Nirupa Nagaratnam works in a pristine lab on an upper floor of ASU’s Biodesign Institute, Building C. She often sits at a microscope, peering into a plastic plate with miniature wells (think of the divots on an artist’s palette) filled with a colorless liquid.
But when she zooms in, a drop of that colorless liquid becomes its own complex world, a landscape that looks like the bottom of a jewelry box, filled with iridescent crystals.
It’s a small part of an experimental design that Nagaratnam, a postdoctoral researcher at Arizona State University, hopes will one day help her and other researchers develop a new way of studying drugs for diseases like cancer. She envisions a world where researchers can test new treatments and watch them in real time, essentially creating a molecular movie, one she can watch frame by frame with a close-up view of proteins shifting and folding in space and time.
The only catch: Those proteins, encased in Nagaratnam’s crystals, are small.
Really, really, really small. Like smaller-than-a-human-hair small.
To achieve the “molecular movie” that Nagaratnam and others hope for, they need access to large, expensive and rare equipment.
Teams of scientists have made significant steps toward reducing the size, cost and challenges of performing experiments like Nagaratnam’s, and now, with a $90.8 million grant from the National Science Foundation, ASU researchers will construct a compact X-ray free electron laser (CXFEL). It’s a tool that will allow researchers to glimpse atomic structures just a fraction of the width of a human hair.
“I think this is revolutionary,” said Nagaratnam. She feels lucky that she has been able to witness the project come together over the course of her doctoral and postdoctoral work.
Even before Nagaratnam arrived at ASU, and before the largest National Science Foundation research award in the university’s history, researchers have been dreaming about the possibilities this machine could bring for clean energy, medicine and basic science. It’s driven by technology that, in most places, requires about a mile of underground infrastructure, and yet at ASU, fits in a basement just a short elevator ride from Nagaratnam’s lab.
Some “really smart ideas” went into shrinking down the complex array of gadgets that makes up this super-precise X-ray machine, said Eaton Lattman, a professor emeritus at the University of Buffalo who advised the ASU team that applied for the grant. It may be many years before the results of the achievable science are published, he said, but those results may lead to novel drugs and important discoveries of basic science.
“It isn’t just a simple engineering project,” he said. “There is a tremendous amount of creativity that made it possible.”
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Replacing magnets with lasers
If you break a bone, your doctor can use an X-ray to peer through layers of skin and muscle and get an image of the structures beneath.
The CXFEL will operate on the same principle, with two major differences. First, the structures scientists are trying to look at, like Nagaratnam’s crystals, are much, much smaller than anything that can be seen with the naked eye. And the X-rays the CXFEL produces won’t just create a static image. Instead, many pulses of X-rays will create snapshots over time, like frames on a film reel.
Most X-ray laser facilities around the world require an approximately mile-long particle accelerator and a 100-yard array of alternating magnets to cause a beam of electrons to “wiggle.” Bill Graves, project director and principal investigator for the construction of the CXFEL, had worked on those machines for most of his career.
But Graves had an idea for how to shrink things down using a completely different technique: A laser would intercept the beam of electrons. And that would mean the big particle accelerator would only need to be 6 feet, and an enormous and pricey collection of magnets wouldn’t be necessary at all.
It would still be big, expensive science, starting with 120 concrete trucks to come in overnight to load in four-foot thick walls to protect scientists from radiation. They would need experts in fields ranging from particle physics to chemistry, and plenty of persistence. The goal would be to witness something happening at the molecular level, in one millionth of one billionth of a second, approaching the shortest spans of space and time that can possibly be measured.
It would be a challenge, “but that’s part of the fun, really, is pushing those boundaries,” Graves said.
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Inside the prototype
If all that sounds complicated, it is.
Anyone who enters certain clean areas of the underground structure at Biodesign Institute Building C must don shoe covers so they don’t track in dirt and dust from the outside world. And the rooms that house the prototype for the CXFEL are like a science fair of physics concepts. One room’s walls, ceiling and floor are all aluminum, creating a Faraday cage that contains two transmitters, each of which can produce enough power to run a small town for a microsecond.
In another room, which the researchers call “the vault,” an electron accelerator, a high-power laser beam, water cooling systems, communications cables and cameras align to form a machine out of Tony Stark’s dreams.
This new technique is the precision equivalent of two sharpshooters standing on opposite ends of a football field, aiming and shooting so that their bullets collide exactly at the 50-yard line, said Mark Holl, chief engineer on the project and deputy director of the CXFEL labs.
Inside the basement control room, Holl said, surrounded by monitors and separated from the actual machinery by four-foot-thick concrete walls that protect against radiation, “the world kind of goes on without you.”
The sun rose and set as the team ran tests, making micro-adjustments, trying to get the timing just right. Then, in the evening on Feb. 2, it happened for the first time: The CXFEL prototype had worked, producing its first X-rays.
“It’s really surreal,” said Holl of the elation and relief he and the other scientists felt as they went outside to pop champagne (well away from any scientific equipment). “It takes years of preparation and effort to run these critical experiments.”
But getting the prototype to produce X-rays was just the beginning.
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Tiny worlds, big possibilities
Petra Fromme has been interested for a long time in figuring out how plants convert sunlight into energy, so humans can learn from nature to create clean energy more efficiently.
To zoom in to look at the tiny structures inside plant cells, she’s secured “beam time” at the bigger facilities at Stanford, in South Korea, in Germany and in Japan. But there was never enough time for the kind of questions she wanted to ask, said Fromme, scientific director of the CXFEL, a regents professor with ASU’s School of Molecular Sciences and director of the Biodesign Center for Applied Structural Discovery.
Then, by chance, she was upgraded to business class on a flight to San Diego in 2018, and ended up sitting next to Leo Beus, a major ASU donor. In her characteristically giddy way, and unaware whom she was sitting next to, she explained her work, dreams and ambitions for creating molecular movies of complex biological processes, the students she mentors and her excitement about what her lab could do if they had access to compact X-ray and laser technology on campus.
That’s how ASU ended up with an extra $10 million donation from Leo Beus and his wife, Annette, that allowed Fromme and other ASU scientists to complete their first prototype for the CXFEL project. And now that the concept has been proven, the National Science Foundation grant will provide the funds to build another set of instruments, allowing the scientists to conduct research with the prototype while also building a new version of the machine with upgraded performance.
“This is one of my big dreams coming true,” Fromme said.
It may be a while yet before she publishes the results of any work done using the CXFEL, but others in the field are looking forward to seeing what happens when she does.
“This is still really early days for the field,” said Mike Dunne, director of Stanford’s Linac Coherent Light Source (LCLS), one of the most powerful X-ray laser systems in the world, in an email. The technology at Stanford can still produce higher brightness levels, he said, but ASU’s more compact design will still generate “interesting data in its own right, and also (help) ensure that we make really good use of the high-end performance at LCLS where access time is hugely oversubscribed.”
Fromme also hopes that eventually, researchers at ASU can collaborate with scientists at the bigger machines, in hopes of combining the advantages of both technologies.
In the meantime, she and her lab members, including Nagaratnam, are setting their sights on the horizon, imagining applications ranging from medicine to clean energy to infectious disease research.
“Her brain is full of so many ideas, and she’s a very enthusiastic person,” Nagaratnam said of Fromme. “If you talk to her… you will feel like, ‘okay, I want to join her lab.’”
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Melina Walling is a general assignment reporter based in Phoenix. She is drawn to stories about interesting people, scientific discoveries, unusual creatures and the hopeful, surprising and unexpected moments of the human experience. You can contact her via email at [email protected] or on Twitter @MelinaWalling.