Online Issues

Journal Vol 47(2)

Introduction

The Blind Men and the Elephant: What “Elephanomics” Can Teach “Muromics”

Katherine Wasson

“It was six men of Indostan, to learning much inclined, who went to see the elephant (though all of them were blind), that each by observation, might satisfy his mind...”

Written by American poet John Godfrey Saxe (1816-1887) in the mid-nineteenth century, “The Blind Men and the Elephant” is the relatively contemporary version of a parable that traces its roots back to the Asian subcontinent and Jainism, thought to be the religious precursor to Buddhism (Saxe 2005). In this parable, six blind scholars attempt to describe the outward appearance (or “phenotype”) of an elephant. The first blind man runs into the elephant's “sturdy side” and declares the animal a “wall.” The second feels the elephant's tusk “so very round and smooth and sharp” and pronounces the elephant to be a spear. The third feels the squirming trunk in his hands and proclaims the elephant to be a snake. The remaining three blind men declare the elephant as, respectively, a tree trunk (based on the leg), a fan (based on the ear), and a rope (based on the tail). And so . . .

“. . . these men of Indostan, disputed loud and long, each in his own opinion, exceeding stiff and strong, though each was partly in the right, and all were in the wrong . . .”

In many respects, this early human attempt at “elephanomics” serves as a cautionary tale to those who work in the realm of “muromics.”

A comparison between elephants and mice is more than just hypothetical fancy. Although disparate in size, both elephants and mice live in relatively stable, complex social groups referred to as clans or demes, respectively (Silver 1995; Sukumar 2003b). Communication between members of each group consists of sophisticated auditory and olfactory cues beyond the detection of Homo sapiens (D’Amato et al. 2005; Gunther 2004; Lin et al. 2005; Rasmussen and Greenwood 2003). Both are capable of considerable damage to human agricultural endeavors in the form of (elephant) rampages or (mouse) plagues (Caughley 1999; Seidensticker 1984). Indeed, “Smintheus” is one of several epithets given to the Greek god Apollo, who was worshipped in the second and first centuries BC as “mouse-catcher,” “destroyer of mice,” or “mouse god,” in hopes that crop destruction would befall enemies (Morse 1981). Likewise, both mammals have been domesticated for use by humans: Elephants as war machines, laborers, and modes of transportation; mice as fancy pets, tools to elucidate basic genetic mechanisms, and most recently as the principal model system for mammalian genomics research (Barthold 2002). Inbreeding has yielded a variety of coat colors and patterns in mice, and although not considered inbred, elephants display a range of hide colors from gray to brown to black to white and even, on occasion, albino. Last but not least, both have been deified, not to mention Disney-ified.

The “dare theory” of the origin of domestication suggests that the ability to control a fierce or large animal was a challenge to, and proof of, the physical prowess of individuals in ancient human civilizations. This theory also suggests how animals such as cattle, horses, buffalo, and elephants became associated with ceremonial and religious rituals (Baker and Manwell 1983). The domestication of elephants was first recorded 4000 yr ago in current day India (Sukumar 2003a). Shortly after domestication, elephant motifs and depictions of elephant armies began appearing in seals, sculptures, friezes, and other archeological finds. From this elephant culture arose the elephant-headed god Ganesha (also referred to as Ganesh, Gaņeśa, or GajĀnana, among his various names). Considered the most popular and worshipped god in modern Hinduism, he is also found in Buddhist and Jain traditions, and can be traced across Southeast Asia into China, Japan, and many of the Pacific Islands (Getty 1971; Narain 1991). Ganesha is worshipped as the “remover of obstacles” and “bestower of success,” and is considered the master of wisdom and intellect (Ganesha 2005; Getty 1971). He is depicted as a gentle yet powerful pot-bellied god, with the head of a one-tusked elephant and with as few as four or as many as 14 hands, each bearing a sacred symbol (Courtright 1985; Getty 1971; Figure 1).

Figure 1. Note the small mouse at the feet of the Hindu god Ganesha (www.disorg.org/bobculley/Indiad/Varanasi.html).

The foregoing description and interpretation of Ganesha are extremely simplistic because it is beyond the scope of this article to discuss the rich and varied symbolism associated with this Asian god. However, it is of interest to note that most descriptions of Ganesha also include a “muőka” at his feet (Getty 1971). Sanskrit for field mouse, thief, or destroyer of the crops, Ganesha's relationship with the mouse (sometimes depicted as a rat) signifies humility by keeping company with even the smallest of creatures. In addition, the mouse symbolizes the ability of the intellect to learn secrets even in the smallest of places (Ganesha 2005).

More often than not, genetically engineered mice possess “secrets” that even highly trained and talented scientists are sometimes too blind to see. This characteristic is particularly applicable when we declare that the manipulated gene of interest results in an apparent null phenotype. Worse yet, we might conclude that an obvious phenotype can only be the result of the manipulation of the gene of interest. We focus on one aspect of the “elephant” without appreciation for its other parts—appropriate construct design, genetic background of embryonic stem cells, inbred strain characteristics, degree of backcrossing, colony health status. And those aspects are only some of the pieces that need to be considered before the real phenotyping begins! The whole genetically manipulated mouse is truly greater than the sum of its “parts.”

This issue of ILAR Journal, devoted to “Phenotyping of Genetically Engineered Mice,” brings together several “learned scholars” from the field of murine transgenic technology, who—far from being blind—have much to share regarding the pitfalls and problems associated with properly evaluating the end-results of our genetic manipulations: The whole mouse. Starting with genetic background, Drs. Yoshiki and Moriwaki (2006) discuss some historical aspects of inbred mice and the implications that pedigree contributes to the phenotype of genetically engineered mice. Kulandavelu and colleagues (2006) discuss the effects of gene alteration on development, embryonic lethal gene alterations, and how to analyze these effects in something as small as the developing mouse embryo. The ethical and humane issues of creating and maintaining genetically modified mice are discussed by Drs. Brown and Murray (2006), who remind us that these issues must be addressed not only during the development but also during the production and experimental use of these mice. Next in the issue, Drs. Bailey, Rustay, and Crawley (2006) provide a multitiered approach for conducting behavioral phenotyping when experiments in which a manipulated gene of interest results in viable mice. The authors point out some of the pitfalls of environmental variability along the way.

Once a transgenic mouse has been created, it must be named correctly to convey consistent information to the scientific community. Dr. Linder (2006) addresses the importance of correct nomenclature and the source and effects of gene modifiers on phenotypic expression in genetically altered mice. Microbial status can also contribute to the phenotype. As Dr. Franklin (2006) reminds us, it is important to be aware that genetically engineered mice may have unique susceptibilities to or manifestations of microbial infections that will confound phenotypic interpretation. Importantly, no phenotyping is complete without a systematic gross anatomical and histopathological evaluation of all organ systems. As Dr. McKerlie (2006) cautions, this analysis must be performed in the context of mouse strain-dependent differences and incidental lesions. Completing the issue is Dr. Bolon's (2006) convenient compilation of the plethora of web-based sites available to assist in the phenotypic interpretation of genetically engineered mice.

Our hope is that the information contained within this ILAR Journal issue will aid in “removing obstacles” and will “bestow success” in our endeavors with these smallest of very useful creatures. With proper design and interpretation, it should be possible to create genetically engineered mice that have minimal heterogeneity of (background) genetic constitution; are analyzed in a standardized, systematic fashion; and are phenotypically stable with successive generations. Investigators currently spend an enormous amount of time and resources focusing first on a particular gene and only later on the resulting genetically manipulated mouse. However, to focus on the manipulated gene without considering the rest of the bits that make a whole mouse is to risk creating the murine equivalent of a “white elephant”—the droll and amusing etymology of which will be saved for another day . . . .

Katherine Wasson, D.V.M., M.S., Ph.D., Dipl. ACLAM, is an Assistant Clinical Professor in the Center for Comparative Medicine, and Staff Veterinarian at the Center for Laboratory Animal Science, University of California-Davis, Davis, California.

References

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