Thursday, 31 July 2014

Mice work may send you down the wrong path becuase of the mouse you use

Kraev A. Parallel universes of Black Six biology. Biol Direct. 2014 Jul 19;9(1):18

Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as "Black Six", stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign "essential" and "redundant" qualifiers to numerous genes, thus creating an internally consistent "parallel universe" of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of "strain-unawareness" will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of "parallel universes" should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor's strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.


To many of the readers of the blog will say who cares...mice don't get MS but to the few interested read on
With the the development of transgenic technology, where by we can add or delete genes to worms, fruitflies, mice and almost any other species has given us a revolution in the understanding of biology. 

The transgenic technology in mice including transgenic (addition of gene) and gene knockout (removal of gene) involves taking embryonic stem cells and blastocyst (a very young embryo) usually from two strains of mice.

The C57BL/6  (little black mice that like to bite you) and the 129 strains. After this the gene knockout or transgene is put onto the C57BL/6 strain background.

This is amongst the most resistant strain in relation to developing CNS autoimmunity, yet is becoming the most used for MS research because of the transgenic technology.

The C57BL/6 mouse develops CNS autoimmunity following sensitization to myelin oligodendrocyte glycoprotein. 

In the UK to work with transgenic or mutant mice, like Shiverer (MBP myelin mutant that shivers), rumpshaker (PLP myelin mutant that sakes its booty), Jimpy (PLP myelin mutant that shakes with time) you need a licence from the UK government and have to record these details. Howevert you don't with standard lab strains. Therefore many animals used in science go missing from statistics! 

However, the silly thing is many of these so called standard lab mice also have mutations and are mutants, but because they are not obvious mutants that effect obvious health issues they slip through the net. 

The SJL mouse used in MS research has a slow retinal degeneration and go blind slowly, the C3H strain goes blind quickly, the C57BL/6 mouse prefers to drink alcohol to water Others are deaf and maybe explains why they wont; do as they are told.  

Likewise many transgenics and knockouts have no effect on animal health, but they are recorded and this is why the number of animals used in research is growing...A major government mess-up..in relation to the fudge factor of animal statistics. 

If transgenics that had no deleterious effect were excluded from statistics the number of animals used in animal experiments would be falling. 

I say record them all and stop the fudge!..this will put pressure on people doing cell culture with meaningless experiments to justify what they do, because at the moment becuase they are not doing experiments on a living animal it is not recorded as an experiment if you kill the animal and use its tissues.

Anyway what this paper says is that C57BL/6 have natural mutations and that these may influence the effect of the introduction of another transgene or gene knockout.

This may make some genes seem important when they may not be that essential and may make you develop a strange "world view of biology". Therefore, ideally you would want to see the effect of the gene knockout in other strains to be convinced that the transgenic is having a consistent effect.

Even within the strain obtained from different commercial breeders there can be different mutations present. So it is important when reporting work to say where the animals come from. 

As we have said many times and reported (click) that EAE in C57BL/6 can be a bit dodgy and so it is well to remember this when you are reading the scientific literature as some things may not be that reproducible. You are looking at the effect of an experiment done many times in the genetically the same individual...just remember another mouse strain is just another individual and which one behaves like most humans is key

2 comments:

  1. "..the C57BL/6 mouse prefers to drink alcohol to water..."

    How do you know this? I can only imagine you have been doing extracurricular experiments with mice and a bottle of Jack in the wee hours of the night.

    ReplyDelete
    Replies
    1. Trouble is the mice never get their round in!

      Delete

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