ILLUMINATING RESEARCH

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By Deborah Komlos

Researchers have an excellent reason to beam.

Canada’s first synchrotron, a $173.5-million facility called the Canadian Light Source (CLS), officially opens this month on the University of Saskatchewan’s (U of S) (Saskatoon, SK) campus. Wholly owned by the U of S, the CLS will provide industrial, government and academic researchers with a powerful new tool for the atomic-level visualization of matter and for the analysis of a host of processes in such areas as the physical, environmental and life sciences.

The U of S made an exceptionally attractive bid to win a national competition for building the CLS, says Bill Thomlinson, PhD, executive director of Canadian Light Source Inc. (CLSI), the firm that runs the facility.

“The extraordinary, enthusiastic support of the University of Saskatchewan, the city and the province . . . that’s really what swung it to be here,” Thomlinson says.

Funding for the CLS was secured in 1999, with the Canada Foundation for Innovation (Ottawa, ON) providing $56.4 million. The remaining support has come from other partners, including $36.7 million from Saskatchewan sources, and a total of $28.3 million from federal partners such as Western Economic Diversification Canada (Edmonton, AB) and the National Research Council of Canada (NRC) (Ottawa, ON). Government and academic sources in Alberta and Ontario, as well as industry, also contributed.

In addition to finances, the local expertise and infrastructure that already existed on the U of S’s campus through the Saskatchewan Accelerator Lab (SAL) were also highly instrumental, and formed the foundation for the CLS.

“You can always build bricks and mortar,” Thomlinson says. But particular elements, like 35 years of SAL operations, are rare. “There was a body of people here who knew how to both design and then operate major accelerator-type facilities,” Thomlinson says of the SAL team.

Resourceful Beams
As with any synchrotron, the CLS’s light spans the entire spectrum from infrared through to X-ray wavelengths. Twelve beamlines are currently funded: seven in Phase I will be operational within the next calendar year, Thomlinson says, with the first call for research proposals going out this fall for the use of two soft X-ray beamlines in early 2005. Five Phase II beamlines are planned and will be ready for use in about three years, he says. There is hope to eventually have about 30 beamlines, Thomlinson adds.

The CLS is powered by strong magnets that accelerate electrons in a vacuum to almost the speed of light. The resultant synchrotron radiation is delivered by the beamlines to end stations for use in experimental work. As a third-generation synchrotron, the CLS is among only a handful of its type worldwide.

“The first synchrotron experiments were done parasitically on high-energy machines. That is, if you have an accelerator in a circle, it’s going to radiate,” Thomlinson explains. “If you put a window in, you can bring light out and use it. And that’s the way all this started at Stanford, at General Electric and all around the world.”

Then came the second-generation type, such as the one Thomlinson helped build at Brookhaven National Laboratory (Upton, NY), “where you actually design the accelerator for materials and chemistry and life science research,” he says. “But at that time, really the only devices in use were the magnets that make the electrons go in a circle, called bending magnets.”

In the third-generation synchrotron, special magnets called insertion devices are used to produce even more light from the electron stream. Further, they permit tailoring to research needs by allowing users to select the wavelength they require.

Mike Jackson, PhD, head of the Biosystems Group at the NRC’s Institute for Biodiagnostics (Winnipeg, MB), is beam team leader for the CLS’s Mid IR Spectromicroscopy beamline.

Much of Jackson’s research focuses on TSEs (transmissible spongiform encephalopathies), which include such neurological disorders as mad cow disease and Creutzfeldt-Jakob disease.

“One of the things that we’re doing, we look at infected mice and we’ll do MRI to look at their brains to see what’s happening as the disease progresses,” Jackson explains. “Then we sacrifice animals at different time points, and we then use infrared to look at the brain in detail to try to understand the chemistry that’s going on.

“Basically, the infrared spectrum gives you a chemical fingerprint, and if you have a disease state, that chemical fingerprint changes, because the biochemistry of the tissue is slightly different,” he continues. “So we try to use infrared to compare the chemical signatures of healthy and diseased tissue, and if you can find specific frequencies of infrared light that are absorbed, when you have a certain disease state, you can use that as a diagnostic tool. But as well as using it for a diagnostic tool, because you understand something about the difference in biochemistry based on the infrared spectrum, you can actually start to understand the molecular nature of the disease process.”

Advanced Attributes
Light diffraction is a problem with current instrumentation, Jackson says. When light is sent through very small pinholes onto a tissue section, it gets scattered at the hole edges and not enough light is transmitted. This limits the view area, he says, to about 25 microns squared.

“The idea with the synchrotron is you get 1,000 times more light than you do with a conventional instrument,” he continues. “So if I’m only getting a very small number of photons through that small aperture, if I use 1,000 times more photons I can get a much better signal.”

With such higher resolution, much more precise measurements are possible.

“If I’m looking at an area of tissue that’s about 100 microns by 100 microns, a normal cell is about 10 microns in diameter,” Jackson explains. “So in that area of 100 by 100 microns, I will actually have 100 cells . . . if only one of those is abnormal and 99 per cent of them are normal, it would be very hard for me to find that one cell. But if I can then take measurements at every five microns within that 100-by-100 micron area, I’ll be able to find that one cell that’s abnormal.”

As a beam team leader, Jackson is involved in training upcoming CLS users. Along with an NRC colleague, he holds two-day training sessions in which trainees are introduced to the CLS, given a demonstration and then walked through how to take measurements on their own samples using the beamline.

Thomlinson says it will likely take two or three years before the size of the community on any given beamline can be established. But it is expected, he says, that some beamlines will be more sought after than others.

“We already know, for example, that the protein crystallography beamline — we’re building one, we’re funded for a second one — both of those, before they turn on, are grossly oversubscribed,” Thomlinson says. “Whereas, if you go to something like, say, a gas phase spectroscopy beamline — that’s a smaller community. We anticipate full utilization of all the beam time, but in particular areas, you’ll have people competing for the limited time resource.”

Kenneth Ng, PhD, an assistant professor in the department of biological sciences at the University of Calgary (Calgary, AB), is one of the researchers who plans to be on board for the CLS protein crystallography beamline, the Canadian Macromolecular Crystallography Facility. Ng uses X-ray crystallography to better understand proteins’ 3-D structure and function.

Relative to laboratory-produced X-rays, the much stronger synchrotron radiation allows researchers to obtain much better data, “especially on difficult systems where we can only produce really small crystals or crystals of poor quality, which basically we can’t do very much with in the lab,” Ng says.

Beaming Milestones
Having a more local synchrotron source will substantially save on time and travel costs, Ng says. So far, his team has relied mostly on the Advanced Light Source, a division of Berkeley Lab (Berkeley, CA), with which the Alberta Synchrotron Institute (Edmonton, AB) has a usage agreement.

Part of Ng’s research is looking at viral diseases, with an end goal of rational structure-based drug design. He’s working with positive-strand RNA viruses, such as the Norwalk and West Nile viruses, determining the 3-D structure of each virus’s replicating enzyme, RNA polymerase.

Other research involves the opportunistic bacterium Clostridium difficile. “The problem with this bacterium is that once it starts growing in your intestine it produces a toxin, which is a big protein that the bacterium secretes out into the intestine and then it binds the cells in your intestine and starts damaging them,” Ng says. Consequently, he adds, severe diarrhea, destruction of the intestine and death can follow.

“What we’re doing is using this X-ray crystallography to determine the structure of the toxin or parts of the toxin that are important for the toxin to bind to the intestinal cells,” Ng says. A next step, he says, is collaborative work with scientists involved with in vivo drug testing to develop a carbohydrate-based inhibitor to the toxin.

CLSI’s first priority, Thomlinson says, is to get industrial usage of the facility, with a long-term goal of 25-per-cent. “It’s a goal. It’s a real stretch on some beamlines; others we know we’ll get there,” he says. “Historically, around the world, it’s been a very difficult task to get a large percentage of industrial participation — 25 per cent has never been achieved anywhere.”

Working toward that goal means dealing with the steep learning curve facing industry, he says.

“There’s a large degree of education still required in the industrial sector in terms of the advantages of using synchrotrons as a part of their overall scientific development programs,” Thomlinson says. “So we’ve been unique. We’re the first facility I know of in the world that started off long before turning on the switch, developing a — I’ll call it a capacity in the industrial sector to use this facility . . . We hope that by being proactive prior to startup we’ll have a better return on the industrial sector.”