Lights in the Darkness . . . and Hope from the Labs

Photo courtesy of Karol Nass/CFEL

A map of intensities merged using the CrystFEL software suite from almost two hundred thousand diffraction patterns obtained from in vivo grown crystals of Trypanosoma brucei cathepsin B. This map is used to synthesize the three-dimensional molecular structure of the enzyme.

Dark nights often bring out bright lights. That's especially true at this time of year, the short days that give way to evenings lit with colored bulbs and commemorative candles.

What's true for the season is true for the Office of Science, especially its incredible light sources. Two of them, the Linac Coherent Light Source (LCLS) and the Stanford Synchrotron Radiation Lightsource (SSRL), are at one of its labs, SLAC National Accelerator Laboratory (SLAC), and both recently revealed structures which could eventually lead to new treatments for terrible diseases.

Millions of people suffer from stomach ulcers, which (contrary to what one may think given the stresses of this season) are actually caused by a bacterium called Helicobacter pylori. H. pylori are tough enough to survive both stomach acid and the blackened bits that result from typical bachelor cooking techniques, and it can also increase one's odds of developing stomach cancer.

So scientists used SLAC's SSRL (its X-ray light source) to take a close look at the bacteria. They focused on a channel made from protein in the bacterium's cell wall which helps H. pylori neutralize stomach acid, and therefore allows it to survive in such a challenging environment. After five years of work and 100 experiments, they finally produced a detailed 3-D image of the channel, which forms a hexagon-shaped ring. The effort should be worth it though, since the channel could eventually be targeted by drugs and show the way to new treatments against ulcers.

SLAC's and its users' work on sleeping sickness may also lead to new medicines. The disease, caused by a parasite (protozoa in the Trypanosoma genus) that infects people via tsetse flies, threatens millions across Africa and kills an estimated 30,000 souls every single year. Here as well, SLAC-supported researchers tried to find the structure of one of the parasite's essential proteins. But in this case, they went after an enzyme – a cellular machine – that allows the parasite to speed its infection by breaking down the proteins of its victims.

Enlarge Photo

Photo courtesy of Greg Stewart/SLAC National Accelerator Laboratory

Researchers have revealed the detailed structure of an important protein involved in the transmission of African sleeping sickness. To do so, scientists used the LCLS X-ray laser and created diffraction patterns (shown in background) that were then reconstructed into the molecular structure (shown at center). The research is an important step toward developing a new drug to target the disease, which is carried by tsetse flies and is responsible for tens of thousands of deaths each year.

And here too the going was tough, especially since the protein used by the African sleeping sickness parasite is quite similar to a protein used by people. As a consequence, an extremely precise determination of its structure was needed: One that would show a few essential differences and perhaps allow researchers to eventually design drugs targeting the parasite's protein while leaving the human version untouched. To do so, SLAC and international scientists used their newest and most powerful tool, their X-ray free electron laser known as the LCLS.

The LCLS produces X-ray pulses so powerful that they can show structures down to the resolution of individual atoms, even while using much smaller crystals than those required by more conventional X-ray light sources, such as SLAC's SSRL. In fact, researchers actually grew tiny crystals of the sleeping sickness protein in live insect cells and then streamed them into the path of the powerful x-ray laser to get their structures. That in itself won't make for a new medicine, but it does make one more likely.

That's the spirit of the season, and yes, the Office of Science: Shining bright lights into dark nights, and showing hope to many.

The Department's Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information please visit http://science.energy.gov/about. For more information about SLAC, please go to http://www.slac.stanford.edu/.

Charles Rousseaux is a Senior Writer in the Office of Science.