SARS-CoV-2 protein caught severing critical immunity pathway

Powerful X-rays from SLAC’s synchrotron reveal that our immune system’s primary wiring seems to be no match for a brutal SARS-CoV-2 protein.

BY DAVID KRAUSE

Over the past two years, scientists have studied the SARS-CoV-2 virus in great detail, laying the foundation for developing COVID-19 vaccines and antiviral treatments. Now, for the first time, scientists at the Department of Energy’s SLAC National Accelerator Laboratory have seen one of the virus’s most critical interactions, which could help researchers develop more precise treatments.

The team caught the moment when a virus protein, called Mpro, cuts a protective protein, known as NEMO, in an infected person. Without NEMO, an immune system is slower to respond to increasing viral loads or new infections. Seeing how Mpro attacks NEMO at the molecular level could inspire new therapeutic approaches.

To see how Mpro cuts NEMO, researchers funneled powerful X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) onto crystallized samples of the protein complex. The X-rays struck the protein samples, revealing what Mpro looks like when it dismantles NEMO’s primary function of helping our immune system communicate.

“We saw that the virus protein cuts through NEMO as easily as sharp scissors through thin paper,” said co-senior author Soichi Wakatsuki, professor at SLAC and Stanford. “Imagine the bad things that happen when good proteins in our bodies start getting cut into pieces.”

The images from SSRL show the exact location of NEMO’s cut and provide the first structure of SARS-CoV-2 Mpro bound to a human protein.

“If you can block the sites where Mpro binds to NEMO, you can stop this cut from happening over and over,” SSRL lead scientist and co-author Irimpan Mathews said. “Stopping Mpro could slow down how fast the virus takes over a body. Solving the crystal structure revealed Mpro’s binding sites and was one of the first steps to stopping the protein.”

The research team from SLAC, DOE’s Oak Ridge National Laboratory, and other institutions published their results today in Nature Communications.

Read more on the SLAC website

A new leap in understanding nickel oxide superconductors

Researchers discover they contain a phase of quantum matter, known as charge density waves, that’s common in other unconventional superconductors. In other ways, though, they’re surprisingly unique.

BY GLENNDA CHUI

A new study shows that nickel oxide superconductors, which conduct electricity with no loss at higher temperatures than conventional superconductors do, contain a type of quantum matter called charge density waves, or CDWs, that can accompany superconductivity.

The presence of CDWs shows that these recently discovered materials, also known as nickelates, are capable of forming correlated states – “electron soups” that can host a variety of quantum phases, including superconductivity, researchers from the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University reported in Nature Physics today.

“Unlike in any other superconductor we know about, CDWs appear even before we dope the material by replacing some atoms with others to change the number of electrons that are free to move around,” said Wei-Sheng Lee, a SLAC lead scientist and  investigator with the Stanford Institute for Materials and Energy Science (SIMES) who led the study.

“This makes the nickelates a very interesting new system – a new playground for studying unconventional superconductors.”

Nickelates and cuprates

In the 35 years since the first unconventional “high-temperature” superconductors were discovered, researchers have been racing to find one that could carry electricity with no loss at close to room temperature. This would be a revolutionary development, allowing things like perfectly efficient power lines, maglev trains and a host of other futuristic, energy-saving technologies.

But while a vigorous global research effort has pinned down many aspects of their nature and behavior, people still don’t know exactly how these materials become superconducting.

So the discovery of nickelate’s superconducting powers by SIMES investigators three years ago was exciting because it gave scientists a fresh perspective on the problem. 

Since then, SIMES researchers have explored the nickelates’ electronic structure – basically the way their electrons behave – and magnetic behavior. These studies turned up important similarities and subtle differences between nickelates and the copper oxides or cuprates – the first high-temperature superconductors ever discovered and still the world record holders for high-temperature operation at everyday pressures.

Since nickel and copper sit right next to each other on the periodic table of the elements, scientists were not surprised to see a kinship there, and in fact had suspected that nickelates might make good superconductors. But it turned out to be extraordinarily difficult to construct materials with just the right characteristics.

“This is still very new,” Lee said. “People are still struggling to synthesize thin films of these materials and understand how different conditions can affect the underlying microscopic mechanisms related to superconductivity.”

Read more on the SLAC website

Image: An illustration shows a type of quantum matter called charge density waves, or CDWs, superimposed on the atomic structure of a nickel oxide superconductor. (Bottom) The nickel oxide material, with nickel atoms in orange and oxygen atoms in red. (Top left) CDWs appear as a pattern of frozen electron ripples, with a higher density of electrons in the peaks of the ripples and a lower density of electrons in the troughs. (Top right) This area depicts another quantum state, superconductivity, which can also emerge in the nickel oxide. The presence of CDWs shows that nickel oxides are capable of forming correlated states – “electron soups” that can host a variety of quantum phases, including superconductivity.

Credit: Greg Stewart/SLAC National Accelerator Laboratory

Introducing Stephen Streiffer

After decades of experience in the DOE lab system and as director of a leading synchrotron light source, he’s back to where he earned his PhD – with a much bigger mission.

Thirty years after earning his PhD at Stanford University, materials scientist Stephen Streiffer will be back on campus next week – this time with an outsized role to play. As Stanford’s new vice president for the Department of Energy’s SLAC National Accelerator Laboratory, he’ll play a key part in advising and supporting the lab as it carries out its scientific mission.

Streiffer comes to Stanford and SLAC after 24 years at Argonne National Laboratory, where he did research at the lab’s Advanced Photon Source, directed APS for eight years and most recently served as chief research officer and deputy lab director for science and technology.

So he’s more than familiar with both the national lab system and the importance of DOE Office of Science user facilities, like APS and SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) and Linac Coherent Light Source (LCLS), for both fundamental research and experiments with more immediate practical value.

Read Glennda Chui’s Q & A interview with Stephen on the SLAC website

Image: Stephen Streiffer, the new Stanford vice president for SLAC National Accelerator Laboratory

Credit: Mark Lopez, Argonne National Laboratory

Piero Pianetta’s #My1stLight

First light from the SPEAR Ring at SLAC July 6, 1973
Ingolf Lindau & Piero Pianetta

#My1stLight memory submitted by Piero Piantetta, Deputy Director of SSRC at SLAC


Pilot project to extract synchrotron radiation from the SPEAR ring at SLAC. In-alcove video camera imaging light emitted from a fluorescent screen just downstream of the Be exit window. No beam steering beyond global steering for colliding beam operation. Our group, including Gerry Fisher, waiting to see if beam would even make it through all the apertures. SUCCESS on first opening of line!!!!!

How a soil microbe could rev up artificial photosynthesis

Researchers discover that a spot of molecular glue and a timely twist help a bacterial enzyme convert carbon dioxide into carbon compounds 20 times faster than plant enzymes do during photosynthesis. The results stand to accelerate progress toward converting carbon dioxide into a variety of products.

Plants rely on a process called carbon fixation – turning carbon dioxide from the air into carbon-rich biomolecules ­– for their very existence. That’s the whole point of photosynthesis, and a cornerstone of the vast interlocking system that cycles carbon through plants, animals, microbes and the atmosphere to sustain life on Earth. 

But the carbon fixing champs are not plants, but soil bacteria. Some bacterial enzymes carry out a key step in carbon fixation 20 times faster than plant enzymes do, and figuring out how they do this could help scientists develop forms of artificial photosynthesis to convert the greenhouse gas into fuels, fertilizers, antibiotics and other products.

Now a team of researchers from the Department of Energy’s SLAC National Accelerator Laboratory, Stanford University, Max Planck Institute for Terrestrial Microbiology in Germany, DOE’s Joint Genome Institute (JGI) and the University of Concepción in Chile has discovered how a bacterial enzyme – a molecular machine that facilitates chemical reactions – revs up to perform this feat.

Rather than grabbing carbon dioxide molecules and attaching them to biomolecules one at a time, they found, this enzyme consists of pairs of molecules that work in sync, like the hands of a juggler who simultaneously tosses and catches balls, to get the job done faster. One member of each enzyme pair opens wide to catch a set of reaction ingredients while the other closes over its captured ingredients and carries out the carbon-fixing reaction; then, they switch roles in a continual cycle.  

Read more on the SLAC website

What drives rechargeable battery decay?

How quickly a battery electrode decays depends on properties of individual particles in the battery – at first. Later on, the network of particles matters more.

Rechargeable lithium-ion batteries don’t last forever – after enough cycles of charging and recharging, they’ll eventually go kaput, so researchers are constantly looking for ways to squeeze a little more life out of their battery designs.

Now, researchers at the Department of Energy’s SLAC National Accelerator Laboratory and colleagues from Purdue University, Virginia Tech, and the European Synchrotron Radiation Facility have discovered that the factors behind battery decay actually change over time. Early on, decay seems to be driven by the properties of individual electrode particles, but after several dozen charging cycles, it’s how those particles are put together that matters more.

“The fundamental building blocks are these particles that make up the battery electrode, but when you zoom out, these particles interact with each other,” said SLAC scientist Yijin Liu, a researcher at the lab’s Stanford Synchrotron Radiation Lightsource and a senior author on the new paper. Therefore, “if you want to build a better battery, you need to look at how to put the particles together.”

Read more on the SLAC website

Image: A piece of battery cathode after 10 charging cycles. A machine-learning feature detection and quantification algorithm allowed researchers to automatically single out the most severely damaged particles of interest, which are highlighted in the image.

Credit: Courtesy Yijin Liu/SLAC National Accelerator Laboratory

Triggering room-temperature superconductivity with light

Scientists discover that triggering superconductivity with a flash of light involves the same fundamental physics that are at work in the more stable states needed for devices, opening a new path toward producing room-temperature superconductivity.

Much like people can learn more about themselves by stepping outside of their comfort zones, researchers can learn more about a system by giving it a jolt that makes it a little unstable – scientists call this “out of equilibrium” – and watching what happens as it settles back down into a more stable state.

In the case of a superconducting material known as yttrium barium copper oxide, or YBCO, experiments have shown that under certain conditions, knocking it out of equilibrium with a laser pulse allows it to superconduct – conduct electrical current with no loss – at much closer to room temperature than researchers expected. This could be a big deal, given that scientists have been pursuing room-temperature superconductors for more than three decades.

But do observations of this unstable state have any bearing on how high-temperature superconductors would work in the real world, where applications like power lines, maglev trains, particle accelerators and medical equipment require them to be stable?

A study published in Science Advances today suggests that the answer is yes.

“People thought that even though this type of study was useful, it was not very promising for future applications,” said Jun-Sik Lee, a staff scientist at the Department of Energy’s SLAC National Accelerator Laboratory and leader of the international research team that carried out the study.

Read more on the SLAC website

Image: To study superconducting materials in their “normal,” non-superconducting state, scientists usually switch off superconductivity by exposing the material to a magnetic field, left. SLAC scientists discovered that turning off superconductivity with a flash of light, right, produces a normal state with very similar fundamental physics that is also unstable and can host brief flashes of room-temperature superconductivity. These results open a new path toward producing room-temperature superconductivity that’s stable enough for practical devices.

Credit: Greg Stewart/SLAC National Accelerator Laboratory

Science’s great strength is the universal language

SSRL’s #LightSourceSelfie

Forrest Hyler is a PhD student at the University of California Davis and regular user of the Stanford Synchrotron Lightsource (SSRL). Forrest’s research involves exploring the structural and electronic properties of materials that are used as catalysts for carbon dioxide reduction in the lab. In his #LightSourceSelfie, Forrest describes his work as all encompassing as it involves studying materials related to a broad range of applications such as batteries, catalysis and the storage of radioactive materials. Forrest’s journey has involved a large range of scientists and he says, “The greatest part about science is that it’s kind of that universal language. You get to interact with people around the globe working together for a common goal to push science beyond the boundaries that we’ve ever been at before.”

The fourth signature of the superconducting transition in cuprates

The results cap 15 years of detective work aimed at understanding how these materials transition into a superconducting state where they can conduct electricity with no loss.

When an exciting and unconventional new class of superconducting materials was discovered 35 years ago, researchers cheered.

Like other superconductors, these materials, known as copper oxides or cuprates, conducted electricity with no resistance or loss when chilled below a certain point – but at much higher temperatures than scientists had thought possible. This raised hopes of getting them to work at close to room temperature for perfectly efficient power lines and other uses.

Research quickly confirmed that they showed two more classic traits of the transition to a superconducting state: As superconductivity developed, the material expelled magnetic fields, so that a magnet placed on a chunk of the material would levitate above the surface. And its heat capacity – the amount of heat needed to raise their temperature by a given amount – showed a distinctive anomaly at the transition. 

But despite decades of effort with a variety of experimental tools, the fourth signature, which can be seen only on a microscopic scale, remained elusive: the way electrons pair up and condense into a sort of electron soup as the material transitions from its normal state to a superconducting state.

Now a research team at the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University has finally revealed that fourth signature with precise, high-resolution measurements made with angle-resolved photoemission spectroscopy, or ARPES, which uses light to eject electrons from the material. Measuring the energy and momentum of those ejected electrons reveals how the electrons inside the material behave.

In a paper published in Nature, the team confirmed that the cuprate material they studied, known as Bi2212, made the transition to a superconducting state in two distinct steps and at very different temperatures.

Read more on the SLAC website

Image: How can you tell if a material is a superconductor? Four classic signatures are illustrated here. Left to right: 1) It conducts electricity with no resistance when chilled below a certain temperature. 2) It expels magnetic fields, so a magnet placed on top of it will levitate. 3) Its heat capacity – the amount of heat needed to raise its temperature by a given amount – shows a distinctive anomaly as the material transitions to a superconducting state. 4) And at that same transition point, its electrons pair up and condense into a sort of electron soup that allows current to flow freely. Now experiments at SLAC and Stanford have captured this fourth signature in cuprates, which become superconducting at relatively high temperatures, and shown that it occurs in two distinct steps and at very different temperatures. Knowing how that happens in fine detail suggests a new and very practical direction for research into these enigmatic materials.

Credit: Greg Stewart, SLAC National Accelerator Laboratory

A new approach creates an exceptional single-atom catalyst for water splitting

Anchoring individual iridium atoms on the surface of a catalytic particle boosted its performance in carrying out a reaction that’s been a bottleneck for sustainable energy production.

A new way of anchoring individual iridium atoms to the surface of a catalyst increased its efficiency in splitting water molecules to record levels, scientists from the Department of Energy’s SLAC National Accelerator Laboratory and Stanford University reported today.

It was the first time this approach had been applied to the oxygen evolution reaction, or OER ­–part of a process called electrolysis that uses electricity to split water into hydrogen and oxygen. If powered by renewable energy sources, electrolysis could produce fuels and chemical feedstocks more sustainably and reduce the use of fossil fuels. But the sluggish pace of OER has been a bottleneck to improving its efficiency so it can compete in the open market.

The results of this study could ease the bottleneck and open new avenues to observing and understanding how these single-atom catalytic centers operate under realistic working conditions, the research team said.

They published their results today in the Proceedings of the National Academy of Sciences.

Read more on the SLAC website

Image: An illustration depicts a new system developed at SLAC and Stanford that anchors individual iridium atoms to the surface of a catalyst, increasing its efficiency at splitting water to record levels. The eight-sided support structures, shaded in blue, each contain a single iridium atom (large blue spheres). The iridium atoms grab passing water molecules (floating above and to the left of them), and encourage them to react with each other, releasing oxygen molecules (above and to the right). This reaction, known as the oxygen evolution reaction or OER, plays a key role in producing sustainable fuels and chemicals.

Credit: Greg Stewart/SLAC National Accelerator Laboratory

Scientists show the first step of turning CO2 into fuel in two very different ways

Their work aims to bridge two approaches to driving the reaction – one powered by heat, the other by electricity – with the goal of discovering more efficient and sustainable ways to convert carbon dioxide into useful products.

Virtually all chemical and fuel production relies on catalysts, which accelerate chemical reactions without being consumed in the process. Most of these reactions take place in huge reactor vessels and may require high temperatures and pressures.

Scientists have been working on alternative ways to drive these reactions with electricity, rather than heat. This could potentially allow cheap, efficient, distributed manufacturing powered by renewable sources of electricity.

But researchers who specialize in these two approaches – heat versus electricity – tend to work independently, developing different types of catalysts tailored to their specific reaction environments.

Read more on SLAC website

Image: This illustration shows one of the active sites of a new catalyst that accelerates the first step in making fuels and useful chemicals from carbon dioxide. The active sites consist of nickel atoms (green) bonded to nitrogen atoms (blue) and scattered throughout a carbon material (gray). SLAC and Stanford researchers discovered that this catalyst, called NiPACN, works in reactions driven by heat or electricity – an important step toward unifying the understanding of catalytic reactions in these two very different reaction environments.

Credit: (Greg Stewart/SLAC National Accelerator Laboratory)

Structure-guided nanobodies block SARS-CoV-2 infection

Monoclonal antibodies are valuable weapons in the battle against COVID-19 as direct-acting antiviral agents (1). Central to virus replication cycle, the SARS-CoV-2 spike protein binds the host cell receptor and engages in virus-host membrane fusion (2). Conformational flexibility of the spike protein allows each of its receptor binding domains (RBDs) to exist in two major configurations: a “down” conformation that is thought to be less accessible to binding of many neutralizing antibodies and an “up” conformation that binds both the receptor and neutralizing antibodies (3-5). Some neutralizing antibodies bind to the RBD in the “up” conformation and compete with the receptor (6, 7), while some neutralizing antibodies bind and stabilize the “down” confor­mation to prevent the conforma­tional changes required for viral entry, thereby hindering infection (8, 9).

Unfortunately, antibody molecules can be more difficult to produce in large quantities and are relatively costly to produce. Single domain antibodies, also known as nanobod­ies, offer an opportunity to rapidly produce antiviral agents for immun­ization and for therapy. Nanobodies are easier to produce, have high thermal stability and have the potential to be administered by inha­lation.

Read more on the SLAC website

Image: Bivalent nanobodies inducing post-fusion conformation of the SARS-CoV-2 spike protein: SARS-CoV-2 spike proteins are in a fusion inactive configuration when the RBDs are in the down conformation (left). Binding of bivalent nanobody (red and green ribbons joined by yellow tether) stabilizes the spike in an active conformation with all RBDs up (middle), triggering premature induction of the post-fusion conformation, which irreversibly inactivates the spike protein (right).

Scientists glimpse signs of a puzzling state of matter in a superconductor

Known as “pair-density waves,” it may be key to understanding how superconductivity can exist at relatively high temperatures.

Unconventional superconductors contain a number of exotic phases of matter that are thought to play a role, for better or worse, in their ability to conduct electricity with 100% efficiency at much higher temperatures than scientists had thought possible – although still far short of the temperatures that would allow their wide deployment in perfectly efficient power lines, maglev trains and so on.

Now scientists at the Department of Energy’s SLAC National Accelerator Laboratory have glimpsed the signature of one of those phases, known as pair-density waves or PDW, and confirmed that it’s intertwined with another phase known as charge density wave (CDW) stripes – wavelike patterns of higher and lower electron density in the material.

Observing and understanding PDW and its correlations with other phases may be essential for understanding how superconductivity emerges in these materials, allowing electrons to pair up and travel with no resistance, said Jun-Sik Lee, a SLAC staff scientist who led the research at the lab’s Stanford Synchrotron Radiation Lightsource (SSRL).

Read more on the SLAC website

Image: SLAC scientists used an improved X-ray technique to explore exotic states of matter in an unconventional superconductor that conducts electricity with 100% efficiency at relatively high temperatures. They glimpsed the signature of a state known as pair density waves (PDW), and confirmed that it intertwines with another phase known as charge density wave (CDW) stripes – wavelike patterns of higher and lower electron density in the material. CDWs, in turn, are created when spin density waves (SDWs) emerge and intertwine.

Credit: Jun-Sik Lee/SLAC National Accelerator Laboratory

Researchers search for clues to COVID-19 treatment

Two groups of researchers drew on SLAC tools to better understand how to target a key part of the virus that causes COVID-19

Vaccination, masks and physical distancing help limit the spread of COVID-19 – but, researchers say, the disease is still going to infect people, and doctors are still going to need better medicines to treat patients. This may be especially true for cancer patients and other at-risk people who may lack a sufficiently strong immune system to benefit from the vaccine. 

Now, two teams working in part at the Department of Energy’s SLAC National Accelerator Laboratory have found some clues that could, down the road, lead to new COVID drugs. 

The researchers, from John Tainer’s lab at MD Anderson Cancer Center and James Fraser’s group at the University of California, San Francisco, focused on a molecular structure that is common to all coronaviruses but has proven especially troublesome in the case of the virus that causes COVID-19. The structure contributes both to the virus’s ability to replicate and to immune system overreactions that have proven particularly deadly.

The trouble, Fraser said, is that scientists don’t know what kinds of molecules would bind to the structure, known as the Nsp3 macrodomain, let alone how to combine such molecules to interfere with its deadly work. 

To remedy that problem, Fraser’s group screened several thousand molecules at facilities including SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) to see where and how well the molecules bound to crystallized forms of Nsp3. The team combined those results with computer models to understand how the molecules might affect the structure of the macrodomain and whether they might help inhibit its function. 

Read more on the SLAC website

Blood disorder mechanism discovered

G6PD deficiency affects about 400M people worldwide and can pose serious health risks. Uncovering the causes of the most severe cases could finally lead to treatments.

With a name like glucose-6-phosphate dehydrogenase deficiency, one would think it is a rare and obscure medical condition, but that’s far from the truth. Roughly 400 million people worldwide live with potential of blood disorders due to the enzyme deficiency. While some people are asymptomatic, others suffer from jaundice, ruptured red blood cells and, in the worst cases, kidney failure. 

Now, a team led by researchers at the Department of Energy’s SLAC National Accelerator Laboratory has uncovered the elusive mechanism behind the most severe cases of the disease: a broken chain of amino acids that warps the shape of the condition’s namesake protein, G6PD. The team, led by SLAC Professor Soichi Wakatsuki, report their findings January 18th in Proceedings of the National Academy of Sciences

Read more on the SLAC website

Image: The G6PD enzyme plays a crucial role in red blood cells, removing molecules such as hydrogen peroxide from the body. In some cases, mutations can bend the molecule awkwardly, interfering with G6PD’s function. In the worst cases, the mutations lead red blood cells to rupture.

Credit: Mio Wakatsuki, from protein images by Naoki Horikoshi/SLAC National Accelerator Laboratory

Scientists probe the chemistry of a single battery electrode particle both inside and out

The results show how a particle’s surface and interior influence each other, an important thing to know when developing more robust batteries.

The particles that make up lithium-ion battery electrodes are microscopic but mighty: They determine how much charge the battery can store, how fast it charges and discharges and how it holds up over time – all crucial for high performance in an electric vehicle or electronic device.

Cracks and chemical reactions on a particle’s surface can degrade performance, and the whole particle’s ability to absorb and release lithium ions also changes over time. Scientists have studied both, but until now they had never looked at both the surface and the interior of an individual particle to see how what happens in one affects the other.

Read more on the SSRL (SLAC National Accelerator Laboratory) website

Image: Images made with an X-ray microscope show particles within a nickel-rich layered oxide battery electrode (left). In a SLAC study, scientists welded a single charged particle to the tip of a tungsten needle (right) so they could probe its surface and interior with two X-ray instruments. The particle is about the size of a red blood cell. (S. Li et al., Nature Communications, 2020)