Go and NMR No More August 11, 2000

One of my favorite short stories was written by Isaac Asimov in 1958 and collected in Nine Tomorrows. It is called 'The Feeling of Power'. It is a startlingly satirical examination of a decadent world in the future where computers are such an integral part of the culture that mankind has forgotten how to use a pencil and paper to perform simple calculations. Everything is done by computers. Everyone has a personal computer and uses it for every type of problem. Just punch the numbers in and get the answer. A high level official, a Programmer, finds someone who is actually able to do math by hand! Although everyone initially believes it is a parlor trick, more become convinced that it may be useful.

Then the satirical part really comes in. See, the government creates a secret project, Project Number, using this technology to help it in its war effort. Any similarity to the Manhattan Project is intentional. The final sections of the short story are, to my mind, some of the best examples of the 'O. Henry' style of stories. A quick change of view that requires you to reexamine the entire premise of the story in a different light, and, because of its obvious parallels with reality, to examine those also.

Now, I do not really think any civilization that uses computers will ever forget how to add. But Asimov takes this as a given to allow himself the ability to use satire to make a point. Technology is not good or bad. It has no ethics or morals. It is what people do with it that determine these.

Now this is one approach for satire. Stretch a topic so far that its original underpinnings become strained and finally burst. Jonathan Swift's 'A Modest Proposal' is a stellar instance of this sort of satire. Another style that is used a lot more today is the rant. While the voice used by Swift or Asimov tends to be fairly quiet, drawing you into a satirical situation before switching point of view, rants take a more direct approach. Emily Latella on Saturday Night Live would often have farcical rants, dealing with her obvious misunderstanding of the basic premise. This is a really easy approach to laughter and satire.

Personal Note: In graduate school, it was the tradition of the 2nd year graduate students to put on a production of some sort for the departmental Christmas party. We chose to do a Saturday Night Life rip-off because we figured we would not have to write some really original stuff. So we had 'Samurai X-Ray Crystallographer' starring the taciturn Oriental student who, unbeknownst to all, turned out to do a terrific John Belushi imitation. We had a demonstration of 'Rat-o-matic', using a cucumber covered with white icing. We had a slide presentation showing the campus visit of future graduate student Mr. Bill. The shot of his escort, Sluggo, showing him the inside working of a centrifuge, did not require a high degree of originality. (In one of my unheralded acting jobs, I provided the voice of Mr. Bill, since I had his 'Oh. Noooooo!' down pat). But the highlight (or lowlight) of the night was when Emily Latella came on our Weekend Update to complain about ... well, for the delicate in the audience, I'll obfuscate the term. Just imagine that it dealt with her confusion of the phrase 'graduate student theses'. Let's just say that 'theses' rhymed with a terminal body product. She showed her concern with how long it took some people to get them out ("...over six years!!!"). She recommended natural relief using bulky fiber, etc. until corrected by the news anchor and ending her diatribe with a 'Never mind'.

The whole production allowed us to poke fun at the way graduate school dealt with its students, in a way that was not in your face or too confrontational. Now another great Weekend Update 'graduate' is Dennis Miller. He has perfected the art of the rant as a satirical device. (By the way, did anyone see him on Monday Night Football? A little rough but it is preseason. Hope he can develop into just as interesting a character as was found on the original MNF. Don Meredith, when a sleeping fan at an absolutely awful game near the end of the 4th quarter woke up and gave a middle finger salute to the camera, turned to Howard Cosell saying 'Look, Howard. He thinks we're No. 1!'). Below is my feeble attempt a Millerarian rant. (Or should it be Millerite? Millavian?)

Anyway, I don't want to start a rant or anything but ...

I had a dental exam the other day and, when they took the X-rays, they not only put a lead apron over my body, they wrapped a lead collar around my neck. They had me bundled up tighter than Jack Benny's wallet.(oops. Too dated. How about 'tighter than pair of Calvin Klein jeans'? Too obscure. E-mail me your best 'tighter than ...' phrase.) I've been getting oral X-rays for decades and they only now decide to strap all this stuff on me!! What is going on here? And why have they dropped the word nuclear from NMR (remember Nuclear Magnetic Resonance). Now it is MRI (Magnetic Resonance Imaging). Do they think that having the word nuclear in it implies that it uses an atom bomb? Now we all know that magnets can cure arthritis. I saw the infomercial on TV. I hear Tiger Woods uses them. Yeah, right. Tiger Woods needing magnets to win is like water needing a river to run downhill. He's a force of nature and will do what he pleases, with or without outside help. So magnetic resonance is good but if you add nuclear its Armageddon time. Maybe some people need to get a life. But that's just my opinion. I could be wrong.

Okay, maybe I shouldn't quit my day job. But I did want to comment on a recent paper dealing with NM...uhh, MRI. Being able to see inside a living cell is pretty difficult, since most approaches damage the cell in some way. And few things really work well on opaque objects. There are approaches using clinical three-dimensional imaging techniques, tomagraphic approaches such as PET or SPECT, but the resolution is usually not high enough. A paper by Louie et al. describes the use of proton MRI (Not NMR!!) to image living organisms and follow their developmental progress.

Now the difficulty in using MRI in living organisms is that the major signal comes from water. Since every cell has pretty much the same water content and environment, contrast is a problem. All the cells look alike. You can see differences in different tissues but seeing subtleties... that is another matter.

Louie et al. describe the use of a novel contrast agent. I won't go into the physics (An author's ruse to ignore the fact that I really don't understand the physics.), and cut to the chase. This agent, when placed inside a cell, can allow the easy identification of this cell by NMR MRI. Most other cells are almost invisible. The functional group of this agent is a gadolinium ion that has eight of its nine coordination sites blocked. If access to this final site remains blocked, the agent is inactive and will be invisible by MRI. If water can access this site, the agent is active, rendering the cell visible by MRI. This ninth site is normally blocked with a galactopyranose residue, meaning that an enzyme that cleaves the galactopyranose will allow water access to the gadolinium, creating a high contrast agent. So, if the cell is expressing an enzyme that cleaves galactopyranose, the cell will be visible under MRI. No cleavage and the cell is invisible.

This agent is called (1-(2-(b-galactopyanosyloxy)propyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane) gadolinium(III). They call it EgadMe, probably to save on page charges. Now a galactopyranose residue was chosen to block the last site because it is a substrate for b-galactosidase. So, any cell expressing b-galactosidase will be visible with MRI.

They used Xenopus embryos to demonstrate the usefulness of this agent. They could inject mRNA for b-galactosidase, along with EgadMe (Love that name. How could you keep a straight face when discussing this work?), into cells that would develop into just the left or right side of the embyro. They could then compare what was seen by the MRI. The results are pretty impressive.

They used a lot of controls (co-injecting green fluorescent protein, staining for b-galactosidase activity with X-gal) to compare with EgadMe. What they found was that EgadMe worked really well, even in deep tissues like the head. They could detect mRNA inheritance patterns as well as expression from plasmid DNA.

This sort of approach should be amenable to examining gene expression using a variety reporter genes. Different moieties could be used to block the gadolinium, making EgadMe susceptible to other enzymes. The ability to examine expression patterns of different genes in living, developing animals holds a tremendous promise. It will be interesting to see what further improvements bring.

I guess I'll just have to get used to proton magnetic resonance imaging. Now if someone will just tell me what they call Nuclear Medicine these days...