The National Institutes of Health (NIH) has formed a Living Lab Structural Biology Center through a cooperative research and development agreement with Hillsboro, Oregon-based scientific instruments company, FEI. This new type of lab has been created to utilize near-atomic resolution microscopy and other structural biology technologies to help accelerate important medical discoveries relating to global health challenges, such as cancer and HIV/AIDS.
The lab, which will be located on the NIH campus, is a unique interdisciplinary collaboration among experts from FEI and scientists from the National Cancer Institute (NCI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both part of the NIH, in the fields of cryo-electron microscopy, nuclear magnetic resonance spectroscopy, X-ray diffraction, and biochemistry. A Titan Krios transmission electron microscope, one of the world’s most powerful commercially-available electron microscopes, will be located at NIH to enable the collaborative research.
"NIH is excited at the prospect of creating the Living Lab to harness intramural strength in the multiple disciplines in structural biology," said Michael Gottesman, M.D., deputy director for intramural research at NIH. "This type of collaboration will help serve NIH’s mission to foster innovative research strategies in an effort to protect and improve the public’s health."
The collaboration involves the development of methods and workflows, from sample preparation through data analysis, that combine information from all of the technologies in the Living Lab. Scientists have historically relied on nuclear magnetic resonance and X-ray diffraction techniques to determine the structures of molecular complexes and proteins that play a role in the causes of various diseases, such as AIDS, diabetes, and cancer. Although structural information about a wide variety of medically important proteins and drugs has been obtained by these methods, they have limitations that put some of the critical biological answers out of reach. Cryo-electron microscopy is a complementary analytical technique that provides near-atomic resolution without requirements for crystallization or limits on molecular size and complexity imposed by the other techniques.
"Technical advances make it possible to tackle extraordinarily challenging problems, such as analyzing structures of complex assemblies like intact HIV particles," said Robert Wiltrout, Ph.D., director of NCI's Center for Cancer Research. “Successful integration of cryo-electron microscopy, X-ray diffraction, and nuclear magnetic resonance results could accelerate discovery of biological mechanisms and provide powerful tools to assist drug design.”
Sriram Subramaniam, Ph.D., senior investigator in NCI’s Laboratory of Cell Biology is the director of the Living Lab. Other NIH researchers participating in the Lab include leading nuclear magnetic resonance spectroscopists Adriaan Bax, Ph.D, and G. Marius Clore, M.D., Ph.D., both NIH distinguished investigators in NIDDK; X-ray crystallographers Alex Wlodawer, Ph.D., chief of the NCI Macromolecular Crystallography Laboratory; Fred Dyda, Ph.D., senior investigator in the NIDDK Laboratory of Molecular Biology; and biochemists Suresh Ambudkar, Ph.D., and Stuart Legrice, Ph.D., both senior investigators in the Center for Cancer Research, NCI.
"The prospects for applying cryo-electron microscopy to study the structures of a broad spectrum of medically relevant complexes has changed dramatically in recent years with advances in microscope hardware and powerful new methods for image analysis," said Subramaniam. "Our goal with the Living Lab is to capture the synergy between the latest methods by studying selected large molecule complexes that span the range from viral and DNA-binding proteins to integral membrane proteins and nucleic acids that are representative of key scientific challenges in modern structural biology."