3-D Microscopy of Living Organisms

Published online in Nature Methods today [doi:10.1038/nmeth1078]:

Tomographic phase microscopy

We report a technique for quantitative three-dimensional (3D) mapping of refractive index in live cells and tissues using a phase-shifting laser interferometric microscope with variable illumination angle. We demonstrate tomographic imaging of cells and multicellular organisms, and time-dependent changes in cell structure. Our results will permit quantitative characterization of specimen-induced aberrations in high-resolution microscopy and have multiple applications in tissue light scattering.


Sound a bit cryptic? The potential importance is made clearer with quotes by some of the paper’s authors in a PhysOrg.com article :

“Accomplishing this has been my dream, and a goal of our laboratory, for several years,” said Feld, senior author of the paper. “For the first time the functional activities of living cells can be studied in their native state.”

“One key advantage of the new technique is that it can be used to study live cells without any preparation,” said Kamran Badizadegan, principal research scientist in the Spectroscopy Laboratory and assistant professor of pathology at Harvard Medical School, and one of the authors of the paper. With essentially all other 3D imaging techniques, the samples must be fixed with chemicals, frozen, stained with dyes, metallized or otherwise processed to provide detailed structural information.

“When you fix the cells, you can’t look at their movements, and when you add external contrast agents you can never be sure that you haven’t somehow interfered with normal cellular function,” said Badizadegan.

The current resolution of the new technique is about 500 nanometers, or billionths of a meter, but the team is working on improving the resolution. “We are confident that we can attain 150 nanometers, and perhaps higher resolution is possible,” Feld said. “We expect this new technique to serve as a complement to electron microscopy, which has a resolution of approximately 10 nanometers.” [bold added]


What I find interesting to ponder is the impact and effect this kind of ability will have on systems biology and computer modelling of organisms. Not unlike studying quasars in a distant galaxy where only a few observables are available and everything else is left to theoretical conjecture and computer modelling, researchers in biology make the best of the incomplete empirical datasets at their disposal. Computer modelling, particularly under the rubric of systems biology, seeks to re-animate the dead datasets and provide a comprehensive picture of a functioning, living organism. Once in place, such in silico proxies would become the subjects of various virtual experiments and perturbations to better understand what we do not understand today.

If the paper’s techniques do live up to expectations, then much about the systemic nature of organisms that was necessarily relegated to hypothesis-based computer models may be replaced by direct empirical observations. Of course, new models would be generated from these new datasets, but I imagine the relationship between observation and theory for system-level modelling will take on a whole new tone, where the empirics will directly mandate the kinds of models created, rather than the models being the consequence of a markup language.



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