Brittany J. Carr

How would you explain the main findings of your paper in lay terms?

Retinal degenerative disorders are inherited diseases that affect tens of thousands of Canadians. The effects are devastating; severe vision loss or complete blindness occurs early in life, resulting in the loss of livelihood, mobility, and independence. There is no cure, and present treatments focus on easing the symptoms of blindness instead of preventing vision loss in the first place. My research is focused on the prevention of vision loss by understanding how specialized structures in the light-sensing cells in the eye, called photoreceptor outer segments, are made, and how defects in outer segment assembly result in photoreceptor death and blindness. Using CRISPR-Cas9 genetically modified frogs, I have replicated human disease caused by mutations in two genes, prominin-1 (prom1) and photoreceptor cadherin (prCAD). I have determined that these genes are necessary for outer segment organization, but that they play very different roles. My results indicate that prom1 and cdhr1 are necessary for the higher-order organization of the outer segment. Prom1 may align and reinforce interactions between nascent disc leading edges, a function more critical in cones for structural support. Cdhr1 may secure discs in a horizontal orientation prior to fusion and regulate cone lamellae size. A secondary important finding of this study is that the retinas of prom1-null, cdhr1-null, and prom1 plus cdhr1 double-null X. laevis do not degenerate quickly, instead they develop deposits of cellular debris in the outer segment layer as the animal ages. The maintenance and growth of the outer segments, the preservation of photoreceptor function, and the cellular debris deposits suggest that retinal degeneration caused by prom1-null mutations may be due to secondary toxic retinal effects – e.g. RPE toxicity or accumulation of cellular waste products – and not due to direct effects of these mutations on outer segment morphogenesis or the improper trafficking of outer segment proteins as theorized previously. This is an important finding, as it may not be critical to prevent the morphological defects in photoreceptors caused by prom1-null mutations to preserve vision; therapies could instead be targeted to prevent the secondary events that ultimately cause cell death and blindness. This finding opens up an entire new realm of therapeutic possibilities to treat prom1-null mutations and prevent blindness and it is an exciting new avenue for future studies.

Were there any specific challenges associated with this project? If so, how did you overcome them?

The biggest challenge for this project was entering an entirely new field that required knowledge and a skillset that I had not mastered yet. My doctoral studies were focused on GPCR signalling in the inner retina, retinal pharmacology, and drug development for the treatment of myopia – the visual refractive error of near-sightedness. I then switched to inherited retinal degenerative disease and photoreceptor outer segment morphogenesis for the express purpose of learning genetic modification of animals with CRISPR-Cas9 and transgenesis. This switch required me to learn genetics, molecular biology and transmission electron microscopy, and really forced me to hone my imaging skills with light microscopy. There is nothing special about how I overcame these challenges; I just worked hard, asked lots of questions, and really dug into the literature.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

My ‘eureka’ moment was the first time I successfully created prom1-null animals and looked at their photoreceptor structure. When I peered into the eye pieces and saw these beautifully dysmorphic rod and cone outer segments, I knew that this was going to be a very exciting mutation to study.

“There is nothing special about how I overcame [these] challenges; I just worked hard, asked lots of questions, and really dug into the literature.”

Why did you choose Journal of Cell Science for your paper?

I chose Journal Cell Science because I appreciate the breadth of cellular biology topics covered in the journal and the high-quality research that it publishes. J Cell Science always has beautiful cover photos, and I thought that my research would be the perfect fit and I could contribute one of my micrographs to be a cover as well. I appreciate other aspects of the journal, such as the 30 day time point for first decision, advanced posting of accepted manuscripts, and its acceptance of preprints.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

I have been incredibly fortunate to have had multiple supervisors and mentors who have gone above and beyond to support me as I navigate a career in academic science. As a first generation academic, I didn't have any experience with navigating academia or the expectations for obtaining a PhD. Both of my supervisors, Dr Bill Stell and Dr Morley D. Hollenberg, were, and still are, my biggest cheerleaders. They have always been supportive of my research, even when I wasn't, and they always make time for me when I have questions or concerns. Even now, they are always open for a phone call to chat and get advice. They welcomed me into their lab and made me feel like I was family; they both truly define what being a great supervisor and mentor is all about. Another special mentor was Dr Koichiro Mihara. His expertise and willingness to teach me molecular biology played a huge role in the completion of my doctoral work on receptor binding. I am hugely thankful to him and the support he provided for me in the lab. I carry the lessons learned from him with me to this day.

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Prom1-null mutations in X. laevis result in significantly dysmorphic retinal photoreceptor outer segments. This image shows bulbous rod outer segments (magenta) and elongated and fragmented cone outer segments (green). The green cell on the left is demonstrating mislocalization of cone opsin immunoreactivity to the cone inner segment and tendrils that appear to wrap around the nearby rod outer segment. This is highly unusual and indicative of severe damage to the cone outer segment. Magenta, wheat germ agglutinin; green, L/M cone opsin; blue, Hoechst nuclear dye.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

My doctoral supervisor, Dr Bill Stell, was the driving force behind my scientific career. As an undergraduate, I thought that I was interested in becoming an optometrist. I was introduced to the concept of doing summer research in ‘Dr Bill's’ lab after I approached a different professor to ask them to provide a letter of recommendation to attend a pre-optometry summer school program. Bill reached out to me and welcomed me into his lab as a summer student with open arms. I started a summer research project and the moment I successfully labelled dopaminergic amacrine cells and looked at them under the microscope I was completely and utterly hooked on research; I never did make it to that summer school program. I stayed in Bill's lab for summer research, my undergraduate honours thesis project, and then finally my doctoral studies. Ten years later, I still get excited every time I use the microscope and label retinal cells. I love the challenge of science and the excitement and satisfaction when I make a new discovery. The feeling of being the first person in the world to see something new and to be able to then to try to figure out what is happening is so gratifying. The final driving force keeping me in academia is that I love to teach and mentor and pass my excitement about science onto new generations of undergraduate and graduate students.

Who are your role models in science? Why?

My role models are Bill and Morley. They prove that you can be kind and supportive and still do amazing science. I am so grateful for their support, and I want to provide the same style of support and mentorship to my future students as well.

What's next for you?

I am still pursuing the academic dream! I am developing and characterizing a new animal model of age-related macular degeneration and I will continue to investigate the function of prominin-1 in photoreceptor outer segment morphogenesis. I am in that transitionary portion of my postdoctoral studies where I am expanding my research program and continuing to build a solid foundation for an independent research career that is focussed on the cellular and molecular biology of retinal diseases and disorders, with the goal to develop novel and targeted treatment therapies. I am on the job market, and I am looking to continue my career in academia as junior faculty in a vision research, neuroscience, or a cellular and molecular biology program.

Tell us something interesting about yourself that wouldn't be on your CV

I'm an artist and a bit of an adventurer who loves polar travel. I've travelled to Antarctica and north of the Arctic Circle in Norway on a ship. I paint landscapes using watercolour, acrylic, or mixed media and I also enjoy wildlife photography. I share these things on my Instagram @b.m4573r.

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