Eric Betzig, Biological Physicist

Important advances in fluorescence microscopy highlight the interaction of physics and biology. This effort is led by Eric Betzig of Berkeley, winner of the 2014 Chemistry Nobel Prize. Betzig obtained his bachelor’s and doctorate degrees in physics, and only later began collaborating with biologists. He is a case-study for how physicists can contribute to the life sciences, a central theme of Intermediate Physics for Medicine and Biology.

If you want to learn about Betzig’s career and work, watch the video at the bottom of this post. In it, he explains how designing a new microscope requires trade-offs between spatial resolution, temporal resolution, imaging depth, and phototoxicity. Many super-resolution fluorescence microscopes (having extraordinarily high spatial resolution, well beyond the diffraction limit) require intense light sources, which cause bleaching or even destruction of the fluorophore. This phototoxicity arises because the excitation light illuminates the entire sample, although much of it doesn’t contribute to the image (as in a confocal microscope). Moreover, microscopes with high spatial resolution must acquire a huge amount of data to form an image, which makes them too slow to follow the rapid dynamics of a living cell.

Eric Betzig’s explanation of the trade-offs between spatial resolution, temporal resolution, imaging depth, and phototoxicity.

Betzig’s key idea is to trade lower spatial resolution for improved temporal resolution and less phototoxicity, creating an unprecedented tool for imaging structure and function in living cells. The figure below illustrates his light-sheet fluorescence microscope.

A light-sheet fluorescence microscope.
The sample (red) is illuminated by a thin sheet of short-wavelength excitation light (blue). This light excites fluorescent molecules in a thin layer of the sample; the position of the sheet can be varied in the z direction, like in MRI. For each slice, the long-wavelength fluorescent light (green) is imaged in the x and y directions by the microscope with its objective lens.

The advantage of this method is that only those parts of the sample to be imaged are exposed to excitation light, reducing the total exposure and therefore the phototoxicity. The thickness of the light sheet can be adjusted to set the depth resolution. The imaging by the microscope can be done quickly, increasing its temporal resolution.

A disadvantage of this microscope is that the fluorescent light is scattered as it passes through the tissue between the light sheet and the objective. However, the degradation of the image can be reduced with adaptive optics, a technique used by astronomers to compensate for scattering caused by turbulence in the atmosphere.

Listen to Betzig describe his career and research in the hour-and-a-half video below. If you don’t have that much time, or you are more interested in the microscope than in Betzig himself, watch the eight-minute video about recent developments in the Advanced Bioimaging Center at Berkeley. It was produced by Seeker, a media company that makes award-winning videos to explain scientific innovations.


A 2015 talk by Eric Betzig about imaging life at high spatiotemporal resolution.

“Your Textbooks Are Wrong, This Is What Cells Actually Look Like.” Produced by Seeker.