Molecular Tug-of-war Gives Cells Their Shape

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Published: Friday, November 04 2022 01:00

In a new study, University of Maryland researchers have demystified the process by which cells receive their shape—and it all starts with a protein called actin.

Actin is a key component of the cytoskeleton that provides structure to cells, much like how our skeletons support our bodies. However, unlike our skeleton, the actin cytoskeleton is a highly malleable structure that can rapidly assemble and disassemble in response to biochemical and biophysical cues. 

It is well known that actin can form both 3D spherical shell-like structures that protect cells from external pressure and 2D rings that modify intracellular functions. But whenever researchers tried to recreate these structures outside the cell, they almost always ended up with clusters of actin. No one knew why—until now.

The researchers used computer simulations to show that actin and its partner protein, myosin, engage in a tug-of-war, with myosin trying to trap actin in local clusters and actin attempting to flee. If actin wins, actin filaments escape myosin’s pulling force and spontaneously form rings and spherical shells. If myosin wins, the actin network collapses and forms dense clusters. 

Actin (shown in magenta and in box “a”) and myosin (shown in green and in box “b”) are depicted in the actin rings of live T cells (box “c”). Box “d” provides a snapshot of MEDYAN simulations, which resemble the actin ring found in T cells. Credit: Haoran Ni.  

“Actin rings and spherical shells are ubiquitous in almost all cell types across species. We think that understanding the mechanism behind the formation of these structures unlocks the door to how cells sense and respond to their environment,” said Garegin Papoian, a co-author of the study and a UMD Monroe Martin Professor in the Department of Chemistry and Biochemistry and the Institute for Physical Science and Technology (IPST).

Their findings, published Oct. 21, 2022 in the journal eLife, could have important implications for human health. Because actin rings are central to our bodies’ ability to fight off foreign cells—with defects potentially resulting in impaired immunity or autoimmune disorders—the findings of this study could aid the development of future drugs.

Actin monomers can be thought of as railroad cars, which link up to form a train-like actin filament. These actin trains move through the cell because of a process called treadmilling. Also at play are the myosin motors, which pull oppositely oriented trains toward each other. Papoian, Qin Ni (Ph.D. ’21, chemical engineering) and biophysics Ph.D. student Haoran Ni believed that a competition between myosin’s pulling force and the rate of treadmilling was responsible for the formation of actin rings.

Fine-tuning these parameters in living cells is not possible, so the researchers turned to a simulation software called MEDYAN, developed by the Papoian Lab. MEDYAN uses physics and chemistry rules to simulate the dynamics of cytoskeletal proteins. They simulated an actin and myosin network (collectively referred to as actomyosin) in a thin disc and spherical shell.

They found that if the actin trains move slowly, the myosin pulling force causes traffic jams, which are the actomyosin clusters that have been observed in networks reconstituted outside cells. On the other hand, if the actin trains move fast, they can escape myosin’s pull. Once they reach the boundary of the disc, myosin’s pulling force makes the actin trains turn, preventing a head-on collision with the disc edge. Repeated occurrence of these events results in all the trains moving in a circle along the perimeter of the disc, which forms the actin ring.

Further analysis offers a thermodynamic theory to explain why cells form rings and shells. According to the laws of physics, systems favor the lowest energy configuration. Myosin proteins generate a lot of mechanical energy by bending actin filaments, which can only be released if actin can run away and relax. In living cells, actin’s ability to move fast enough to escape myosin and run to the edge allows for this built-up energy to be released, allowing for the formation of rings or shells, which, thermodynamically speaking, is the lowest energy configuration.

“The reason rings were not previously seen outside the cell is because actin just wasn’t moving fast enough,” Papoian said. “Myosin was winning 10 times out of 10.”

Together with Professor Arpita Upadhyaya and physics graduate student Kaustubh Wagh, biological sciences graduate student Aashli Pathni and biophysics graduate student Vishavdeep Vashisht, the team set out to test this model in living cells by turning their attention to T cells, where rings naturally form.

T cells are the cells in our body that hunt down foreign cells. When they recognize a cell as foreign and become activated, the T cell cytoskeleton rapidly reorganizes itself to form an actin ring at the cell-cell interface. Starting with cells that had formed rings, the researchers investigated the effect of perturbing actin and myosin using high-resolution live-cell imaging.

Reducing the actin train speed resulted in dissolution of the ring into small clusters, while increasing myosin’s pulling force led to rapid contraction of the ring, in remarkable agreement with associated simulations.

As a follow-up to this study, the team plans to add more complexity to the model and include other cytoskeletal components and organelles.

“We have been able to capture one fundamental aspect of cytoskeletal organization,” Papoian said. “Piece by piece, we plan to build a computational model of a complete cell using fundamental principles from physics and chemistry.”

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Original story:https://cmns.umd.edu/news-events/features/5000

This article is adapted from text provided by Qin Ni and Kaustubh Wagh.

The research paper, “A tug of war between filament treadmilling and myosin induced contractility generates actin rings,” was published in eLife on Oct. 21, 2022.  

This work was supported by the National Science Foundation (Award Nos. CHE-1800418, PHY-1806903 and PHY-1607645) and the National Institutes of Health (Award No. R01 GM131054). This story does not necessarily reflect the views of these organizations.

Media Relations Contact: Emily C. Nunez, 301-405-9463, This email address is being protected from spambots. You need JavaScript enabled to view it.

UMD Team Leads a New Test of Universality of Leptons at the LHCb Experiment

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Published: Wednesday, October 19 2022 02:53

The LHCb collaboration has presented a new test of the universality of the electroweak properties of leptons.

Nearly seven years of analysis of LHCb data by University of Maryland physicists Phoebe Hamilton and Hassan Jawahery and CERN collaborator Greg Ciezarek led to the results unveiled October 18, 2022 at a seminar at CERN and presented the next day at a flavor physics workshop at CERN.The results reflect analysis of seven years of data by Phoebe Hamilton and Hassan Jawahery and their CERN collaborator, Greg Ciezarek.

In 2015, the LHCb team reported on a test of lepton universality with the measurement of a key observable. But the new results represent the first simultaneous measurements of two correlated observables at the LHC collider, significantly improving the sensitivity to new physics effects. This is particularly important for the extensions of the Standard Model that contain additional Higgs bosons. The results are consistent with previous measurements, which hinted at deviation from lepton universality.  The combined values are at 3.2 standard deviation from the Standard Model. 

These studies are a major theme of the physics program of the Maryland group in LHCb with the current and the future data with the upgraded detector. Over the past decade they have carried out a broad program of studies of lepton flavor universality in decays of particles containing the b quark, which have been published in PRL and highlighted in the CERN Courier and Symmetry magazine.  Professor Manuel Franco Sevilla, whose PhD thesis work at BaBar provided the first hint of deviation of these observables from universality, has recently co-authored a comprehensive review of the past studies and the prospects for future measurements in Review of Modern Physics. 

Quantum Gases Keep Their Cool, Prompting New Mysteries

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Published: Tuesday, September 27 2022 02:46

Beyond Higgs: The Search for New Particles That Could Solve Mysteries of the Universe

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Published: Wednesday, September 07 2022 00:01

An elusive elementary particle called the Higgs boson is partly to thank for life as we know it. No other elementary particles in the early universe had mass until they interacted with a field associated with the Higgs boson, enabling the emergence of planets, stars and—billions of years later—us.

Despite its cosmic importance, scientists couldn’t prove the Higgs boson even existed until 2012, when they smashed protons together at the most powerful particle accelerator ever built: the Large Hadron Collider (LHC). A decade later, this massive machine, built in a tunnel beneath the France-Switzerland border, is up and running again after a series of upgrades. 

As the search for new particles starts anew, researchers like Assistant Professor of Physics Manuel Franco Sevilla find themselves wondering if they will discover anything beyond Higgs.UMD Assistant Professor of Physics Manuel Franco Sevilla is helping to upgrade the Large Hadron Collider (LHC) at CERN in Switzerland. In the above photo, he is shining a light on silicon sensors to measure whether their dark current increases—a sign that they are properly connected. Photo courtesy of Manuel Franco Sevilla.

“It’s a tough question because particle physics is at a juncture,” said Franco Sevilla, who is working at the LHC this semester. “It’s possible that we are currently in what physicists call a ‘nightmare scenario,’ where we discovered the Higgs, but after that, there’s a big desert. According to this theory, we will not be able to find anything new with our current technology.”

This is the worst-case scenario, but not the only possible outcome. Some scientists say the LHC could make another discovery on par with the Higgs boson, potentially identifying new particles that explain the origin of dark matter or the mysterious lack of antimatter throughout the universe. Others say new colliders—more powerful and precise than their predecessors—must be built to bring the field into a new era.

There are no easy answers, but Franco Sevilla and several other faculty members in UMD’s Department of Physics are rising to the challenge. Some are working directly with the LHC and future collider proposals, while others are developing theories that could solve life’s biggest mysteries. All of them, in their own way, are advancing the ever-changing field of particle physics.

Looking For Beauty

As Franco Sevilla will tell you, there’s beauty all around—if you know where to look. He is one of the researchers who uses the LHC’s high-powered collisions to study a particle called the beauty quark—b quark for short. It’s one of the components of “flavor physics,” which observes the interactions between six “flavors,” or varieties, of elementary particles called quarks and leptons. 

Because these particles sometimes behave in unexpected ways, Franco Sevilla believes that flavor physics might lead to breakthroughs that justify future studies in this field—and possibly even the need for a new particle collider. 

“Some of the most promising things that will break the ‘nightmare scenario’ and allow us to find something are coming from flavor physics,” he said. “We still haven't fully discovered something new, but we have a number of hints, including the famous ‘b anomalies.’”

These anomalies are instances where the b quark decayed differently than predicted by the Standard Model, the prevailing theory of particle physics. This suggests that something might exist beyond this model—which, ever since the 1970s, has helped explain the fundamental particles and forces that shape our world.

Some mysteries remain, though. Physicists still don’t know the origin of dark matter—an enigmatic substance that exerts a gravitational force on visible matter—or why there’s so much matter and so little antimatter in the universe.

Sarah Eno, a UMD physics professor who has conducted research at particle accelerators around the world, including the LHC, said these answers will only come from collider experiments.Sarah Eno, a physics professor at UMD, sits atop a model of a Large Hadron Collider (LHC) dipole magnet at CERN about 10 years ago. At the time, she was participating in LHC experiments and frequently spent her summers at the lab in Switzerland. Credit: Meenakshi Narain.
“What is the nature of dark matter? Nobody has any idea,” Eno said. “We know it interacts via gravity, but we don’t know whether it has any other kinds of interactions. And only an accelerator can tell us that.”

Better, Faster, Stronger

After the third (and current) run of the LHC ends, the collider’s accelerator will be upgraded in 2029 to “crank up the performance,” according to the European Organization for Nuclear Research (CERN), which houses the collider.

With the added benefit of stronger magnets and higher-intensity beams, this final round of experiments could be a game-changer. But once that ends, Eno said the LHC will have reached its limit in terms of energy output, lowering the odds of any new discoveries. The logical next step, she said, would be to construct a new collider capable of propelling the field of particle physics forward.

“The field is now trying to decide what the next machine is,” Eno said.

Around the globe, there are various proposals on the table. There is a significant push for another proton collider in the same vein as the LHC, except bigger and more powerful. Electron-positron colliders—both linear and circular in shape—have also been proposed in China, Japan and Switzerland.

Eno is one of the physicists leading the charge for the construction of an electron-positron collider at CERN. It would be the first stage of the proposed Future Circular Collider (FCC), which would be four times longer than the LHC. By the late 2050s, it would be upgraded to a proton collider, with an energy capacity roughly seven times that of the LHC. Eno, who was appointed one of the U.S. representatives for this project, said the electron-positron collider would allow physicists to study the Higgs boson with significantly higher precision.

“When an electron and positron annihilate, all their energy becomes new states of matter,” Eno said. “This means that when you’re trying to reconstruct the final state, you know the total energy of that final state. This allows you to do much more precise measurements.”

This proposal does come with some challenges. Circular colliders radiate off a lot of energy, making it difficult to accelerate electrons to high energy. Eno said this can be avoided by building a massive collider with a long tunnel (to the tune of 62 miles, in the case of the FCC), preventing electrons from losing steam as they whip around sharp corners.

The radiation problem has pushed some physicists towards another theoretical possibility: a muon collider. Muons are subatomic particles that are like electrons, but 207 times heavier, which keeps them from radiating as much. This would make them ideal candidates for collider research—if only they didn’t decay in 2.2 microseconds.

“If you talk to the muon collider proponents, their faces light up because it’s such a challenge,” Eno said. “And who doesn’t like a challenge?”

Clean Collisions 

One of Eno’s colleagues at UMD—Distinguished University Professor and theoretical physicist Raman Sundrum—endorses the muon collider idea. So much so that he and a team of physicists wrote a paper titled “The muon smasher’s guide,” which appeared in Reports on Progress in Physics in July 2022.

“We build colliders not to confirm what we already know, but to explore what we do not,” the research team wrote in their paper. “In the wake of the Higgs boson’s discovery, the question is not whether to build another collider, but which collider to build.”

They made the case for the world’s first muon smasher, arguing that these collisions would be “far cleaner” than proton collisions, which occur at the LHC. Unlike protons—a composite object made of quarks and gluons—muons are elementary particles with no smaller components. This would let physicists see only what they want to see, without any distractions.

“Muon collisions would make it easier to diagnose what’s going on,” Sundrum said. “When something extraordinary happens, it doesn’t get dwarfed by all of the mundane crashing of many parts.”

Considering that the Higgs boson only appears once in about a billion collisions at the LHC, this level of clarity and precision could make a world of difference. However, the more the field of particle physics advances, the more challenging it is to find something new.

“The Higgs was a needle in the haystack, but discovering newer particles could be even subtler and harder,” Sundrum said.Artistic rendering of the Higgs field. Credit: CERN

Despite these challenges, the LHC could still make a major discovery. Sundrum continues to develop theories that guide and inspire the field, including the idea that the LHC could find a “parent particle” that gave rise to all protons in the universe. If this comes to fruition, it would be worth building new colliders that could validate the LHC’s initial findings and provide a more complete picture of why matter dominates over antimatter in the universe, Sundrum said.

In the coming years and decades, physicists will continue to debate the pros and cons of various collider proposals. The outcome will depend partly on scientific advancements, and partly on political will and funding. Sundrum said it’s not cheap to build a collider—with some projects expected to cost $10 billion—but the discoveries that could come from these experiments are priceless.

“An enormous number of people find it very moving and interesting to know what it’s all about, in terms of where the universe came from, what it means and how the laws work,” Sundrum said. “Individually these experiments are expensive, but as a planet, I think we can easily afford to do it.”

Written by Emily Nunez

Compact Electron Accelerator Reaches New Speeds with Nothing But Light

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Published: Friday, September 02 2022 00:01

Scientists harnessing precise control of ultrafast lasers have accelerated electrons over a 20-centimeter stretch to speeds usually reserved for particle accelerators the size of 10 football fields.

A team at the University of Maryland (UMD) headed by Professor of Physics and Electrical and Computer Engineering Howard Milchberg, in collaboration with the team of Jorge J. Rocca at Colorado State University (CSU), achieved this feat using two laser pulses sent through a jet of hydrogen gas. The first pulse tore apart the hydrogen, punching a hole through it and creating a channel of plasma. That channel guided a second, higher power pulse that scooped up electrons out of the plasma and dragged them along in its wake, accelerating them to nearly the speed of light in the process. With this technique, the team accelerated electrons to almost 40% of the energy achieved at massive facilities like the kilometer-long Linac Coherent Light Source (LCLS), the accelerator at SLAC National Accelerator Laboratory. The paper was published in the journal Physical Review X on September 16, 2022

“This is the first multi-GeV electron accelerator powered entirely by lasers,” says Milchberg, who is also affiliated with the Institute of Research Electronics and Applied Physics at UMD. “And with lasers becoming cheaper and more efficient, we expect that our technique will become the way to go for researchers in this field.”  An image from a simulation in which a laser pulse (red) drives a plasma wave, accelerating electrons in its wake. The bright yellow spot is the area with the highest concentration of electrons. In an experiment, scientists used this technique to accelerate electrons to nearly the speed of light over a span of just 20 centimeters. (Credit Bo Miao/IREAP)

Motivating the new work are accelerators like LCLS, a kilometer-long runway that accelerates electrons to 13.6 billion electron volts (GeV)—the energy of an electron that’s moving at 99.99999993% the speed of light. LCLS’s predecessor is behind three Nobel-prize-winning discoveries about fundamental particles. Now, a third of the original accelerator has been converted to the LCLS, using its super-fast electrons to generate the most powerful X-ray laser beams in the world. Scientists use these X-rays to peer inside atoms and molecules in action, creating videos of chemical reactions. These videos are vital tools for drug discovery, optimized energy storage, innovation in electronics, and much more.  

Accelerating electrons to energies of tens of GeV is no easy feat. SLAC’s linear accelerator gives electrons the push they need using powerful electric fields propagating in a very long series of segmented metal tubes. If the electric fields were any more powerful, they would set off a lightning storm inside the tubes and seriously damage them. Being unable to push electrons harder, researchers have opted to simply push them for longer, providing more runway for the particles to accelerate. Hence the kilometer-long slice across northern California. To bring this technology to a more manageable scale, the UMD and CSU teams worked to boost electrons to nearly the speed of light using—fittingly enough—light itself.

“The goal ultimately is to shrink GeV-scale electron accelerators to a modest size room,” says Jaron Shrock, a graduate student in physics at UMD and co-first author on the work. “You’re taking kilometer-scale devices, and you have another factor of 1000 stronger accelerating field. So, you’re taking kilometer-scale to meter scale, that’s the goal of this technology.”

Creating those stronger accelerating fields in a lab employs a process called laser wakefield acceleration, in which a pulse of tightly focused and intense laser light is sent through a plasma, creating a disturbance and pulling electrons along in its wake. 

“You can imagine the laser pulse like a boat,” says Bo Miao, a postdoctoral fellow in physics at the University of Maryland and co-first author on the work. “As the laser pulse travels in the plasma, because it is so intense, it pushes the electrons out of its path, like water pushed aside by the prow of a boat. Those electrons loop around the boat and gather right behind it, traveling in the pulse’s wake.”

Laser wakefield acceleration was first proposed in 1979 and demonstrated in 1995. But the distance over which it could accelerate electrons remained stubbornly limited to a couple of centimeters. What enabled the UMD and CSU team to leverage wakefield acceleration more effectively than ever before was a technique the UMD team pioneered to tame the high-energy beam and keep it from spreading its energy too thin. Their technique punches a hole through the plasma, creating a waveguide that keeps the beam’s energy focused.

“A waveguide allows a pulse to propagate over a much longer distance,” Shrock explains. “We need to use plasma because these pulses are so high energy, they're so bright, they would destroy a traditional fiber optic cable. Plasma cannot be destroyed because in some sense it already is.”

Their technique creates something akin to fiber optic cables—the things that carry fiber optic internet service and other telecommunications signals—out of thin air. Or, more precisely, out of carefully sculpted jets of hydrogen gas.

A conventional fiber optic waveguide consists of two components: a central “core” guiding the light, and a surrounding “cladding” preventing the light from leaking out. To make their plasma waveguide, the team uses an additional laser beam and a jet of hydrogen gas. As this additional “guiding” laser travels through the jet, it rips the electrons off the hydrogen atoms and creates a channel of plasma. The plasma is hot and quickly starts expanding, creating a lower density plasma “core” and a higher density gas on its fringe, like a cylindrical shell. Then, the main laser beam (the one that will gather electrons in its wake) is sent through this channel. The very front edge of this pulse turns the higher density shell to plasma as well, creating the “cladding.” 

“It's kind of like the very first pulse clears an area out,” says Shrock, “and then the high-intensity pulse comes down like a train with somebody standing at the front throwing down the tracks as it's going.” 

Using UMD’s optically generated plasma waveguide technique, combined with the CSU team’s high-powered laser and expertise, the researchers were able to accelerate some of their electrons to a staggering 5 GeV. This is still a factor of 3 less than SLAC’s massive accelerator, and not quite the maximum achieved with laser wakefield acceleration (that honor belongs to a team at Lawrence Berkeley National Labs). However, the laser energy used per GeV of acceleration in the new work is a record, and the team says their technique is more versatile: It can potentially produce electron bursts thousands of times per second (as opposed to roughly once per second), making it a promising technique for many applications, from high energy physics to the generation of X-rays that can take videos of molecules and atoms in action like at LCLS. Now that the team has demonstrated the success of the method, they plan to refine the setup to improve performance and increase the acceleration to higher energies.

“Right now, the electrons are generated along the full length of the waveguide, 20 centimeters long, which makes their energy distribution less than ideal,” says Miao. “We can improve the design so that we can control where they are precisely injected, and then we can better control the quality of the accelerated electron beam.”

While the dream of LCLS on a tabletop is not a reality quite yet, the authors say this work shows a path forward. “There’s a lot of engineering and science to be done between now and then,” Shrock says. “Traditional accelerators produce highly repeatable beams with all the electrons having similar energies and traveling in the same direction. We are still learning how to improve these beam attributes in multi-GeV laser wakefield accelerators. It’s also likely that to achieve energies on the scale of tens of GeV, we will need to stage multiple wakefield accelerators, passing the accelerated electrons from one stage to the next while preserving the beam quality. So there’s a long way between now and having an LCLS type facility relying on laser wakefield acceleration.” 

This work was supported by the U.S. Department of Energy (DE-SC0015516, LaserNetUS DE-SC0019076/FWP#SCW1668, and DE-SC0011375), and the National Science Foundation (PHY1619582 and PHY2010511).

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Story by Dina Genkina

In addition to Milchberg, Rocca, Shrock and Miao, authors on the paper included Linus Feder, formerly a graduate student in physics at UMD and now a postdoctoral researcher at the University of Oxford, Reed Hollinger, John Morrison, Huanyu Song, and  Shoujun Wang, all research scientists at CSU, Ryan Netbailo, a graduate student in electrical and computer engineering at CSU, and Alexander Picksley, formerly a graduate student in physics at the University of Oxford and now a postdoctoral researcher at Lawrence Berkeley National Lab.