Researcher Eva Medico-Salsench shares how she and her research group diagnosed patients with rare neurodevelopmental conditions using whole genome sequencing, patient clinical data, and experiments with zebrafish.
The aim of my work is to impact patients
I'm very interested in molecular medicine, but I'm not a clinician, I like studying what causes disease at a cellular level.
Most of all I am interested in the impact of research on patients.
I studied biomedical sciences at the University of Barcelona, before starting an Erasmus+ internship at the Erasmus Medical Center in Rotterdam. I studied at the department of Clinical Genetics where I did my master’s internships in molecular medicine, and I am still currently working on my PhD.
My main focus is neurodevelopmental conditions, researching the genetic causes behind them and how this effects the body. These causes and effects are so important for us to understand if we want our research to have real clinical impact.
My research in a nutshell
My recent research revolved around 2 siblings who both displayed something called hereditary spastic paraplegia, a general term for hereditary weakness and stiffness in the leg muscles.
Routine testing was not able to reveal the genetic cause of their paraplegia, but our research team was able to find it, thanks to whole genome sequencing.
Both siblings displayed a genetic alteration in part of a gene called AMFR, which was likely causing problems with their mobility. After identifying this alteration, we set out to discover how it might be causing the condition, and what was happening in the body.
How did the gene variant cause symptoms?
In order to get better insights into the condition, we looked at human neuronal stem cells. Originating in the central nervous system, these cells have the potential to develop into neurons or other cells in the nervous system.
For our research, we silenced the AMFR gene in the stem cells and looked at the effect this had on cell function. This helped us figure out how genetic changes might be causing symptoms in the patient.
We noticed that when the AMFR gene was silenced, it lead to altered levels of fats and cholesterol in the neurons. These altered levels were likely the cause of the symptoms we had observed.
I really like science, but more importantly, I like to think that whatever I work on will have an impact on someone’s life."
Finding the answer with zebrafish larvae…
Over 70% of zebrafish DNA is similar to that of a human. This makes them very useful when studying human genetics. Their transparent nature also means it is easy to see what’s happening inside zebrafish larvae whilst they’re alive and developing.
Similar to in the human stem cells, we silenced the AMFR gene in zebrafish, causing the gene to lose its function. This allowed us to observe how a faulty AMFR gene effected the larvae, and how this might relate to the symptoms seen in our patients.
We found that genetic changes causing neural conditions in humans, also caused movement difficulties in the fish. The nature of these motor problems were similar in both the fish and the patients.
Pioneering a treatment for hereditary spastic paraplegia
From our research, we found a potential candidate drug to treat the symptoms of this newly identified hereditary spastic paraplegia condition.
After observing that cells with faulty AMFR genes had excess amounts of fat and cholesterol, we decided to try and tackle this using statins.
Statins are a well-established drug routinely used to reduce someone’s risk of a heart attack or stroke. They have been available for over 30 years, and are recommended by the National Institute of Healthcare Excellence.
In our study, we administered statins to zebrafish larvae with the disease-causing gene alteration. We found that larvae receiving statins showed improved movement and better neuronal development than larvae who did not.
These results are extremely promising, and suggest that statins could be used clinically to treat patients with hereditary spastic paraplegia caused by AMFR.
Patient impact is important to me
I really like science, but more importantly, I like to think that whatever I work on will have an impact on someone’s life.
Even if my work doesn’t directly affect patients, it provides a basis for other researchers to build off, which may ultimately lead to patient benefit.
In this work, we were able to provide a genetic diagnosis for 2 patients that had previously gone 10 years without any answers. Since then, we have found 18 other individuals with the same condition.
Now that our work has been published, we hope that many more people with hereditary spastic paraplegia can be genetically diagnosed as well.
Having answers is so impactful. Once we know the cause of a condition, we are in a better position to see what kind of approaches may be helpful, or where to start with treatment.
The help of Genomics England
Genomics England played a major role in allowing us to research hereditary spastic paraplegia.
The genetic variant we looked at could not have been found by routine diagnostic testing. It was only thanks to new sequencing technologies, in this case whole genome sequencing, that we were able to reach a diagnosis.
Genomics England have been pioneers in bringing genomic technology into healthcare. Their work could help bring answers to so many undiagnosed patients with various rare conditions, just as it did for us.
It was only thanks to new sequencing technologies, in this case whole genome sequencing, that we were able to reach a diagnosis."
What’s coming up next for me?
In the one year I have left of my PhD, I will continue to work with zebrafish. I am now looking at a different condition called Kaya-Barakat-Masson syndrome, which is another rare neurodevelopmental condition.
Beyond my PhD, I would like to continue working on science that impacts patients. I am fascinated by the process of translating scientific findings into real patient impact, and I would like to be at the forefront of this.
I think that closer links between the lab bench and the clinic are the key to better understanding rare conditions. Close work between researchers with expertise in a specific condition and patient-facing clinicians could be hugely beneficial for getting answers to patients. This, in turn, allows us to provide the best possible treatment opportunities.
I would like to give special thanks to the Erasmus Medical Centre in Rotterdam, in particular the Clinical Genetics department.
I would also like to thank everyone in the team, specifically my group leader Professor Stefan Barakat, our bioinformatician Ruizhi Deng, our lab manager Anita Nikoncuk, and finally Dr Leslie Sanderson, who was my research supervisor for the zebrafish work.
None of the research would have been possible without them or our other collaborators.
To read more about the work we did, check out our publication on the AMFR gene and hereditary spastic paraplegia. Or, take a look at the early career researcher page to read about the support that Genomics England offers.
You can also read up on the use of animals in scientific research.
If you have any questions or want to discuss the research, reach out to me at [email protected]