From January 20, 2006, on the need to check the model-derived findings in non-model organisms.
There are pros and cons to the prevalent use of just a dozen or so species as standard laboratory models. On one hand, when a large chunk of the scientific community focuses its energies on a single animal, techniques get standardized, suppliers produce affordable equipment and reagents, experiments are more likely to get replicated by other labs, it is much easier to get funding, and the result is speedy increase in knowledge.
On the other hand, there are drawbacks. One is narrow focus which can breed arrogance. The worst offenders are people who work with rats. They rarely put the word “rat” in the title of the paper, and often it is not even found in the abstract, introduction and discussion of the paper. One has to dig through the materials and methods to find out, although if you know about this, the very fact that the species is not noted in the title is a dead giveaway that it is a paper about rats. Some of the papers dealing with humans also make the same mistake of not pointing out the species in the title.
One of the most important animal laboratory models for the study of genetics and molecular biology is the fruitfly Drosophila melanogaster. For a century now, almost all advances in knowledge in these areas came from fruitfly research first, then this knowledge got applied to other species, e.g., mice and humans.
Last month, a paper came out that highlights both the pros and the cons of the “model” approach. On one hand, all the techniques used in the work were developed by fruitfly researchers and are now standard methods, easily replicable between labs.
On the other hand, it shows how important it is to sometimes move away from the models and take a reality check: is the mechanism described in the model animal generalizable to other animals or is it idiosyncratic to the model. The papers dealing with models, including fruitflies (and of course rats!), often make the implicit claim for generalizibility (helps funding!) without data to support this claim.
The model of the molecular mechanism of the circadian clock has been initially developed in the fruitfly and massive research is still going on in this animal. It is regarded as a reference model in a way – models developed later in mice, bread-mold, Arabidopsis plant, Synechococcus bacterium, etc, are always compared to the fruitfly model to look for similarities and differences. In a sense, it is the ‘deafult’ model in chronobiology.
This paper took a look at a non-model animal and found out that the fruitfly mechanism does not appear to be even typical of other insects. Steven Reppert and colleages at the University of Massachusets Medical School are studying circadian system in Monarch butterflies (mainly in order to better understand migratory orientation).
In this paper they discover that the Monarch, unlike the fruitfly, has two copies of a clock gene called Cryptochrome (CRY). One copy (CRY1) is very similar to that of Drosophila. The other copy (CRY2), however, is much more similar to the mouse version of the gene.
In the brain pacemakers of fruitflies, CRY is not the core component of the clock but is a blue-light photoreceptor. In the peripheral tissues, the same gene may be a component of the clock (it represses expression of some other clock genes).
In mammals, CRY is not directly photosensitive, but is a core clock gene and a strong repressor of expression of other clock genes.
In Monarchs, as they show in this paper, CRY1 is responsive to light, just like the CRY of fruitflies. The CRY2, though, does not respond to light, but represses expression of other genes, just like the mouse CRY.
The best thing about this paper, though, is that the authors then went on and looked into genebanks of several other insect species and, lo and behold, discovered CRY2 in a few more insects, including moths, honeybees, mosquitoes and flour beetles. Actually, the honeybees and flour beetles appear to have ONLY the mammalian-like version of the gene.
They also plotted the phylogeny of the CRY gene, showing the genealogical relationship between the fruitfly-like and mouse-like versions of CRY, both versions presumably resulting from a gene duplication some time in the past (the apparent precursor, bacterial photolyase, appears as only one copy in E.coli and its function is in DNA repair).
The PERIOD protein does not enter the nucleus in the Chinese silkmoth and the Monarch butterfly. Thus, at least in these two insects, the molecular mechanism of the circadian clock must be different from that of the fruitfly. Presence of the mammalian-like version of the CRY gene, a potent gene repressor, suggests that it may be fulfilling the function of PER in these species. Thus, there appears to be more than one way to run a clock in an insect and the fruitfly mechanism is not as ‘standard’ at previously thought.
And working with Monarch butterflies must be great fun!
Haisun Zhu,1 Quan Yuan,1 Oren Froy, Amy Casselman, and Steven M. Reppert, 2005, The two CRYs of the butterfly.Current Biology, Vol 15, R953-R954, 6 December 2005.