Seeing is Believing

By Kristopher Hite

And in science this can be the biggest barrier to moving forward. If we can't show an event happening how do we know it is happening at all? Since the 1950's a large gap between what we can see under microscopes and what we can see when we crystallize things (i.e. DNA) has existed. The gap has historically been in the range of tens to hundreds of nanometers leaving many macromolecular events taking place inside every living cell on earth in a black box; inaccessible to the human eye and therefore inaccessible to our full understanding. Though some very complex assemblages of proteins and DNA have been successfully crystallized to superb atomic resolution (below 2-3 ångströms) there are innumerable molecules within the cell that have not. These are the myriad molecules that interact in dynamic ways with portions of their structure constantly moving and changing. They have been dubbed "intrinsically disordered proteins."

When biochemists and molecular biologists study these proteins they currently have no good way to visualize them in action. There are however a few ways to look at them. Either take them out of their cellular context, purify them to homogeneity, and pack them into a crystal in order to fire X-rays at them to see where all the atoms sit in a lattice, or freeze them and scan them with an electron beam or force probe. These techniques inherently kill any molecular freedom these little cellular components have to wiggle about and do that voodoo that they do. With the advent of scanning electron microscopy (which produced the image of pollen grains above) and transmission electron microscopy the blind spot in the realm of teeny tiny science has shrunk but the experimental conditions do not allow native observations.

Looking at objects with regular old light waves is impossible at these tiny scales because of Abbe's diffraction limit. The reason very small things can not be seen with a regular optical system is that the wavelength of light is longer than the details in need of being resolved.

Researchers have recently found a way around this. By constructing extremely small lenses they can overcome the diffraction limit. What's more these lenses are self-assembling adding to their intrigue allowing imagination to run wild with speculation of future application. Unlike conventional geometrical optical lenses these lenses bow the light's trajectory in a curved manner. This results in an unprecedented near-field magnification that defies the diffraction limit! In short we may be close to peering into a black box that has never been opened before.


In my field of chromatin associated proteins this technique may allow us to literally watch the elusive histone tails as they interact with binding partners on a single molecule scale. We might someday watch the linker histone as it takes a chromatin array and folds it into the accordion-like 30 nanometer fiber. We might be able to say once and for all whether or not there is an operable "histone code" that dictates transcriptional accessibility and if so how exactly it works.


Begin listening to the following Nature podcast at 6 minutes and 14 seconds in to get the scoop from the primary researchers.

Lee, J., Hong, B., Kim, W., Min, S., Kim, Y., Jouravlev, M., Bose, R., Kim, K., Hwang, I., Kaufman, L., Wong, C., Kim, P., & Kim, K. (2009). Near-field focusing and magnification through self-assembled nanoscale spherical lenses Nature, 460 (7254), 498-501 DOI: 10.1038/nature08173