The world through a mouse’s (degenerating) eyes: An interview with Dr Amy Findlay
As someone who has studied physics for most of my academic career the world of animal models seems perplexing and complicated and the people who work in it something akin to animal magicians. But that is the world in which Dr Amy Findlay – a Postdoctoral Research Fellow at the MRC Human Genetics Unit – spends most of her working time. Her focus is the genetic causes behind retinal degeneration in mouse models and how that can be linked to human disease.
So, what prompted Amy’s decision to start studying the eyes of mice? It all starts with her choice of Honours project at the University of Aberdeen where her interest lay in the projection of retinal ganglion cells into the brain. She took delight in laboratory work which prompted her to ask her head of course for advice for continuing in the field. He recommended a PhD, also at the University of Aberdeen, studying the regulation of the formation of the epithelial layer in eyes- more specifically how the cells position themselves to ensure transparency. After her PhD, Amy found a postdoctoral position in Professor Ian Jackson’s laboratory focussed on mutagenic screening – the process of systematically mutating genes and investigating the phenotypes – which is used to produce a catalogue of genes and the pathways in which they are involved. Since then, she has concentrated on this mutagenic screening process and has already published two papers on the topic – one looking at Idh3a mutations and the other investigating the gene Fam151b.
Dr Amy Findlay
Recently, Amy received funding alongside Dr Veronique Vitart’s laboratory for studies looking at the genes involved in retinal detachment in myopia. She is currently focussed on Bmp3 and its role in the regulation of eye size. Bmp3 carries a missense variant that is associated with myopia and retinal detachment. Amy’s interest lies in how Bmp3 and its effect on eye size may lead to an increased chance of retinal detachment.
She also has an interest in the interaction of different genes to produce phenotypes. In her previous papers, Amy looked at Idh3b and its interaction with her main gene of interest Idh3a and her work on Fam151b also investigated whether Fam151a was associated in the same pathway. For reference, neither Idh3b or Fam151a showed a similar phenotype to the main gene of interest.
Now, however, with her focus firmly on Bmp3, Amy wants to investigate other members of the Bmp family. Bmp is extremely important for patterning and development – particularly in the eye. Knocking out Bmp2, Bmp4, Bmp7 and some of the different receptors produces a variety of phenotypes. Of particular interest is Bmp2 and Bmp4 knock-outs. These produce microphthalmia (small eyes) while knocking out Bmp3 leads to the aforementioned larger eye phenotype. It is believed that Bmp3 is involved in regulating Bmp2 and Bmp4 by behaving as an antagonist to their receptors and preventing binding. Amy hopes to produce mice that can be used to investigate the pathways involved with Bmp3 and how they affect eye development.
Eye phenotyping equipment is a rapidly improving field and Amy’s lab is taking advantage of these advancements. The electroretinogram (ERG) helps to measure the response the retina has in the presence of light while the optical coherence tomography machine allows visualisation of the layers of the retina. This is especially useful in live mouse models as it allows researchers to conduct longitudinal studies on the same mice – helping to reduce the number of animals who are experimented on while also allowing more consistent data to be collected. A new machine, which will be arriving in the next couple of months, is the optokinetic drum. It is essentially a sight test. However, instead of a string of letters, it involves a stream of progressively thinner black and white lines that the mouse tracks until the lines get so thin it is presumed the mouse can no longer see them. Amy will be using this to test the mice’s vision with myopia induced by the Bmp3 variant.
Amy is enthusiastic about the future of her field. Even though she claims it is outside her area of expertise she’s excited to see whether gene editing can be used to correct the phenotypes she has been studying. For example, the loss of light sensitive photoreceptor cells that is part of retinal degeneration could be corrected by editing genes so that lost cells could be replaced. Furthermore, the range of therapies that will be available in the upcoming years and decades also provide a source of excitement. However, most of Amy’s interest is reserved for the sheer volume of information that is becoming available through GWAS studies. So many whole genomes have been sequenced in the past couple of years. This offers up a huge amount of insight into genes involved in retinal degeneration. Bmp3 itself has been confirmed in multiple studies and it is this abundance of GWAS data that Amy is motivated to put into biological context.
Looking back on my interview with Amy I had a new appreciation for the work undertaken by researchers using animal models and the challenges they face trying to understand the mechanisms and pathways that genes are involved in. Moreover, the role of new technology and protocols in conducting animal model research thoroughly and ethically cannot be understated. Finally, I was struck by the excitement Amy had for her field and its future and how it could prove vital in the effort to battle the various eye diseases that result from the genes that she is studying.
Amy’s previous papers:
Findlay, Amy S., et al. “Fam151b, The Mouse Homologue of C.elegans Menorin Gene, Is Essential for Retinal Function.” Scientific Reports, vol. 10, no. 1, 2020, doi:10.1038/s41598-019-57398-4.
Findlay, Amy S et al. “Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function.” Disease models & mechanisms vol. 11,12 dmm036426. 18 Dec. 2018, doi:10.1242/dmm.036426
Amy’s current project:
Establishing a role for genetic variants associated with myopia and retinal detachment at the BMP3 locus.
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