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Spec Tech: Of Mice and Scientists

December 9, 2010

The summer after I graduated from high school, before I headed west to begin my undergraduate studies at Michigan State University, I worked in a research laboratory at the Memorial Sloan Kettering Cancer Center in New York City. In many ways this was a magical summer, one that remains sharply delineated in memory although it occurred 30 years ago.

(Thirty years ago! Have I really traveled forward in time three decades since that summer?).

I stayed with my Uncle and Aunt who had an apartment on Riverside Drive, and in my free time explored bookstores and went for long runs in Riverside Park. I rode the bus to and from work each day, picking my way through Delany’s monumental novel DHALGREN and, really, I can imagine no more relevant and inspirational novel emblematic of life in the modern-day Atlantis that is New York City.

And at work…

I did experiments with mice.

Why mice? Well mice are the go-to animal when it comes to mammalian experimentation. They’re small, cheap, have a short generation time, and they’ve been carefully bred for over a century. Mice were particularly popular as pets in Victorian England, being bred for their color and behavior, and were then adopted as a genetic model by scientists, the first inbred research strain being developed by Clarence Cook Little at Harvard in 1909. Many different strains of mice have now been developed for many different purposes.

Not too surprisingly, the mice I worked with at Sloan Kettering were specially bred to be susceptible to cancer. This makes good practical sense if you are examining the factors that contribute to or can retard tumor formation. But, from a personal vantage point, it also meant that I spent a lot of time handling mice with tumors. Large tumors. Sometimes they were larger than the mouse’s head. Sometimes they impeded movement, causing a mouse to stumble when it wanted to run. When a mouse died, and the cause wasn’t immediately apparent (i.e. no visible tumor), I would perform a simple dissection to see if anything was amiss internally.

There’s more, but I think that’s enough to suggest why I am a plant scientist today. Now don’t get me wrong, I support the use of mice in research but it was not something that I could do myself. Or rather I did it for one summer, but I would not be able to continue doing so throughout a scientific career. But, I repeat, I am glad that other scientists are able to do such work.

All this as both introduction and caveat for the two rodent studies and videos that I have linked to below. I think these studies represent two very different approaches to the modification of an animal, but both approaches have substantial implications on how we can now control the behavior of another species. In the long run, they also suggest how similar strategies could be used to modify and control humans.

The Rat Automaton

Not quite a mouse, but…a rat. I assume that the choice of mammal for these experiments was made because the brain of a rat is larger and thus easier to work with than that of a mouse. Mary Shelley got the idea for how to reanimate the dead body in her novel FRANKENSTEIN (or THE MODERN PROMETHEUS) from experiments showing that muscles were activated by electricity. We now know that neurons in our body transmit electrical impulses and are the means by which we sense information, send signals, and store memories. They also provide a potential means by which we can directly interface with machines.

Through our brains.

And given that the brain is the ultimate organ that dictates what we think is occurring in the world, if we can control what goes on in the brain, then we control an animal’s worldview.

And we can control this by applying electricity to specific areas of the brain.

In this experiment, the scientists did two things to develop a rat that could be electrically ‘steered’ by remote control. First, they took advantage of the fact that rats use their whiskers as a means to sense whether they are encountering an obstacle to their left or right. So if you stimulate the area of the brain involved in whisker sensation, you can make a rat ‘think’ that one set of whiskers has encountered an obstacle and respond by turning away from the obstacle.

But wait, there’s more. To positively reinforce a correct response by the rat, the scientists applied an electrical stimulation to the pleasure center in the brain (reminds me of the Orgasmatron in Woody Allen’s movie SLEEPER).

There is something disturbing about this, but I just have to keep reminding myself that such feelings are all in my mind.

Mighty Mouse

In 2007, Parvin Hakimi and colleagues published a paper in the Journal of Biological Chemistry describing a genetically modified mouse in which the enzyme phosphoenolpyruvate carboxykinase (PEPCK) of muscle was overexpressed. PEPCK is an enzyme involved in carbohydrate metabolism, in particular the pathway that allows animals to convert simple building blocks to glucose. The scientists studying the effects of modifying PEPCK activity made some surprising and unanticipated discoveries, certainly nothing anyone would have predicted based on the known function of PEPCK. The mice ate more than usual, lived and bred longer, and—this was the big one—were more muscular and seven-times more active.

So what can this mouse now do?

Well, the transgenic mice could run on a treadmill for as many as five kilometers before stopping. That’s right, five kilometers! (Two miles!) By way of comparison, a normal mouse will typically give up after 0.2 kilometers. What’s more, the transgenic mice ran at twice the speed of normal mice. It turns out that changing the expression level of this one enzyme substantially re-patterned the mouse’s energy metabolism, apparently allowing the muscle to use oxygen more efficiently.

But there’s a downside (of course), the transgenic mice were also more aggressive, being more likely to attack and bite anything that provoked them. So maybe the PEPCK mouse isn’t so much the benevolent cousin of Mighty Mouse, but rather his evil twin. A super-villain. And nothing you want to meet up with in a dark alley.

Recommended Reading

1. “The Psychologist Who Wouldn’t Do Awful Things to Rats” by James Tiptree, Jr. How can you resist that title? It can be found in Tiptree’s collection STAR SONGS OF AN OLD PRIMATE, as well as in the Hartwell and Cramer anthology THE ASCENT OF WONDER. All of Tiptree’s short-story collections are well worth seeking out as used books because, although some of her stores are reprinted with frequency, many excellent ones are not.

2. FLOWERS FOR ALGERNON, by Daniel Keyes. I’ve recommended this book before for its nuanced treatment of scientists, but now recommend it again for its titular character, the mouse Algernon. If you haven’t read the book, do. It’s that good and deserves not just to be considered a classic, but a story every bit as moving now as it was when first published. I’m getting misty-eyed just thinking about it.

5 Comments leave one →
  1. December 9, 2010 1:31 pm

    Fascinating piece — but if you cut the mice open after they died, it wasn’t vivisection. You might want to edit the post, lest careless animal-loving readers become outraged.

  2. Eric Schaller permalink
    December 10, 2010 12:48 pm

    Laura–Thanks for the catch–I made the change.–Eric

  3. Lynda Williams permalink
    January 4, 2011 11:25 pm

    Could just picture you exploring those bookstores. Been some of my happiest hours, as well, but never in New York so far. I used to be fine with experiments on rats until my daughter kept pet rats. They’ve got a lot of personality! But like you, I’m okay with it on the whole so long as it’s rats not chimps and done in the pursuit of something useful to medical science. Not for less morally defensible reasons. I’ve conjectured, in my own writing, that creating bioengineered humans (my Sevolites, originally the products of Self-Evolved Limited as portrayed in The Lorel Experiment) would require a high tolerance for discarded attempts and other unethical practices to develop specific, extreme traits. But I’d like to think there COULD be an ethical way to improve the human genome in baby-steps. And I’d rather we learned on mice, first.

    • Eric Schaller permalink
      January 5, 2011 8:56 am

      Lynda–

      I find our relationship with mice and rats is quite fascinating. Both are kept as pets and both are routinely killed when they sneak into our homes. It points to the strange dualism we humans have in how we interact with the world around us, we can love and hate the same creature depending on the circumstances.–Eric

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