Tag: SLAC

Ashley James wins 2023 Klein Award for studying mercury poisoning

Ashley James (Ashlyn George)

Ashley James is fascinated by her toxicology research because it combines biology, chemistry, physics and morbid topics like poisonings that affect the environment and world health. She also loves the unexpected twists. “We’ve been surprised so many times by what we’ve found. It’s been a fun, wild ride,” she said.

As a PhD student and now postdoctoral research fellow from the University of Saskatchewan, James’ research on mercury poisoning in animals and humans uses X-rays produced by the Stanford Synchrotron Radiation Lightsource (SSRL) at the Department of Energy’s SLAC National Accelerator Laboratory.

For her work, James will receive the 2023 Melvin P. Klein Scientific Development Award during the 2023 SSRL/LCLS Annual Users’ Meeting held at SLAC September 24-29.

“The SSRL-based research of Dr. James addresses a global health question with breakthrough discoveries while demonstrating state-of-the-art methodology for her discipline, thus bearing all the hallmarks of ‘outstanding research accomplishments by a new investigator’ that the award is intended to recognize,” wrote her PhD supervisors Graham George and Ingrid Pickering, Canada Research Chairs and professors at the University of Saskatchewan, in a nomination letter for the award.

James said she felt surprised, excited and honored by SSRL when she found out about winning the award. “It’s awesome to be included in the list of Klein awardees, alongside the diverse projects and incredible scientists who’ve won in the past,” she said.

Re-thinking the Minamata mass poisoning

As a PhD student, James studied the mass poisoning of thousands of people who ingested mercury by eating tainted fish and shellfish from the Minamata Bay in Japan during the late 1950s and 1960s. This famous, deadly tragedy was caused by a chemical plant dumping mercury-contaminated industrial waste into the bay – as demonstrated by a physician working for the factory who fed cats food laced with the industrial waste to confirm that it was responsible for the neurological disease.

Because the chemical plant used inorganic mercury in its processes, scientists initially believed that the contaminated waste contained inorganic mercury. The idea was that this inorganic mercury was transformed in the environment into a common and more toxic form of organic mercury called methylmercury.

James and her collaborators investigated the Minamata poisoning by studying preserved samples from a cat in the historic study. First, they showed that the mercury in the cat’s brain tissue was mostly organic by performing studies at SSRL’s X-ray spectroscopy (XAS) beamline 7-3 and high-energy-resolution fluorescence detection (HERFD-XAS) beamline 6-2, with help from SLAC scientists Matthew Latimer, Thomas Kroll and Dimosthenis Sokaras.

“These synchrotron techniques allowed us to look at historical samples with X-ray eyes to determine what mercury compounds existed in the cat’s brain tissue, which then told us a lot about its toxicology,” explained James. “HERFD-XAS has been particularly useful because its higher resolution enhances the shape of the mercury spectra, so we can fit the complex mixture of compounds with more confidence.”

The team then used computer-based calculations to model the chemical plant’s processes. Instead of methylmercury, their computational chemistry studies predicted that the factory released a different organic mercury compound called alpha-mercuri-acetaldehyde, whose toxicology has not been studied. Their findings challenged the long-standing view of what form of mercury poisoned the human population in Minamata.

The ensuing controversy attracted media attention and some scientific criticism, which was a bit overwhelming and stressful for James as an early-career PhD student. However, she handled it like a veteran, according to her nomination letters. Her supporters described the criticism published in letters to the journal as personal and unscientific. And they praised James’ response as excellent and surgically precise.

“Science is meant to create debate and it certainly did that,” said James. “But our main point was that it is important to study the toxicology of organic mercury compounds other than methylmercury, because they may have important environmental and health impacts.”

Comparing acute and chronic mercury poisoning in humans

Her second PhD research project investigated the more prevalent issue of chronic mercury exposure due to a lifetime of eating marine fish with low levels of methylmercury, which can lead to as much as ten times higher concentrations of mercury in the brain. Specifically, she used the same X-ray spectroscopy techniques and SSRL facilities as the Minamata project to study brain samples from residents of the Seychelles islands.

She compared these results to similar beamline studies on two historic acute organic mercury poisoning cases, which involved a short-term exposure of large concentrations of organic mercury. All brain tissue samples for her PhD work were acquired through her collaborators at the University of Rochester.

“We wanted to see if there was a difference in the chemical form of mercury found in chronic versus acute human exposure cases,” said James. “Honestly, we found the complete opposite of what we expected.”

The human body uses a chemical process called demethylation as a defense mechanism to slowly turn organic mercury into less toxic inorganic mercury. The researchers therefore thought people showing no evident symptoms of mercury poisoning would have mostly inorganic mercury that had been demethylated, James explained. Instead, they found individuals with chronic exposure had low concentrations of mercury in their brains, but it was entirely organic.

Similarly, the scientists predicted individuals after acute poisoning would have less time to demethylate the mercury, meaning they would have high levels of organic and low levels of inorganic mercury. Instead, they found complex mixtures with low concentrations of organic and high concentrations of inorganic mercury.

“The takeaway of this crazy twist is that it could be misleading to use acute exposure studies to understand the vast majority of human exposures that are chronic in nature,” said James. “Over a billion people worldwide depend on fish as their primary or sole source of protein. So, better understanding the ramifications of ingesting fish that may contain low levels of mercury is an important global food security question.”

As a postdoc, James is extending her mercury toxicology research. She is now studying the role of metals in multiple sclerosis using a diverse range of SSRL X-ray spectroscopy and X-ray imaging beamlines.

“Dr. James’ remarkably impactful research is further distinguished by her use of an incredible range of different techniques — from advanced X-ray spectroscopy methods at SSRL to quantum chemistry, alongside more conventional toxicology methodology,” said George and Pickering. “This work represents one of the very first demonstrations of these techniques to her field.”

The Klein award is named in honor of the late Melvin P. Klein, a world-renowned biophysicist at Lawrence Berkeley National Laboratory and the University of California, Berkeley and a longtime user at SSRL.

For questions or comments, contact the SLAC Office of Communications at communications@slac.stanford.edu.

SSRL is an Office of Science user facility.

This is a a reposting of my news feature courtesy of SLAC National Accelerator Laboratory.

SLAC’s Riti Sarangi wins 2021 Farrel W. Lytle Award

Ritimuka “Riti” Sarangi is this year’s Lytle Award recipient. (Jacqueline Ramseyer Orrell/SLAC National Accelerator Laboratory)

Ritimukta “Riti” Sarangi, a senior scientist at the Department of Energy’s SLAC National Accelerator Laboratory, is the latest recipient of the Farrel W. Lytle Award, which recognizes important contributions to synchrotron science and efforts to support users at the Stanford Synchrotron Radiation Lightsource (SSRL), a DOE Office of Science user facility.  

Since its inception in 1998, the Farrel W. Lytle Award has been given annually to SSRL staff members and users from around the world.

“Farrel is a legend in X-ray spectroscopy science. He has made contributions to every aspect of X-ray instrumentation, measurement and analysis,” Sarangi said. “I was completely unaware of my nomination and was thrilled when I received the email” notifying her of the award.

Sarangi started running experiments at SSRL in 2001, when she was a graduate research assistant at Stanford University. After earning her PhD in chemistry, she joined the SSRL staff in 2007. She is currently a senior member of the Structural Molecular Biology group at SSRL and a hard X-ray spectroscopist.

In a nomination letter for the award, Graham George, the Canada research chair in X-ray absorption spectroscopy at the University of Saskatchewan, praised Sarangi’s contributions in research, user support, outreach and leadership. “While SSRL scientific staff includes many outstanding individuals, even among this strong competition Riti stands out,” he wrote. “I have heard Riti described by senior SSRL management as an ‘anchor at SSRL,’ and I think that this description is an accurate one.”

Catalyzing discoveries

Sarangi uses X-ray spectroscopy techniques to study the fundamental properties of enzymes, molecules produced by a living organism that act as a catalyst to bring about specific biochemical reactions. Much of her research focuses on metalloenzymes, a broad group of enzymes with one or more metal ions in their active site, where other molecules bind and undergo a chemical reaction.

“Metalloenzymes perform a wide range of chemical transformations from electron transfer to small molecule activation to more complex molecular transformations,” explained Sarangi. “My goal is to apply X-ray methods towards understanding the structural and electronic details of these metal-containing active sites to shed light on the functional details of metalloenzymes and related systems.”

She is particularly interested in understanding methyl coenzyme M reductase (MCR), a unique nickel-containing enzyme responsible for the generation of 1 billion metric tons of methane annually.

Methane is the main component of natural gas and accounts for almost a quarter of U.S. energy consumption, but it is also a potent greenhouse gas. Understanding the mechanistic aspects of methane activation and synthesis is, therefore, imperative from fundamental, applied-energy, economic and environmental perspectives, Sarangi said.

Sarangi investigates metalloenzymes like MCR using modern X-ray spectroscopic tools and advanced computer simulations that model the quantum physics underlying chemical reactions.

“While spectroscopy provides an experimental window into specific properties about your system, quantum simulation methods provide additional information about structure, bonding and reactivity properties,” she said. “Experiments answer the what and theory answers the why given this specific what.”

Her nominators noted the powerful and unusual nature of her combined methodology. Stephen Ragsdale, professor of Biological Chemistry at the University of Michigan, wrote, “Riti’s approach is continuing to close the gap between experimental and computational aspects of X-ray spectroscopy. It is also absolutely crucial in understanding the complex biological systems that we and others are studying.”

In one recent study, Sarangi and colleagues combined a variety of experimental and theoretical techniques to uncover how enzymes help synthesize methane, revealing a surprising way the enzyme binds to the chemical it converts to methane. Ragsdale called the research “an extraordinary feat.”

Supporting users

Sarangi does a lot more than groundbreaking research, spending much of her time supporting the SSRL user community. “Riti is engaged at every level with user support and is someone who is not afraid to get her hands dirty,” George wrote.

For example, she developed a computer cluster for implementing various theoretical packages that simulate, interpret or augment experimental X-ray spectroscopy data.

“When I started at SSRL in a user support role, I realized these theoretical tools were rarely leveraged by our biological user community and therefore the full potential of their X-ray datasets was often not realized,” said Sarangi. “While I have continued to apply theoretical tools to my own research program, I have also established and made available a high-speed computational cluster to the entire bio-spectroscopy and bio-inspired catalysis user community.”

She has also been crucial to keeping SSRL running during the COVID-19 pandemic, her nominators said.

“She played a pivotal role in generating online access programs and coordinating communication and timeline details so users could continue to accomplish our science during the time when SSRL was closed for visitors,” Timothy Stemmler, assistance vice president for research and professor of pharmaceutical sciences at Wayne State University, wrote in a letter. “Her efforts to allow online access will surely transform how data is collected at the entire lab moving forward, and will lead to many future discoveries, he wrote.

The nominators also applauded Sarangi’s mentoring, training and recruitment of the next generation of scientists. “She has clear skills in organizing and delivering training content and this sets her apart as not just an amazing colleague, but an amazing educator,” wrote Stemmler.

Envisioning the future

Looking forward, Sarangi thinks the lessons learned during the pandemic suggest that more researchers could work remotely – something she said accelerated her scientific and operational engagement with staff, users and collaborators. In 20 years, she expects SSRL X-ray science to become an automated and high-throughput experience that integrates multiple complementary X-ray and non-X-ray measurements.   

She is also leading efforts to plan the future of structural science at lightsources, based on a series of workshops whose reports will develop a robust case for investing in X-ray science.

“This is no easy task and has required mastering the details of techniques adjacent to her expertise, diplomacy in bringing diverse ideas in different disciplines together, and hard work,” wrote Edward Snell, chief executive officer of the Hauptman-Woodward Medical Research Institute, in a nominating letter.

George also praised Sarangi’s leadership and vision. “I have had the distinctive privilege of knowing Farrel quite well, and I am certain that he would approve of this nomination,” he wrote. “The SSRL Users’ executive committee would be hard pressed to find a better candidate.”

The award will be presented to Sarangi at the 2021 SSRL/LCLS Annual Users’ Meeting during the plenary session on September 24. 

For questions or comments, contact the SLAC Office of Communications at communications@slac.stanford.edu.

This is a reposting of my news story, courtesy of SLAC National Accelerator Laboratory.

Stanford graduate student Aisulu Aitbekova wins 2021 Melvin P. Klein Award

Aisulu Aitbekova

Aisulu Aitbekova, a 2021 doctoral graduate from Stanford University, discovered her passion for research when she traveled from Kazakhstan to the U.S. for a summer internship as a chemical engineering undergraduate. She said that experience inspired her to go to graduate school.

After earning a master’s in chemical engineering at the Massachusetts Institute of Technology, she continued her studies at Stanford University under the supervision of Matteo Cargnello, an assistant professor of chemical engineering and Aitbekova’s doctoral advisor. Much of her thesis work involved beamline studies at the Stanford Synchrotron Radiation Lightsource (SSRL) at the Department of Energy’s SLAC National Accelerator Laboratory.  

Now, Aitbekova has been selected to receive the 2021 Melvin P. Klein Scientific Development Award, which recognizes outstanding research accomplishments by undergraduates, graduate students and postdoctoral fellows within three years of completing their doctoral degrees.

In a nomination letter for the award, SLAC Distinguished Staff Scientist Simon Bare praised Aitbekova’s initiative. “She has quickly become proficient in the application of X-ray techniques available at the synchrotron at SLAC. This proficiency and mastery include everything from operating the beamline to analyzing and interpreting the data,” he wrote.

Aitbekova said she felt “absolutely thrilled and grateful” to all of her mentors when she found out about winning the award.

“I’m so thankful for my PhD advisor Matteo Cargnello. My success would not have been possible without his mentorship,” Aitbekova said. “I’m also particularly grateful to Simon Bare, who I consider to be my second advisor. His continuous excitement about X-ray absorption spectroscopy has been the driving force for my work at SSRL.” 

Catalyzing change

Aitbekova said she is passionate about finding solutions to combat climate change. She designs materials to convert harmful pollutant gases into useful fuels and chemicals. To perform these chemical transformations, she develops catalysts and studies their properties using X-ray absorption spectroscopy (XAS). Catalysts are substances that increase rates of chemical reactions without being consumed themselves.

“I have identified that a catalyst’s size, shape and composition profoundly affect its performance in eliminating these gases,” but exactly how those properties affect performance remains unknown, she said. “This problem is further complicated by the dynamic nature of catalytic materials. As a catalyst performs chemical transformations, its structure changes, making it challenging to precisely map a catalyst’s properties to its performance.”

To overcome these barriers, she engineers materials the size of one ten-thousandth the diameter of a human hair and then tracks how they change during reactions using XAS.

In one study, Aitbekova and her colleagues engineered a catalyst using a combination of ruthenium and iron oxide nanoparticles, which they think act in a tag-team fashion to improve the synthesis of fuels from carbon dioxide and hydrogen. Using a prototype in the lab, they achieved much higher yields of ethane, propane and butane than previous catalysts.

Switching gears

While engineering catalysts that convert carbon dioxide into chemicals, she developed a new approach for preparing materials, where small particles are encapsulated inside porous oxide materials – for example, encapsulating ruthenium within a sheath of iron.

However, Aitbekova recognized a completely different application for this new approach: creating a palladium-platinum catalyst that works inside a car’s emission control system.

To eliminate the discharge of noxious emission gases, cars are equipped with a catalytic converter. Exhaust gases pass into the catalytic converter, where they are turned into less harmful gases. The catalysts inside these units are platinum and palladium metals, but these metals gradually lose their efficiency due to their extreme working conditions, she said.

“My platinum and palladium catalysts show excellent stability and performance after being subjected to air and steam at 1,100 degrees Celsius, the harshest operating environment automotive exhaust emission control catalysts could be subjected to,” explained Aitbekova. “Further improvements in these materials and successful testing under true exhaust conditions have a potential to revolutionize the field of automotive exhaust emission control.”

Her nominators agreed, citing it as the highlight of her graduate career.

“This work, currently under review for publication, is truly the remarkable result of Aisulu’s hard work and experience in pivoting from one area to another to make an impact and of her ability to connect multiple fields and solve important problems,” Cargnello wrote.

Amplifying impact

Despite this success, Aitbekova is already focused on how to make an even greater impact through mentoring and future research.

Her nominators all applauded her passion and commitment to mentor the next generation of STEM scholars, as demonstrated by mentoring “a countless number of undergraduates” according to Cargnello and by exchanging letters with middle school students from underrepresented groups.

Part of this passion, Cargnello and others wrote, stems from her experiences growing up in a highly conservative environment with the understanding that homemaking would be her eventual job. Aitbekova’s nominators wrote that they admired the fact that she made her way to Stanford and has acted as an ambassador for the values and principles of diversity and inclusion.

Aitbekova said she embraces the role. “Since my first summer research experience in the USA, I’ve wanted to serve as a bridge to science and graduate school to those who, like me, didn’t have access to such knowledge and resources.”

She will continue to act as a bridge in her next endeavor as a Kavli Nanoscience Institute Prize Postdoctoral Fellow at Caltech, where she plans to expand her work of converting carbon dioxide into fuels by running the chemical transformations with solar energy. That will “bring society one step closer to sustainable energy sources,” she said.

Bare and others praised her drive to make an everyday impact. “She has a natural passion for wanting to understand the physical principles behind the phenomena that she has observed in her research. But this passion for understanding is nicely balanced by her desire to discover something new, and to make a real difference — the practicality that is often missing in someone early in their career,” wrote Bare.

The award will be presented to Aitbekova at the 2021 SSRL/LCLS Annual Users’ Meeting during the plenary session on September 24. 

This is a reposting of my news story, courtesy of SLAC National Accelerator Laboratory.

X-rays shed light on how anti-asthmatic drugs work

A new study uncovers how a critical protein binds to drugs used to treat asthma and other inflammatory diseases.

By studying the crystal structure of an important protein when it was bound to two drugs widely prescribed to treat asthma, an international team of scientists has discovered unique binding and signaling mechanisms that could lead to the development of more effective treatments for asthma and other inflammatory diseases.

The protein, called cysteinyl leukotriene receptor type 1 (CysLT1R), controls the dilation and inflammation of bronchial tubes in the lungs. It is therefore one of the primary targets for anti-asthma drugs, including the two drugs studied: zafirlukast, which acts on inflammatory cells in the lungs, and pranlukast, which reduces bronchospasms due to allergic reactions.

Using the Linac Coherent Light Source (LCLS) X-ray free-electron laser at the Department of Energy’s SLAC National Accelerator Laboratory, the team bombarded tiny crystals of CysLT1R-zafirlukast with X-ray pulses and measured its structure. They also used X-rays from the European Synchrotron Radiation Facility in Grenoble, France to collect data about CysLT1R-pran crystals. They published their findings in October in Science Advances.

The researchers gained a new understanding of how CysLT1R interacts with these anti-asthma drugs, observing surprising structural features and a new activation mechanism. For example, the study revealed major differences between how the two drugs attached to the binding site of the protein. In comparison to pranlukast, the zafirlukast molecule jammed open the entrance gate of CysLT1R’s binding site into a much wider configuration. This improved understanding of the protein suggests a new rationale for designing more effective anti-asthma drugs.

The study was performed by a collaboration of researchers at SLAC; Moscow Institute of Physics and Technology, Russia; University de Sherbrooke, Canada; University of Southern California; Research Center Juelich, Germany; Universite Grenoble Alpes-CEA-CNRS, France; Czech Academy of Sciences, Czech Republic; and Arizona State University.

Citation: Aleksandra Luginina et al., Science Advances, 09 October 2019 (10.1126/sciadv.aax2518).

For questions or comments, contact the SLAC Office of Communications at communications@slac.stanford.edu.

Image caption: Using X-rays, researchers uncovered details about two drugs widely prescribed to treat asthma: pranlukast (shown up top) and zafirlukast (shown beneath). Their results revealed major differences between how the two drugs attached to the binding site of the receptor protein. In comparison to pranlukast, the zafirlukast molecule jammed open the entrance gate of protein’s binding site into a much wider configuration. (10.1126/sciadv.aax2518)

This is a reposting of my SLAC news story, courtesy of SLAC Linear Accelerator Laboratory.

To battle mosquito-borne disease, SLAC x-ray laser provides new view of insecticides

Illustration, of LCLS x-ray pulses blasting BinAB nanocrystals composed of protein BinA (yellow) and BinB (blue), courtesy of SLAC National Accelerator Laboratory.
Illustration of LCLS x-ray pulses blasting BinAB nanocrystals composed of protein BinA (yellow) and BinB (blue), courtesy of SLAC National Accelerator Laboratory.

Mosquitoes continue to spread devastating diseases such as malaria, West Nile virus, dengue fever and Zika virus throughout the world. Sadly, there are no medications or vaccines for many of these deadly diseases, so it’s critical to prevent mosquito bites.

A cost effective way to eliminate these disease-bearing insects is the use of specialized insecticides that target against the larval stage of a mosquito. These larvicides, like BinAB, kill some mosquito species, but they are currently ineffective against Aedes mosquitoes that transmit Zika and dengue fever. Now, an international team of researchers is working to develop a new toxin that will kill a broader range of mosquito species, including Aedes.

The existing larvicide BinAB is composed of two proteins, BinA and BinB, which pair together to form nanocrystals inside Lysinibacillus sphaericus soil bacteria. When these bacteria are distributed on the surface of stagnant water locations where mosquitoes breed, the mosquito larvae eat the bacteria — dissolving the nanocrystals that bind to their gut, activating the deadly BinAB toxin and killing the larvae.

The proteins are toxic to the mosquitoes, but harmless to humans and other animals. Unfortunately, previous research has shown that BinAB is also harmless to an Aedes mosquito, because the protein never binds to the insect’s gut so the toxin isn’t activated.

“Part of the appeal is that the larvicide’s safe because it’s so specific, but that’s also part of its limitation,” said Michael Sawaya, PhD, a scientist at the UCLA-DOE Molecular Biology Institute, in a recent news release.

Now, the researchers are adapting the BinAB toxin to attack mosquito species that are insecticide resistant. In order to do this, they needed to understand the 3-D structure of the BinAB proteins and how they work. This was a challenge, because the nanocrystals were so tiny and their structural details were a mystery.

The research team increased the size of the nanocrystals using genetic engineering, and then blasted them with an intense beam of bright, fast pulses of light using the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory. This allowed the team to collect detailed structural data from the tiny crystals and create 3-D maps of the electron density of the BinAB protein, as reported in a recent paper in Nature.

The LCLS experiments helped the researchers fully understand how the BinAB protein forms and functions. They are now engineering a modified version of the protein that will kill a broader range of mosquito species.

“The most immediate need is to now expand the spectrum of action of the BinAB toxin to counter the progression of Zika, in particular,” said Jacques-Philippe Colletier, PhD, a scientist at the Institut de Biologie Structurale in France, in the news release. “BinAB is already effective against Culex [carrier of West Nile encephalitis] and Anopheles [carrier of malaria] tos. With the results of the study, we now feel more confident that we can design the protein to target Aedes mosquitoes.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Researchers Study How Metal Contamination Makes Gasoline Production Inefficient

SSRL X-rays are focused to illuminate a small sample of catalysts inside a movable cylindrical holder. A lens magnifies the resulting sample image onto a screen, a CCD camera captures the 2-D image, and software is used to reconstruct a 3-D image of the single catalyst particle from a series of these 2-D images. (Florian Meirer/Utrecht University)
SSRL X-rays are focused to illuminate a small sample of catalysts inside a movable cylindrical holder. A lens magnifies the resulting sample image onto a screen, a CCD camera captures the 2-D image, and software is used to reconstruct a 3-D image of the single catalyst particle from a series of these 2-D images. (Florian Meirer/Utrecht University)

Scientists at SLAC and Utrecht University have identified key problems in the crude oil refining process in an effort to increase the production yield of gasoline.

Their recent experiments at SLAC National Accelerator Laboratory studied catalysts that crack apart the long-chain hydrocarbons in crude oil into smaller, more valuable hydrocarbons like gasoline. The efficiency of this refinement process decreases as the catalysts age.

The researchers used X-ray beams at SLAC’s Stanford Synchrotron Radiation Lightsource to image whole catalyst particles and their internal structure with high resolution – like taking a landscape photograph where you can see a panoramic view and zoom in to see the ants.

To learn more about this research, check out my communications article for SLAC National Accelerator Laboratory.

Researchers at SLAC Study Promising Alternative to Morphine

Morphine is a common narcotic pain reliever with significant side effects (sfxeric/Flickr).
Morphine is a common narcotic pain reliever with significant side effects (sfxeric/Flickr).

Morphine is a powerful narcotic, commonly used to treat moderate to severe pain from surgery, injury and chronic health conditions like cancer or osteoarthritis. However, morphine has many negative side effects. It can cause drowsiness, nausea, vomiting, dizziness and constipation. More troubling, people can become dependent on it.

According to the Centers for Disease Control and Prevention, narcotic dependence and overdose deaths are a growing health problem in the United States. Narcotic sales quadrupled from 1999 to 2010 and narcotic-related deaths more than tripled from 1999 to 2012. More than 2 million people in the U.S. currently abuse narcotics.

In order to address this problem, researchers have long searched for alternative drugs that effectively relieve pain without inducing dependence as morphine does. A team of researchers now believe they’ve found a good candidate for such a drug, although it will be a long time before this drug, if it proves to be effective, is available in stores.

These researchers are studying their new kind of pain reliever using an ultrabright, ultrafast X-ray source called the Linac Coherent Light Source (LCLS), which is located at SLAC National Accelerator Laboratory.

The LCLS creates the brightest X-ray source on the planet, which researchers need to accurately study the structure of tiny, nanoscale drug compounds.

How Narcotics Work

Narcotics are also called opioid pain relievers, because they block the sensation of pain by binding to opioid receptors within the pain pathway of the brain. A drug can provide pain relief by binding to one of three types of opioid receptors in the brain: delta, mu and kappa. Narcotics like morphine target the opioid mu receptors.

The problem is that long-term use of morphine reduces the number of available opioid mu receptors. As a result, tolerance develops so a higher dose of the drug is needed to achieve the same level of pain relief. Ultimately, prolonged use leads to physical dependence — which is when the neurons adapt to the presence of the drug and function normally only when it’s in the body.

Previous research has shown that administering morphine with another drug that simultaneously blocks the opioid delta receptors prevents this morphine-induced tolerance and dependence. Researchers just need to find the right drug combination with minimal side effects.

Recently, a team of researchers, led by University of Southern California chemistry professor Vadim Cherezov, developed a drug that activates opioid mu receptors while blocking opioid delta receptors. Their drug is derived from a specialized peptide – a naturally occurring chain of amino acids. Their research results were reported in the February issue of Nature Structural and Molecular Biology.

Studying Tiny Crystals

Unfortunately, it is very difficult to study new opioid compounds like the one Cherezov recently developed.

In order to understand the structure of new compounds, scientists usually grow crystals of the compound and then hit them with X-rays. By measuring the angles and intensity of how the X-rays bounce off the crystals, they can produce a three-dimensional picture of the crystal structure.

However, it can be difficult to grow crystals large enough to use this standard method, called X-ray crystallography. Plus, you typically need to freeze the crystal to make it more rigid, rather than study it in natural conditions and temperatures. On top of that, a conventional X-ray beam might blast and destroy the small crystal before you can collect enough data.

Instead, Cherezov’s team used the Linac Coherent Light Source to perform their experiment on tiny crystals at room temperature. LCLS X-ray pulses last just a quadrillionth of a second, or 100 times faster than it takes light to travel the width of a human hair. Yet they are a billion times brighter than a conventional X-ray source.

Using this unique X-ray source with higher-intensity, very short pulses, Cherezov was able to use smaller crystals and still collect terabytes of structural data before the crystals vaporized.

Each crystal the research team prepared was a millionth of a meter and contained many copies of their new opioid compound bound to an opioid receptor. The team placed the crystals in a toothpaste-like gel to simulate the receptors’ natural environment, and then injected a thin stream of this gel into the path of the LCLS X-ray beam.

The resulting structural model was precise enough to show how the new drug molecules bind with the receptor. This atomic-scale map should help scientists develop pain-relieving drugs with fewer negative side effects. It’s likely to to take years, though, before it can be tested in humans.

“This work will provide a solid basis for the design of a new generation of pain relievers with reduced dependency,” Cherezov said in a press release.

Cherezov’s experiment is just one of many performed at the Linac Coherent Light Source.

The LCLS is a Department of Energy User Facility where approximately 600 scientists conduct groundbreaking experiments each year, across many fields, including chemistry, biology, material science, technology and energy science.

This is a repost of my KQED Science blog.

Ultrafast Laser Synchronization Breakthrough

AMO experiment schematic
Set-up of a nitrogen pulse-pump experiment that uses pulse arrival time information from a cross-correlator mounted downstream from the experiment. Figure courtesy of SLAC National Accelerator Laboratory.

A journal article, just published in Applied Physics Letters, details a major breakthrough for experiments at SLAC’s Linac Coherent Light Source (LCLS).

LCLS delivers intense ultrashort x-ray pulses that can be used to study the motion of atoms as they respond to external triggers, such as an optical laser. In these “pump-probe” experiments, the optical laser “pump” pulse starts a reaction in the material, while the x-ray “probe” pulse investigates the state of the material after a defined time delay. A sequence of x-ray pulses, with different time delays between the laser and x-ray pulses, is used to “film” the reaction in the material.

LCLS ultrafast x-ray pulses basically act like high-speed flashes of a camera strobe, allowing scientists to capture images with a “shutter speed” of less than 100 femtoseconds – the time it takes light to travel the width of a human hair.

In order to be able to “film” optically-induced ultrafast processes, however, scientists need more than just ultrashort x-ray and laser pulses. They also need to synchronize the x-ray pulses to the optical laser pulses with almost femtosecond accuracy, in order to have snapshots with good time resolution (“sharp focus”). This is a major challenge, since the main laser system for the x-ray free electron laser is a kilometer away from the optical laser and experiment.

State-of-the-art synchronization is performed at LCLS by accurately measuring the arrival times of the electron bunches (and corresponding x-ray pulses) relative to the radiofrequency that drives the accelerator, since the optical laser is locked to this reference radiofrequency. The best time resolution so far achieved with this approach is 280 fs (full width at half maximum, FWHM).

Recently, scientists at the LCLS Atomic, Molecular and Optical Science Instrument (AMO) dramatically improved the time resolution for their pump-probe experiments. Their new synchronization strategy is to directly measure the relative arrival time of both the x-ray and optical laser pulses at the experiment on a shot-by-shot basis. They do this by introducing into the x-ray beam what they call a cross-correlator, which is mounted downstream of the main experiment.

AMO scientists split their laser beam, sending it to both a pump-probe experiment and the cross-correlator (with a time delay). In the cross-correlator, the laser beam is reflected off a Si3N4 thin film. The spot of the laser pulse is then imaged with a long-distance microscope on a CCD camera. X-ray pulses also hit the same surface of the Si3N4 film, quasi-instantaneously changing the surface reflectivity.

The x-ray pulse very briefly changes the surface reflectivity. By imaging and measuring the position of this reflectivity change with the reflected laser, AMO scientists can directly measure the relative arrival time of the x-ray and optical laser pulses at their experiment. The scientists then use this pulse arrival time information from the cross-correlator to correct their corresponding experimental data on a shot-by-shot basis.

The AMO team demonstrated their improved time resolution with a nitrogen pump-probe experiment. With the time information from the cross-correlator, they were able to decrease the time resolution of their nitrogen experiment down to only 50 fs (FWHM). That’s almost down to the theoretical limit, allowing scientists to investigate all sorts of new ultrafast science.