Smart microscopes capture elusive biological phenomena at high resolution

February 16, 2023 | Biology

Physicist Robert Prevedel designed a microscope that could solve the research problems at European Molecular Biology Laboratory in Heidelberg, Germany. The challenge lies in capturing neural activity deep inside a live mouse brain when the organ itself is moving. He said that the deeper the imaging goes, the more distortions occur and building a microscope that is quick to measure and adapt is essential.

In 2021, Prevedel and his colleagues constructed a microscope that fused two strategies called three-photon fluorescence imaging with an adaptive optical system. Instead of using rigid optical materials, the adaptive optical system makes use of mirrors and lenses made of deformable membranes. The software tools swiftly alter the membranes’ shapes depending on the variations in the sample, bouncing off light in specific ways to peer through surface structures. This ‘sample-adaptive approach relies on the microscope itself, adjusting optics in real time to constantly produce high-quality images.

To compensate for the vibrations of the mouse’s pumping heart, Prevedel’s microscope had to go one step further by timing photos to the heartbeat. This allowed the team to image cells in the hippocampus, nearly 1.5 millimeters beneath the brain’s surface. This was 0.5 mm deeper than previous efforts.

Prevedel’s microscope is only one among the suite of smart microscopes that use adaptive optical systems with machine-learning approaches to peek deeper into intracellular structures and zoom into crucial moments to spot fleeting biology. Having custom-built hardware and software components, these are tools that not only produce clear images but are gentler on living systems which allow experts to examine prolonged processes without damaging the samples. All these efforts contribute to the expansion of the reach of microscopy.