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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Ranking the Journals - Try It at Home! | Main | Muraglitazar's Turn »

September 7, 2005

The Tiniest Doors Begin to Open

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Posted by Derek

Ahmed Zewail and his group at Caltech are the kings of the very, very short time scale. For many years now, he's been using extremely short laser pulses to accomplish a long list of previously unheard-of results in spectroscopy. (A non-specialist wouldn't go far wrong by thinking of him as a molecular-scale Harold Edgerton.) His work has not gone unrecognized.

And now there's a fighting chance that he and his people have recently accomplished something that would be worthy of a second Nobel: UEM, for Ultrafast Electron Microscopy. They're taking electron microscope snapshots, one trillionth of a second at a time.

And what is this technique good for? Well, electron microscopy has long been used for imaging all sorts of materials and biological samples. Fast freezing of the samples has revealed an extraordinary amount of information in the past, and Zewail's new method basically allows this to happen in real time, at room temperature, under normal conditions. The energies required to do it aren't huge, and it's quite likely that we'll be able to get useful data without destroying delicate targets. We could end up with extreme slow-motion movies of molecular processes, imaged at electron-diffraction resolutions. We're actually going to be able to watch nanotechnology experiments as they happen.

We'd be able to see catalyst molecules moving and rearranging as they do their work, and watch the shifting environment of metal atoms inside enzyme active sites. Subtle changes in crystal structures, happening too fast for us to follow, would become clear. We could conceivably see cell membranes flex and shift as ligands bind to their embedded receptors, and see processes inside cells that no one has ever been able to observe or even suspected were there. People in completely unrelated branches of science are going to be climbing over each other to get access to these machines.

I've never met Prof. Zewail, but his paper isn't the work of a retiring personality. Its abstract states that ". . .the long sought after but hitherto unrealized quest for ultrafast electron microscopy has been realized." That's inelegantly phrased (the quest wasn't the thing that was sought after, for one thing), but I take his point. The concluding section echoes Watson and Crick, surely on purpose:

". . .even biological changes at longer times have their origin in the early atomic motions. It should be readily apparent that such dynamical evolution is critical to function. It does not escape our notice that UEM is a significant advance for this purpose. . .we foresee the emergence of new vistas in many fields, from materials science to nanoscience and biology."

No, he's not a modest man. But this discovery isn't something to be modest about. It isn't bragging if you can do what you say.

(Want more details? This is wandering off into physics, but the fast laser pulses generate electrons through the photoelectric effect. They hit the photocathode of the electron microscope, which is made of the rather exotic material lanthanum hexaboride. One of the keys to getting this to work was to use pulse energies that deliver about one electron per wave packet. That allows the microscope to focus them - Zewail points out that their earlier attempts generated larger "bunches" of electrons which were difficult to focus, and whose pulses broadened out due to the electrons repulsing each other's negative charge. The delicate touch was crucial. Of course, none of this would do much good without modern scintillators and CCD chips, which can detect single electrons after they pass through the samples. For the real fanatic, Zewail's paper is in PNAS 102, 7069.)

Comments (18) + TrackBacks (0) | Category: General Scientific News


COMMENTS

1. steve on September 7, 2005 10:23 PM writes...

I saw a talk he gave at NCSU a year or two ago. Impressive stuff.

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2. TallDave on September 7, 2005 10:40 PM writes...

Cool.

Thanks for sharing.

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3. AST on September 7, 2005 11:22 PM writes...

Dumb question:

Light propagates in a spherical wavefront from a point source. Is the wavefront a collection of photons moving outwards together, or is the expanding sphere a single photon which collapses into a particle when it hits something? Or am I missing something altogether?

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4. Klug on September 7, 2005 11:22 PM writes...

Boy, if Derek's speculation about the applications to structural biology are true, this should change the way people design drug molecules. (You'd think, anyway.)

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5. Albert on September 8, 2005 3:27 AM writes...

AST: That's why they call it a paradox.

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6. Peter Ellis on September 8, 2005 4:11 AM writes...

AST: I believe the best way to describe it is to say that the spherical wave front is the probability of a photon, which collapses into a particle when it's measured

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7. Derek Lowe on September 8, 2005 6:54 AM writes...

AST, that's the problem we have talking about electrons (and other quantum-level things.) An electron isn't a wave, and it isn't a particle. It's something else that we don't have a word for, and that our minds find very hard to picture.

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8. Steve on September 8, 2005 7:40 AM writes...

"Dumb question: Light propagates in a spherical wavefront from a point source. ..."

Only on a blog like this would one see a "dumb question" like this. :-)

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9. Don McArthur on September 8, 2005 8:23 AM writes...

AST, it's neither, until an observer adds himself to the mix. Then, depending on what measurement the observer chooses...

(Quantum mechanics gives me the willies.)

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10. Chaz706 on September 8, 2005 8:53 AM writes...

AST: It's not so dumb a question if that was one of the questions Einstein thought about. You're in good company I think.

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11. tim mayer on September 8, 2005 9:54 AM writes...

I think the term is "wavicle."

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12. jsinger on September 8, 2005 10:24 AM writes...

Apropos of the previous few days' discussion -- if this is so freaking important (important enough to justify adding an "It has not escaped our notice..." to the end!), what is it doing in PNAS?

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13. Derek Lowe on September 8, 2005 10:44 AM writes...

Hah! PNAS isn't such a bad venue, y'know. As a member of the National Academy, Zewail can presumably sort of drop whatever paper he likes into it. Given the citations this this is going to attract, he's doing PNAS a real favor. It's the sort of paper that journal editors fight over. . .

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14. jim on September 8, 2005 2:54 PM writes...

I wonder if this type of thing isn't going to yield the same type of information that gene chips did.... an over- (or sometimes under-)whelming amount of information that while leading to fun mental gymnastics, doesn't really change the whole drug discovery process. If this adds another variable to SAR without removing at least 2, we're no further ahead.

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15. kpfoley on September 8, 2005 6:06 PM writes...

I'd be willing to bet that more Nobel Prize-winning research has been published in PNAS than in Science or many another sexy journal.

As far as the Watson and Crick allusion, how many papers can you think of that also steal from that famous phrase? The human genome sequence paper in Nature for one. But that seemed appropriate. This one just seems sophomoric.

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16. Elia Diodati on September 8, 2005 6:52 PM writes...

Hi there, I came across your blog recently and have been lurking for a while. Thought I'd comment on this post.

I'm not at all convinced that this technique will revolutionize experimental biology. There is no way you can see living things using this technique and hope to get anything close to in vivo conditions: the cells have to be frozen, plus stuff still has to be stained with really toxic dyes, and it's being constantly bombarded with high-energy electrons. Not exactly the most comfortable environment for living cells to go about doing their thing.

The PNAS paper states that they are using one-electron pulses with energies of 500 pJ, which is still way more energetic than ultraviolet photons (~ 0.000 000 5pJ), which are already sufficiently violent to cause extensive DNA damage.
And at these kinds of energy levels, I am sure that one cannot neglect the effect of back-action of the measurement beam into the system, essentially having the apparatus forcing the system to do something it wouldn't normally be doing.

The other thing is that they briefly mention the technique as a cryomicroscopic one, meaning that the samples have to be dunked into liquid nitrogen or something like that.

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17. jsinger on September 9, 2005 10:35 AM writes...

kpfoley:


I'd be willing to bet that more Nobel Prize-winning research has been published in PNAS than in Science or many another sexy journal.


Absolutely. It's just a laughingstock among molecular biologists. (Without, as Derek points out, much fairness.) I think it's because no one reads PNAS -- it's just too big and diverse -- so it seems like a journal you only dump stuff into. As you say, there has been a _lot_ of classic work published in it.

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18. Play Nice on September 9, 2005 12:30 PM writes...

"It isn't bragging if you can do what you say."



That’s inelegantly phrased (if it's done boastfully, it is bragging even if you can do what you say), but I take his point.

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