I had the chance yesterday to attend a one-day symposium on Cryo-EM (and MicroED) techniques here in Cambridge. The whole thing was co-hosted by ThermoFisher, whom I gather are having a glorious time selling these instruments and want to extoll their virtues as much as possible, and by MIT. It helps that there are a lot of virtues to extoll. I’ve been writing about these techniques here on the blog as they’ve been developing over the years, and what we’ve been seeing is the rise of a completely new analytical technique – first slowly, then quickening, and now moving at a really impressive clip. Some of that can be seen at the statistics page of the EMDB. That cumulative count of maps released is on pace to keep up the exponential growth shown so far: there have been 761 released so far this year (as I write), and that alone is more than were released in all of 2015. If there really are >2200 maps added this year, as it looks like there will be, the increase during 2019 by itself will be more than the total cumulative number that existed at the end of 2012. The increase in resolution of the deposited maps is impressive as well – the higher-resolution ones used to be a distinct minority, but the gap is closing rapidly.
Last fall I mentioned the applications to structure-based drug design, noting that at the time the review under discussion was written, that there were only five (total) cryo-EM structures at or below 3 Angstrom resolution with small molecule ligands in them. But I just went over to the EMDB and counted four released so far this year (an example), with still more if you count back to the publication date of the review itself, and my impression of yesterday’s meeting was that there are a lot more coming over the horizon. The idea of looking for such ligands has gone from “Don’t bother” to “Let’s try it” and is moving smartly towards “Sure, why would you even wonder” territory. It’s not there yet, but as this equipment gets more capable and more widely distributed, and as people get more experience with it, that’s where we’re headed for sure.
Also last fall, I wrote about the related MicroED technique, which uses the electron microscope equipment to do diffraction instead of imaging. Its applications to things that crystallize are immediately apparent, because the size of the crystals needed to produce a structure are ridiculously small. I had the chance yesterday to hear Tamir Gonen of UCLA (a leader in this field) speak on their recent results and it was quite impressive. Here’s a recent publication from the group to give you the idea. Gonen mentioned that some of the protein crystals that they’ve been working with are only about ten protein molecules on a side, and they’re pulling up to two-Angstrom resolution structures out of them. Try that with X-rays, if you want, but prepare for disappointment. Here’s another paper from the group from last year, showing a 0.75A structure (!) of a prion protofibril, and it has structural features that are invisible to X-ray crystallography in any form, including some electron density in the hydrogen-bonding network that is hard to explain at all with existing models. The small-molecule ED work described in that October blog post is continuing, too, an area that I’m following with great interest.
So where is the field going? One theme that kept coming up was the need to get all of these techniques out of the “artisinal handwork” mode that they’ve been in. Gonen is setting up a center at UCLA that’s trying to automate things as much as possible, and that same thought came up many times. Sample handling and tracking, evaluating particles on the grid (for cryo-EM), doing tiny crystallization experiments on the grid itself (for microED), making sure that you’re collecting useful data in general and not just shooting junk, automatically processing as much of the real data as possible: all of these need help. But my impression is that these problems, though not solved yet, are actively being hammered on by the best practicioners in the field, and there’s no reason that things can’t get a lot easier than they are now.
As Gonen himself put it, though, “I don’t want you going away from this saying “Oh, everything’s done, everything’s peachy, Tamir has it all figured out, we’re going to go get all our structures in an afternoon” We’re not there yet. But what’s been accomplished so far is startling, and there’s a lot more to come.
I should mention, for people in the Boston/Cambridge area, that you’ll have another chance to hear about this stuff soon. The MassBio folks are planning an event on cryo-EM in drug discovery the morning of July 9 (8-10 AM) at their venue in Tech Square. Registration will be open on their web site on May 1, or you can email them for more details.