Mighty Mice
by MikeGene
[Check out the trailer for my book here]
Recently, scientists created a transgenic "supermouse." The researchers were studying the gene for phosphoenolpyruvate carboxylase (PEPCK-C), a metabolic enzyme that is expressed in the liver, kidneys, and adipocytes. Using standard techniques in genetic engineering and stem cell technology, they were able to express this gene is skeletal muscle with remarkable consequences:
The mouse can run up to six kilometres (3.7 miles) at a speed of 20 metres per minute for five hours or more without stopping. Scientists said that this was equivalent of a man cycling at speed up an Alpine mountain without a break. Although it eats up to 60 per cent more food than an ordinary mouse, the modified mouse does not put on weight. It also lives longer and enjoys an active sex life well into old age "“ being capable of breeding at three times the normal maximum age.
and
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.
The mighty mice also provide much food for thought. Consider some of the issues their existence brings to the table.
1. The researchers note, "It is remarkable that the over-expression of a single enzyme involved in a metabolic pathway should result in such a profound alteration in the phenotype of the mouse." Here is an example where the traits of aggression, hyperactivity, skeletal muscle histology, and even fecundity were altered, but not because of selection. They materialized, en masse, simply as a consequence of over-expressing a single metabolic enzyme in a tissue: "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." This takes us back to Fodor's point.
2. It is also interesting to note that the researchers were not trying to design a mighty mouse, they simply stumbled upon it while trying to better study this enzyme. In other words, the mighty mice exist because of intelligent design (all experiments are examples of intelligent design), yet the mice were not intended by intelligent design. This means design can be divorced from intent.
3. One has to wonder why there are no mighty mice in Nature. The genetic manipulation was simple. And the pay-off from increased aggression, physical stamina, and reproductive activity would appear to be useful in at least some contexts. So why have these mice failed to materialize in Nature?
4. Finally, there is the whole issue of bioethics. With advances in human embryonic stem cell technology, this modification could be easily applied to humans. How will society be changed if/when rich people start bearing physically superior humans who also happen to be more aggressive? In fact, if you think scifi, it's not hard to envision some dictatorial state out there who would view this research and think, "soldiers!"
Like I said, just some food for thought and discussion.
November 3rd, 2007 at 9:54 am
The mice are transgenic, a process generally not available to biological evolution in mammals.
Evolutionary processes are capable of exploring only a tiny sliver of possible adaptations. This is an essential point.
The mice are more aggressive than control mice, eat much more, and live longer. These traits may not necessarily be of evolutionary benefit in nature.
Increased levels of testosterone in humans will not only increase muscle mass, but increase hair growth in specific areas of the body associated with sexual dimorphism. Nearly all biological systems are highly interrelated as would be expected of an evolved system that uses cooption and adaptation as primary mechanisms.
Artisan, art, artifact. Design is not divorced from this intrinsic causality. That includes characteristics of the artifact, the art and of the artisan. Transgenic mice show clear signs of design. A pinch of this, and a dash of that.
Comment by Zachriel — November 3, 2007 @ 9:54 am
November 3rd, 2007 at 10:38 am
So, let's say we found superhungry supermice rampaging through New York City, attacking pets, and threatening small children. When we analyzed their genetics, we discover they are chimeras.
We would immediately suspect "human design". But we would then attempt to test this initial hypothesis by finding a causal link between the artifact (supermice), the art (transgenetics) and the artisan. To do this, we might examine the details of how the mice were created. (We might possibly find some natural process to account for the chimera, or extraterrestrials, but probably not.)
We might be able to trace back the lineage of the mice (mutations can leave a trail in the form of a nested hierarchy of descent) and the genetic manipulation might be a signature of certain nations or laboratory techniques. We would investigate how the mice were created, by whom, and why; testing each hypothesis against the evidence, then forming new and more specific hypotheses, and then testing those. And once determining a likely agent, we would then propose and test hypotheses concerning their capability and intent.
And let's say we find out it might have been an accident. But this doesn't eliminated intent. Indeed, in the ensuing trials, intent would be a critical issue. Negligence or malice?
Comment by Zachriel — November 3, 2007 @ 10:38 am
November 3rd, 2007 at 10:46 am
Hi Zachriel,
All these guy did was paste the PEPCK-C gene behind a skeletal muscle gene promoter. Since there are abundant transposons in the mammalian genome, it would seem the core process is available. But even this is not all that important, as the phenotype was elicited by a mere 100-fold increase in PEPCK-C expression. I would imagine there are many possible mutational pathways for elevating gene expression.
So there is an edge to evolution. What defines the edge?
Sure, that's why I said "it would appear to be useful in at least some contexts."
In the end, we are left wondering why the mighty mice don't exit in nature. You've hit on the obvious proposals "“ either a) the mutation did not occur or b) if it did occur, it was selectively disadvantageous. But these are guesses, not answers.
Sure. Yet what is interesting is how several integrated, individual traits appear as a saltation. If such a mutation did occur in nature, and was selected for, selection would be acting only as the final editor to spread the bundled aggregate that came into existence while the more substantial cause of the change would be intrinsic and biotic. In fact, if mighty mice were found in nature, it would not be hard to imagine the various adaptive scenarios that would be invoked to explain the incremental sculpting of these various traits by natural selection. What's more, those scenarios would generate testable hypotheses and science would be done.
Yes, but we are still left with the fact that these designers were not trying to design mighty mice. The mighty mice exist because of design, but they were not intended.
Comment by MikeGene — November 3, 2007 @ 10:46 am
November 3rd, 2007 at 11:03 am
In the one account, the researchers note:
Again, the researchers did not intend these mice into existence. They did not use their understanding of biochemical mechanisms of energy metabolism repatterning to predict the over-expression of PEPCK-C would result in mighty mice. On the contrary, mighty mice exist because of design and serendipity. It's because of the latter that they now have a model to go back and learn about the biochemical mechanisms of energy metabolism repatterning
Anyway, I have stuff to attend to today. But packaged in this one little mouse are interesting lines of thought about evolution, evolutionary mechanisms, front-loading, design, and bioethics (stem cell research, eugenics, etc). They are mighty in more than one way.
Comment by MikeGene — November 3, 2007 @ 11:03 am
November 3rd, 2007 at 11:27 am
They used a non-native gene.
Evolution generally works by incremental adaptation of existing structures. The vast majority of possible evolutionary pathways will never be explored, much less exploited.
And I provided a plausible reason. That inverts your original question to "Why would such mice materialize in Nature?"
As these mice are transgenetic, we *know* these particular mice would not evolve. As to whether some such traits might or might not have evolved, you are the one who is speculating. Increased energy needs may not be adaptive in a natural environment where food supplies can fluctuate dramatically (often due to rodent overpopulation). This is as reasonable as assuming that the ability to run a treadmill is necessarily adaptive.
And cooks don't always follow a recipe. A characteristic of humans is that they like to fiddle around. It's a trait. Artisans have traits. Arts have traits. Artifacts have traits. And there is a necessary causal link between the artisan, art and artifact.
Comment by Zachriel — November 3, 2007 @ 11:27 am
November 3rd, 2007 at 11:51 am
Zach:
Chimeras? Do normal mice not express the PEPCK-C enzyme? The article does not say where the gene came from, just that it was "highly active" – meaning (likely) that it came attached to a hyperactive promoter segment.
Do you have access to the research paper? I'd like to know if the gene and promoter sequence used came from some other 'super' critter, whether mice normally don't have this gene in their genome, or if the promoter was engineered and attached to the gene. It would make a large difference in whether or not such supermice could evolve naturally by mutations in their PEPCK-C genes' promoter sequence(s). Or by over-expression via epigenetic command.
If mice do have this gene in their genome, we would NOT know they were engineered. We'd assume they are mutants and that the mutations were in the expression of the gene – and that can be entirely epigenetic or it can be mutational. We might be able to see a design signature in the viral sequences used to insert the engineered sequences, but only if that technology was used as opposed to a more subtle technology using endogenous 'jumpers' to do the insertion.
Anyway, you talk of 'chimera' as if you do have access. Thanks for providing the details I request.
Comment by Joy — November 3, 2007 @ 11:51 am
November 3rd, 2007 at 12:09 pm
First sentence in thread, "Recently, scientists created a transgenic 'supermouse.'"
transgenic, being or used to produce an organism or cell of one species into which one or more genes of another species have been incorporated {a transgenic mouse}
J. Biol. Chem; Hakimi, et al
Over-expression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse
Comment by Zachriel — November 3, 2007 @ 12:09 pm
November 3rd, 2007 at 12:28 pm
Zach:
Okay. Questions…
1. Do mice not have the PEPCK-C gene in their genome?
2. What "different species" did they get the inserted sequences from?
3. Per the definition of "transgenic," could hybrids between different genus' of the same species be said to be transgenic if the extra genes are inserted using viral sequences, even though a natural hybrid could easily exist by simply crossing the organisms via in vitro fertilization and implantation?
Thanks again.
Comment by Joy — November 3, 2007 @ 12:28 pm
November 3rd, 2007 at 1:56 pm
Explain how this relates? I'm not following a recipe when I'm making lasagna. But that is my intented final product.
Explain how it relates, because it seems that you don't get it. As exemplified by the quoted comment.
Zack, would this be expected if the biological system was designed?
Comment by Doug — November 3, 2007 @ 1:56 pm
November 3rd, 2007 at 2:01 pm
Hi Zachriel,
Are you saying that the 3' sequence of the bovine growth hormone gene is responsible for the mighty mouse phenotype? You're missing the point. As I mentioned, all we need is some mutation that merely increases PEPCK-C levels in skeletal muscle 100-fold.
The keyword here is "˜generally', as a process that extends over 3-4 billions years might mean the exceptions could be key. How often would you estimate "generally" to be?
Why?
I agree. But it is only a plausible reason that functions, at best, as the start of a working hypothesis.
Mutation happens. In fact, Allen MacNeill lists 47 different sources of variation. Are you under the impression it would be impossible for one of these sources to cause the PEPCK gene to be over-expressed in mice in the wild?
No one said anything about these particular mice.
Yes, another hypothesis. But then again, increased physical stamina, activity, aggression, and reproductive rates might be adaptive in some context during millions of years on planet Earth.
Yet we are left with the historical fact that these designed mighty mice were not designed to be mighty mice.
Comment by MikeGene — November 3, 2007 @ 2:01 pm
November 3rd, 2007 at 4:10 pm
They do.
The chimeric gene includes human alpha-skeletal actin gene promoter linked to the PEPCK-C from the mouse, and a bovine growth hormone (bGH) gene. A fragment of the human gene promoter was also used as a hybridization probe.
Transgenic usually refers to artificial gene insertions, such as by DNA micro-injection. Natural hybridization between related species is not referred to as transgenic.
Comment by Zachriel — November 3, 2007 @ 4:10 pm
November 3rd, 2007 at 4:25 pm
Sometimes
cookschefs may experiment and then be surprised by their results. That doesn't mean they aren't cooking or applying their culinary art. Quite the contrary.If we were to design an entire structure from the foundation up, we would attempt to design it so we could adjust muscle tone without making hair sprout where it doesn't belong.
Design is far more flexible in many respects than evolutionary processes. But very complex artificial structures often show aspects of evolution. When such structures are accreted, they often exhibit scale-free architecture.
Comment by Zachriel — November 3, 2007 @ 4:25 pm
November 3rd, 2007 at 4:38 pm
Hi Zachriel. You wrote:
The capacity to integrate genomic sequences from one organism into another illustrates a point. We observe genomes from a preconceived perspective that assumes a historic development free of intentional directives. There could be clues of course that genome x is inconsistent with the genomic patterns of similar organisms but it would be difficult to distinguish with certainty whether an evolutionary process accounted for this as opposed to deliberate tinkering by an intelligent agent. This is particularly true when integrated sequences could mimic the effects of a mindless physical process.
Comment by Bradford — November 3, 2007 @ 4:38 pm
November 3rd, 2007 at 4:40 pm
BTW, Mighty Mouse was a good cartoon.
Comment by Bradford — November 3, 2007 @ 4:40 pm
November 3rd, 2007 at 4:55 pm
We would expect (approximately) scale invariant rates of change, but the individual changes would still be largely incremental.
Because evolution is limited to incremental changes and by its history. There has been quite a bit of research into genetic algorithms.
Well, I suppose it might be of some interest, but it merely represents a change in the natural metabolism for performance over efficiency.
More probable would be a gradient of expression. Perhaps this variation has already evolved and been tested by natural selection with some variation within extant populations.
We do know that these transgenic mice would not appear in nature.
So? Humans have various characteristics, including intent. And sometimes things don't always work out quite the way people expect them to. This is also a human trait.
Comment by Zachriel — November 3, 2007 @ 4:55 pm
November 3rd, 2007 at 5:02 pm
Zach:
Thanks for the info, Zach. So… a gene duplication could occur in the wild, could it not? And this could affect expression of the enzyme, could it not?
Hmmm… so there is increased expression of alpha-skeletal actin in the mice to increase expression of the enzyme? And last I checked, BGH is identical to HGH. Did the bovine hormone gene come with bovine expression promoters?
IOW, I don't know how identical mouse growth hormone genes are to bovine and human growth hormone genes, but I seem to recall something about all mammals having growth hormone genes. So it's not the actual enzyme gene that comes from another species, but the expression promoters, right?
We know that gene duplications happen in nature. We also know that genetic and epigenetic expression of genes can change dramatically due to sequence duplications or viral infections, or even horizontal transfer of genes and associated promoters. I am attempting to figure out why you are so sure supermice couldn't arise naturally.
I know the terminology. I am attempting to assess how actually "chimera" these supermice are. Chimera is a cross between, say, a fish and a human, a goat and a dragon, a horse and a human – your basic mythological critter humans have known since forever can't cross-breed in real life.
You've asserted that supermice can't arise naturally by any known evolutionary pathways, and it seems to me that could indeed happen. By several evolutionary pathways we already know about. I suspect this research holds great money-making potential for Big Pharma to get around the steroid rules in professional and amateur sports. We already know there's a huge market and they're rich enough to pay a lot. But that doesn't mean that all this fancy technology is 'evolutionarily' necessary. If the supermouse could have evolved naturally, it probably did (or will, according to your theory). Selection is what would determine its ultimate survival, as you've pointed out.
Comment by Joy — November 3, 2007 @ 5:02 pm
November 4th, 2007 at 5:53 pm
Fodor's point again?
Darwin had a point when he argued that the "unconscious" selections of the breeders were of great aggregate and cumulative effect and that is what he (and they) meant by "natural selection."
Seems to me the experiment cited demonstrates the principle in a way that is perfectly consistent with Darwin's conception.
More importantly (in this context) the experiment demonstrates that the principle of natural selection applies per force to design.
Comment by Rock — November 4, 2007 @ 5:53 pm
November 7th, 2007 at 11:05 am
I love this discussion. We have Zachriel arguing that a similar mutation is unlikely to occur naturally, and we have MikeGene pointing out that there are fairly simple mutational mechanisms that can generate complex new phenotypes like the "mighty mouse." Let's all remember that next time someone argues that random mutation can't generate new traits.
a few thoughts:
1. Mike suggested transposons as a way that similar changes could occur naturally. Amylase genes are an example of such an evolutionary event. IIRC, the human salivary amylase gene is derived from pancreatic amylase, with insertion of a transposable element that confers expression in salivary glands.
2. Why don't we see mighty mice in nature? In addition to the possibilities discussed above, a third possibility is that is has happened but we haven't found it. Laboratory mice are derived from a fairly small subset of wild populations, and as far as I know, no one is collecting wild mice and assaying their PEPCK expression. Any conclusions about the presence or absence of similar mutations in wild populations is premature.
3.Transgenic mice are, by definition, not chimeras. Chimeric mice contain two different genomes; some of their cells have genome A and some genome B. Transgenic mice contain a single genome, and all of their cells contain the transgene. That the transgene is cobbled together from different sources does not make the mouse chimeric. The first ("founder") generation of a new transgenic line may be "mosaic" if not all cells of the embryo incorporate the injected transgene, but subsequent generations are not.
4. IDers often like to point out ways that nature resembles design, but that equation can be turned on its head. Human design, in many ways, resembles natural processes. The comparison may tell us more about human designers than about any putative design in nature.
Comment by Nick — November 7, 2007 @ 11:05 am
November 7th, 2007 at 12:21 pm
New 'traits'? Way to be tepid.
So moving an already extant gene into another DNA region of functional genes is random? More so, that it shows that new traits can generate randomly?
With this particular situation were the scientists just slipping around the lab and tossing genes about capriciously?
Comment by Doug — November 7, 2007 @ 12:21 pm
November 7th, 2007 at 12:32 pm
Often? You know what ID stands for…. right?
Then:
Nick, how exactly does this show that 'notion' being turned on its head? Even if you had something to run with here, you'd still have to tackle the instances where design is apparent. You can't waive away all instances by falling back on, "remember, human design can resemble natural processes".
No it doesn't, because you're still left with the raw materials that were being moved around in attempts to induce some effect. It might say something about the mechanism of shifting genes that already exist and consequences that may occur, but it doesn't address the system as a whole.
What exactly are you arguing?
Anti-IDers often like to neglect the big picture.
Comment by Doug — November 7, 2007 @ 12:32 pm
November 7th, 2007 at 12:58 pm
Just to clarify my previous claims, these particular mice with the chimeric gene would not evolve naturally, but the trait itself might — and perhaps this variation has already evolved.
Comment by Zachriel — November 7, 2007 @ 12:58 pm
November 7th, 2007 at 2:43 pm
Doug:
So moving an already extant gene into another DNA region of functional genes is random
They certainly can be. Mikegene already pointed out one way.
More so, that it shows that new traits can generate randomly?
Of course it does.
Comment by Nick — November 7, 2007 @ 2:43 pm
November 7th, 2007 at 2:59 pm
What exactly are you arguing?
That this should be viewed as a cautionary tale for ID. As Mikegene points out, a fairly simple genetic change (shift in tissue specificity of a single gene product) produced a whole host of complex new traits in a single generation. In this case, the genetic change was engineered, though the consequences were wholly unintended. But, there are a whole host of simple mutational events that can produce similar results.
Comment by Nick — November 7, 2007 @ 2:59 pm
November 7th, 2007 at 3:39 pm
Are you equating 'unintended consequences' with random? Or the process used to achieve these consequences as random?
Also, are you assuming that something that occurs naturally is random opposed to designed?
Like, 'transposition occurs naturally, therefore it's random'.
Comment by Doug — November 7, 2007 @ 3:39 pm
November 7th, 2007 at 4:07 pm
Those were new traits? Or where they just enhancements of existing traits? If that's the case then just show me a few bird beak variations.
Okay, but unknown consequences were expected.
Where existing traits are enhanced?
Earlier you mentioned:
Regarding the simplicity of these mutational events…. exactly how simple are they?
Comment by Doug — November 7, 2007 @ 4:07 pm
November 7th, 2007 at 4:18 pm
Interesting example for the ID community, and it highlights the need for discussion about that edge everyone loves to talk about.
It also shows why I take the tact that any talk of intention in nature – presence or lack thereof – is filled with problems. We have a clear-cut situation here; scientists mess with a mouse's genes, resulting in mouse with some surprising features. Did the scientists design the mouse?
Well, yes, because their actions led to the resulting mouse.
Well, no, because they didn't foresee this resulting mouse.
Well, yes, because they expected to get some manner of 'different' mouse.
Well, no, because they didn't specify the mouse they wanted.
And imagine if the scientists decided to say, 'Oh, we foresaw this. We had a pet theory about what these changes would do to the mouse, and the results pretty much matched our expectations.' How do you deal with intention if the designer's statement is unavailable or deceptive? Or if their capabilities and general limits are unknown?
I don't think it's at all easy to do, and believe it may well be impossible to entirely discern.
Comment by nullasalus — November 7, 2007 @ 4:18 pm
November 9th, 2007 at 3:06 pm
Doug;
Are you equating 'unintended consequences' with random?
No
Or the process used to achieve these consequences as random?
Yes
Also, are you assuming that something that occurs naturally is random opposed to designed?
No.
Like, 'transposition occurs naturally, therefore it's random'.
No. Regardless of the origins of transposable elements (by design or undirected evolution), the process of transposition in a genome and the end results of transposition have no discernable pattern or order (i.e it can be described approximately as "random")
Comment by Nick — November 9, 2007 @ 3:06 pm
November 9th, 2007 at 3:15 pm
Doug:
Those were new traits? Or where they just enhancements of existing traits?
How, exactly, do you define the difference, and does it matter? Are there any "new" traits that distinguish humans from chimpanzees or just enhancements of existing traits?
Okay, but unknown consequences were expected.
So?
Where existing traits are enhanced?
Yes. I gave one example already, remember? Is salivary amylase an an enhanced trait or a new trait? Does it matter?
Regarding the simplicity of these mutational events"¦. exactly how simple are they?
What, mutational events that can alter the tissue specificity or expression level of a single gene (as in the mighty mouse)? As Mikegene said, "I would imagine there are many possible mutational pathways for elevating gene expression." That would include point mutations, insertions, deletions, etc. Basically the whole array of possible mutations could have that effect. Changing a single gene's expression pattern is well within the limits of microevolution that every critic says of course they believe.
What exactly are you trying to argue here?
Comment by Nick — November 9, 2007 @ 3:15 pm