This week journal Nature published a long overdue perspective where the authors argued that one of the critical, but frequently unaccounted reasons for pre-clinical research irreproducibility, was role of microbiome in shaping physiology and phenotype of laboratory animals.
Written by Thaddeus Stappenbeck & Herbert Virgin, this article explained that when designing and analyzing research data we need to consider effect of “metagenome” defined “as the sum of all host genes plus all organism genes of the microbiome.”
The term ‘microbiome’ refers to not only endogenous bacteria, clarified the authors, but “also the virome, archaea, the mycobiome (fungi) and meiofauna (for example, protists and helminths)”.
I am going to highlight some of the important messages from this article.
First, the authors start with acknowledgment that “nearly all aspects of human physiology, as well as model organisms such as mice, are influenced by the microbiome and metagenome”. This is especially true for conditions where immune system is heavily implicated, but even organs such as lung, pancreas, and brain are directly influenced by microbiome.
A gold standard for working with gene-modified organisms, argue the authors, is to use “littermate controls” to control the effects of the microbiome and metagenome. For example, the authors correctly pointed out that “the common practice of comparing wild type mice to mice with a mutation when the wild-type and mutant mice are bred separately or one group is purchased from an outside facility” is totally flawed and no self-respected research investigator or science journals should publish results obtained from such sloppy experiments. Use of littermate controls is not a new concept and many publications specifically mention such controls, but it must be a mandatory requirement for gene-modified animal experimentation going forward.
Another important recommendation, the authors say, would be to conduct key experiments “in multiple animal facilities in order to draw firm conclusions about the generality of a role of host and/or microbiome genes in a phenotype.” This is akin to clinical trials on humans that “relies on multi-centre trials as its gold standard for treatment efficacy”.
I personally fully support the recommendations proposed in this article because they are sound observations derived from analysis of decade-long scientific experimentation.
Of course, implementation of these rules would be expensive and time-consuming. But without it, vast number of experiments are totally wasted to begin with, not to mention millions of lab animals sacrificed for no good cause. I will go even further and say that it is moral and ethical obligation for every scientist to do the best he/she can to minimize undue experimentation on live animals.
Finally, one way to accomplish such transformation, funding agencies and scientific journals should demand higher standards for “practices and controls for mouse experiments”.