Science Seen: New microscope reveals biological life as you’ve never seen it before

A new microscope allows us to see how cells behave in 3D and real time inside living organisms.

Astronomers developed a “guide star” adaptive optics technique to obtain the most crystal-clear and precise telescopic images of distant galaxies, stars and planets. Now a team of scientists, led by Nobel laureate Eric Betzig, PhD, are borrowing the very same trick. They’ve combined it with lattice light-sheet to create a new microscope that’s able to capture real-time, incredibly detailed and accurate images, along with three-dimensional videos of biology on the cellular and sub-cellular level.

The work — a collaboration between researchers at Howard Hughes Medical Institute, Boston Children’s Hospital and Harvard Medical School —  is detailed in a new paper just published in Science.

“For the first time, we are seeing life itself at all levels inside whole, living organisms,” said Tom Kirchhausen, PhD, co-author on the new study, who is a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and a professor of cell biology and pediatrics at Harvard Medical School (HMS).

“Every time we’ve done an experiment with this microscope, we’ve observed something novel — and generated new ideas and hypotheses to test,” Kirchhausen said in a news story by HMS. “It can be used to study almost any problem in a biological system or organism I can think of.”

Seeing is believing: Here’s what the new microscope can do

So far, the team has been taking a close look at developing zebrafish because the fish have translucent skin, making it easy to capture microscopic images of their organs and tissues in vivo.

Co-first author on the study, Gokul Upadhyayula, PhD, an instructor in pediatrics at Boston Children’s and HMS, explained that zebrafish can be genetically modified so that human disease models can be studied. Already, the team has used the microscope to watch metastatic human breast cancer cells move around inside a zebrafish, revealing new insights into how cancer spreads through living tissues.

A new microscope captures a human breast cancer cell (green) as it escapes from a blood vessel into the surrounding tissue.
A human breast cancer cell (green) is seen escaping from a blood vessel into the surrounding tissue.
The new microscope reveals an immune cell crawling around inside the inner ear of a zebrafish.
An immune cell is captured through lattice-light sheet microscopy, a technique that has allowed scientists an unprecedented view of living biology inside whole organisms. The immune cell is seen crawling around inside the inner ear of a zebrafish, where it was observed frequently changing its speed and direction.
The new microscope reveals neural progenitor cells from a region in the developing brain of a zebrafish embryo
Here are neural progenitor cells from a region in the developing brain of a zebrafish embryo. The cells are expressing different colored fluorescent markers that reveal the spatial distribution of sub-cellular organelles. The cells are expressing markers for organelles including: cell membrane (grey), the Golgi apparatus (neon green), endoplasmic reticulum (magenta) and mitochondria (aqua). Although this image was taken of a whole, living zebrafish, the image was then computationally separated to allow better analysis of  how each individual cell is composed.
The new microscope reveals all the individual cells across a whole zebrafish eye
This image shows all the individual cells across a whole zebrafish eye. The cells have been computationally separated to allow better examination of each individual cell. The sub-cellular organelles are visible through fluorescent markers. The cell membranes appear in aqua, the Golgi apparatus are neon green, the endoplasmic reticula are magenta and the mitochondria are orange.
The new microscope reveals zebrafish muscle fibers
Here, zebrafish muscle fibers are imaged and computationally separated to make each cell and its contents visible.

VIDEO: Kirchhausen and Upadhyayula describe their work and show some of the amazing images and 3D videos they’ve been able to capture with the microscope. Credit: Richard Groleau/Kevin Jiang/Harvard Medical School.

According to an HHMI press release, Betzig believes that adaptive optics is one of the most important areas in microscopy research today, and the lattice-light-sheet microscope, which excels at 3-D live imaging, is the perfect platform to showcase its power.

Without adaptive optics, sub-cellular microscopy is “just too damn fuzzy.”

Additional authors on the paper are researchers from Stony Brook University, University of California, Berkeley, California Institute of Technology and the University of Exeter.

This work was supported by the Howard Hughes Medical Institute, the National Institutes of Health (R01GM075252, R01DC015478, 5R00CA154870-05, 1R01GM121597-01, R01CA196884 and R35GM118149), the National Science Foundation (IOS1452928), the Carol M. Baldwin Breast Cancer Research Fund, the Damon Runyon Cancer Research Foundation, Pew Charitable Trusts, Biogen, Ionis Pharmaceuticals and a Human Frontier Science Program fellowship.

Read a related story from HMS News.

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