Of Transgenic Mice and Men: The Rats of NIMH Meet Universal Soldier

When I was in grade school, one of the many reading assignments given to students included a book titled Mrs. Frisby and the Rats of NIMH.1

The novel relates the plight of a widowed field mouse, Mrs. Frisby, whose family must travel every year to a summer home to avoid being mowed by the farmer who owns the land she and her family live on. When Mrs. Frisby's son, Timothy, becomes ill, Mrs. Frisby must venture for help. [...snip...] ...from a nest of rats which lives nearby under a rose bush.

She discovers that the nest is a community of long-lived, super-intelligent rats, [...snip...]

The rats had been captured and experimented upon by people from the National Institute of Mental Health (NIMH).

Part of the series of experiments at NIMH involved an acceleration of their intelligence. They were able to learn to read, write, and operate complicated machines. Their new intelligence was much more developed than their captors realised, because they were able to escape from the NIMH laboratories and migrate to their present location. She learns, too, that her husband had been part of a group of mice who had been at NIMH with the rats...

[Emphasis mine.]

It was an interesting book, and the tale has been popularized through reprintings and made into a movie. Although the technology for breeding "super-" anything has been dreamt of for years,2 but it wasn't one I gave much additional thought to until I ran across a curious article just the other day...

I spend a lot of time online for two primary purposes: researching for writing projects and investigations, and looking for work (right now, nearly anything would be good). As a result, I often happen across a variety of news bits and bytes ranging a wide gamut of topics. A few days ago, I chanced upon a collection of articles that really spurred my imagination. One, in particular, brought back a wave of memories and a vivid reminder of that book from elementary school about the marvelously long-lived and intelligent rodents of NIMH.

On November 2, 2007, ScienceDaily reported that Case Western University reseachers created genetically engineered super-mice.3

Case Western Reserve University researchers have bred a line of "mighty mice" (PEPCK-Cmus mice) that have the capability of running five to six kilometers at a speed of 20 meters per minute on a treadmill for up to six hours before stopping.

The mice outlive normal mice and are active well into what is normally considered old-age; they are even able to breed long after "natural" mice. They are more fit, consuming 60% more calories without getting fat, and smaller than other mice. All this does come with a price -- a noticeable increase in aggression.

Animal behavior studies later demonstrated that the PEPCK-Cmus mice are seven times more active in their home cages than controls; in addition, the mice were also markedly more aggressive. "The enhanced level of activity noted in the PEPCK-Cmus mice extends well beyond two years of age; this is considered old-age for mice," the researchers said.

So, what's the reason for their high-energy longetivity?

Here comes the technical-heavy explanation: the reason behind the extraordinary boost to the metabolic energy and efficiency of these mice is the over-expression of the gene for the enzyme phosphoenolypyruvate carboxykinases (PEPCK-C) as part of on-going research aimed at understanding the metabolic and physiological function of PEPCK-C in skeletal muscle and adipose tissue.4

The transgenic mice, which now number nearly 500, were derived from six founder lines that contain a chimeric gene in which a copy of the cDNA for PEPCK-C was linked to the skeletal actin gene promoter, containing the 3'-end of the bovine growth hormone gene. The skeletal actin gene promoter directs expression of PEPCK-C exclusively to skeletal muscle. Various lines of PEPCK-Cmus mice expressed PEPCK-C at different levels, but one very active line of PEPCK-Cmus mice had levels of PEPCK-C activity of 9 units/gram skeletal muscle, compared to only 0.08 units/gram in the muscles of control animals.

OK -- that was for the technophiles. What, in short, does it mean for folks who aren't as conversant with the terminology of biochemistry and genetics? Here's part of "what happened" as a result of the genetic tweak:

This new mouse line also has an increased content of mitochondria and high concentrations of triglycerides in their skeletal muscles, which also contributed to the increased metabolic rate and longevity of the animals.

This is all very well and good, but what does it mean for humans?

From a related article on CNET:

The results were both unexpected and remarkable, Hanson added. Potentially, the research could help enhance cancer treatment in humans or allow us to better understand the human metabolic process. It also could even change some of the current thinking on dietary recommendations for sick patients. Maybe it isn't the calories you eat, but what you do with them, Hanson speculated.

[Emphasis added.]

This is not, however, something that can be directly and easily translated into a super-drug for humans -- it's not a "cure" for aging, diabetes, obesity or virility. The researchers make that clear in the November 2 news release:

"The technique used to create the animal model reported in our study is not appropriate for application to humans. The ethical implications are such that this approach should not be used in humans, or is it technically possible at this time to efficiently introduce genes into human skeletal muscle, in order to mimic the effect seen in our mice" said Hanson. "Any attempt to tamper with the metabolic processes in human muscle will surely do more harm than good. We believe that this mouse model will provide important insights into the impact of prolonged exercise on the development of cancer in the animal, the effect of diet and exercise on longevity and will increase our knowledge of the factors that regulate energy metabolism in skeletal muscle."

So this is not a wonderous "superman" formula -- it is, however, a surprising and promising development that could lead to increased understanding and perhaps even treatments for a variety of ills, ailments, disabilities and diseases.

If my mind had stopped there, at that point, it would have left me feeling full of hope and promise, but it didn't stop there -- no, it went barrelling onward to dredge up further references to transgenic and drug experiments, drawing comparisons to movies, comics and history that darkened the edges of such promising research.

And then my mind lurched and pulled up a reference to a piece I'd just read over on Docudharma about H.R. 3256, the "Psychological Kevlar Act of 2007."

The mini-blurb describing the bill sounds hopeful and innocuous: "To reduce post traumatic stress disorder and other combat-related stress disorders among military personnel, and for other purposes."

I must say, tho, that the pesky little "and for other purposes" bit always gives me pause...and the willies, particularly while our nation is under the 'care and governance' of the neoconservatives (the crazies in the basement) of the George W. Bush regime.

There are already existing programs that help "render toothless" the traumas of certain events for soldiers (articles here (Alternet) and here (Village Voice)). Such programs and pharmacological methods of treatment have the potential taking the humanity out of a soldier's built-in ethical regulators -- something that the military itself may not shirt at, but soldier's families and the public at large might have a huge problem with. From the Village Voice piece:

"It's the morning-after pill for just about anything that produces regret, remorse, pain, or guilt," says Dr. Leon Kass, chairman of the President's Council on Bioethics, who emphasizes that he's speaking as an individual and not on behalf of the council. Barry Romo, a national coordinator for Vietnam Veterans Against the War, is even more blunt. "That's the devil pill," he says. "That's the monster pill, the anti-morality pill. That's the pill that can make men and women do anything and think they can get away with it. Even if it doesn't work, what's scary is that a young soldier could believe it will."

[...snip...]

"If you have the pill, it certainly increases the temptation for the soldier to lower the standard for taking lethal action, if he thinks he'll be numbed to the personal risk of consequences. We don't want soldiers saying willy-nilly, 'Screw it. I can take my pill and even if doing this is not really warranted, I'll be OK,' " says psychiatrist Edmund G. Howe, director of the Program on Medical Ethics at the Uniformed Services University of the Health Sciences. "If soldiers are going to have that lower threshold, we might have to build in even stronger safeguards than we have right now against, say, blowing away human shields. We'll need a higher standard of proof [that an action is justified]."

[...snip...]

"The impulse is to help people to not fall apart. You don't want to condemn that," says Kass. "But that you would treat these things with equanimity, the horrible things of the world, so that they don't disturb you . . . you'd cease to be a human being."

[Emphasis added.]

Indeed, with a mental "morning after" pill and potential adaptation of the PEPCK findings, what kind of soldiers are we asking the men and women of our nation to become? Perhaps more to the point, what are we becoming, when the potential for removing the moral and ethical repurcussions of war -- and indeed, genetically altering the mental and physical aspects of human beings to improve their capacity for killing and for destruction with impunity -- becomes a more viable alternative than simply seeking to master the art of diplomacy and understanding?

Science steps ever-closer to the realization of things once thought to exist solely in the realm of the imagination, bringing us closer to the dizzying heights of the fantastic and wonderful even as we balance precariously on the edge of a dark and foreboding abyss. Science has brought us to the point where we may be approaching a new threshold in our definition of what constitutes "death" -- and our ability to restore people to life -- while simultaneously learning that aggression rewards the brain in much the same way as "sex, food and drugs."

As my mind reviews, sorts, files and indexes all these new tidbits and crossreferences, two more items slink in from the darkened back-alleys of my long-term memory -- quotes worth living by. The first is one likely to be known by children and adults worldwide:

With great power comes great responsibility

-- "Uncle Ben" Parker, a comic book character and uncle of Peter "The Amazing Spiderman" Parker; characters and quote by Stan Lee

The second quote is a touch darker in context and in content:

He who fights with monsters might take care lest he thereby become a monster. And if you gaze for long into an abyss, the abyss gazes also into you.


        -- Friedrich Nietzsche,
        Beyond Good and Evil, Aphorism 146
        German philosopher (1844 - 1900)         (via The Quotations Page)

Whenever we take it upon ourselves to be the executors of the human legacy, we often take into our hands the power to influence that which imperfectly understand. To do so with brazen disregard for the hundreds of thousands of years of natural selection and evolution would be to embrace foolishness and tempt fate, and such temptations should not be made lightly, for here there be monsters.

Any efforts to increase our understanding of and control over our own biology and that of others should always be made with an eye toward caution and an acceptance of accountability. We are an amazing species, but we must accept and understand that we are also imperfect -- pride in the knowledge that we can do something should be tempered with the wisdom that such knowing does not mean we should do something simply because we can.5

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Footnotes
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  1. From Wikipedia:
    Mrs. Frisby and the Rats of NIMH is a children's book by Robert C. O'Brien, illustrated by Zena Bernstein published in 1971 with many subsequent reprintings, sometimes titled The Secret of NIMH, after the movie which was based on the book. It won the 1972 Newbery Medal.

  2. References abound, from Star Trek TOS's Space Seed and TNG's The Hunted to Philip K. Dick's novel Do Androids Dream of Electric Sheep, from movie incarnations like Universal Soldier and Blade Runner, to TV shows like Dark Angel and even cartoons and comics like Mighty Mouse and Captain America. Historical references in the Bible of cross-breeding experiments (think Nephalim -- here's a CT-like ref for folks) call to mind aspects of primitive transgenic experimentation while ever-darker real-world incarnations took form within the mindset and medical experimentation of the Nazis during WWII in their quest for the "Master Race."
  3. Genetically Engineered 'Mighty Mouse' Can Run 6 Kilometers Without Stopping, ScienceDaily 2 November 2007. 30 January 2008.
  4. The following definitions may be helpful to readers:

    metabolic (metabolism)

    The chemical processes occurring within a living cell or organism that are necessary for the maintenance of life. In metabolism some substances are broken down to yield energy for vital processes while other substances, necessary for life, are synthesized.

    metabolism. Dictionary.com. The American Heritage® Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company, 2004. http://dictionary.reference.com/browse/metabolism (accessed: January 30, 2008).

    adipose tissue (adipose)

    Relating to or consisting of animal fat. ◇ Adipose tissue is a type of connective tissue consisting of adipose cells, which are specialized to produce and store large fat globules. These globules are composed mainly of glycerol esters of oleic, palmitic, and stearic acids. Adipose tissue is the main reservoir of fat in animals.

    adipose. Dictionary.com. The American Heritage® Science Dictionary. Houghton Mifflin Company. http://dictionary.reference.com/browse/adipose (accessed: January 30, 2008).

    transgenic (transgenic)

    Relating to an organism whose genome has been altered by the transfer of a gene or genes from another species or breed. Transgenic organisms are used in research to help determine the function of the inserted gene, while in industry they are used to produce a desired substance.

    transgenic. Dictionary.com. The American Heritage® Science Dictionary. Houghton Mifflin Company. http://dictionary.reference.com/browse/transgenic (accessed: January 30, 2008).

    mitochondria (mitochondria)

    A structure in the cytoplasm of all cells except bacteria in which food molecules (sugars, fatty acids, and amino acids) are broken down in the presence of oxygen and converted to energy in the form of ATP. Mitochondria have an inner and outer membrane. The inner membrane has many twists and folds (called cristae), which increase the surface area available to proteins and their associative reactions. The inner membrane encloses a liquid containing DNA, RNA, small ribosomes, and solutes. The DNA in mitochondria is genetically distinct from that in the cell nucleus, and mitochondria can manufacture some of their own proteins independent of the rest of the cell. Each cell can contain thousands of mitochondria, which move about producing ATP in response to the cell's need for chemical energy. It is thought that mitochondria originated as separate, single-celled organisms that became so symbiotic with their hosts as to be indispensible. Mitochondrial DNA is thus considered a remnant of a past existence as a separate organism. See more at cell, cellular respiration.

    mitochondria. Dictionary.com. The American Heritage® Science Dictionary. Houghton Mifflin Company. http://dictionary.reference.com/browse/mitochondria (accessed: January 30, 2008).

    triglycerides (triglycerides)

    Any of a class of organic compounds that are esters consisting of three fatty acids joined to glycerol. The fatty acids may be the same or may be different. Triglycerides are the chief lipids constituting fats and oils and function to store chemical energy in plants and animals.

    triglycerides. Dictionary.com. The American Heritage® Science Dictionary. Houghton Mifflin Company. http://dictionary.reference.com/browse/triglycerides (accessed: January 30, 2008).

    esters (esters)

    An organic compound formed when an acid and an alcohol combine and release water. Esters formed from carboxylic acids are the most common, and have the general formula RCOOR', where R and R' are organic radicals. Esters formed from simple hydrocarbon groups are colorless, volatile liquids with pleasant aromas and create the fragrances and flavors of many flowers and fruits. They are also used as food flavorings. Larger esters, formed from long-chain carboxylic acids, commonly occur as animal and vegetable fats, oils, and waxes. Esters have a wide range of uses in industry.

    esters. Dictionary.com. The American Heritage® Science Dictionary. Houghton Mifflin Company. http://dictionary.reference.com/browse/esters (accessed: January 30, 2008).

    phosphoenolpyruvate carboxykinases (phosphoenolpyruvate carboxykinases)

    Phosphoenolpyruvate carboxykinase is an enzyme used in the natural process of gluconeogenesis. [...snip...] Whereas most reactions of gluconeogenesis can use the glycolysis enzymes in the opposite direction, the pyruvate kinase enzyme is irreversible. Therefore, the enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase are used to provide an alternate path for effectively reversing its actions. [...snip...] PEPCK gene transcription (genetics) occurs in many species, and the amino acid sequence of PEPCK is distinct for each species. [...snip...] In mammals, it is most abundant in the liver, kidney, and adipose tissue. [...snip...] ...PEPCK catalyzes the reversible rate-controlling step of gluconeogenesis, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2 as a result of the overexpression of PEPCK.

    A recent study suggests that the role that PEPCK plays in gluconeogenesis may be mediated by the citric acid cycle, the activity of which was found to be directly related to PEPCK abundance.

    PEPCK levels alone were not found to be highly correlated with gluconeogenesis in the mouse liver, as previous studies have suggested. Therefore, the role of PEPCK in gluconeogenesis may be more complex and involve more factors than was previously believed.

    PEPCK of Mycobacterium tuberculosis has been shown to trigger the immune system in mice by increasing cytokine activity.

    As a result, it has been found that PEPCK may be an appropriate ingredient in the development of an effective subunit vaccination for tuberculosis.

    Phosphoenolpyruvate carboxykinase -- Wikipedia; page was last modified 02:36, 27 December 2007. Internal footnote references removed. This definition is an approximation created from the full page entry. Richard Hanson, principle author of the paper from Case Western regarding the mice, provides a simplified definition: "The enzyme is ordinarily used to metabolize glucose in the liver."

  5. ...just because we can... -- the same argument, in reverse (sort of), applies to the concept of human-factored climate change. Denial of responsibility and claims that "probability" doesn't imply action must be taken is a cowardly attempt to abdicate responsibility for our role as the supposedly most intelligent species on the planet. If there is a chance that we are responsible for accelerating the climate changes, should we not take care to minimize and mitigate our impact? Are we not responsible for our waste and pollution? If not, who is? And if not us, then why not us? Wasn't everyone taught to share, to clean up after themselves and to look after those who couldn't look after themselves? Why do those lessons disappear upon reaching adulthood, and why is that ok with so many of the self-proclaimed 'morally superior' members of the right? Inquiring minds want to know...don't you?
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Maybe that's the wrong name and I don't remember the title. But Charlie is a retarded guy who is the cleaning man at a research lab. He is made fun of by the nice guys on staff but he doesn't realize this and is happy with all of his "friends."

Then they develop a pill something like what you describe above and when they give it to their rats they become super intelligent (in rat terms), so they decide to try it on Charlie. He takes it and slowly his intelligence rises. First of all he realize that his "friends" are bums and that's distressing. Then he falls in love with a lady researcher (by this time he has reached genius level and is part of the research team), and they go to concerts and plays etc., etc. Alas it seems that the effects of the pill don't last on the rats. He studies this and concludes correctly that his will fall back into his former limited mental capacity too. It's a very sad beautiful story. But then he does not have PTSD and no one is deliberately trying to encourage brutality.

carol

Excellent comparison and analogy -- thanks, Carol.

That's perfect.

As I recall, not only did the pill wear off, it had a further degenerative effect, eroding the intelligence until it not only sunk below initial pre-pill levels but it also resulted in the death of the patient.

It was very sobering.