3 ms·

This is comment is needlessly inflammatory and is not informative of how biomedical research is conducted. First, it’s important to point out to the lay reader

This is comment is needlessly inflammatory and is not informative of how biomedical research is conducted. First, it’s important to point out to the lay reader that the reason researchers frequently use mice strains in the first place is not “to cut corners”; it as an attempt to manage the incredible variability inherent in biology, especially when one moves to complex systems like living mammals. If the mice in a study have the same genetic background, then it far more likely the effect under study can be observed, and not otherwise buried in the noise as it would if wild mouse strains were used. Using a common mouse strains helps compare studies across different areas of research too. It’s the same reason why so much research is done using HeLa cells. Your post gives the lay reader the impression the researchers were being irresponsible; rather than just using a common strain to demonstrates their point. Second, you apparently weren't being too much of a "hard core' reader (or least explainer to the lay reader) because if you had you would highlight this bit in the Methods section that list the multiple mouse models used: 1. C57BL/6J 2. Gabrd-/- mice on a C57BL/6J background 3 Pvalb-IRES-Cre mice 4. B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J 5. ApoE4-TR:5xFAD mice These are not stock C57/Bl6 mice and do carry specific mutations. Finally, as the second half of your post acknowledges and the paper demonstrates, different strains are being used in AD research. There are entire centers dedicated to developing specific mouse strains, many with humanized genes, to attempt to capture specific mutations known to be present in humans, some on C57 background, but many others that are not. Jackson labs has developed several as has several other prominent groups in the field [1]. [1] https://www.jax.org/news-and-insights/2024/july/researchers-are-closing-in-on-a-mouse-model-for-alzheimers-research https://www.jax.org/news-and-insights/2024/july/researchers-...; https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.056498 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz... Lastly, I have no idea if this paper is any good.

robwwilliams 2y ago
Yes that paper is great. My comment was directed more at those criticizing mouse models than this particular paper. Techniques are lovely; results are hopeful. But I need to see this generalized before talk about translation in HN or elsewhere, or yet another discussion about lousy mouse models and the necessity of “in mice” in every title. From my point of view my comments were needfully and purposefully inflammatory to break the fever. Hard to believe, but scientists (myself included) can be exceedingly stubborn and resistant to necessary paradigm changes such as incorporating genetic diversity into studies. The principal reason mouse models are critiqued in HN and at NIH is that they are regarded as translationally ineffective. Many of my colleagues often say that mice are poor models of human diseases X, Y, and Z. To be blunt they usually do not really know what they are talking about. What they mean is that B6 is a bad model. But B6 is regarded as THE MOUSE. Is any one human a great model of human traits and diseases? Why do we allow this for experimental work. It truly is N=1. We also have a community-wide fixation on moving all mutations and transgenes on to the glorious or notorious C57BL/6 strain. Without background genetic variation we have fragile models that often do not generalize across strains of mice. “Our current models are mannequins we dress up with sparse data from a few experiments and send down a publication catwalk, praying they don't toddle and trip. What we need are powerful, diverse, and well dressed models that can navigate a landscape, not a catwalk. As a community we have not begun to grapple with this issue, but one certainty is that we will require extraordinarily well structured data sets for humans and for experimental models, to make accurate predictions.” from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751652/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751652/ As to your request that I review the Methods section more carefully — done. And I do not see any errors of commission on my part. All of the lines that you list above are C57BL/6J (B6) or congenic mice on a nearly pure B6 background. The first is the reference B6 inbred strain. #2 is a B6 congenic (B6.xxx) #3: The Pvalb mouse is at least a five-generation backcross to B6, and therefore also nearly congenic. This line is likely to have been backcrossed for more generations to B6 at JAX; to the point that it is likely to be >95% B6. #4: The nomenclature of this line clearly states that it is a B6 congenic. The typical minimum number of backcrosses to list as a cogenic is 10, but this is a popular line of mouse and may have been backcrossed for even higher purity. #5: Finally, the APOE4-5XFAD mice are 97% C57BL/6J. “…mice homozygous for APOE4, and hemizygous for the 5XFAD transgenes, on a background strain 97% C57Bl/6J and 3% SJL; mice were then inbred between 5xFAD+ and 5xFAD- resulting in littermates E4+/+:FAD+ and E4+/+:FAD−.”

robwwilliams 2y ago

Yes that paper is great. My comment was directed more at those criticizing mouse models than this particular paper. Techniques are lovely; results are hopeful. But I need to see this generalized before talk about translation in HN or elsewhere, or yet another discussion about lousy mouse models and the necessity of “in mice” in every title. From my point of view my comments were needfully and purposefully inflammatory to break the fever. Hard to believe, but scientists (myself included) can be exceedingly stubborn and resistant to necessary paradigm changes such as incorporating genetic diversity into studies. The principal reason mouse models are critiqued in HN and at NIH is that they are regarded as translationally ineffective. Many of my colleagues often say that mice are poor models of human diseases X, Y, and Z. To be blunt they usually do not really know what they are talking about. What they mean is that B6 is a bad model. But B6 is regarded as THE MOUSE. Is any one human a great model of human traits and diseases? Why do we allow this for experimental work. It truly is N=1. We also have a community-wide fixation on moving all mutations and transgenes on to the glorious or notorious C57BL/6 strain. Without background genetic variation we have fragile models that often do not generalize across strains of mice. “Our current models are mannequins we dress up with sparse data from a few experiments and send down a publication catwalk, praying they don't toddle and trip. What we need are powerful, diverse, and well dressed models that can navigate a landscape, not a catwalk. As a community we have not begun to grapple with this issue, but one certainty is that we will require extraordinarily well structured data sets for humans and for experimental models, to make accurate predictions.” from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751652/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751652/ As to your request that I review the Methods section more carefully — done. And I do not see any errors of commission on my part. All of the lines that you list above are C57BL/6J (B6) or congenic mice on a nearly pure B6 background. The first is the reference B6 inbred strain. #2 is a B6 congenic (B6.xxx) #3: The Pvalb mouse is at least a five-generation backcross to B6, and therefore also nearly congenic. This line is likely to have been backcrossed for more generations to B6 at JAX; to the point that it is likely to be >95% B6. #4: The nomenclature of this line clearly states that it is a B6 congenic. The typical minimum number of backcrosses to list as a cogenic is 10, but this is a popular line of mouse and may have been backcrossed for even higher purity. #5: Finally, the APOE4-5XFAD mice are 97% C57BL/6J. “…mice homozygous for APOE4, and hemizygous for the 5XFAD transgenes, on a background strain 97% C57Bl/6J and 3% SJL; mice were then inbred between 5xFAD+ and 5xFAD- resulting in littermates E4+/+:FAD+ and E4+/+:FAD−.”