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2017 Annual Report

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Investigating Life's

Investigating Life's Smallest Components At first glance, the image rotating on Dr. Huilin Li’s computer screen looked like a tangled mass of ribbons, with teal whorls looping through blue ones and an elegantly spiraling pink whorl running through the middle. But Li’s trained eyes saw so much more — a critical piece of molecular machinery responsible for helping copy DNA, the instructions for life, revealed in never-before-seen detail thanks to a revolutionary technology called cryo-electron microscopy (cryo-EM). For Li and his colleagues in Van Andel Research Institute’s (VARI) growing team of structural biologists, cryo-EM offers an unprecedented look at a world that is minuscule in size and massive in impact, a realm of tiny molecular workers that control every aspect of biological function in health and disease. “Cryo-EM is like space exploration in reverse — rather than seeking out the cosmos with powerful telescopes, technology is turned inward, revealing the structures of life’s smallest components in remarkable clarity,” Li said. “Because the shape of molecules is intimately linked to their role in the body, understanding exactly what they look like has immense potential for improving human health.” The right tools and the right people at the right time Although cryo-EM has been around for decades, advances in technology and technique have only recently turned it into a scientific juggernaut, even landing cryo-EM a coveted spot as Nature Method’s Breakthrough of the Year in 2015. Discovery after discovery continue to reinforce cryo-EM's value as a research tool, evidenced by the breathtaking images of previously elusive molecules that frequently adorn the covers of scientific journals around the world. 16 | VAN ANDEL INSTITUTE ANNUAL REPORT 2017 One thing was clear — to be a structural biology powerhouse, VARI needed to join the cryo-EM community. With the generous support of CEO David Van Andel and the hard work of people across the Institute, VARI’s million David Van Andel Advanced Cryo-Electron Microscopy Suite was up and running by early 2017 — a massive undertaking and an even more impressive achievement given the extensive renovations, installations and recruitment efforts required for completion. “The opening of our cryo-EM facility is a testament to the Institute’s commitment to life-changing science and the exemplary vision of our leadership, board and scientific team,” said Chief Scientific Officer Dr. Peter Jones. “Cryo-EM gives us insight that has never before been attainable. We believe the result will be nothing short of a revolution in our biological understanding that will lead to more effective medications for a multitude of diseases.” The crown jewel of the facility is an FEI Titan Krios from Thermo Fisher Scientific, a behemoth of a microscope that can visualize molecules 1/10,000 th the width of a human hair. There are fewer than 120 Krioses in use globally, placing the Institute in the elite company of some of the world’s top-tier research organizations. As the suite was being built, VARI also grew its structural biology team, recruiting cryo-EM experts whose strengths aligned with the Institute’s mission of impacting human health. These new recruits joined VARI scientists Dr. H. Eric Xu and Dr. Karsten Melcher, both internationally recognized structural biologists who played key roles in bringing cryo-EM to VARI. The first to arrive were facility manager Dr. Gongpu Zhao, “Each day, our scientists are pushing the boundaries of what was once thought to be impossible, always with an eye on building a better tomorrow.” Dr. Peter Jones whose previous achievements included producing the first cryo-EM images of the HIV-1 virus’s inner shell, and Li, whose work has revealed mechanisms at the very basis of life. They were joined in 2017 by Dr. Wei Lü and Dr. Juan Du, who use cryo-EM to investigate molecules crucial to development and function of the brain and the nervous system. The team didn’t waste any time getting to work. From idea to application The beauty of cryo-EM lies in its speed and its ability to allow scientists to view molecular structures in their natural state, rather than the tough-to-produce crystallized form that some gold standard methods require. It works by flash freezing molecules and scanning them with an electron beam, a process that generates hundreds of thousands of two-dimensional images that are then assembled via computer into a three-dimensional portrait. The results are stunning in their clarity, allowing novel

RESEARCH observations that push scientific research into new directions and open additional avenues for therapeutic development. Because the function of a molecule is closely tied to its shape, the ability to see a molecule's structure in intricate detail gives scientists powerful insights that may be translated into new medications for a host of diseases. Think of it like a lock and key: If you know what the lock looks like, you can cut a key to fit it. In much the same way, scientists can design medications that link up with specific proteins, correcting a dysfunctional process. The result? A new, hopefully more effective treatment. In 2017, the first two structures determined wholly on the Institute’s Krios were announced in prestigious journals. In October, Li and collaborators at Cold Spring Harbor Laboratory and Imperial College London published a portrait of Mcm2-7 helicase, a molecular complex that triggers DNA replication and plays a key role in the cell divisions that sustain life, in the Proceedings of the National Academy of Sciences. In December, Lü and Du’s images of the TRPM4 receptor, a protein that may be an important drug target for stroke and traumatic brain injury, appeared in the pages of Nature. Both are exceptional achievements on their own, but together, they are a herald of discoveries to come. “Science often comes down to the details, meaning that sometimes the smallest things may help solve the biggest problems,” Jones said. “Each day, our scientists are pushing the boundaries of what was once thought to be impossible, always with an eye on building a better tomorrow.” (LEFT TO RIGHT) 3D STRUCTURE OF TRPM4 RECEPTOR; 3D STRUCTURE OF MCM2-7 HELICASE. VAN ANDEL INSTITUTE ANNUAL REPORT 2017 | 17

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