Passion and purpose: Clinician-researcher Marcela Votruba shares her commitment to reversing sight loss for people with a rare inherited condition
Professor Marcela Votruba has spent decades understanding the cause of inherited genetic sight loss.
We spoke to her about her career, her work, the support she receives from Fight for Sight, and how she relaxes when she’s not in the clinic or lab.
Professor Marcela Votruba’s passion for her patients and research to treat their sight loss is palpable. She is, in that respect, the embodiment of a clinician-scientist, splitting her time between working in a clinical (NHS) setting and her Cardiff-based Lab.
Funded by a Fight for Sight Project Grant, her current research is advancing our understanding of Leber Hereditary Optic Neuropathy (LHON). She told us, “Patients struggle with this devastating diagnosis because sight loss is so rapid and profound.”
“Patients struggle with this devastating diagnosis because sight loss is so rapid and profound.”
How does Leber Hereditary Optic Neuropathy impact sight?
The rare genetic condition can lead to sudden, unpredictable vision loss.
Marcela explained, “A young individual, often in their late teens or early twenties, might go from a normal vision to very poor vision very rapidly, with a very large blind spot in the centre of their vision, which means that they could not see any detail.”
She added, “Looking at you, I would not see your eyes, your nose, your mouth. I might just catch a glimpse of the top of your hair and your shoulders. Everything else inside that would be a complete blur. People do retain vision on the periphery, on the edges, but this is not useful for reading or fine tasks.”
What are some of the breakthrough discoveries relating to Leber Hereditary Optic Neuropathy?
Earlier work by Marcela has already led to ‘breakthrough discoveries’ that have advanced our understanding of what causes LHON – and could lead to treatments.
Retinal ganglion cells project down into the eye’s optic nerve.
Where there is optic nerve ‘atrophy’ or degeneration (as occurs in LHON), it is possible to detect changes in the retina earlier.
“We may be able to intervene at an earlier stage and save sight. The idea is to work on treatments that we could apply to either prolong sight or even reverse the vision loss.”
"We may be able to intervene at an earlier stage and save sight."
How might we pinpoint why some cells recover in patients living with Leber Hereditary Optic Neuropathy?
Part of the work involves comparing cells from patients who improved with those from a patient with the same mutation who did not improve over five years or more. Doing so will enable researchers to pinpoint what we could do to intervene at an earlier stage to encourage more of the cells to recover and to resume normal activity.
“This method would have to be applied to a patient at a relatively early stage of their vision loss, and it might not lead to a full recovery of all ganglion cells. That would be unlikely. However, improving the vision from merely counting fingers or hand movements to reading halfway down the chart would be transformative. So that's the aim and the study.
“We're looking at the cell biochemistry, how the cells make energy, what they look like, how they connect with other cells. We grow them in the dish, and we're exploring the features that allow us to see why the ones that recover are more robust. Perhaps they have defence mechanisms that the others don't,” said Marcela.
The team is also exploring cell function using a device called a ‘high density multi-electrode array’ whereby they grow cells on a dense electrical grid. This enables them to plot 16,000 points in a square centimetre, looking at the electrical signals of cells that have recovered or that have kept growing.”
"We're looking at the cell biochemistry, how the cells make energy, what they look like, how they connect with other cells."
Today, Marcela’s lab uses retinal ganglion cells grown in the lab to conduct research. They do this by using human skin cells and turning them into ‘Induced Pluripotent Stem Cells’ (iPSCs) or artificially produced stem cells.
“They are differentiated so they follow a pathway where they start to look and behave like retinal ganglion cells in a dish,” explained Marcela.
How is a grant helping to fund better treatments for vision loss?
We’re funding Marcela’s current work through one of our Project Grants. It is already yielding promising results that could lead to treatments to stop or reverse sight loss.
“The grant is looking at the paradox of how patients can lose so many of their [retinal] ganglion cells and go on this journey from normal sight to poor vision - yet in some individuals, there is some recovery.”
Our funding is supporting Marcela to culture cells from patients with genetic mutations which cause LHON. “We'll then look at the ganglion cells and investigate how and why they die”.
Understanding this is critical, she said. “We know that you don't regrow retinal ganglion cells in the eye, so what must be happening is that those cells that didn't die were very sick for a time. They may not have been functioning for up to a year.
“They weren't firing on all cylinders, and remarkably, some of them are then able to recover.”
How did a clinician researcher discover a passion for DNA?
Marcela’s expertise lies in the field of ophthalmic genetics, a fascination that began when she started her PhD at UCL, where she explored diseases that damage the optic nerve.
“My journey began when I applied to do a PhD at UCL at the Institute of Ophthalmology,” she said. “It was working to understand the genetics behind inherited optic atrophies or optic neuropathies,” said Marcela.
“It interested me because it was a project collecting information about the families. What was wrong with them? Assessing their vision, looking at their optic nerves, imaging the back of the eye, taking visual field assessments and doing what's called psychophysics. [This is] where you try to probe their vision using markers such as fields and light responses.”
Like all good scientists, Marcela has a curious mind. “I collected blood and extracted DNA to explore how these families passed on a particular condition called dominant optic atrophy,” she said.
“It was an opportunity to go back to university at a time when I was already a clinician, and I could basically explore in the lab and be a student again, which was amazing because you could get into something completely new, completely exciting.”
“It [research] is a bit like learning how to cook. You can't just expect it all to work first time, and you can't expect to get it right first time.”
How do you build the qualities for scientific research?
Marcela describes learning lab techniques as “a bit like learning how to cook.”
She added: “You must be one of these people who want to try things, practical things. You can't expect it all to work first time, and you can't expect to get it right first time. And sometimes you must try it on your own without being shown.”
At the time, the field of genetics was relatively new and “very few genes for eye diseases” had been discovered – although that was changing, fast. “The Institute of Ophthalmology was one of the first to discover a gene for retinitis pigmentosa. Shomi Bhattacharya was my supervisor, and he was excellent at gene hunting”.
Marcela’s PhD led to a publication in the journal Nature Genetics.
What are some of the non-financial rewards of working in vision research?
Marcela acquired “the bug” for research and applied for fellowships to continue her career and to become an independent scientific researcher and a clinician scientist.
After training at Moorfields, Marcela embarked on an overseas fellowship. “It was important to see research done elsewhere. I was fortunate to spend time with Professor Paul Sieving[1] at the Kellogg Eye Centre in Michigan, who was also an incredible leader in ophthalmic genetics and discovered the gene for a retinal condition called retinoschisis.”
Sieving then moved to the National Eye Institute as its director, and Marcela followed him.
“That was beautiful and exciting. The American system has many pros and cons, as does ours. But it's very energetic, fast-paced and exciting. And I met some fantastic people.”
What are some of the benefits of involving patients in vision research?
Returning to the UK, Marcela took up a five-year MRC Clinician Scientist Fellowship, which allowed her to establish her lab and an ophthalmic genetics clinic in Wales.
She sees patients from South Wales and “as far afield as they would like to come.”
“I love the fact that I have seen patients for many years because I now have continuity. I've seen the same family for more than 20 years, and sadly, I've also seen people go from almost normal vision to being completely blind.”
Marcela added, “Patients are keen to know about research. They'll ask about the latest trials into gene or cell therapies. I think the next 5 to 10 years will bring a huge swathe of new clinical trials based on the research that's going on in the laboratories.”
A long relationship with Fight for Sight
Marcela has a long history with Fight for Sight and said that she is “very privileged to be associated with the charity since 2012”.
“For five years, I was on the Grant Advisory Board, which meets to assess grant applications and reviews, and from 2020 to 23 I was its vice chair.”
She has also, she said, “Been lucky enough to have been funded by Fight for Sight.”
One PhD Student, she told us, was exploring the role of photobiomodulation therapy – a type of light therapy that might help ganglion cells recover. It remains an active area of research.
Speaking about the role of Fight for Sight, she said, “Researchers can apply for small grants, which will allow them to kick off a project that would otherwise not be able to get going. Fight for Sight spans the whole remit, from early career researchers through to large laboratories and principal investigators.”
What is the future of vision loss research?
Marcela is also working with Fight for Sight and colleagues from Scotland, Northern Ireland and England to help establish a first in the UK: the UK Vision Research Network. So, what is it – and why is it important?
“The idea is to establish a UK vision research institute. Initially, it will be virtual. With Fight for Sight’s support and sponsorship, we have made a significant step forward, holding a meeting in Edinburgh last June [2024] where we invited colleagues from the UK Dementia Research Institute and we exchanged ideas.”
And now Fight for Sight is actively recruiting PhD students for projects on retinal degeneration, which includes inherited retinal disease.
Through UKVRN, students will work across institutions and different scientific disciplines.
She is optimistic for the future, saying, “We are on the brink of huge developments in both delivery of genes to the eye and gene therapies. As well as our understanding of vision loss, we have a fantastic pool of data in the UK that will underpin [clinical] trials.”
"We are on the brink of huge developments in both the delivery of genes to the eye and gene therapies."
Why is it important to involve people in patient-led clinical trials?
Part of her role as the Health and Care Research Wales Ophthalmology Speciality Lead is to encourage UK-based clinical trials.
“We're trying to encourage clinical trials and for companies to come to the UK. It’s important for the economy that we encourage companies with new trials to come to the UK because if we miss out, our patients will miss out,” said Marcela.
However, trials are expensive, and there is ongoing debate over what success should and could look like.
“There is a much discussion about what are called endpoints in clinical trials. We need to work with patients, asking them what they believe are clinically meaningful results for them, but also debate across the sector to really think about what the best endpoints are. Different patients with different diseases will not all fit the same mould.”
"You must seriously start to understand what is meaningful to patients and what is most effective."
She added, “No society has a bottomless pit of money, so you must seriously start to understand what is meaningful to patients and what is most effective. To push tis forward patients are increasingly taking part in questionnaire-based types of research on quality of life, called PROMs and PREMs, which are patient-reported measures used in healthcare to assess the quality of care.
“The website Clinicaltrials.gov is a huge database of gene therapy trials. No country in the world could afford to develop and fund all new treatments alone. None. Therefore, we must begin to understand what the best treatments are, work across borders, and then normalise the technology so it becomes more affordable.”
Charities such as Fight for Sight also play a crucial role. “The fantastic thing about Fight for Sight is that you have been been determined to stick with it,” she said.
How does Marcela relax when she's not working in The Lab?
So, when she isn’t working, how does Marcela relax and maintain a work-life balance?
“Well, I can't get to go skiing very often, but I love skiing. I still go, but not as often as I'd like to. I love the outdoors, and I love mountains,” said Marcela.
She also has a ‘secret’ passion that mirrors her interest in her patients and research.
“And my other secret passion. (but it won't be a secret if I tell you!), is ballet. I did ballet until I was 18 andI completed all my grades to Grade 8, and then I continued a little bit at university. And, for the last five years, I've been going to adult ballet classes.”
“It's one of my absolute passions. It's a little bit like skiing and yoga when you're doing ballet, and you're learning new dances. It's very good for clearing the brain.”
