Mice are the workhorses of biomedical research, having long ago replaced guinea pigs. Laboratory mice are selectively bred versions of the ordinary house mouse (Mus musculus). There are many genetically distinct versions of laboratory mice, called lines, bred for particular research purposes, say, a tendency for epileptic seizures, or obesity. Once such a line is established, the mice are inbred for many generations, to the point that all members of a line are virtually genetically identical, a condition called isogenic.
For research purposes, creating isogenic lines is often the first step because any genetic variation complicates the research results. But variation in the environmental conditions to which these isogenic mice are subjected, also complicates things. So great effort is made to make the laboratory environments as identical as possible. For the purposes of biomedical research, the goal is genetically identical mice reared in identical environments.
To attain environmental uniformity, international rules have been established that specify precisely the environmental conditions in which any lab mouse is raised, the size of the cage, the amount of litter material in which to burrow, the daily intake of food and water, to name just a few variables that are stipulated.
Despite these heroic efforts to create uniform (identical) lines of lab mice, the isogenic mice remained recalcitrantly variable. This scandalous variability was long swept under the biomedical rug, dismissed as noise, until a German biologist, K. Gartner, took it upon himself to systematically investigate this variation over the course of several decades.
He started with body size. Gartner carefully documented what he had already casually observed: truly astounding variation in body size that could not be attributed to either genomic or environmental factors. He referred to the source of this variation as the third component, the other two being genes and environment. But what is the nature of this third component? It is clearly related to what Sewall Wright called intangible variation, which, recall, he likened to chance.
Next, Gartner compared the variation in body size of his isogenic mice to that of outbred (genetically diverse) mice, when both groups were reared in enriched environments, in which the living space was complexly structured and enlarged. The most important element of the environmental enrichment was social. The mice were reared in groups. It seems obvious that under these conditions the outbred mice would evidence much greater body size variation than the isogenic mice. Surprisingly, though, the amount of body size variation in the outbred and isogenic mice was about the same.
More recently, a group of German investigators, led by Gerd Kempermann, extended Gartner’s research on isogenic mice. They created highly enriched environments in large enclosures for their mice to explore freely. They then monitored each individual mouse’s activities, particularly the degree to which they engaged in exploration.
They found lots of individual differences in exploratory behavior; some mice were highly exploratory, some not at all keen on investigation. Interestingly, those that were at the high end of exploratory behavior exhibited more new neurons in the hippocampus than those that were less venturesome. The hippocampus is thought by many to be the part of the brain most involved in spatial navigation, though that is but one of many of its memory-related functions. In any case, the experience-driven brain changes are noteworthy, and we will return to them later in this book.
Perhaps related to the new hippocampal neurons, the behavioral differences between the explorers and non-explorers increased with age, that is, the individual differences in exploratory behavior became magnified over time. It seems there is something of a positive feedback loop at work in that regard. The initial difference in the inclination to explore causes a change in the brain that reinforces the individual differences in exploration, inducing further brain divergence, and so on. This dynamic—the amplification of an initial random difference throughout life—will be a common theme in this book. The source of the initial random difference are developmental instabilities in early development. I will explore the molecular and cellular nature of these instabilities later but for now it will be helpful to obtain an intuitive grasp of what, exactly, is meant by “developmental instability”.
Why Both Hands Are fingerprinted
The most universally recognized products of developmental instability is called fluctuating asymmetry, which refers to differences between the left and right sides of a single organism.
Most animals are bilaterally symmetrical. That is, if you draw a line down the middle the left and right sides are symmetrical. But never perfectly so. Left-right symmetry is an ideal that is never met in nature. Instead, upon close examination, the left and right sides of any animal always differ in a host of ways.
Let’s consider humans as exemplars of bilateral symmetry. Chances are the teeth on the left side of your mouth are not mirror images of those on your right and never were. Same goes for your bones, including those on your face. That is why the vain among us want to be photographed from only one (“the good”) side. One way to identify faces (or breasts) that have experienced significant plastic surgery is that upon close inspection they look unnaturally symmetrical. Plastic surgeons can’t help themselves in that respect, compulsively compensating for randomness.
Of more practical import are fingerprints. In a world without developmental randomness, both hands would not need to be fingerprinted for identification purposes. You could use a mirror image of either the left or right hand. But in this world, the prints from, for example, your thumbs, are different. That’s also true of palm prints. Even prints made from the tip of your nose would be left-right asymmetrical. (Nose prints are actually used for identification purposes in cattle, which of course lack fingers and palms.) The dermal ridges that comprise your fingerprints, palm prints and nose prints, develop during weeks 12-14, in utero, so the environment is not a factor in their divergence. It’s down to developmental randomness alone.
Developmental randomness is ubiquitous, inherent in all biological processes. Of particular note, random developmental variation is an irreducible source of individuality that transcends genetic and environmental uniformity.