Dr. Steven Griffiths Monthly Column, published in the Times & Transcript

Of Mice and Men at The Genetic Casino

Tuesday June 17, 2008

Last summer Snowhead and Punkie escaped. We had left them outside during supper, along with two dozen siblings in gender appropriate cages. Coming up short on the evening mouse count, my son and I shook our heads. Among other hazards, our readings had revealed that even our captive chipmunk would take a squeaky snack (Chippy himself eventually escaped custody with a 4 foot high leap, tail whirling like a propeller). We tried our collection of live traps to no avail. As autumn approached we assumed the worst.

Fast forward to March of this year. Returning from the store as darkness fell I caught a glimpse of a tiny but familiar black and white body bolting across the emerging tulips. It looked a lot like Punkie (originally named after the fluorescent pens we had used to identify the boys). David and I pondered the sighting. When Punkie scarpered, he was already in middle age, a good 5 months old: it seemed a bit of a stretch for him to be so sprightly so long after his sell by date. A more plausible hypothesis might be that brother and sister had an al-fresco romance (I think Punkie was also Snowhead’s Dad); their banjo-playing pups might have survived the winter. As the weeks passed however, the saga grew a little more complicated. We now began to spot others foraging under the bird table: pretty tan and white piebalds, coal-blacks as well as those sporting the typical wild mouse brown. It appeared that we had inadvertently created a multicultural society under the garage. A potentially delicate moral and practical dilemma then: the local population had increased to the possible chagrin of our kind neighbours; meanwhile a potentially wimpy race of miscreants had been consigned to the teeth of the wild (if you can call a garage crawl space “the wild”). Eventually the two concerns may have canceled each other out but we felt responsible either way. Once again our trapdoor boxes were baited with bird seed. Perhaps because food was scarce at the end of winter, we got them all.

Mice are not the most interactive pets, but at least they offer some endearing behaviour. Submissive mice tend freeze in hunched terror while the more bullish ones clean them (true for both the boys and the girls); some come up to the bars and throw brave little punches at the cats; it’s certainly adorable when they race side by side or nose to tail in their wheels. These hybrid dudes though? Duds. They stuffed themselves into the tiniest little space available and hardly ever came out. There were other odd things about them too: some were dead ringers for the house bound pets in coat color, but remained small and sleek compared to their more Rubenesque doppelgangers. Their ears were bigger too, like little satellite dishes. Oh and another thing: they were darned fast, like furry lightning.

Quite unexpectedly we had been presented with a lesson in the mechanics of genetic transfer and natural selection. Being appropriate fodder for anything that could fit them in their mouths, mice without the goods get voted off the Island pretty quickly. Didn’t fit through the crack? Didn’t hear me coming? Stayed out in the open too long? Sorry Buddy. Munch. Only those with the right combination of protein variants, the cogs of life that optimize muscle twitch, nerve impulse and metabolism will permit the fastest reflex, the life-preserving sprint, the heightened perception of imminent and avoided demise. These properties or, if you want to get all fancy, this phenotype, creates a winner in the fang, claw and beak infested corridor between Mountain Road and St George Street. Combined, the properties create what we call an “emergent” phenotype, a nice way of summarizing the well-known concept of the whole being greater than the sum of its parts but this time as selected by the many dice thrown in the environmental casino.

Other examples of inherited and imprinted behaviour have come indirectly from our marginal interest in physics. My supplies for cancer research are often shipped on dry ice: carbon dioxide condensed at high pressure into a solid with a temperature of -80oC . With a 2 liter pop bottle filled to the neck with warm water, 15 grams of dry ice and some assistance from Barney the Dinosaur, it is possible to demonstrate the deliquescence of solid carbon dioxide directly to gas creating an incredible amount of pressure, incredibly fast. The spectacular trajectory of Barney across the garden also serves as a noble demonstration of the transfer of free energy. The unlikely segue into the hardwiring of behaviour into DNA is this: upon placing the cooler of dry ice on the desk in the front hall, Izzie, despite not having seen me do this, stands up and waddles around like a circus dog in attempt to see what is up there. Meanwhile the cats begin to slink around as if they are back in a jungle: close to the wall, eyes as big as saucers. It occurred to us that, to their ancestors, carbon dioxide, breathed out during respiration, must have been a good indicator of where the next meal is coming from or indeed whether they themselves might be the next meal. The whiffs of carbon dioxide floating down from the box had put them on immediate high alert.

That such jungle-wise behaviour had been preserved in dogs and cats while negligible but quickly replaced in pet mice is likely due to relative fecundity. Inbreeding and early maturation certainly exists in dogs and cats but certainly not to the same degree of profligacy associated with mice. As David and I can flabbergastedly attest, mice are mature at 3 weeks yielding an average of 7 pinkies. After the easy history of several thousand generations behind closed doors, genetic street cred would have been quickly diluted due to lack of selection pressure (unless exercised by torture-happy snake owners, which I doubt). For Snowhead and/or Punkie’s kids then, it seemed that the Rambo combo of the wild mice had commandeered the lazy genetic back water of the pets. The dominant genes had been reintroduced back into the little pink chassis, clicking together into circuits that made them warier and speedier, over writing the incumbent properties of nonchalance and sloth. In parallel, Izzy and the cats are not so far removed from their ancestors, red in tooth and claw, to have lost their ability to sense exhalations of potential foe or feast, and continue to act accordingly (Mr. Bigelow was actually living in a tree when we found him-see picture).

Having been away from big picture biology for awhile I was surprised to see the obvious transferal of wild behaviour to mice that otherwise looked like pets. Intuitively, in the ancestors of a giraffe say, one might accept the benefits of longer necks to reach higher leaves or the gradual diversification of beak shapes so that birds could acquire alternative sources of food such as berries or wood burrowing worms. In our hybrids though, it appeared as if a complex set of genes had actually conspired to influence personality. I had never really thought about heredity in these terms before although it might explain the delight my son and I both share for the propulsive aerobatics of cuddly toys and action figures.

As a cancer biologist I found this parallel of complex and multifactorial genetic legacy acutely interesting. Cancers are governed by a combination of Murphy’s Law and over caffeinated evolution: whatever can go wrong will go wrong and whatever works best keeps going. Whatever keeps going may accumulate another damaged gene producing an additional rogue protein that further increases misbehavior to the point of medical concern (a stepwise process that generally takes decades). At each step, properties may combine to make the cancer cells more efficient under whatever selection pressures are operating. These selection pressures may act inside the body (e.g. the availability of oxygen or sugar) or from the surrounding environment (ciggies, barbecues, pollution, infection etc.). Ladies and Gentlemen once again I give you: the emergent phenotype at the tables of the genetic casino.

In our cancer research community, for the past 80 years, there has been an emergent phenotype that lives above the laboratory ceiling tiles like a 200 lb squirrel. Occasionally it falls out, we poke it with a spatula and then it crawls back up there again to line its nest with the latest funding. The squirrel is this: among the huge variety of cancers, all of the problematic ones use a highly inefficient means of energy production called glycolysis. The phenomenon is called the Warburg effect. It is so widespread that, regardless of the type of cancer, oncologists can use special imaging equipment to identify what it’s up to and where it might be headed. Although it sits there on our benches openly nibbling on our nuts, we can’t quite figure this Warburg squirrel out. You would think that cancer cells, in an attempt to out compete their neighbours, would use, if not tweak, the most efficient form of metabolism available. This is not the case. There is something so universally emergent about this weird behaviour, originating from so many different directions, that it has to be hugely important to cancer. But, so far, no one knows why. Stepping back and looking at the bigger picture (much as we did with the pets), your friendly neighbourhood Research Institute has a juicy theory. That inefficient form of metabolism so typical of cancer is also crucial to the formation of little bubbles of cell membrane called microvesicles. The cancer cell can coat itself with these bubbles for protection. Alternatively and/or simultaneously, the cancer cell can use the bubbles to throw out the proteins that would otherwise shut it down, prevent an effective immune response or prepare landing strips for migrants to colonise other parts of the body. The wild thing is that the enzymes involved are kind of like Swiss army knives. Not only do they generate energy for strategically packing stuff into the bubbles, they also spin off precursors of fat molecules that can be incorporated into new bubbles. Then, independently mind you, another side of the same enzymes moonlight as fasteners so that bubbles can fuse with the cell membrane, the first step in their use for whatever mischief or subterfuge that keeps the cancer ticking. It may be that the many selective advantages conferred by the release of the bubbles, removing controlling influences and stacking the deck for success, has lead to this common but weird platform for energy production. It is inefficient but the benefits outweigh the risks. Are we right? If so, you heard it here first. Meanwhile it’s time to put the mice out in their summer playpens again. This year however the playpens will be a little sturdier.

Footnote
In hindsight, it seems remarkable, if not professionally delinquent, that I had not researched for any previous observations of animals sensing carbon dioxide. I naively assumed that the selective advantage of such a skill would be self-evident and well established in any textbook on animal behaviour. As a nice twist it turns out that the first and only report I can find on this matter was published last autumn in the highly respected journal Science. The authors report that mice can detect carbon dioxide at levels close to atmospheric conditions. Sometimes The Science of Life surprises you with observations made in your own front hall. (Hu J et al. 2007. Detection of near-atmospheric concentrations of CO2 by an olfactory subsystem in the mouse. Science.,Vol. 317; pp953-7)

Article as published:
http://timestranscript.canadaeast.com/front/article/328290

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(Published in Times & Transcript)