest SA of Geneva, Switzerland. The Canadian Blood Services research program is funded by the federal, provincial and territorial ministries of health. Experiments were performed at the Faculty of Medicine & Dentistry Flow Cytometry Facility, which receives financial support from Canada Foundation for Innovation awards to contributing investigators. The researchers also acknowledge blood donors for their contributions to research.

References: Minh Doan, Joseph A. Sebastian, Juan C. Caicedo, Stefanie Siegert, Aline Roch, Tracey R. Turner, Olga Mykhailova, Ruben N. Pinto, Claire McQuin, Allen Goodman, Michael J. Parsons, Olaf Wolkenhauer, Holger Hennig, Shantanu Singh, Anne Wilson, Jason P. Acker, Paul Rees, Michael C. Kolios, Anne E. Carpenter, “Objective assessment of stored blood quality by deep learning”, Proceedings of the National Academy of Sciences Sep 2020, 117 (35) 21381-21390; DOI: 10.1073/pnas.2001227117

Provided by University of Alberta

Researchers Discover New Way to Deliver DNA-based Therapies For Diseases (Chemistry)

University of Minnesota Twin Cities researchers in the Department of Chemistry have created a new polymer to deliver DNA and RNA-based therapies for diseases. For the first time in the industry, the researchers were able to see exactly how polymers interact with human cells when delivering medicines into the body. This discovery opens the door for more widespread use of polymers in applications like gene therapy and vaccine development.

The above image shows cells illuminated by quinine (fluorescent blue) and green fluorescent protein. This allows the University of Minnesota researchers to—for the first time—observe how polymers interact with human cells when delivering medicines. The discovery could be used in advancing DNA and RNA-based treatments such as gene therapy and vaccines. Credit: Reineke Group and Frontiera Group, University of Minnesota

The research is published in the Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed multidisciplinary scientific journal.

Gene therapy involves altering the genes inside the body’s cells to treat or cure diseases. It requires a carrier that “packages” the DNA to deliver it into the cell—oftentimes, a virus is used as a carrier. Packaging of nucleic acids is also used in vaccines, such as the recently developed messenger RNA (mRNA) COVID-19 vaccine, which is enclosed in a lipid.

The research team is led by chemistry professor Theresa Reineke and associate professor Renee Frontiera. Reineke’s lab synthesizes polymers, which are long-chain molecules that make up plastics, to use for packaging the nucleic acids instead.

“It’s kind of like ordering something from Amazon, and it’s shipped in a box,” Reineke explained. “Things get broken if they’re not delivered in a package. That’s basically what we’re doing here but on a nano-level. We’re taking these really sensitive RNA and DNA cargo that are susceptible to enzymatic degradation, that won’t get to their target unless you have something to protect them.”

The researchers designed the copolymer using quinine, a naturally occurring substance used in tonic water, and 2-hydroxyethyl acrylate (HEA), which makes the material soluble and is used in a variety of personal care and medical materials. Because quinine is fluorescent, the research team was able to track the DNA package throughout the body and into the cells using Raman spectroscopy, a chemical imaging technique.

“We’ve discovered a new packaging tool with this natural product that’s important for all of these high-flying, important fields like gene therapy and vaccines,” said Reineke, who is also a Distinguished McKnight University Professor. “And, it works in a variety of cell-types. On top of that, it’s got all of these cool features—it’s fluorescent, we can track it, it’s Raman active, and that allowed us to understand a lot of fundamentals about these packaging systems that were impossible to probe before we incorporated this natural product.”

Polymer-based drug delivery is significantly cheaper than using viruses, especially for gene therapy, which can cost up to $2 million for a single injection. However, the main barrier preventing widespread polymer use was that scientists didn’t know a lot about how the polymer package actually interacts with cells in the body.

This research helps clear up that uncertainty. Frontiera’s lab specializes in chemical imaging. Using Raman spectroscopy, they discovered that a cell’s own proteins play a key role in unpacking the nucleic acid cargo once the polymer carrier enters the cell.

“It’s very satisfying to know how this is actually happening, what the process of delivery is, and to actually see that in real-time,” Frontiera said. “A key point is that these polymers also work very well. For all the beneficial attributes, they’re also incredibly effective at getting the payload into cells, and we were able to tell why, which doesn’t always happen in this field.”

Reineke and Frontiera have been collaborating since 2013. Reineke’s lab has patented the quinine polymers, and the researchers hope that a company might license this technology in the future. The College of Science and Engineering team also collaborated with University of Minnesota Medical School professor Jakub Tolar to test the effectiveness of the polymer carriers in relevant cell types.

Other members of the research team include chemistry researchers Craig Van Bruggen (Ph.D. student) and David Punihaole (postdoctoral associate), chemical engineering and materials science student Andrew Schmitz, and genetics Ph.D. student Allison Keith. This research was funded by the National Science Foundation and the National Institutes of Health.

Read the full research paper entitled “Quinine copolymer reporters promote efficient intracellular DNA delivery and illuminate a protein-induced unpackaging mechanism” on the PNAS website.

References: Craig Van Bruggen, David Punihaole, Allison R. Keith, Andrew J. Schmitz, Jakub Tolar, Renee R. Frontiera, Theresa M. Reineke, “Quinine copolymer reporters promote efficient intracellular DNA delivery and illuminate a protein-induced unpackaging mechanism”, Proceedings of the National Academy of Sciences Dec 2020, 202016860; DOI: 10.1073/pnas.2016860117

Provided by University of Minnesota

World’s First Transmission of 1 Petabit/s Using a Single-core Multimode Optical Fiber (Engineering)

Points

  • A world record transmission of 1 petabit per second in a multimode optical fiber increases the current record data rate in multimode optical fibers by more than 2.5 times.
  • Wideband optical transmission in fibers with more 15 modes is demonstrated for the first time, enabled by mode multiplexers and a transmission fiber optimized for high optical bandwidth.
  • This demonstration advanced high-density and large capacity transmission in optical fibers that can be produced with standard methods.

Abstract

A group of researchers from the Network System Research Institute of the National Institute of Information and Communications Technology (NICT, Japan) led by Georg Rademacher, NOKIA Bell Labs (Bell Labs, USA) led by Nicolas K. Fontaine and Prysimian Group (Prysimian, France) led by Pierre Sillard succeeded in the world’s first transmission exceeding 1 petabit per second in a single-core multi-mode optical fiber. This increases the current record transmission in a multi-mode fiber by a factor of 2.5.

Previous high capacity demonstrations in multi-mode fibers © National Institute of Information and Communications Technology (NICT)

To date, transmission experiments in optical fibers supporting large number of modes was limited to small optical bandwidths. In this study, we demonstrated the possibility of combining highly spectral efficient wideband optical transmission with an optical fiber guiding 15 fiber modes that had a cladding diameter in agreement with the current industry standard of 0.125 mm. This was enabled by mode multiplexers and an optical fiber that supported wideband transmission of more than 80 nm over a distance of 23 km. The study highlights the large potential of single-core multi-mode fibers for high capacity transmission using fiber manufacturing processes similar to those used in the production of standard multi-mode fibers.

The results of this study were accepted for the post-deadline session at the 46th European Conference on Optical Communication (ECOC 2020).

Background

Over the past decade, intensive research was carried out worldwide to increase the data rates in optical transmission systems using space-division multiplexing in order to accommodate the exponentially increasing data transmission requirements. Compared to multi-core optical fibers, multi-mode fibers can support a higher spatial-signal-density and are easier to manufacture. However, using multi-mode fibers for high capacity space-division multiplexed transmission requires the use of computationally intensive digital signal processing. These requirements increase with the number of transmission modes and realizing transmission systems supporting large number of fiber modes is an active field of research.

Achievements

At NICT, a transmission experiment was designed and carried out that utilized the transmission fiber made by Prysmian and mode multiplexers developed by Bell Labs. A wideband transceiver subsystem was developed at NICT to transmit and receive several hundred highly spectral efficient WDM channels of high signal quality. The novel mode multiplexers were based on a multi-plane light conversion process where the light of 15 input fibers was reflected multiple times on a phase plate to match the modes of the transmission fiber. The transmission fiber was 23 km long and had a graded-index design. It was based on existing multi-mode fiber designs that were optimized for wideband operation and had a cladding diameter of 0.125 mm and a coating diameter of 0.245 mm, both adhering to the current industry standard. The transmission system demonstrated the first transmission exceeding 1 petabit per second in a multi-mode fiber increasing the current record demonstration by a factor of 2.5.

Experimental setup © National Institute of Information and Communications Technology (NICT)

When increasing the number of modes in a multi-mode fiber transmission system, the computational complexity of the required MIMO digital signal processing increases. However, the used transmission fiber had a small modal delay, simplifying the MIMO complexity and maintained this low modal delay over a large optical bandwidth. As a result, we could demonstrate the transmission of 382 wavelength channels, each modulated with 64-QAM signals. The success of large-capacity transmission using a single-core multimode optical fiber, which has a high spatial signal density and easy manufacturing technology, is expected to advance high-capacity multimode transmission technology for future high capacity optical transmission systems.

Future Prospects

In the future, we would like to pursue the possibility of extending the distance of large-capacity multi-mode transmission and integrating it with multi-core technology to establish the foundation of future optical transmission technology with large capacity.

The paper on the results of this experiment was published at the 46th European Conference on Optical Communication (ECOC2020, December 6th – 10th 2020), which is one of the largest international conferences related to optical fiber communication. It was planned to be held in Brussels, Belgium but had to be conducted virtually due to the Novel Corona Virus epidemic. The paper received a very high evaluation from and was adopted for presentation in a special session for the latest research (Post Deadline Paper) that took place on the 10th of December.

References

Georg Rademacher, Benjamin J. Puttnam, Ruben S. Luís, Tobias A. Eriksson, Nicolas K. Fontaine,  Mikael Mazur, Haoshuo Chen, Roland Ryf, David T. Neilson, Pierre Sillard, Frank Achten, Yoshinari Awaji, and Hideaki Furukawa, “1.01 Peta-bit/s C+L-band transmission over a 15-mode fiber”, International Conference: European Conference on Optical Communication(ECOC2020).

Provided by National Institute of Information and Communications Technology

Key Building Block for Organic Molecules Discovered in Meteorites (Planetary Science)

Scientists from Japan and NASA have confirmed the presence in meteorites of a key organic molecule which may have been used to build other organic molecules, including some used by life. The discovery validates theories of the formation of organic compounds in extraterrestrial environments.

The chemistry of life runs on organic compounds, molecules containing carbon and hydrogen, which also may include oxygen, nitrogen and other elements. While commonly associated with life, organic molecules also can be created by non-biological processes and are not necessarily indicators of life. An enduring mystery regarding the origin of life is how biology could have arisen from non-biological chemical processes, called prebiotic chemistry. Organic molecules from meteorites may be one of the sources of organic compounds that led to the emergence of life on Earth.

Photo of a piece of the Murchison meteorite that was used in this study. Credits: NASA

Associate Professor Yasuhiro Oba from Hokkaido University, Japan, led an international team of researchers who discovered the presence of a prebiotic organic molecule called hexamethylenetetramine (HMT) in three different carbon-rich meteorites. Their discovery validates models and theories that propose HMT as an important molecule in the formation of organic compounds in interstellar environments.

“HMT is a key piece of a puzzle which draws the whole picture of chemical evolution in space,” said Oba, lead author of a paper about the research published December 7 in the journal Nature Communications. “To explain the formation of meteoritic organic molecules such as amino acids and sugars, two easily vaporized (volatile) molecules, formaldehyde and ammonia, are necessary in asteroids, the parent bodies of many meteorites. However, since they are easily lost from asteroidal environments due to their high volatility, scientists question how enough could have been available to build the meteoritic organic molecules being found. HMT does not vaporize even at room temperature, and it can produce both molecules if it is heated with liquid water inside asteroids. Finding HMT in meteorites confirms the hypothesis that it is a stable source for ammonia and formaldehyde in asteroids.”

Early in the solar system’s history, many asteroids could have been heated by collisions or the decay of radioactive elements. If some asteroids were warm enough and had liquid water, HMT could have broken down to provide building blocks such as formaldehyde and ammonia that in turn reacted to make other important biological molecules which have been found in meteorites, including amino acids. Some types of amino acids are used by life to make proteins, which are used to build structures like hair and nails, or to speed up or regulate chemical reactions.

“These results shed light on the various ways amino acids can form in extraterrestrial environments,” said Jason Dworkin, a co-author of the paper at NASA’s Goddard Space Flight Center in Greenbelt, Maryland. “This can be explored further when comparing the samples from Japan’s Hayabusa2 and NASA’s OSIRIS-REx missions. These spacecraft collected material from asteroids with what appears to be different histories of liquid water. If there is a mission to return a sample from a comet nucleus someday, perhaps we can see if there is a connection between HMT in comets and asteroids.”

While the diversity of organic compounds in meteorites is well-documented, many questions remain about the processes by which these compounds were formed. The most important meteorites in this area of research are carbonaceous chondrites, stony meteorites that contain high percentages of water and organic compounds. Experimental models have shown that a combination of water, ammonia and methanol, when subjected to photochemical and thermal conditions common in extraterrestrial environments, give rise to a number of organic compounds, the most common of which is HMT. Interstellar ice is rich in methanol. Hypothetically, HMT should be common in water-containing extraterrestrial materials, but, until this study, it had not been detected.

HMT is likely to break apart when exposed to processes commonly used in the analysis of organic compounds in meteorites, and therefore, may not have been detected in other studies even though it was present. The scientists developed a method that specifically extracted HMT from meteorites with minimal breakdown. This method allowed them to isolate significant quantities of HMT and HMT derivatives from the meteorites Murchison, Murray and Tagish Lake.

Daniel Glavin gets ready to powder the Murchison meteorite in a HEPA filtered laminar flow bench at NASA’s Goddard Space Flight Center. Credits: NASA

Since Earth has abundant life, the researchers had to be confident that the HMT found in the meteorites was in fact extraterrestrial, and not just from contamination by terrestrial life. “The Murchison fragment used in this study was from the Chicago Field Museum that had been stored for many years inside a sealed container, and is the least contaminated and most pristine piece of Murchison we have ever studied for amino acids, giving us more confidence that the HMT detected in this meteorite is in fact extraterrestrial in origin,” said Daniel Glavin of NASA Goddard, a co-author on the study.

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP15H05749, JP16H04083, JP17H04862, JP20H00202), the National Aeronautics and Space Administration (NASA) Astrobiology Institute through the Goddard Center for Astrobiology (13-13NAI7-0032), NASA’s Planetary Science Division Internal Scientist Funding Program through the Fundamental Laboratory Research (FLaRe) work package at NASA Goddard Space Flight Center, and the Simons Foundation (SCOL award 302497).

Yasuhiro Oba is part of the Astrophysical Chemistry/Ice & Planetary Science Group at the Institute of Low Temperature Science, where he studies chemical evolution of compounds at scales from molecular clouds to planetary systems.

Provided by NASA/GODDARD Space Flight Center

Recently Discovered Comet Seen During 2020 Total Solar Eclipse (Planetary Science)

As Chile and Argentina witnessed the total solar eclipse on Dec. 14, 2020, unbeknownst to skywatchers, a little tiny speck was flying past the Sun — a recently discovered comet.

(left) The LASCO C2 camera on the ESA/NASA SOHO observatory shows comet C/2020 X3 (SOHO) in the bottom left-hand corner. (right) A composite image of the total solar eclipse on Dec. 14, 2020, based on 65 frames taken by Andreas Möller (Arbeitskreis Meteore e.V.) in Piedras del Aguila, Argentina, and processed by Jay Pasachoff and Roman Vanur. Credits: ESA/NASA/SOHO/Andreas Möller (Arbeitskreis Meteore e.V.)/processed by Jay

This comet was first spotted in satellite data by Thai amateur astronomer Worachate Boonplod on the NASA-funded Sungrazer Project — a citizen science project that invites anyone to search for and discover new comets in images from the joint European Space Agency (ESA) and NASA Solar and Heliospheric Observatory, or SOHO.

Boonplod discovered the comet on Dec. 13, the day before the eclipse. He knew the eclipse was coming, and was eager to see whether his new comet discovery might appear in the Sun’s outer atmosphere as a small speck in eclipse photographs.

The recently discovered comet C/2020 X3 (SOHO) seen in the LASCO C2 camera on the ESA/NASA SOHO observatory. Credits: ESA/NASA/SOHO/Karl Battams

The comet, named C/2020 X3 (SOHO) by the Minor Planet Center, is a “Kreutz” sungrazer. This family of comets originated from a large parent comet that broke up into smaller fragments well over a thousand years ago and continues to orbit around the Sun today. Kreutz sungrazing comets are most commonly found in SOHO images. SOHO’s camera works by mimicking total solar eclipses: A solid occulting disk blocks out the otherwise blinding light of the Sun, revealing dimmer features in its outer atmosphere and other celestial objects like comets. To date, 4,108 comets have been discovered in SOHO images, with this comet being the 3,524th Kreutz sungrazer spotted.

Around the time the eclipse image was taken, the comet was traveling at roughly 450,000 miles per hour, about 2.7 million miles from the Sun’s surface. The comet was around 50 feet in diameter — about the length of a semitruck. It then disintegrated to dust particles due to intense solar radiation, a few hours before reaching its closest point to the Sun.

Provided by NASA/Goddard Space Flight Center

Discovery Finds a Cellular Building Block Acts As a Gel, Not Liquid As Previously Believed (Medicine)

Landmark discovery of the physical state of complex DNA and protein “packages”–called chromatin–in a cell’s nucleus could lead to better understanding of diseases such as cancer.

University of Alberta researchers have found an answer to a fundamental question in genomic biology that has eluded scientists since the discovery of DNA: Within the nucleus of our cells, is the complex package of DNA and proteins called chromatin a solid or a liquid?

BSIP/UIG/Getty Images

In a study published in the journal Cell, the research team, led by Department of Oncology professor Michael Hendzel and collaborator Jeffrey Hansen from Colorado State University, found that chromatin is neither a solid nor a liquid, but something more like a gel.

Previously, fields such as biochemistry operated under the assumption that chromatin and other elements of the nucleus operated in a liquid state, Hendzel said. This new understanding of the physical properties of chromatin challenges that idea, and could lead to a more accurate understanding of how the genome is encoded and decoded.

“We all know the difference between water and ice, and we all understand that if you want to tie two things together, for example, you can’t do it with a liquid. You need a rope, something that has mechanical strength,” said Hendzel, who is also a member of the Cancer Research Institute of Northern Alberta (CRINA). “That’s what we’re talking about here. Right now, all of our understanding of gene regulation is largely based on the assumption of freely moving proteins that find DNA and whose accessibility is only regulated by the blocking of that movement. So this research could potentially lead to very different kinds of ways of understanding gene expression.”

“Another way to look at it is that bone, muscle and connective tissue all have very different physical properties, and if those physical properties break down somehow, it’s almost always associated with disease,” said Alan Underhill, associate professor in the Department of Oncology, CRINA member and contributor to the study. “In the case of chromatin, it’s about scaling this principle down to the level of the cell nucleus, because it is all connected.”

“What we’re seeing here bridges the biochemistry of cellular contents and the underlying physics, allowing us to get at the organizational principles–not just for cells, but the entire body,” he added.

All of our chromosomes are made from chromatin, which is half histone (or structural) proteins and half DNA, organized into long strings with bead-like structures (nucleosomes) on them. Inside the nucleus of a cell, the chromatin fibre interacts with itself to condense into a chromosome. The chromatin fibre also supports gene expression and replication of chromosomal DNA. Although there is some understanding of the structures that make up a nucleus, how those structures are organized and the full extent of how the structures interact with each other is not well known.

The team’s findings bridge research done over the past 50 years on chromatin gels produced in the laboratory to demonstrate its existence in living cells, which has major implications for interpreting their elastic and mechanical properties, Hendzel explained.

For example, recent studies have shown that the deformability of chromatin in cancer cells is an important determinant of their ability to squeeze through small spaces to travel outside a tumour and metastasize elsewhere in the body–something that is much easier to explain if chromatin is gel-like rather than a liquid. Cancer cells do that by chemically changing the histone part of the chromatin to make it less sticky, Hendzel said.

Based on the new research, this can now be explained as a process that reduces the strength of the gel, making it more deformable and enabling cancer cells to spread through the body. Defining how this gel state is regulated could lead to new approaches to prevent metastasis by finding drugs that maintain the chromatin gel in a more rigid state.

A better understanding of chromatin could also affect cancer diagnosis, Underhill said.

“The texture and appearance of chromatin is something pathologists have used to do clinical assessment on tumour samples from patients,” he said. “It’s really looking at how the chromatin is organized within the nucleus that allows them to make insight into that clinical diagnosis. So now that’s a process that we can reframe in a new context of the material state of the chromatin.”

Hendzel said he is confident the discovery of the gel-like state of chromatin will provide a guiding principle for future research seeking to understand how the material properties of chromatin shape the function of the nucleus to ensure the health of cells and the organisms they make up.

“One of the most significant things to me is that this research highlights how limited our knowledge is in this area,” he said. “Currently, we are focused on testing the widely held belief that the physical size of molecules determines their ability to access the DNA. Our ongoing experiments suggest that this too may be incorrect, and we are quite excited about learning new mechanisms that control access to DNA based on the properties of the chromatin gel and the liquid microenvironments that assemble around it.”

“I think it forces us to go back and look at what’s in textbooks and reinterpret a lot of that information in the context of whether ‘this is a liquid,’ or ‘this is a gel’ in terms of how the process actually takes place,” added Underhill. “That will have a lot of impact on how we actually think about things moving forward and how we design experiments and interpret them.”

The research was supported by grants from the National Science Foundation, the Canadian Institutes of Health Research and the Cancer Research Society.

Provided by University of Alberta Faculty of Medicine and dentistry

Blood Pressure Drug May Be Key to Increasing Lifespan, New Study Shows (Medicine)

Metolazone, a drug used to treat hypertension, activates a mitochondrial stress response that prolongs lifespan in the roundworm Caenorhabditis elegans.

A stress response of mitochondria, the part of our cells that produce energy to power bodily functions, is important to a longer life. A team of scientists from Osaka City University, Japan, searched through a chemical “library” of existing drugs to find one that can activate this stress response in the worm Caenorhabditis elegans. They found that an anti-hypertension drug called metolazone prolongs C. elegans lifespan, marking the first step in developing anti-aging pharmaceuticals.

Credit: Eriko Kage-Nakadai, Osaka City University

Since time immemorial, people have been fascinated by ways to stop aging. Nearly every culture has stories to tell about people who lived for thousands of years, showing that extending lifespan has always been a deep desire across humanity. While modern medicine does not strive to find the fountain of youth, keen interest in promoting longevity has prompted research into the mechanisms of aging and the possibility of anti-aging drugs. Researchers now know that mitochondria play an important role in aging. Specifically, when mitochondria are harmed in some way and their function is impaired, a process called mitochondrial unfolded protein response (UPRmt) occurs that repairs mitochondria and benefits cell survival. Therefore, some scientists think it is possible to increase lifespan by identifying drugs that activate UPRmt.

Dr. Eriko Kage-Nakadai and her colleagues from Osaka City University in Japan are one of the many research teams fascinated by aging research. As Dr. Kage-Nakadai explains, “Even though aging is not a disease, drugs may slow down aging and mitigate or prevent its negative effects on our health.” Current research shows promising signs. Experiments with Caenorhabditis elegans—a worm commonly used in biological research as a model—have found several compounds that increase the worm’s lifespan by triggering UPRmt.

Against the backdrop of these previous studies, this team, in their new study published in Biogerontology, screened about 3,000 drugs in worms that are engineered to glow if drug treatment activates hsp-6, a gene that is highly expressed when UPRmt occurs. It is interesting to note that of these 3000 drugs, 1300 were off-patent drugs approved by the USFDA, EMA, and other agencies, and the remaining 1700 were unapproved bioactive ones.

Through this method, Dr. Kage-Nakadai’s team identified metolazone, a drug used to treat heart failure and high blood pressure. They then tested the drug on C. elegans and found that it increased wild-type worm lifespan. Additionally, they found that metolazone did not extend lifespans in worms in whom the genes atfs-1, ubl-5, and nkcc-1 were mutated (non-working). The former two genes are known to be essential for UPRmt function, suggesting that metolazone is acting on the UPRmt pathway. The third gene, nkcc-1, encodes a protein that is part of a protein family targeted by metolazone in its usual function as an anti-hypertension drug. The fact that metolazone did not increase the lifespans of nkcc-1 mutated C. elegans suggests that the drug may need to block the nkcc-1 protein to activate the UPRmt pathway. Furthermore, metolazone induced hsp-6 (Hspa9 in humans) expression in HeLa cells (a human cell line commonly used in biological research), suggesting that the drug’s UPRmt-related effects possibly span multiple species.

When asked about the broader significance of her work, Dr. Kage-Nakadai comments, “What is particularly exciting is that we tested already available approved drugs here, and we have revealed the potential of repurposing existing drugs for aging control. Worms always give us many hints.”

As the researchers state, this work is just the start, but it opens up a new road to a future of anti-aging drugs. Perhaps a future where humans live longer than the expected 120 years is one step closer to becoming a reality.

This work was funded by Osaka City University Strategic Research Grant 2018 and 2020 and the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 18K10998.

References: Ito, A., Zhao, Q., Tanaka, Y. et al. Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans. Biogerontology (2020). https://link.springer.com/article/10.1007%2Fs10522-020-09907-6 https://doi.org/10.1007/s10522-020-09907-6

Provided by Osaka City University

New Discovery Brings Analogue Spintronic Devices Closer (Physics)

The observation of nonlinearity in electron spin-related processes in graphene makes it easier to transport, manipulate and detect spins, as well as spin-to-charge conversion. It also allows analogue operations such as amplitude modulation and spin amplification. This brings spintronics to the point where regular electronics was after the introduction of the first transistors. These results by University of Groningen physicists were published in the journal Physical Review Applied on 17 December.

This EM image of an experimental device as used in this study shows graphene (light green) with boron nitride (blue) on top. Measurements were made across the orange lines. © S. Omar, University of Groningen

Spintronics is a type of electronics that uses the spin of electrons (a magnetic moment that can have the values ‘up’ or ‘down’) to transport signals. Spin transport in the 2D carbon material graphene is excellent; however, manipulation of spins is not. This requires the addition of ferromagnets (for spin injection and detection) or heavy-atom materials with high spin-orbit coupling, which allow the manipulation of spins.

Nonlinear

Scientists from the University of Groningen have now shown that nonlinear effects that are particular to electron spin can be achieved using 2D boron nitride. Previously, they had already shown that injecting a current through a boron nitride bilayer, to which a small DC bias current was applied, resulted in a very high spin polarization, which means that there is a large difference between the numbers of spin-up and spin-down electrons. They have now shown that the polarization increase can be attributed to nonlinear processes that influence the electron spins.

The nonlinearity means that two spin signals multiply, rather than add up (which would be a linear effect). Furthermore, in the nonlinear regime, spin signals can be measured without using ferromagnets. Earlier, all these effects were either absent or very weak in a typical graphene spintronic device. ‘All because of this nonlinear effect, which increases in proportion with the bias current,’ says Siddhartha Omar, a former postdoctoral researcher at the University of Groningen and first author of the paper. ‘Polarization can even reach 100 per cent. Since it is nonlinear, you give less and get more during the injection when this current is applied.’

Neuromorphic

In the study, Omar and his colleagues in the Physics of Nanodevices group at the Zernike Institute for Advanced Materials, University of Groningen, show applications of the nonlinear effect for basic analogue operations, such as essential elements of amplitude modulation on pure spin signals. ‘We believe that this can be used to transport spin over larger distances. The larger spin signal also makes spin-charge conversion easier and that means that we no longer need ferromagnets to detect them.’

This is Dr. Siddhartha Omar, first author of the study published in Physical Review Applied © University of Groningen

The ability to modulate a spin signal, rather than just switch it on or off, also makes it easier to construct spintronic devices. Omar: ‘They could be used in spin-based neuromorphic computing, which uses switches that can have a range of values, rather than just 0 or 1.’ It also seems possible to create a spin current amplifier, which produces a large spin current with a small bias voltage. ‘It may be there already, but we still have to prove it,’ says Omar.

Spintronics

All these effects were measured both at low temperatures and at room temperature and could be used in applications such as nonlinear circuit elements in the fields of advanced spintronics. ‘Spintronics is now at the point where regular electronics was after the introduction of the first transistors. We could now build real spintronic devices,’ concludes Omar.

References: S. Omar, M. Gurram, K. Watanabe, T. Taniguchi, M.H.D. Guimaraes, and B.J. van Wees: Nonlinear analog spintronics with van der Waals heterostructures. Physical Review Applied 17 December 2020. https://journals.aps.org/prapplied/abstract/10.1103/PhysRevApplied.14.064053

Provided by University of Groningen