Microscopy illuminates life

Despite all that we know about DNA, proteins, and cells, it’s still a challenge to visualize the “inner life” of the cell, even with the best of microscopes. How does a cell’s nucleus, spanning just ten microns (millionths of a meter), manage to store a genome that’s two meters long? Or how might an errant, smaller-than-microscopic fold in a protein ultimately lead to disease?

Visualizing the world of microns is the specialty of this year’s recipient of the Byers Award in Basic Science, an honor that recognizes the outstanding research of a mid-career faculty member.

In his Byers Award Lecture, delivered on January 17, Bo Huang, PhD, explained how new approaches to microscopy developed by his lab could finally—and literally—shed light on the hidden realm of single cells, allowing scientists to observe biological processes up close and in action.

A faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry, Huang is also a Chan Zuckerberg Biohub Investigator, and holds a joint faculty appointment in the School of Medicine’s Department of Biochemistry and Biophysics.

Susan Merrell

Bo Huang, PhD, delivers the Byers Award Lecture, titled “Lights, Camera, Action: Redefining Microscopy to Illuminate Life and Disease.”

Huang began his talk by reflecting on the advantages of being a researcher at UCSF, where multiple disciplines routinely cooperate to tackle big questions outside of individual fields. “I never imagined ending up [in a health professions school as a trained chemist] until I came here and discovered it was the perfect place.”

Research in the Huang Lab pushes the boundaries of what is possible in visualization. “We’re further expanding our microscopy approach, not just at the cellular level, but so we can see things more clearly even at the molecular level,” said Huang.

When it comes to peering into the microscopic world of the cell, scientists have long been limited by physics. Precise beams of light can illuminate small parts of the cell for observation under a microscope, but the technique is limited by the size of the wavelength of visible light, which is more than twenty times the size of an average protein molecule.

Another limitation of current viewing methods is that they sometimes require scientists to add a relatively large DNA sequence, which codes for a fluorescent protein, into the genome. The sequence makes associated proteins glow under laser light, allowing scientists to track their positions. But because of the size of this sequence, accurately inserting it into the right part of the genome is difficult and time consuming.

Over the years, Huang has surmounted these barriers of scale by reconsidering the physics behind traditional microscopy. One of his approaches uses precisely-timed bursts of light to briefly illuminate portions of miniscule cellular structures in succession, revealing 20-nanometer-wide contours that would be washed out by traditional methods in microscopy. (A nanometer is one billionth of a meter.)

Huang Lab, UCSF

Examples of colorful microscopy images from the Huang Lab.

Researchers in Huang’s lab used this method to show how mutations in one protein reshaped an important cellular organelle, the cilium, causing Joubert syndrome, a relatively rare inherited disorder that leads to a variety of debilitating developmental problems.

In another series of experiments, Huang and his colleagues discovered that they could observe proteins in the cell by linking them to mere fragments of the relatively large fluorescent proteins scientists normally use. With the smaller size came more efficiency. The team used this method to label 30 distinct proteins in just three weeks—all the more impressive, considering that scientists must typically wait months for individual proteins to be labeled for a given experiment. These methods have already been used to try to identify the root causes of diseases like cancer.

Lastly, Huang used a modified version of CRISPR-Cas9 to label different portions of the genome and visualize how the genome is packaged inside the cell’s nucleus—a phenomenon with implications for our understanding of development and cancer. “It is immensely interesting to understand how our DNA is packaged,” said Huang. “The physical explanation is important to the regulation and fate of the cell.”

Thanks to Huang’s determination to make good on the University of California’s motto—“Let there be light”—scientists are better armed to make sense of the tiny world inside our cells, all in pursuit of the next generation of cures.

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Bo Huang Delivers 2018 Byers Award Lecture on Boundary-Pushing Microscopy