Biocurious is a weblog about biology, quantified.

The Most Exciting Future Biophysics Tool

by Andre on 19 December 2008

If you could wish for any capabilities in an instrument to help you with your research, what would they be? It might not be hard to come up with a useful super power that’s way out of reach of current or near-future technology, but what about something you might actually have in the next 10 or 20 years?

One of my interests is high resolution imaging, either by scanning probe or fluorescence microscopy, and I’ve seen and taken advantage of some great electron microscopy as well (although I haven’t done any myself). Each of these methods in their current most common form has advantages and disadvantages: scanning probe microscopies tend to be slow but offer high resolution with little sample preparation, fluorescence microscopy suffers from lower resolution but has pretty good acquisition rate and molecular specificity, and electron microscopy involves more complicated sample preparation that can distort the sample and only provides a snapshot, but it can provide truly exquisite images at a range of spatial scales.

These methods are all providing new insights into every area of cell biology and biophysics—fluorescence microscopy especially is now a staple of almost every lab in these fields—but it’s the ways that these methods are being pushed beyond their current limits that are truly exciting. New tools have always provided new insights, but I think cell biology is poised to be completely revolutionized in the next few decades.

Take atomic force microscopy. High resolution in water, but painfully slow. Wouldn’t it be nice if it were faster? It is. The animated gif on the right is an AFM movie taken at 12 frames per second in Toshio Ando’s lab at Kanazawa University in Japan. You’re seeing a single myosin molecule undergo a conformational change in real time. Single molecule fluorescence methods have provided a lot of insight into the mechanism of molecular motor motion (they walk) but there are still finer scales to investigate and high-speed AFM may prove to be the tool of choice in the very near future.

That’s very nice for in vitro work, but ultimately cells are where the action is. I want an instrument that will reduce the vast majority of cell biology to computer science. That will “only” require the convergence of three existing technologies: cryo-electron tomography, environmental scanning electron microscopy, and femtosecond electron diffraction. The ultimate fantasy or course is an atomic scale femtosecond movie of a living cell over hours. That would give you a complete genetic, proteomic, biophysical, and biochemical picture of cell function. You would still need interesting perturbations to ask questions, but all the answers would be provided by a single instrument and clever data mining. Even relaxing the goal by orders of magnitude in every direction to 10 nm spatial resolution and millisecond time resolution in a one minute movie would be radical.

Sounds far-fetched, but don’t forget that we’ve already got Wolfgang Baumeister talking about the molecular sociology of the cell and visual proteomics and people like Philip’s advisor doing femtosecond electron diffraction. Environmental scanning electron microscopy works in water vapour. At a talk at the College of Physicians, Ahmed Zewail spoke about an instrument his group is developing for electron diffraction and imaging. He showed a picture of a cell they took with it and he says their goal is to do a single particle version of electron diffraction in a cell within a few years.

Maybe he wasn’t even exaggerating…

While on the topic of things that might be possible in the future, nanotech enthusiasts might be interested to know that Eric Drexler now has a blog called Metamodern.

  1. Alex    3530 days ago    #

    What about STimulated Emission Depletion (STED)? That method is getting 20 nm or better resolution in some cases.

  2. PhilipJ    3529 days ago    #

    The diffraction-limitless microscopy techniques being developed are definitely wonderful (and exist right now!), and they will be even better if we can get around the non-native fluorophore requirements, but it would be difficult to get true 3D pictures of a cell using them.

  3. Andre    3528 days ago    #

    Alex, yes these are great techniques. (older post here) As Philip says, they already exist (and there has already been a paper on 3D STORM but I don’t think extensions of these techniques will really get at what I’m imagining since ultimately you will be limited by fluorophore density even if you’ve got great resolution. What I mean is that it would be a tall order to get even basic information about the shape of a molecule inside a cell because you would require it to have several fluorophores attached. That kind of labelling throughout a cell would be totally toxic.

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