Not some Mickey Mouse operation

FRAMINGHAM (09/24/2003) - It's hard not to smile when reading this cast list. There's "Dickie's small eye" and "nude streaker." For the particular among you, they're also known by the genetic descriptors B6EiC3Sn-a/A-Pax6Sey-Dey and AKR/J-Foxn1nu-str/+. Let's not forget the well-named "waddles" (aka C57BLKS/J-wdl) or "hotfoot 4 Jackson" (DBA/2J-Grid2ho-4j/+).

At The Jackson Laboratory, the mice are (almost) everything.

From the whimsical to the bluntly prosaic (#2235, cerebellar deficient folia), 2,700 strains of mice are available from The Jackson Laboratory (JL). The mice cited here -- and yes, those are their official descriptions -- were among a handful of strains shown at the 44th Annual Short Course in Medical and Experimental Mammalian Genetics, presented by JL and Johns Hopkins University in July.

For two weeks each summer, about 125 students and researchers and 125 guest lecturers gather at JL's Bar Harbor headquarters, off the rugged coast of Maine, to review the state of knowledge in genetics and medicine.

Much of that knowledge, of course, was gleaned using Jackson mice as model organisms. In fact, at any given time there are 750,000 mice scurrying in their cages at JL, and another 2 million embryos on ice waiting for the call to duty. You hear the phrase "Breed 'em up" a lot around here. The rodents aren't cheap, either. Inbred pregnant females can fetch US$175 each, though other mice cost just $2.65.

While it's easy to smirk at the largest nonprofit mouse factory in the world, the science done here is substantial, and many of the lecturers who teach at the short course are no less famous than the mice.

Victor McKusick, the grandfather of human genetics, and Aravinda Chakravarti, an authority on complex gene traits and now director of the McKusick-Nathans Institute of Genetic Medicine at Hopkins, presented this year. So did Andrew Feinberg, another prominent Hopkins researcher who first attended the short course as a student, and Marc Vidal, a Dana-Farber Cancer Institute researcher.

To spread the word about all this good stuff, JL invites journalists to participate in the second week of the course. Given the venue, it's hard to resist. Mingle with researchers during the day ... fight with lobsters and clams at night. (They very carefully keep the mice out of our contaminating reach.)

It's impossible to recount here all that was presented at the short course. (JL/Hopkins really should post the papers online but don't.) Some of the material was basic, but many novel ideas were discussed.

Shape of Things to Come

Vidal, for example, has plotted the interconnections for 3,000 proteins in Caenorhabditis elegans, producing a dizzying network of interactions. Vidal brought his intricate protein map to Albert-László Barabási, a physicist at the University of Notre Dame, who has dusted off some old mathematical ideas about networks and begun applying them to the Internet.

Vidal said: "They realized the topology of such a network is not random at all. One thing that really jumped out to their eyes is that a very small number of Websites -- something like .001 percent -- are totally hiding behind links while most of the Websites have a much lower number of links." The emerging idea is that the shape of network diagrams has meaning, independent of the physical phenomena being modeled.

"Turns out if you look at the yeast (protein interaction map) and ours, it totally looks the same," Vidal continued. "A small number of proteins seem to be super highly connected. There are different kinds (of network hubs), and we've looked at those kinds in certain detail; for example, (some seem to be) master hub proteins.

"There really are new biological questions that will be addressable, stepping back and looking at the topology of those networks," he said. "We're putting a paper together."

On the last day of the course, "Mr. Mitochondria," Doug Wallace of UC Irvine, declared researchers obsessed with the nuclear genome are looking in the wrong place for cures. They should be studying mitochondrial DNA.

Animated and disheveled, it's not clear if Wallace's self-portrayal as the Rodney Dangerfield of genetics helps his cause. He argues that the flow of energy through cells -- modulated by mitochondria -- has far more effect on physiology than "this or that polypeptide" encoded in the nuclear genome.

"If you went out and got hit by a truck but were not significantly mangled except for your brain, you would be looking exactly the way you do right there lying on that slab, but you would be different," Wallace said. "You would be dead."

"Your structure is there. You're different because you no longer have energy. We have completely compartmentalized our thinking to say structure is important and energy is not. I'm saying the nuclear genome is structure and the mitochondrial genome is energy, and just as in chemistry and physics we never got anywhere until we started looking at both of them, we're having exactly the same problem in medicine now."

It was a great week, although one of the press handlers twitched a bit when National Cancer Institute researcher Stephen O'Brien off-handedly suggested cats might be the ideal research mammals. I couldn't tell if the mice reacted with terror or jubilation.

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