The program聽funds聽exceptionally creative scientists proposing to use highly innovative approaches to tackle major challenges in biomedical research. The program supports high-risk ideas with high-impact potential, and applicants are encouraged to think outside the box and to pursue exciting, trailblazing ideas in any area of research relevant to the NIH mission.

The 2017 UW recipients:

, assistant professor of chemistry, and聽, professor of chemistry and bioengineering, are co-recipients of a聽鈥淭ransformative Research Award.”

Chiu and Vaughan are developing radical new technologies for high-resolution mapping of brain tissue, including circuit-level spatial information down to a resolution of 50 nanometers and comprehensive analysis of the types of proteins present across large regions of the brain. These techniques are needed because it is technically difficult to directly detect large numbers of proteins in brain tissue.

Instead of trying to measure proteins directly, most approaches measure RNA molecules 鈥� a precursor to proteins. But RNA detection in spatially complex brain tissue has its flaws. Current approaches聽struggle with dim signals that are difficult to detect over background noise in complex, thick tissues. Chiu and Vaughan will develop new fluorescent probes to light up RNA molecules聽in tissues and will use a novel, large-area light sheet microscope 鈥� together with sample processing techniques 鈥� to rapidly probe large volumes of brain tissue at high spatial resolution.

joined the faculty of the UW School of Medicine last year as an assistant professor of immunology.聽He is interested in the early warning system that mammals use to detect invasion by parasitic worms and allergens.聽Both trigger the same defensive reactions. discovered that tuft cells, found in the intestinal lining, are essential to these immune responses.聽These cells鈥� intriguing capacity to 鈥渢aste鈥� intestinal contents suggests they are the sentinels that first spot worms.聽With the funds provided by the 鈥淣ew Innovator Award,鈥� his lab aims to find the specific worm-alert receptor on tuft cells and the molecule that activates this receptor. The researchers hope that this work will point out new therapeutic targets for preventing and treating worm infestations and allergic disease.聽 Last year, von Moltke聽received the Damon Runyon-Dale F. Frey Award for Breakthrough Scientists. This award recognizes the potential of his immune-response research to transform the understanding of cancer progression.

Microscopy also has its limit. Light’s inherent wavelike behavior limits any microscope’s resolving power. The most minute details of our existence 鈥� from twisted strands of DNA to bulbous cellular organelles 鈥� are difficult or impossible for even the best and most expensive microscopes to visualize directly.

But scientists from the 天美影视传媒 recently reported a relatively simple method that would allow ordinary laboratory microscopes to illuminate many of these cellular structures quickly and efficiently. They did not modify microscopes to boost resolution. Instead, they used an approach to swell the tiny, complex structures within cells, bringing them within range of a microscope’s existing resolving range.

“This is a radically new way of doing microscopy,” said UW chemistry professor , who is senior author on a detailing their approach in . “The focus had largely been on hardware 鈥� improving the resolution of microscopes. Here, we expand the cell’s interior to bring it into view.”

Appropriately, this technique is known as expansion microscopy.

“This is a simple and robust approach that is surprisingly effective,” added Vaughan.

His was inspired by the developed at the Massachusetts Institute of Technology. The MIT researchers stained cells with a complex, DNA-based fluorescent probe that would make cellular contents visible. They then treated cells with an expandable polymer that linked to the custom probes and would “inflate” the specimens to as much as four times their original size. But, this approach was laborious, and required specialized, expensive reagents.

“When I saw their approach, I thought it was amazing,” said Vaughan. “But we were wondering if there was a way to do this using simpler staining strategies and conventional probes. That would make expansion microscopy accessible to thousands of labs.”

Instead of complex fluorescent probes, Vaughan’s team turned to conventional fluorescent dyes bound to antibodies, which are easier to use, and developed a simple chemical treatment that would allow the antibodies to become linked to the polymer. They then treated their stained samples 鈥� slices of mammalian brain tissue and cultured cells 鈥� with the expandable polymer as well as enzymes that could create small “snips” in proteins to help them expand.

They used this basic approach to come up with two staining protocols for expansion microscopy 鈥� one that worked better for individual cells and another for slices of tissue. Under the microscope, their images showed substantially brighter stains while maintaining excellent resolution. As an added bonus, their approach also enables expansion microscopy with fluorescent proteins, another popular fluorescent probe used by biologists. Critically, the UW team was able to obtain these high-resolution images on conventional, widely used laboratory microscopes.

“We think this will make expansion microscopy a widely used technique for researchers who want to visualize what they’re studying with a relatively simple, low-cost approach that also has excellent performance,” said Vaughan.

Vaughan said he hopes that other research groups will modify his team’s basic approach for other organisms or cell types, especially structures like cell walls that would resist expansion. Given the details illuminated by expansion microscopy, a hidden world awaits.

Two scientists from the UW Department of Chemistry, doctoral student and postdoctoral researcher , were co-first authors on the paper. Other authors were postdoctoral researcher Haruhisa Okawa and professor 鈥� both in UW Medicine’s biological structure department 鈥� and UW undergraduates Hyeon-Jin Kim and Grant Tremel. The work was funded by the National Institutes of Health, the National Science Foundation, the Burroughs-Wellcome Fund and the 天美影视传媒.

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For more information, contact Vaughan at 206-543-4644 or jcv2@uw.edu.

Grant numbers: DGE-1256082, EY10699, EY17101.