UC Davis researchers have received a two year $2 million grant from the National Institutes of Health to pioneer the world’s first electron microscope capable of recording biological processes in real time.
The revolutionary technology will allow scientists to image living specimens at greater resolutions that could reveal nano-scale details underlying many cellular mechanisms.
The research team, led by Nigel Browning, will expand the capabilities of an existing technology called the dynamic transmission electron microscope (DTEM) to tailor the device for filming live systems in action. Browning, a professor of chemical engineering and materials science at UC Davis, helped develop a DTEM that is now housed at Lawrence Livermore National Laboratory.
The microscope at LLNL – one of only three operating DTEMs in the world – can capture 10 to 100 images per millionth of a second at resolutions that enable researchers to see details as small as 10 nanometers, or about four times the width of a DNA molecule. So far, the instruments have only been used to image non-living systems such as dynamic chemical reactions and phase transitions in inorganic materials.
“What this grant is all about is taking the step to move out of material sciences to biological sciences,” Browning said. “Basically all the technology is out there to do this but it’s never been all thrown together onto a single microscope and shown to work for biological systems.“
Transmission electron microscopy, in which a beam of electrons is passed through ultra thin samples to create highly-magnified images, requires biological specimens to be immobilized and essentially killed during preparation. To bypass this limitation, Browning has incorporated a custom-built stage into the DTEM to hold a living sample within a thin layer of fluid.
Key features in the new “Bio-DTEM” design will optimize image contrast and clarity for viewing dynamic processes in living systems such as cells. A modified pulse laser gun inside the instrument creates brief flashes of electrons that expose the specimen, enabling high-speed snapshots to be taken and processed into a video.
“The whole idea is that anything that you would be interested in for biological sampling is something you can study in this microscope, and the key is to be able to see it really quickly before you cause damage with the beam,” Browning said.
Browning explained that shortening exposure time – down to the order of microseconds – can boost image resolution. By tweaking the duration of electron pulses for each biological system, the researchers expect to capture details as small as 1 nanometer, a nearly 100-fold improvement in resolution over current live imaging microscopes.
Six professors in the departments of microbiology and molecular and cellular biology will collaborate with Browning to adapt the DTEM for imaging live biological events related to their fields.
“With an operational Bio-DTEM, we should be able, for the first time, to [image] DNA repair nano-machines in real time at a resolution that allows us to observe individual proteins in action, like seeing wheels move on a mechanical device,” Professor Wolf Heyer said. “Up to now, we could only obtain still pictures of our proteins. With Bio-DTEM, it will be an action movie.“
Professor Peter Armstrong will use the technology to investigate how a type of immune system protein called C-reactive protein forms destructive holes in the protective membrane of certain bacteria.
“We hope to use the DTEM to characterize the structural changes that must, of necessity, accompany the insertion of the large C-reactive protein molecule into the very different environment of the [bacterial] cell membrane,” he said.
Other planned projects will apply Bio-DTEM to study the dynamics of mitochondria and microtubules, the molecular powerhouses behind energy production and cell division and transport, respectively.
“This instrument will enable milestone advancements in our understanding of diseases like cancer, bacterial or viral infections, and basic biological processes,” the researchers said in a grant statement.
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