Bigger, Faster, More Accessible

Just about 40 years ago, Keith Hodgson, a chemist at Stanford University, did something unprecedented. He and his colleagues were the first to use the powerful x-rays produced by a synchrotron to reveal the three-dimensional shape of a protein. Today, looking at molecules with a massive particle accelerator is no less remarkable for HHMI’s structural biologists, but it has become much more commonplace.

About the size of a football stadium, synchrotrons produce high-intensity x-rays by accelerating electrons to super-fast speeds. The powerful radiation is perfect for x-ray crystallography—a method that involves shooting x-rays at a protein crystal—and structural biologists have come to rely on it in the decades since Hodgson published his results. Because their x-rays are about 1,000 times stronger than those created in the average laboratory, synchrotrons cut down on data collection time and enable the use of smaller, more easily grown crystals.

When HHMI started its structural biology program in 1986, Institute leaders anticipated the large role these impressive machines would play. With a ticket-price of about half a billion dollars, however, purchasing a synchrotron was out of the question. Creating an x-ray crystallography facility at an existing synchrotron, on the other hand, was not.

By 1992, the Institute completed a $3.2 million facility at the National Synchrotron Light Source at Brookhaven National Laboratory in New York (see Web Extra sidebar, “Accelerating Discovery”). It became very popular, and because they had access to the synchrotron’s workstations 75 percent of its operational time, HHMI scientists had ample opportunity to use the high-intensity x-rays for their experiments.

A few years later, HHMI’s investigators began lobbying for access to a synchrotron on the West Coast as well. They urged the Institute to create an x-ray crystallography facility at the Advanced Light Source (ALS), at Lawrence Berkeley National Laboratory in California.

The ALS synchrotron was newer than the one at Brookhaven but the majority of research being done there was related to materials science. The small number of workstations used for protein crystallography had long wait times and were in such high demand that fewer than 35 percent of requests could be filled. Many biologists found themselves asking for beam time at ALS a year in advance to schedule the few days they needed to solve a single structure.

To meet its scientists’ growing needs, the Institute’s Board of Trustees gave the go-ahead to spend $8.05 million on the construction and operation of a facility containing two beamlines—beams of x-rays coming off the synchrotron ring at the same port. Work at ALS was completed by the end of 2001 and the facility was embraced by the HHMI community. “Everyone would agree the investment was money very well spent,” says Janelia Farm Research Campus lab head David Clayton, who was HHMI vice president and chief scientific officer at that time.

ALS’s popularity continued to grow, and in 2006 the Institute committed another $4.8 million for upgrades that resulted in faster and more efficient data collection. Scientists were realizing that automating certain aspects of data collection led to better, more accurate results. In the time it would take a researcher to screen one or two crystals by hand, a robot could look at 10 or 20 crystals. As a result, crystal-handling robots were added to both ALS beamlines.

The robots improved efficiency and allowed researchers to run the data collection from their own labs. “It’s totally automated, so we sit in our lab and collect all our data remotely,” says HHMI Investigator Dorothee Kern, a structural biologist at Brandeis University. “It’s really incredible how user-friendly that is.”

A second improvement converted one of the beamlines into a microbeam—a small, powerful band of x-rays that can generate data from really tiny crystals. The modifications include several mirrors and optical devices that focus the beam to a finer point, enabling scientists to target crystals the size of a human cell rather than a poppy seed.

The ALS facility remains extremely productive and popular for HHMI investigators and other scientists (who can use the facilities 25 percent of the time). HHMI spends about $1 million each year to operate the beamlines and has no plans to stop. In fact, a proposal for a third beamline, equipped with the latest technology, is in the works.

-- Nicole Kresge
HHMI Bulletin, Spring 2013

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