With a wealth of experience in utilising animal models, including a 3R prize for reduction of animal use in 2016, Dr Frances Wiseman joins the UK DRI at UCL as new programme leader for animal models. We caught up with Frances to discuss her current research interests, why animal models are still critical to dementia research and how she will be supporting the whole institute in improving resource facilities in this area.
Q: Hi Frances, please could you introduce yourself and tell us a little bit about your background?
A: I am originally from the UK but before starting University I worked in a Biotech start-up in Vancouver, as the Lab manager’s assistant for 6-months; doing all the least popular jobs.
I have a BSc from the University of Oxford and completed my PhD in Edinburgh. Following lab rotations I picked a project investigating how post-translational modification alters the transmission of Prion disease between species, using knock-in gene-targeted mouse models. After graduating I decided to field-switch to Down syndrome with the long-term goal of developing a basic research programme to understand the early onset of dementia in people with the condition. I joined the group of Elizabeth Fisher (UCL) and Victor Tybulewicz (Francis Crick Institute), who had just published a highly novel trisomy 21 mouse model. My first job was to genetically characterise the model, in particular chromosome 21 gene content beyond APP. Most recently I took up an ARUK Senior Fellowship in autumn 2018.
In 2011 I helped to found the LonDownS Consortium - multidisciplinary group who have a common interest in understanding and developing treatments for early-onset dementia in people with Down Syndrome (DS).
Q: Alongside your new role, you will be carrying out a research programme looking at Alzheimer’s disease (AD) in individuals with Down Syndrome (DS). Can you share the goals for this project?
A: People who have Down syndrome are at a greatly increased risk of developing Alzheimer’s disease, with all exhibiting extensive build-up of both amyloid-plaques and neurofibrillary tangles by 50 and around two-thirds developing dementia by 60. Down syndrome is caused by an extra copy of human chromosome 21 which encodes ~230 genes including APP. Possessing three copies of this gene is known to be central to the development of early onset AD in people who have DS, however, my research is particularly focused on the triplication of other chromosome 21 genes modulating neurodegenerative pathways; which genes have an effect on disease development in DS and how.
Q: Some of the blame for recent trial failures in the dementia field have been attributed to poor translation between animals and humans. With the development of new technologies and methods into relevant alternatives, including patient-derived induced pluripotent stem cells (iPSCs), what do you think animal models can still contribute to advance our understanding of dementia?
A: Dementia is a disease of arguably the most complex organ of the body; both in terms of diversity of cell-types and complexity of function. Epidemiology and genetics strongly indicate that cardiovascular, metabolism and immune systems play important roles in disease development. Currently iPSCs cannot model the full complexity of the brain or whole organism physiology. Particularly, how the brain interacts with the rest of the body. In mice we can do this and moreover understand how neurodegeneration affects cognition and behaviour. Thus mice remain critical to fully understand dementia mechanisms and for proof-of principle intervention studies.
However clearly mice aren’t mini-humans. The two species are separated by ~75 million year of evolution and it’s important to understand that this evolutionary divergence differs between biological systems because of differences in selection. Some human biological processes are very well conserved in mice and some are not. Although we have the huge advantage of being able to vary the genetic background of mice to tackle a particular research question, it is also important to bear-in mind that some models used in dementia research display phenotypes that are not related to underlying disease mechanism but because of the genetic composition of the model.
The major take home is to pick the right model (or ideally models) for your question, understand that model's limitations and then rigorously investigate those caveats by employing a different approach. Mouse models will continue to be integral to basic research into the mechanisms of and the development of new treatments for dementia.
Q: Your time will be split between UCL and MRC Harwell. What benefits will the latter bring to the UK DRI and are there any other collaborations you are hoping to forge?
A: The UK DRI Animal Models Programme will be based at the Mary Lyon Centre at MRC Harwell alongside the MRCs “Genome Editing Mice for Medicine” programme; the centre is an international leader in mouse genetics, with an innovative programme in developing novel phenotyping methods and a long-track record of mouse sensory biology and metabolism research.
The programme will provide UK DRI researchers the possibility to add-value to their research by generating new models, characterise existing models in new ways (genetically and phenotypically) and to provide a central site to facilitate collaborative work and resource sharing. I am particularly keen to forge collaborations with researchers using alternative preclinical model systems and those new to mouse work; as this in my opinion will particularly accelerate research.
Q: Please can you tell us a little more about your new role as UK DRI programme leader for animal models? What are the main aims and how will you be supporting UK DRI researchers? Finally, will you and your team be reaching out to UK DRI researchers, what is your time scale for setting up and how can researchers get in touch if they want to discuss issues related to the use of animal models?
A: My first aim to understand what UK DRI researchers are currently using animal models for, where this is working well and also were there are road-blocks to research. I plan to use this information to formulate a long-term strategy for increased animal model research capacity at the UK DRI and to ensure that this complements future developments in other preclinical systems, such as iPSC and organoids.
A UK DRI-specific “Mouse Models for Dementia” programme will be developed to facilitate this capacity expansion, modelled on the MRC’s “Genome Editing Mice for Medicine”. Via this scheme, UK DRI researchers will be able to apply for the generation of new genetic mouse models for dementia, mouse model tools (e.g. Cre/Cre-ERT/reporter constructs) and new lines (or currently heavily used lines) to undergo additional phenotyping at the Mary Lyon Centre. This will draw on the IMPC pipeline and the Cre-validation capabilities available at MRC Harwell. The application call for these resources will open in January 2020, with cross-centre and collaborative applications particularly welcomed.
In addition, I will be hiring a cognitive neuroscientist to develop novel in cage behavioural and cognitive tasks in collaboration with the MRC Mary Lyon Centre Mouse Phenotyping Development Team, for the UK DRI research community.
We would like to thank Frances for taking the time to talk about her role. She will be undertaking site visits during September so please feel free contact your centre manager if you would like to book a face-to-face meeting. Alternatively please contact f.wiseman@ucl.ac.uk for further information or to discuss what your research needs to progress faster.
