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Electron Microscopes Close To Imaging Individual Atoms

Posted by timothy on from the it's-down-there-somewhere-let-me-take-another-look dept.

An anonymous reader writes with this excerpt from Science: Today's digital photos are far more vivid than just a few years ago, thanks to a steady stream of advances in optics, detectors, and software. Similar advances have also improved the ability of machines called cryo-electron microscopes (cryo-EMs) to see the Lilliputian world of atoms and molecules. Now, researchers report that they've created the highest ever resolution cryo-EM image, revealing a druglike molecule bound to its protein target at near atomic resolution. The resolution is so sharp that it rivals images produced by x-ray crystallography, long the gold standard for mapping the atomic contours of proteins. This newfound success is likely to dramatically help drugmakers design novel medicines for a wide variety of conditions.

28 of 55 comments (clear)

  1. Obligatory by ckatko · · Score: 1, Offtopic

    Scientists are proud to announce a new echelon of understanding that will finally allow humans to see the microscopic penis of people who yell, "First Post!" on Slashdot.

  2. Nice but... by Anonymous Coward · · Score: 5, Informative

    While cryo-EM is really a big step forward the summary make it sound like it's the first time EMs can image atoms, that is not really the case at all. HRTEM (high resolution tunneling electron microscopes) have even better resolution that 0.2 nm, one order of magnitude better even ( eg. http://journals.aps.org/prl/abstract/10.1103/PhysRevLett.102.096101 ). It's also worth noting that the applications and use cases are very different for cryo-EM and HRTEM.

    1. Re:Nice but... by the+gnat · · Score: 4, Informative

      There's another technical objection to the summary: "atomic resolution" in this context isn't the same thing as "imaging individual atoms". The actual cryo-EM images themselves are much noisier and do not have nearly this effective resolution - it is the average of many thousands of images that gives you atomic resolution electron density maps. (The same is true for X-ray crystallography, although you start with just Fourier amplitudes there, not images.) That's not a slam on the paper, which is an impressive technical achievement, but as the authors note, many conformationally homogeneous single particles (i.e. protein complexes) are required to get a map of this quality. Any differences between particles will simply be averaged out, and the more different they are, the worse the resolution.

    2. Re:Nice but... by Anonymous Coward · · Score: 1

      Dude... HRTEM is high resolution TRANSMISSION electron density. And yes as you note, HRTEM is only useable for materials that are stable in a 200 keV electron beam. Which for one excludes anything biological.

    3. Re:Nice but... by the+gnat · · Score: 4, Informative

      I really do hope the people doing this have examined and discussed the possible pitfalls of drawing conclusions from averages of this type of data.

      Yes, the pitfalls are well known, mostly because this has always been an issue with crystallography as well - it is impossible at present to determine the 3D molecular structure from a single molecule, so we are always dependent on either crystalline diffraction or averaging thousands of images to obtain the density map. (NMR has its own, well-understood problems.) The good news is that we known enough about macromolecular structure to be able to make subjective judgements very quickly based on the level of detail in the maps. (There are also plenty of higher-resolution structures of many smaller components, so we can calibrate our expectations based on known parts.) If the molecules are very heterogeneous, or the averaging is done poorly, the maps will not display known high-resolution features such as secondary structure or amino acid sidechains. For crystallography, there are also ways to calculate the deviation from the average (and I presume EM either has something analogous, or will soon). It is also common for some regions to have higher "local resolution" than others, and this can be quantified in various ways.

      These methods still lose information - if, say, 10% of copies of a particular loop or sidechain are in a different conformation, this will probably not be captured. But EM experts have gotten much better about identifying clusters of similar conformations, at least on a larger scale. And in the end, the static average structure is still vastly more useful than no structure at all. Scientists can and do still publish spectacularly stupid interpretations occasionally, but these aren't due to the misuse of averaging, but rather to pure incompetence and wishful thinking.

    4. Re:Nice but... by Anonymous Coward · · Score: 2, Insightful

      the pitfalls are well known

      Other than the obvious loss of information, I'd be interested in knowing what pitfalls come up that are specific to this case. To make things a little more concrete, take the case of a GPCR dopamine receptor. Supposedly dopamine (or one of a variety of drugs) interacts with this receptor in such a way that a different region changes conformation which in turn alters the conformation of a G-protein so that it binds GTP. This all seems to require very specific protein conformations and I can see how observing the average of many could be misleading.

    5. Re:Nice but... by dbIII · · Score: 1

      Yes, in the 1990s I listened to a presentation by someone imaging material in the roots of teeth which contained mostly Ca, H and O and he complained that unlike larger atoms the Ca could not be imaged directly with a TEM so he digitally generated defocused images for a range of possible structures to see what would match the images from the real sample with as close a focus as he could get.
      Interesting stuff.

    6. Re:Nice but... by the+gnat · · Score: 2

      Other than the obvious loss of information, I'd be interested in knowing what pitfalls come up that are specific to this case. To make things a little more concrete, take the case of a GPCR dopamine receptor. Supposedly dopamine (or one of a variety of drugs) interacts with this receptor in such a way that a different region changes conformation which in turn alters the conformation of a G-protein so that it binds GTP. This all seems to require very specific protein conformations and I can see how observing the average of many could be misleading.

      Well, the main pitfall is what I already mentioned - if the conformations being averaged really are very different, this will decrease the effective resolution of the reconstruction, which will be very obvious even to an untrained eye. EM used to be notorious for producing vague blobs, in part because of the limitations of the technology (before they had direct electron detectors and had to use film), but also because the software tools (and users) weren't as good about picking out different conformations. And when the individual protein domains (often of known structure) resemble spheres in the reconstruction, it's difficult to tell that something isn't working. So it was indeed possible to generate a map that was a misleading average, and there are probably structures like that out there. But that's why everyone relied on crystallography for detailed structural information.

      The good news is that at the resolution range people are using now, it should be possible to build individual structural components, but only if the particles are nearly homogeneous. So the ability to build (or dock) atomic models that clearly fit the map on the level of individual amino acids becomes a test for whether the averaging is justified.

      The case you mentioned isn't really applicable, because the GPCR only assumes that conformation when bound to dopamine, and tends to work like a molecular switch. And of course if we did have a range of conformations being looked at, the reconstruction would resemble a soup can, without any atomic detail, which isn't really a publishable result. GPCRs are so small that it's currently better to use crystallography, but there are indeed structures of GPCRs in various static states at high resolution.

      The remaining problems are that a) proteins aren't really static and b) the experimental methods for structural studies may induce non-physiological artifacts. I don't think (a) is that much of a problem because we have plenty of ways of studying protein dynamics and everyone is implicitly aware of this limitation anyway. The second problem is potentially worse: purification can sometimes have weird effects, crystallization packs molecules into a lattice that may not represent the native conformation, both crystallography and EM typically work at cryogenic temperatures which is known to change the structure in various ways (mostly but not always subtle), radiation damage can have side effects too. Much worse are the older "negative stain" EM structures where the proteins were covered with uranium or something similarly massive and sandwiched between thin sheets of carbon. Fortunately this is much less common now that cryo-EM has gotten so much better.

      Ultimately the value of any model is determined by its ability to explain biochemical data and suggest new testable hypotheses. That's ultimately the most important way to validate their accuracy, and researchers ignore it at their peril.

  3. this technology has been in use for years by crgrace · · Score: 4, Informative

    This is not a worthy story. Cryo-EM is a fast growing, exciting field but higher resolution electron microscopes that what this article trumpets have been available for years. For example, the TEAM microscope built in 2008 at Lawrence Berkeley National Lab has a resolution of 50 pm:

    http://foundry.lbl.gov/facilities/ncem/expertise.html#team1

    I personally saw individual gold atoms deposited as a nanobridge on a graphene substrate. In 2010.

    1. Re:this technology has been in use for years by gstoddart · · Score: 3, Funny

      LOL, and it's Topper for the win!!

      --
      Lost at C:>. Found at C.
    2. Re:this technology has been in use for years by crgrace · · Score: 1

      How is my statement implausible or ridiculous?

    3. Re:this technology has been in use for years by Ravaldy · · Score: 2

      Correct me if I'm wrong but I believe this is tailored specifically for the BIO industry which makes me wonder why the title speaks of atoms since it doesn't appear to be the main focus of the technology.

      Obviously this is a big deal if it makes it more affordable and available for bio researcher. It's like saying that going from computers taking whole floors of a building to them fitting in the palm of you hand isn't advancement or a big deal. I realize my comparison isn't fitting but you get what I'm speaking of.

    4. Re:this technology has been in use for years by Ravaldy · · Score: 1

      LOL. Link saved.

    5. Re:this technology has been in use for years by gstoddart · · Score: 1

      Relax, it's a joke. :-P

      --
      Lost at C:>. Found at C.
    6. Re:this technology has been in use for years by crgrace · · Score: 2

      You're correct but earlier cryo-EM cameras are also tailored to the bio industry. This advancement is huge, don't get me wrong, it's just it was made 8 years ago. Take for example the K2 Summit camera.

      http://www.gatan.com/products/tem-imaging-spectroscopy/k2-direct-detection-cameras

      It's a winner in structural biology. The reason you care about seeing atoms in structural biology is you're trying to design drugs that physically interlock with important molecules. You have to see the atoms to truly know the structural layout of a molecule.

    7. Re:this technology has been in use for years by crgrace · · Score: 1

      I had my sense of humor surgically removed in graduate school, apparently.

    8. Re:this technology has been in use for years by damn_registrars · · Score: 1

      I had my sense of humor surgically removed in graduate school, apparently.

      That is common in graduate school in the hard sciences. It is often removed a year or so after they remove your sense of dignity and self-worth. I've been through it myself. I'd like to say it all comes back later but that isn't completely true.

      --
      Damn_registrars has no butt-hole. Damn_registrars has no use for a butt-hole.
    9. Re:this technology has been in use for years by Ravaldy · · Score: 1

      So did this make the news because another company finally made it?

  4. Re:Get Ready to Pay More by Anonymous Coward · · Score: 1

    The topic is electron microscopes, and their increasing resolution over time.

  5. Poor headline here and at the article; good piece by Anonymous Coward · · Score: 3, Informative

    The ability to image the atomic structure of an individual (fragile and 3-d) protein is still notable and the article gets this mostly right.
    But, yes: the 1986 Nobel prize went to developers of the TEM and STM that had both already achieved atomic resolution MANY years before. The first microscope to allow atomic resolution was the field ion microscope (in the 1950s!), but the inventor had died before the Nobel prizes were awarded.

  6. Re:Mega electrons by Anonymous Coward · · Score: 1

    Get over it. Your dick is way too small and I'm not coming back.
            -Laura

  7. A Young Lady's Illustrated Primer? by snikulin · · Score: 1

    When can I order one?

  8. Imagine a... by Tablizer · · Score: 1

    I imagined a Beowulf cluster of atoms, and it looked like, well, a molecule.

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    Table-ized A.I.
  9. The actual paper by damn_registrars · · Score: 1

    In case you missed the link, 2.2 Ã... resolution cryo-EM structure of Î-galactosidase in complex with a cell-permeant inhibitor

    Right now it is paywalled but as the authors are all NIH employees it shouldn't remain that way for long. If you really want to see the article sooner than that, your local public library likely subscribes to Science

    --
    Damn_registrars has no butt-hole. Damn_registrars has no use for a butt-hole.
  10. Privacy by Snufu · · Score: 1

    The technique is not scalable because you have to obtain permission from each atom to use their image.

  11. Electron Microscopes Imaging Individual Atoms by Trax3001BBS · · Score: 1

    Stick the subject line into a search machine and look at all of the pictures of single atoms.

      I remember many many years ago of the atoms at the end of a pin.

    A link to images https://www.google.com/search?...

  12. Re:You are not the real Laura by davester666 · · Score: 1

    By midcontrolled, you mean that her vagina is controlled by Italian toads from outer space?

    Interesting.

    --
    Sleep your way to a whiter smile...date a dentist!
  13. Maybe I'd better add this ... by dbIII · · Score: 1

    He was interested in imaging the Calcium, it should be obvious that the other elements I mentioned would be a bit harder, but it may not to some readers or may be seen as an opening for nitpickers to prove some sort of point. By that point in time I think Tungsten and other relatively large atoms could be resolved so that's what I meant by "unlike larger atoms"