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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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April 27, 2010

Masses of Data, In Every Sample

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Posted by Derek

I've said several times that I think that mass spectrometry is taking over the analytical world, and there's more evidence of that in Angewandte Chemie. A group at Justus Liebig University in Giessen has built what has to be the finest imaging mass spec I've ever seen. It's a MALDI-type machine, which means that a small laser beam does the work of zapping ions off the surface of the sample. But this one has better spatial resolution than anything reported so far, and they've hooked it up to a very nice mass spec system on the back end. The combination looks to me like something that could totally change the way people do histology.

For the non-specialist readers in the audience, mass spec is a tremendous workhorse of analytical chemistry. Basically, you use any of a whole range of techniques (lasers, beams of ions, electric charges, etc.) to blast individual molecules (or their broken parts!) down through a chamber and determine how heavy each one is. Because molecular weights are so precise, this lets you identify a lot of molecules by both their whole weights - their "molecular ions" - and by their various fragments. Imagine some sort of crazy disassembler machine that rips things - household electronic gear, for example - up into pieces and weighs every chunk, occasionally letting a whole untouched unit through. You'd see the readouts and say "Ah-hah! Big one! That was a plasma TV, nothing else is up in that weight range. . .let's see, that mix of parts coming off it means that it must have been a Phillips model so-and-so; they always break up like that, and this one has the heavier speakers on it." But mass spec isn't so wasteful, fortunately: it doesn't take much sample, since there are such gigantic numbers of molecules in anything large enough to see or weigh.
MS%20image.jpg
Take a look at this image. That's a section of a mouse pituitary gland - on the right is a standard toluidine-blue stain, and on the left is the same tissue slice as imaged (before staining) by the mass spec. The green and blue colors are two different mass peaks (826.5723 and 848.5566, respectively), which correspond to different types of phospholipid from the cell membranes. (For more on such profiling, see here). The red corresponds to a mass peak for the hormone vasopressin. Note that the difference in phospholipid peaks completely shows the difference between the two lobes of the gland (and also shows an unnamed zone of tissue around the posterior lobe, which you can barely pick up in the stained preparation). The vasopressin is right where it's supposed to be, in the center of the posterior lobe.

One of the most interesting things about this technique is that you don't have to know any biomarkers up front. The mass spec blasts away at each pixel's worth of data in the tissue sample and collects whatever pile of varied molecular-weight fragments that it can collect. Then the operator is free to choose ions that show useful contrasts and patterns (I can imagine software algorithms that would do the job for you - pick two parts of an image and have the machine search for whatever differentiates them). For instance, it's not at all clear (yet) why those two different phospholipid ions do such a good job at differentiating out the pituitary lobes - what particular phospholipids they correspond to, why the different tissues have this different profile, and so on. But they do, clearly, and you can use that to your advantage.

As this technique catches on, I expect to see large databases of mass-based "contrast settings" develop as histologists find particularly useful readouts. (Another nice feature is that one can go back to previously collected data and re-process for whatever interesting things are discovered later on). And each of these suggests a line of research all its own, to understand why the contrast exists in the first place.
Ductal%20tissue.jpg
The second image shows ductal carcinoma in situ. On the left is an optical image, and about all you can say is that the darker tissue is the carcinoma. The right-hand image is colored by green (mass of 529.3998) and red (mass of 896.6006), which correspond to healthy and cancerous tissue, respectively (and again, we don't know why, yet). But look closely and you can see that some of the dark tissue in the optical image doesn't actually appear to be cancer - and some of dark spots in the lighter tissue are indeed small red cells of trouble. We may be able to use this technology to diagnose cancer subtypes more accurately than ever before - the next step will be to try this on a number of samples from different patients to see how much these markers vary. I also wonder if it's possible to go back to stored tissue samples and try to correlate mass-based markers with the known clinical outcomes and sensitivities to various therapies.

I'd also be interested in knowing if this technique is sensitive enough to find small-molecule drugs after dosing. Could we end up doing pharmacokinetic measurements on a histology-slide scale? Ex vivo, could we possibly see uptake of our compounds once they're applied to a layer of cells in tissue culture? Oh, mass spec imaging has always been a favorite of mine, and seeing this level of resolution just brings on dozens of potential ideas. I've always had a fondness for label-free detection techniques, and for methods that don't require you to know too much about the system before being able to collect useful data. We'll be hearing a lot more about this, for sure.

Update: I should note that drug imaging has certainly been accomplished through mass spec, although it's often been quite the pain in the rear. It's clearly a technology that's coming on, though.

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Drug Assays


COMMENTS

1. Brian on April 27, 2010 8:10 AM writes...

Caprioli pioneered this technique. On finding small molecule drugs after dosing:

http://www.hubmed.org/display.cgi?uids=14595858

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2. Mark on April 27, 2010 8:48 AM writes...

It's posts like this that keep me coming back to Derek's blog.

Great stuff!

Mark

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3. anon the II on April 27, 2010 9:04 AM writes...

I'm not an expert and technology moves forward, but MALDI (Matrix-assisted laser desorption/ionization) means that you need some kind of "matrix" to adsorb that laser light. The matrix heats up real fast and explodes those intact molecules into space where the mass spect can suck them up and analyze them. So you have to diffuse your matrix into the sample to use MALDI. Typically, the matrix ions tends to wipe out most of the lower molecular weight masses with noise and so they're harder to detect.

If you look at MALDI spectra, they tend to get real busy down in Lapinski territory. Now I'll go read the article.

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4. anchor on April 27, 2010 10:37 AM writes...


Cool! Very cool indeed! Thanks for the blog and also for the citation as well.

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5. pete on April 27, 2010 10:44 AM writes...

On the drug PK/PD theme, I can imagine using this technique to better quantify the ability of a therapeutic antibody (for example) to successfully penetrate tissue compartments such as eye, joint articular capsule, CNS, and so on.

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6. Nick K on April 27, 2010 11:36 AM writes...

Very impressive technique. It would be most interesting to compare it with NMR microscopy. Perhaps the two are complementary.

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7. Ed Robinson on April 27, 2010 4:27 PM writes...

Derek, as a non-chemist in life sciences mgt, I have long enjoyed your blog - you write very clearly in a manner non-chemists can often comprehend. Today's post on mass spec is your best yet - wonderful explanation with details and speculation and fine images all wrapped up. I'm a director of an English company out of Imperial College, deltaDOT Ltd, focused on label free imaging. Your comments on novel uses of mass spec are of very great topical interest to our top scientists, Drs. Stuart and John Hassard, a biologist and physicist respectively. If you wish to learn more, you can contact them at j.hassard@deltadot.com or s.hassard@deltadot.com. Great stuff, many thanks!

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8. anon on April 28, 2010 1:27 PM writes...

Yes you can image parent drug and metabolites, it's just a matter of applying the right matrix to the tissue MALDI is currently the ionization method used, but there are groups looking into other methods. Of course once you see the image, the next question is how much is there, but quantitation is still problematic as it is difficult to know just how well the molecule of interest ionizes. People have tried to spot standards next to the sample, but you may have matrix effects in the tissue. Definately a problem that needs to be worked out.

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9. Morten G on May 6, 2010 9:03 PM writes...

If you like this you should take a look at nanoSIMS too
Link: http://www.curie.fr/recherche/themes/detail_equipe.cfm/lang/_gb/id_equipe/304.htm

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