First person – Patricia Shaw · The use of mouse models to study the detailed complexities of...
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FIRST PERSON First person – Patricia Shaw First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Patricia Shaw is first author on ‘Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome’, published in DMM. Patricia is a PhD student in the lab of Tarik Haydar at Boston University School of Medicine, USA, researching the underlying genetic and cellular mechanisms that contribute to brain development, and investigating how these processes are altered in diseases and disorders, such as Down syndrome, in order to identify novel targetable approaches for therapeutics. How would you explain the main findings of your paper to non-scientific family and friends? In order to fully understand how the brain is changed in Down syndrome, we rely on mouse models that allow us to look more closely at the genetic, molecular, cellular and functional components that contribute to intellectual disability in people with Down syndrome. However, in order for these models to be useful, they must display disease-relevant characteristics that resemble what we see in people with Down syndrome. Our findings show that the most commonly used mouse model, Ts65Dn, does not reliably display Down syndrome-like alterations in neurodevelopment and behaviour, highlighting a major limitation of its use. We investigated how brain development, structure and function are changed during gestation, as well as throughout adulthood in Ts65Dn mice, and found that, depending on which generation of Ts65Dn is studied, results are subject to variability. We detail factors that could be contributing to this, including genetic diversity due to the background strain, as well as selective breeding practices. Additionally, we outline steps researchers should take to address the problem of variability within their own studies. Our work here represents the first longitudinal cohort-based comparison of Ts65Dn across time and challenges the use of Ts65Dn as an effective model for studying Down syndrome. This is important as there are currently no therapeutics available for people with Down syndrome to help curtail the cognitive deficits. These lack of treatments could be due to the widespread use of Ts65Dn in developing and testing therapies. “Our findings show that the most commonly used mouse model, Ts65Dn, does not reliably display Down syndrome- like alterations in neurodevelopment and behaviour, highlighting a major limitation of its use.” What are the potential implications of these results for your field of research? The Ts65Dn mouse model has been a cornerstone of Down syndrome research since its development in 1990, and discoveries made using this model helped to expand our understanding of the neuropathophysiology of Down syndrome. However, our findings suggest that the Ts65Dn model is subject to variability and phenotypic drift that may limit the use of this model for studying Down syndrome. The various drawbacks of the Ts65Dn model have been known for quite some time but have never been experimentally assessed or discussed before now. This study confronts the long-standing beliefs and assumptions in the field, and encourages other researchers to critically evaluate the future use of Ts65Dn for studying Down syndrome. Although our research has looked at the Ts65Dn model specifically, the problems we have identified could be present in other mouse models of disease as well. We hope our findings presented here highlight the need for the robust and rigorous assessment of animal models if they are to be responsibly used for translational research. What are the main advantages and drawbacks of the model system you have used as it relates to the disease you are investigating? The use of mouse models to study the detailed complexities of human diseases is necessary to advance the development of Patricia Shaw Patricia Shaw’s contact details: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA. E-mail: [email protected] This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 © 2020. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2020) 13, dmm047076. doi:10.1242/dmm.047076 Disease Models & Mechanisms
Transcript of First person – Patricia Shaw · The use of mouse models to study the detailed complexities of...
FIRST PERSON
First person – Patricia ShawFirst Person is a series of interviews with the first authors of aselection of papers published in Disease Models & Mechanisms,helping early-career researchers promote themselves alongside theirpapers. Patricia Shaw is first author on ‘Longitudinal neuroanatomicaland behavioral analyses show phenotypic drift and variability in theTs65Dn mouse model of Down syndrome’, published in DMM.Patricia is a PhD student in the lab of Tarik Haydar at BostonUniversity School of Medicine, USA, researching the underlyinggenetic and cellular mechanisms that contribute to braindevelopment, and investigating how these processes are altered indiseases and disorders, such as Down syndrome, in order to identifynovel targetable approaches for therapeutics.
How would you explain the main findings of your paper tonon-scientific family and friends?In order to fully understand how the brain is changed in Downsyndrome, we rely on mouse models that allow us to look moreclosely at the genetic, molecular, cellular and functionalcomponents that contribute to intellectual disability in people withDown syndrome. However, in order for these models to be useful,they must display disease-relevant characteristics that resemble whatwe see in people with Down syndrome. Our findings show that themost commonly used mouse model, Ts65Dn, does not reliablydisplay Down syndrome-like alterations in neurodevelopment andbehaviour, highlighting a major limitation of its use. Weinvestigated how brain development, structure and function arechanged during gestation, as well as throughout adulthood inTs65Dn mice, and found that, depending on which generation ofTs65Dn is studied, results are subject to variability. We detailfactors that could be contributing to this, including genetic diversitydue to the background strain, as well as selective breeding practices.Additionally, we outline steps researchers should take to address theproblem of variability within their own studies. Our work hererepresents the first longitudinal cohort-based comparison ofTs65Dn across time and challenges the use of Ts65Dn as aneffective model for studying Down syndrome. This is important asthere are currently no therapeutics available for people with Downsyndrome to help curtail the cognitive deficits. These lack oftreatments could be due to the widespread use of Ts65Dn indeveloping and testing therapies.
“Our findings show that the mostcommonly used mouse model, Ts65Dn,does not reliably display Down syndrome-like alterations in neurodevelopment andbehaviour, highlighting a major limitationof its use.”
What are the potential implications of these results for yourfield of research?The Ts65Dnmousemodel has been a cornerstone of Down syndromeresearch since its development in 1990, and discoveries made usingthis model helped to expand our understanding of theneuropathophysiology of Down syndrome. However, our findingssuggest that the Ts65Dnmodel is subject to variability and phenotypicdrift that may limit the use of this model for studyingDown syndrome.The various drawbacks of the Ts65Dn model have been known forquite some time but have never been experimentally assessed ordiscussed before now. This study confronts the long-standing beliefsand assumptions in the field, and encourages other researchers tocritically evaluate the future use of Ts65Dn for studying Downsyndrome. Although our research has looked at the Ts65Dn modelspecifically, the problems we have identified could be present in othermousemodels of disease as well.We hope our findings presented herehighlight the need for the robust and rigorous assessment of animalmodels if they are to be responsibly used for translational research.
What are the main advantages and drawbacks of the modelsystem you have used as it relates to the disease you areinvestigating?The use of mouse models to study the detailed complexities ofhuman diseases is necessary to advance the development of
Patricia Shaw
Patricia Shaw’s contact details: Department of Anatomy and Neurobiology, BostonUniversity School of Medicine, Boston, MA 02118, USA.E-mail: [email protected]
This is an Open Access article distributed under the terms of the Creative Commons AttributionLicense (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use,distribution and reproduction in any medium provided that the original work is properly attributed.
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© 2020. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2020) 13, dmm047076. doi:10.1242/dmm.047076
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treatments. Mouse models provide a level of experimentalmanipulation that is necessary to uncover many of thefundamental components of disease that cannot be achievedwith human studies alone. However, our research emphasizes themajor drawbacks of using Ts65Dn mice, which include thegenetic makeup and breeding of the mice that might contribute tothe phenotypic variability and drift within the line. We hope thatwith advances in engineering technology, new mouse models canbe generated that more closely resemble the genetic andphenotypic makeup of Down syndrome, and can be used in
parallel with other model systems, such as patient-derived inducedpluripotent stem cells, to elucidate the underlying mechanisms ofDown syndrome.
Describe what you think is the most significant challengeimpacting your research at this time and how will this beaddressed over the next 10 years?Our understanding of the underlying mechanisms that contribute tothe hallmark features of Down syndrome has greatly increased overthe years. However, there are still no options available for peoplewith Down syndrome in terms of treatments and therapies toimprove their quality of life. Changing this will require more reliableand robust platforms with which we can study Down syndrome,greater collaboration between researchers in academia and industry,and increased transparency that will allow quality research to moveforward. The number of clinical trials for Down syndrome,specifically the neurological consequences, is very low and wehope that in the coming years, with innovative advances in modeldevelopment and partnerships with the pharmaceutical industry, wewill be able to identify targetable approaches to treating Downsyndrome that will provide individuals with a great quality of life.
What’s next for you?I enjoy studying neuroscience and the challenge that comes withtrying to understand the beautiful intricacies of the brain. I lookforward to continuing in this line of research and contributing towork that will benefit people who are affected by neurologicaldiseases and disorders.
ReferenceShaw, P. R., Klein, J. A., Aziz, N. M. and Haydar, T. F. (2020). Longitudinal
neuroanatomical and behavioral analyses show phenotypic drift and variability inthe Ts65Dn mouse model of Down syndrome. Dis. Model. Mech. 13,dmm046243. doi:10.1242/dmm.046243
Maturing oligodendrocyte cultured in vitro from Ts65Dn mouse brainsstained for RmAb.
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FIRST PERSON Disease Models & Mechanisms (2020) 13, dmm047076. doi:10.1242/dmm.047076
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