Accelerating Discovery

HHMI invested in a synchrotron beamline to speed protein crystallography.

Form and function are intimately related in biology. A molecule’s twists and turns give valuable insight into how it does its job. In the 1980s, the best way for researchers to peer into a protein’s atomic world was with x-ray crystallography. Unfortunately, even for scientists who could generate x-rays in their labs, it was a slow process. Purifying proteins and coaxing them to form crystals could take months. Add data collection and computing time and solving a single structure could stretch to several years.

Structural biologists were eager for tools that could help speed the pace of discovery. A high-powered source of x-rays, funded by HHMI in 1986, added a much-needed boost.

Physicists built the first cyclic particle accelerators, or synchrotrons, in the 1940s, to help them understand the fundamental forces of nature. The machines used giant magnets to accelerate electrons and other subatomic particles around a tubular ring about the size of a football field. Once up to speed, the particles emitted bursts of energy that spanned the electromagnetic spectrum. Scientists promptly found uses for the extra energy emissions, constructing window-like ports in the synchrotrons to divert the energy to their various projects. Demand for the energy became so great that by the mid-1970s there were three accelerators in the U.S. built solely for the purpose of generating synchrotron radiation.

X-ray crystallographers were quick to realize the advantages of these impressive new machines. Synchrotrons could produce x-rays about 1,000 times more powerful than those created in the average laboratory. Not only did they cut down on data collection time, synchrotrons also required smaller crystals, which could be grown quickly.

But while some crystallographers embraced this new source of x-rays, others complained that the facilities were built for physicists and engineers and had no amenities for biologists. Others griped that they had to book their reservation far in advance and spend large amounts of money shipping supplies and traveling to the few available synchrotrons.

Columbia University’s Wayne Hendrickson was firmly in the camp of scientists who believed in the power of synchrotron radiation. When Columbia was being considered for the nascent HHMI structural biology program in 1986 (see feature, “A Structural Revolution”), Hendrickson’s proposal to host one arm of the program included building a new x-ray crystallography facility at the National Synchrotron Light Source at Brookhaven National Laboratory in New York. HHMI investigators would get priority, but the facility would be open to the entire scientific community 25 percent of the time. Hendrickson’s plan was approved, and he became an HHMI investigator and the project’s director.

“It was a time when people were just beginning to use synchrotron radiation routinely,” recalls Janet L. Smith of the University of Michigan, who was an associate research scientist in the Hendrickson lab at Columbia. “It was definitely not routine at that point, but Wayne felt that it would become routine, and there was no way there was enough capacity for all the groups in the country.”

Hendrickson’s design called for not one but three beamlines, or beams of x-ray light, coming off the accelerator ring from the same port, each encased in its own steel tube. Each individual beam was tailored for a specific crystallographic use. One was for conventional experiments that required run-of-the-mill x-rays. Another produced full-spectrum radiation for something called Laue diffraction experiments, which allowed scientists to watch split-second enzymatic reactions. The third beamline was for multiple wavelength anomalous diffraction (MAD), a technique developed by Hendrickson that required fewer crystals and less data collection time than conventional methods.

“Back then, there was one beamline in the U.S. where you could do that experiment,” says Smith, a founder of a group called the Structural Biology Synchrotron Users Organization. That beamline was at the Stanford Synchrotron Radiation Laboratory in California. “Hendrickson knew that MAD would become a very important method and that the only way this could be realized was if we had more decent beamlines.”

Work on the $3.2 million project started in 1987 and was completed five years later. “Because Hughes investigators could use that beamline without writing applications, it became very important for them because it was easier to schedule time on short notice,” says Smith. For many years, the Brookhaven facility was one of the most successful beamlines in the country, churning out hundreds of structures. HHMI investigators Roderick MacKinnon of Rockefeller University and Thomas Steitz of Yale University conducted some of their Nobel Prize-winning work there.

In fact, the project was such a hit that, in 1998, HHMI investigators urged the Institute to finance another facility at the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory in California. Two years later, the Trustees gave the go-ahead to begin funding two beamlines at the ALS, which were completed at the end of 2001 and today serve hundreds of scientists each year.

FOR MORE INFORMATION: To learn more about HHMI’s beamlines at the Advanced Light Source at Lawrence Berkeley National Laboratory, stay tuned for Part 2 in the Spring 2013 HHMI Bulletin.

-- Nicole Kresge