Of mice and men

Thomas Erren and colleagues point out that studies on light and circadian rhythmicity in humans have their own interesting pitfalls, of which all researchers should be mindful.We would like to compliment, and complement, the recent Opinion in EMBO reports by Stuart Peirson and Russell Foster (2011), which calls attention to the potential obstacles associated with linking observations on light and circadian rhythmicity made on nocturnal mice to diurnally active humans. Pitfalls to consider include that qualitative extrapolations from short-lived rodents to long-lived humans, quantitative extrapolations of very different doses (Gold et al, 1992), and the varying sensitivities of each species to experimental optical radiation as a circadian stimulus (Bullough et al, 2006) can all have a critical influence on an experiment. Thus, Peirson & Foster remind us that “humans are not big mice”. We certainly agree, but we also thought it worthwhile to point out that human studies have their own interesting pitfalls, of which all researchers should be mindful.Many investigations with humans—such as testing the effects of different light exposures on alertness, cognitive performance, well-being and depression—can suffer from what has been coined as the ‘Hawthorne effect''. The term is derived from a series of studies conducted at the Western Electric Company''s Hawthorne Works near Chicago, Illinois, between 1924 and 1932, to test whether the productivity of workers would change with changing illumination levels. One important punch line was that productivity increased with almost any change that was made at the workplaces. One prevailing interpretation of these findings is that humans who know that they are being studied—and in most investigations they cannot help but notice—might exhibit responses that have little or nothing to do with what was intended as the experiment. Those who conduct circadian biology studies in humans try hard to eliminate possible ‘Hawthorne effects'', but every so often, all they can do is to hope for the best and expect the Hawthorne effect to be insignificant.Even so, and despite the obstacles to circadian experiments with both mice and humans, the wealth of information from work in both species is indispensable. To exemplify, in the last handful of years alone, experimental research in mice has substantially contributed to our understanding of the retinal interface between visible light and circadian circuitry (Chen et al, 2011); has shown that disturbances of the circadian systems through manipulations of the light–dark cycles might accelerate carcinogenesis (Filipski et al, 2009); and has suggested that perinatal light exposure—through an imprinting of the stability of circadian systems (Ciarleglio et al, 2011)—might be related to a human''s susceptibility to mood disorders (Erren et al, 2011a) and internal cancer developments later in life (Erren et al, 2011b). Future studies in humans must now examine whether, and to what extent, what was found in mice is applicable to and relevant for humans.The bottom line is that we must be aware of, and first and foremost exploit, evolutionary legacies, such as the seemingly ubiquitous photoreceptive clockwork that marine and terrestrial vertebrates—including mammals such as mice and humans—share (Erren et al, 2008). Translating insights from studies in animals to humans (Erren et al, 2011a,b), and vice versa, into testable research can be a means to one end: to arrive at sensible answers to pressing questions about light and circadian clockworks that, no doubt, play key roles in human health and disease. Pitfalls, however, abound on either side, and we agree with Peirson & Foster that they have to be recognized and monitored.     

Synchronization between beating cilia.

A novel quantitative parameter is proposed to define and measure the degree of synchronization between two small ciliary areas. These areas can be close to or far from one another. The Pearson correlation factor is used to define the degree of synchronization by a single number. This approach is based on a computerized, dual photoelectric method which simulataneously measures the scattered light from two small areas on the ciliary epithelium or its tissue culture. The measurements were performed on tissue culture from frog's palate epithelium. It was found that: (a) the degree of synchronization decreases, as a function of distance; (b) the correlation is fairly high even at relatively large separations, when measured on the same patch; (c) on a given patch the synchronization factor is independent of the direction of the metachronal wave; (d) close disconnected ciliary cells exhibit fairly high correlation; (e) disconnected randomly choosen ciliary cells at relatively large separation distances exhibit relatively low correlation, smaller by a factor of 2 than the correlation factor at the same distances when measured along the metachronal wave; (f) the average frequencies' ratio and the metachronal wavelength can be used as first-order indicators of ciliary synchronization; (g) there is a spread of metachronal wavelengths even over a single well-organized patch.     

Y chromosome variation of mice and men

DNA sequences from the nonrecombining portion of the Y chromosome were compared with autosomal and X-linked sequences from mice and humans to test the neutral prediction that ratios of polymorphism to divergence are the same for different genes. Intraspecific variation within Mus domesticus was compared with divergence between M. domesticus and Mus caroli for Sry, a region 5' to Sry, and four X-linked genes, Hprt, Plp, Amg, and Glra2. None of these comparisons revealed significantly reduced variation on the Y chromosome. Intraspecific variation within humans was compared with divergence between humans and chimpanzees for three Y-linked loci (Zfy, the YAP region, and the Sry region), seven X- linked loci (Il2rg, Plp, Hprt, Gk, Ids, Pdhal, and Dmd), and the beta- globin locus on chromosome 11. In these comparisons, the observed level of variation on the human Y chromosome was slightly lower than expected, but was significantly lower in only one case (Sry region vs. Dmd). These results suggest that the levels of variability on the Y chromosome in mice and humans are close to expected values given the effective population size and mutation rates for these loci. There is at most only a modest reduction in variability that may be attributed to natural selection (either genetic hitchhiking or background selection).      

When cilia go bad: cilia defects and ciliopathies

Defects in the function of cellular organelles such as peroxisomes, lysosomes and mitochondria are well-known causes of human diseases. Recently, another organelle has also been added to this list. Cilia--tiny hair-like organelles attached to the cell surface--are located on almost all polarized cell types of the human body and have been adapted as versatile tools for various cellular functions, explaining why cilia-related disorders can affect many organ systems. Several molecular mechanisms involved in cilia-related disorders have been identified that affect the structure and function of distinct cilia types.