Canadian Light Source (CLS) – Lightsources.org

Attacking cancer cells from the inside out

2023/03/072023/03/14

Researchers from the University of Toronto (U of T) are harnessing the power of proteins to stop cancer cells in their tracks.

“Proteins are the workhorses of the cell,” said Walid A. Houry, professor of biochemistry at U of T. “They define the cell and allow it to divide or migrate if needed.”

The team is especially interested in proteases, enzymes that chew up old or misfolded proteins and act as cellular quality control. Houry and his colleagues used the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan to identify key compounds affecting these quality control mechanisms that cause cell dysfunction and, ultimately, cell death. Their research paper was recently published in Structure.

“Let’s say you have a small puppy and when you leave it in the room, it starts chewing your sofa, your carpet; it’s just hyper and eating everything up,” Houry said. The compounds cause the proteases to act like the puppy, “and the cell cannot handle this type of disruption to its machinery.”

By targeting the cell’s self-destruct button, Houry’s team, including collaborators at Madera Therapeutics, is designing a new approach to cancer therapy. Synchrotron techniques allowed the researchers to visualize the interaction between their compounds and the proteases.

Houry said hard-to-treat cancers like glioblastomas and certain types of breast cancers are good candidates for this new approach.

“Instead of inhibiting a protease, we are hyperactivating the protease, and that is unique.”

The CLS is crucial to the team’s work.

“Synchrotron technology is extremely important for us and our structure-based drug design,” he said. “We want to know why the protein is going wild when we add our compound.”

Image: Houry research team

Battling biofilm to prevent dangerous lung infections

2023/02/152023/03/21

Researchers from the University of Toronto (U of T) and The Hospital for Sick Children have identified a promising therapeutic target to help treat lung infections in cystic fibrosis (CF) patients.

“Individuals with cystic fibrosis have an impairment in their lungs where they have a hard time clearing out the mucus that accumulates within the lungs,” says Andreea Gheorghita, PhD candidate in the Department of Biochemistry at U of T.

Pseudomonas aeruginosa is a bacterium that causes opportunistic infections in individuals with weakened immune systems or other health concerns. For individuals with CF, repeated Pseudomonas infections often lead to long hospital stays and severe lung damage.

“Because of the impaired ability to clear mucus in the airways, these lung infections can become very persistent and prolonged, which eventually leads to lung tissue damage, loss of lung function, and eventually can cause patient mortality,” says Gheorghita.

Using the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan (USask), the team has been able to visualize the interaction between two important proteins that are key players in Pseudomonas’s ability to make biofilm. This sticky secretion allows the bacterium to attach to the lungs and makes it difficult for antibiotics and the patient’s immune system to fight the infection.

Canadian Light Source at USask announces appointment of new CEO

2023/02/032023/02/09

Bill Matiko, current Chief Financial Officer and Chief Operating Officer for the CLS, will become the Chief Executive Officer, effective immediately, for a period of five years.

“After an extensive search, the best candidate turned out to be right here, and we’re extremely pleased that he’s accepted our offer,” said Pierre Lapointe, Chair of the CLS Board of Directors. “Bill has proven he has the leadership skills to guide the CLS through the important next phase of the facilities, to ensure the CLS remains a major contributor to Canadian science, innovation, and the economy.”

As COO, Matiko has effectively led the CLS since September 2021, with full operational oversight and authority.

“As the CLS enters this next critical phase, with the major linear accelerator upgrade that will ensure its continued leadership in the global synchrotron community, we believe Bill is in the best position to ensure the continuity of leadership and excellent management of this important University of Saskatchewan national resource,” said Dr. Baljit Singh, USask vice-president, research.

Image: Bill Matiko, newly appointed CEO of the Canadian Light Source (CLS)

Credit: CLS

Blood-type conversion process informed by crystallography now in pre-clinical trials

2023/01/242023/01/26

Application of a discovery that was aided in part by the Canadian Light Source (CLS) at the University of Saskatchewan has advanced to pre-clinical trials and is now the basis of a dynamic new startup.

In 2019 Dr. Stephen Withers and colleagues at the University of British Columbia identified a series of enzymes that can be used to modify the chemical structure of a sugar antigen on the surface of blood cells, thereby converting a Type A blood cell to a Type O blood cell — the universal donor type. The team used crystallography on the CMCF beamline at the CLS to better understand how the enzymes cause this change.

These same antigens are also present on the surface of solid organs, and Withers and colleagues have demonstrated that the enzymes they discovered are very efficient at making this conversion both on the surface of red blood cells and on the surface of donated human organs such as lungs or kidneys.

Avivo – the company launched to bring this technology to the marketplace – is now busy finetuning both applications. If successful, this exciting advance would be a huge step forward in addressing shortages in blood and organ supply here in Canada and around the world. “The idea is that we could broaden the supply considerably,” says Withers, a professor in the Departments of Chemistry and Biochemistry and the Michael Smith Laboratories at UBC. “It would remove the need to worry about blood type in transfusions (and organ donations).”

John Barclay, VP of business development with Avivo says the company is focusing first on applying their approach to organ donations because it’s considerably more straightforward to remove the conversion enzymes prior to transplantation than it is to remove them before transfusing blood.

When a donor organ is harvested, it will often be placed on a perfusion device that continuously pumps a preservation solution, or perfusate, through it to maintain the tissue’s viability. The enzymes discovered by the Withers team can be added to the fluid mixture, where they essentially convert the blood type of the organ to the universal blood type. After that conversion, the solution – including the enzymes — is essentially “rinsed” out of the organ as part of the existing transplant process. Removing the enzymes from red blood cells or whole blood is considerably more challenging, says Barclay.

The Avivo team has demonstrated the process works using a set of human lungs that were deemed not viable for transplanting into a patient. “We’ve shown that we can remove those antigens and convert an A type lung to an O type lung quite readily,” says Withers. “We’re working on kidneys at the moment…so that’s very exciting.”

This application of their technique is in pre-clinical trials now; they’re hoping to move on to clinical trials (i.e., in human patients) in 2024.

How the Canadian Light Source contributed

“The information we learned from it (crystallography) was very supportive in knowing exactly the structure of the enzymes we’re adding,” says Withers. This information, he says, will be very useful if they need to modify the structure of the enzyme.

It will also be valuable when they seek regulatory approval, to be able to present the complete structure of the enzymes. “We’ve learned a lot more through having that information, which may be useful in the future,” says Withers.

Image: Steve Withers, John Barclay, and John Coleman.

Building better catalysts to close the carbon dioxide loop

2023/01/122023/01/12

The best way to stave off the worst effects of climate change is to reduce CO2 emissions around the world. And one way to do that, says Zhongwei Chen, a professor in the Department of Chemical Engineering at the University of Waterloo, is to capture the CO2 and convert it into other useful chemicals, such as methanol and methane for fuels. Stopping emissions at the source, and further reducing future ones by replacing CO2-producing fuels with cleaner ones “…is a way to close the circle,” Chen says.

In order to turn CO2 into methanol, you need a catalyst to jump-start the electrochemical reaction. Traditionally, these catalysts have either been made out of precious metals like gold or palladium, or base metals like copper or tin. However, they are expensive and break down easily, hindering large-scale implementation. “Right now we can’t meet industrial requirements,” says Chen, who holds a Canada Research Chair. “So we are trying to design catalysts with better activity, selectivity, and durability.”

Image: Chithra Karunakaran on the SM beamline at the Canadian Light Source

Credit: David Stobbe

Innovative fuels for Small Modular Reactors

2022/12/012022/12/06

If Canada is to meet its target of net-zero emissions by 2050, our country must transition to a diverse, innovative range of alternative sources of energy.

Mouna Saoudi, a materials scientist at Canadian Nuclear Laboratories (CNL), is using the Canadian Light Source at the University of Saskatchewan to explore how advanced nuclear fuels for small modular reactors (SMRs) could be used to help fill the gap between fossil fuels and renewables.

“SMRs would be an efficient way to reach net zero by 2050, which is an ambitious but hopefully achievable goal,” says Saoudi.

SMRs can power electrical grids, provide process heat, and offer energy solutions for various industries — such as remote mining operations.

Saoudi is currently investigating how types of advanced nuclear fuels behave under different reactor conditions.

“My main focus is characterization of advanced nuclear fuels for potential use in small modular reactors,” Saoudi says.

The advanced fuels combine uranium oxide — the main element used in nuclear fuel for decades —with the naturally occurring and abundant element thorium in oxide form. Saoudi says that there are many advantages to mixing the two elements, including increased efficiency and better in-reactor performance.

Using the HXMA beamline, Saoudi was able to confirm the similar distribution of the two elements, uranium and thorium, in the mixed fuel oxides. Saoudi believes this was the first time the CLS has been used for this type of study.

Saoudi has been working with USask researcher Andrew Grosvenor from the Department of Chemistry. Their findings were recently published in the Journal of Nuclear Materials.

The CLS allowed Saoudi and her collaborators to investigate the electronic and local structure of the fuel — crucial information needed to identify the optimum fuel composition that would have better in-reactor performance than that of uranium oxide.

Image: (Left to right) Dr. Than Do, Dr. Mouna Saoudi, and Dr. Julien Lang, R&D scientists at Canadian Nuclear Laboratories (CNL).

Towards improved osteoporosis treatment

2022/11/022022/11/03

More than 2.3 million Canadians are affected by osteoporosis, resulting in billions of dollars in economic burden and incalculable suffering.

A research team from the College of Medicine at the University of Saskatchewan has developed a new approach to imaging that detects changes in bone tissue far more quickly than bone densitometry scans, the method currently used in health care. While the study was done using a rabbit model, the results could lead to improved drug treatment in humans with osteoporosis.

Using the BMIT beamline of the Canadian Light Source at the University of Saskatchewan, Dr. David Cooper and colleagues were able to see the incredibly tiny pores inside cortical bone, the dense outer surface of bone that accounts for the majority of bone mass. These pores change over time, showing how bone tissue is continuously removed and replaced.

The researchers stimulated this bone turnover using parathyroid hormone, then tracked the changes in the pores of the cortical bone in as little as 14 days.

Image: Longitudinal erosion rate (LER) assessment based on synchrotron radiation (SR) micro-CT and micro-CT co-registered scans

Unlocking the doors to effective COVID-19 treatments

2022/09/282022/10/03

Developing therapeutics for COVID-19 should lessen the length and severity of the illness, keeping more people out of the hospital and improving patient outcomes.

A team of interdisciplinary researchers from the Institut National de la Recherche Scientifique (INRS) are hoping to identify effective COVID-19 therapeutics. With help from the Canadian Light Source (CLS) at the University of Saskatchewan, the team has been able to visualize the interaction between inhibitory molecules and viral proteins. This allows researchers to see if their drug designs work as intended.

“We have libraries of molecular fragments and drug candidates that we are testing,” said Michael Maddalena, a research intern in Steven LaPlante’s lab at INRS. “We are screening to see if they are active and actually stick to the virus’ proteins or to essential human receptors where we think there are opportunities for drugs.”

This research targets the proteins of the SARS-CoV-2 virus that are involved in its replication and survival. Their work also targets the essential human receptors that the virus depends on to enter human cells. Drugs that stick to human receptors are unlikely to be susceptible to viral mutants — ensuring that new therapeutics will be effective against new variants.

Image: The LaPlante research team

Producing hydrogen from seawater

2022/09/132022/09/20

McGill scientists have identified potential method for producing hydrogen from the oceans.

In her research on bone tissue engineering, Dr. Marta Cerruti has worked for years with graphene, a single sheet of carbon atoms with incredible properties – electrical conductivity and the ability to support tremendous weight. Now, her quest to improve its qualities has opened the door to a possible solution to one of the challenges of producing hydrogen from seawater.

Cerruti, a professor of materials engineering at McGill University, explained that while graphene is structurally sound, “one sheet of atoms is not something you can easily work with.” In fact, piling the sheets up results in, basically, pencil lead.

Searching for a way to make an easy-to-handle structure, Cerruti’s PhD student Yiwen Chen combined graphene with oxygen in a suspension with water to create reduced graphene oxide (GO), a porous, three-dimensional, electrically conductive scaffold. Cerruti suggested a further modification, with GO flakes stacked on the pore walls, “which allowed us to exploit another interesting property of GO – it creates a membrane that allows water through but no other molecules.”

When she canvassed her team for suggestions on how best to test the new scaffold, Gabriele Capilli, a post-doctoral fellow in her lab, suggested seawater electrolysis, a process similar to others he worked on while doing his PhD. It turns out the new GO “selective scaffold” has the potential to improve the process of producing hydrogen from the ocean. The team’s findings were published recently in the journal ACS Nano.

In conventional electrolysis, chloride ions in seawater penetrate the electrode and interact with the catalyst, creating hypochlorite ions, an unwanted byproduct that poisons the catalyst, Cerruti explained. Using X-ray phase contrast imaging at the Canadian Light Source at the University of Saskatchewan, Chen confirmed the GO scaffold had the right structure, with closed GO pores enclosing cobalt oxide nanoparticles as the catalyst. “We saw what we wanted to see.” Electrochemical tests performed in the laboratory of collaborator Thomas Szkopek (electrical engineering, McGill) confirmed the scaffold worked as expected to block unwanted ions.

Image: Gabriele Capilli, Marta Cerruti, and Thomas Szkopek (l to r), in their lab at McGill University.

Risks of lead exposure from bullets used in big game hunting

2022/08/242022/09/01

For the first time, researchers have used synchrotron imaging to study both the size and spread of bullet fragments in big game shot by hunters.

The lead in some bullets used for hunting deer, moose, and elk is toxic to the humans who eat the harvested meat and to scavenger animals that feast on remains left in the field.

A team of researchers from the Canadian Light Source at the University of Saskatchewan (USask) and the College of Medicine at USask has for the first time used synchrotron imaging to study both the size and spread of bullet fragments in big game shot by hunters. Their findings were published today at 2pm E.T. in PLOS One.

Like a scene right out of the hit television series CSI, the research team fired bullets into blocks of ballistic gelatin – the same material used by law enforcement agencies for ballistic testing – and examined the resulting fragments using synchrotron imaging.

The BMIT beamline at the CLS enabled them to distinguish lead fragments from other materials used in bullets and bone fragments. To better simulate hunting, the team encased deer bone within the ballistic gelatin (which is a similar density to flesh).

Image: Adam Leontowich holding block of ballistic gelatin at the BMIT beamline at the CLS

Understanding how motor proteins shape our cells

2022/08/092022/08/11

Understanding the busy networks inside our cells can help researchers develop new cancer treatments and prevent dangerous fungal infections.

With the help of the Canadian Light Source (CLS) at the University of Saskatchewan, a research team led by John Allingham from Queen’s University and Hernando Sosa from the Albert Einstein College of Medicine has shed light on a protein that regulates the intricate microscopic networks that give cells their shape and helps ship important molecules to diverse locations.

Using the CMCF beamline at the CLS and the cryo-EM facility at the Simons Electron Microscopy Center (SEMC) at the New York Structural Biology Center, the team found the missing pieces of an important puzzle.

In their published work, they are the first group to clearly describe the mechanism of action of a tiny motor protein called Kinesin-8 that enables it to control the structures of microtubule fiber networks inside the cell.

Image: Cells, Canadian Light Source.

X-rays allow us to quickly develop high-strength steels

2022/08/032022/08/11

Knowing how strong a piece of steel is, especially the stainless steel used in everything from cars to buildings, is vitally important for the people who make and use it. This information helps to keep people safe during crashes and to prevent buildings from collapsing.

Accurately predicting the strength of a steel prototype based on its microstructure and composition would be indispensable when designing new types of steel, but it has been nearly impossible to achieve — until now.

“Designing/making the best-strength steel is the hardest task,” said Dr Harishchandra Singh, an adjunct professor at NANOMO and the Centre for Advanced Steels Research at the University of Oulu in Finland.

Estimating the contribution of various factors towards designing high-strength novel steel has traditionally required numerous tests that can take months, according to Singh. Each test also requires a new sample of the prototype.

Image: Dr Harishchandra Singh, an adjunct professor at NANOMO and the Centre for Advanced Steels Research at the University of Oulu in Finland. He is standing next to steel components in the spectroscopy lab at NANOMO.

Canadian Light Source’s #My1stLight on the Far Infrared Beamline in 2005

2022/07/292022/07/29

The Queen of England helped us get the beamline operating in May of 2005, while she was visiting Saskatchewan and the Canadian Light Source with Prince Philip. The ring had been operating but the IR beamlines needed vacuum bellows installed due to delays in shipment. These would complete the UHV chambers to the window outside the shield wall. There were no beam outages on the schedule long enough to do this for 6 months into the fall, so the IR operation was being badly delayed.

But! the CLS had to shut down for a day before the Royal visit on Friday May 20*, to allow security screening and preparation for the Royals. So with two days of no-beam, the technicians quickly vented the ring magnet cell and installed the bellows and we had nearly 48 hours to pump down and bake the system. Then on Sat May 21 at 12:30 pm there was beam in the ring (thankfully no leaks from the bellows!) and the search for beam began. The M2 mirror was steered until a spot of light was seen glowing near the edge of the UHV window. This glow was adjusted to line up along one side, and a lateral scan was made while recording a video at the window.

At the controls was Dr. Dominique Appadoo, now at the Australian Synchrotron, who was the Far IR beamline scientist at the time. Assisting were Tim May the optics designer/project manager for the IR beamlines, and Craig Hyett a graduate student working on the IR beamlines. Subsequently the first light was steered out of the window port on the Mid IR beamline.

Image: Tim and Dominique searching for first light

* Read more on the CLS website

Cutting-edge imaging yields new insights into stroke

2022/06/092022/06/13

Synchrotron’s “superhuman vision” made it easy to detect markers of brain damage.

Hemorrhagic stroke, where a weakened vessel in the brain ruptures, can lead to permanent disability or death. Across the globe, over 15 million people are coping with its effects.

A study by researchers from the University of Saskatchewan (USask) and Curtin University in Australia has moved us one step closer to identifying when the bleeding associated with a hemorrhagic stroke starts – critical information for improving patient outcomes.

Time is of the essence when it comes to stroke; the sooner doctors can start treatment, the better the odds they can limit damage.

Using the Mid-IR beamline at the Canadian Light Source at USask, the team examined brain tissue samples with a special technique called Fourier-transform infrared imaging. The researchers were led by Dr. Lissa Peeling, a neurosurgeon at the Royal University Hospital and an Associate Professor in the Department of Surgery at USask.

The novel approach enabled the researchers to identify changes in the brain specific to hemorrhagic stroke.

Dr. Jake Pushie, a member of Dr. Kelly’s and Dr. Peeling’s research team at USask’s College of Medicine, said the combination of the beamline and infrared imaging made it easy to detect markers of brain damage caused by hemorrhagic stroke.

“In a sense, this is giving us ‘superhuman vision’ to look at these brains and map out what’s happening metabolically,” said Pushie.

With synchrotron technology, the team could see where a bleed originated and the extent of oxidative damage it caused – something impossible to do with a microscope or traditional approaches to imaging. Their findings were published in Metallomics.

Armed with this new approach, and a better understanding of what they are looking for, Pushie and colleagues will now go back through their extensive “library” of stroke tissue samples to gain a clearer picture of the speed at which oxidative damage begins to ramp up.

Image: Team member Nicole Sylvain, with USask’s College of Medicine, in a lab at the CLS

Understanding how the HIV virus evades immune surveillance

2022/05/252022/05/26

About 36 million people have died from AIDS-related illnesses and approximately 38 million people globally are living with HIV.

Dr. Jonathan Cook, a resident physician specializing in medical microbiology at the University of Toronto, is investigating key proteins on the HIV virus that are crucial to developing an effective vaccine.

“These proteins are so interesting because they are necessary for a virus to infect a human,” said Cook. “By blocking their function, we can avert the kinds of infections that you see routinely.”

He and Adree Khondker in the lab of Prof. Jeffrey E. Lee from the Temerty Faculty of Medicine published a paper in Communications Biology that reveals new information on how the HIV virus interacts with immune systems.

Using the CMFC beamline at the Canadian Light Source at the University of Saskatchewan, the research team analyzed the outer proteins on the HIV virus. They discovered that an area of one protein acts as a decoy — diverting the immune system’s response towards a false target.

This tactic allows the virus to successfully infect human cells and to cause disease.

“The immune system recognizes this sequence on the virus, which is usually a good thing. But, in this situation, the antibodies that the immune system makes don’t protect you from infection,” Cook said.

With the help of the CLS, the researchers confirmed that this decoy area on the HIV protein shapeshifts to entice an ineffective immune response.

Image: Micrographs of crystals from this project that were diffracted at CLS

X-rays capture ageing process in EV batteries

2022/04/052022/04/07

CLS researcher Toby Bond uses x-rays to help engineer powerful electric vehicle batteries with longer lifetimes. His research, published in The Journal of the Electrochemical Society, shows how the charge/discharge cycles of batteries cause physical damage eventually leading to reduced energy storage. This new work points to a link between cracks that form in the battery material and depletion of vital liquids that carry charge.

Bond uses the BMIT facility at the Canadian Light Source at the University of Saskatchewan to produce detailed CT scans of the inside of batteries. Working with Dr. Jeff Dahn at Dalhousie University, he specializes in batteries for electric vehicles, where the research imperative is to pack in as much energy as possible into a lightweight device.

In lithium-ion batteries, this is because charging physically forces lithium ions between other atoms in the electrode material, pushing them apart. Adding more charge causes more growth in the materials, which shrink back down when the lithium ions leave. Over many cycles of this growing and shrinking, micro-cracks begin to form in the material, slowly reducing its ability to hold a charge.

Image: Toby Bond adjusts a battery sample on the BMIT beamline