Sisters’ plight motivates Novartis intern

A NIBR postdoctoral fellowship leads to the discovery of a key genetic mutation behind a form of blindness.

Nov 03, 2014

When two sisters presented with vision problems at an ophthalmology clinic in South Africa, little did they know they were starting a chain of events that would lead to new insight into the genetic basis of a rare eye disease. What’s more, they were about to play a part in enhancing scientific capability in their country and advancing the career of a bright young researcher.

The story of Rose and Maria (not their real names) starts back in 2007. That was when older sister Rose, then studying to be a teacher, presented with vision problems at Professor Trevor Carmichael’s ophthalmology clinic at the University of the Witwatersrand (Wits) in Johannesburg, South Africa. She was diagnosed with macular corneal dystrophy (MCD), a very rare autosomal recessive disorder that affects the stroma of the cornea and can lead to blindness by adulthood. The only viable treatment option at present is corneal transplantation. Three years later, Maria also started to have vision problems and, after Rose brought her to see Prof Carmichael, she too was diagnosed with the condition.

Fast-forward another three years, and both sisters were becoming anxious that their children, about to start high school, might also have MCD. Were they sitting on some sort of genetic time-bomb? They brought their children to the clinic, and this was when Nadia Carstens, a postdoctoral fellow in human genetics at the Sydney Brenner Institute for Molecular Bioscience, also part of Wits, got wind of their case. Carstens’ research interest is the genetic causes of disease in South African populations and she saw an opportunity to understand more about MCD in this family through next-generation sequencing, a powerful technique for analyzing genetic material.

Accessing world-leading expertise

However, Carstens' institute lacked access to state-of-the-art sequencing technology and, more fundamentally, she knew she needed to enhance her capability in bioinformatics, the application of computer science, mathematics and engineering to analyze biological data. Undeterred, the ambitious scientist put in a successful application for a Next Generation Scientist internship at Novartis, where she hoped to pursue this project in the company of some of the world’s leading exponents of sequencing. After preparatory discussions, Carstens spent three intensive months in the Applied Human Genome Technologies group within the Biomarker Development (BMD) unit at Novartis Institutes for BioMedical Research (NIBR). During that time, she worked alongside Novartis researchers and was able to apply exome sequencing, a technique used to find the mutations responsible for monogenic disorders, to samples from three generations of the family.

The project came to fruition with the identification of a novel genetic mutation responsible for MCD in the family. This was the first description of the genetic cause of MCD in a Black sub-Saharan African family. Other mutations in the same gene had previously been reported to lead to MCD in Caucasian patients. This makes it likely that the knowledge gained from MCD studies in these populations could be transferable to African patients.

The data generated by Carstens’ research will eventually be incorporated into the Southern African Human Genome Programme, a pan-African research collaboration initiative to improve quality of life by understanding human genetic diversity. It will also be available to researchers with an interest in genetic diversity in African populations. Following Carstens’ discovery, the family has been given genetic counseling to reduce the risk of MCD in future generations. More immediately, the benefit for Rose and Maria is that, by virtue of their participation in the research, they will gain preferential access to corneal grafts to restore their sight.

Also, as Carstens explains, discovering that their vision problems have a clear, scientifically explicable cause has been empowering for Rose and Maria. “They’re better equipped now to navigate the South African public healthcare system and access the care they need – something that can be challenging with such a rare condition and in the rural area where the family lives,” she comments.

Enhancing scientific and clinical capability

For Carstens, her internship at Novartis enabled her to greatly increase her knowledge of exome sequencing and bioinformatics and bring it back to fellow researchers in South Africa. “Since I got home, I’ve had so many colleagues getting in touch to ask me about my time at Novartis,” she says. “What I learned will help us use next-generation sequencing analysis in studies to identify disease-causing mutations in African populations – one of the main aims of the Sydney Brenner Institute. “I am so grateful to the scientists who generously shared their knowledge and time. I now have enough data for at least one if not two or three publications. What’s more, I’ve gained the know-how, connections and confidence that I need to further my scientific career in Africa.”

Sisters’ plight motivates Novartis intern - Frank Staedtler

Frank Staedtler, Head of Applied Human Genome Technologies in BMD at NIBR.

Michele Ramsay, Professor in Human Genetics at the Sydney Brenner Institute, agrees that her postdoc’s internship was a very valuable opportunity. “Nadia broadened her scientific network and had an opportunity to work with experienced scientists in a sophisticated technological environment,” she says. “It has shown her that she can hold her own in an international research setting.”

Frank Staedtler, Head of Applied Human Genome Technologies in BMD at NIBR, is a strong advocate of the Next Generation Scientist program. He says: “The Next Generation Scientist initiative is a great partnership. It enables scientific advances in sub-Saharan Africa. At the same time, it introduces us to scientists, diseases and perspectives we would never otherwise come across and helps build bridges for the future.”

One of Carstens’ two mentors at NIBR was Stine Büchmann-Møller, a lab head in the next-generation sequencing group where the postdoc was based during her internship. Says Stine: “This was my first experience of mentoring an intern. It was very satisfying to help someone develop their scientific understanding and skills in a way that advanced their research and provided transferable knowledge. “There were direct benefits for me, too. In linking Nadia with others here at Novartis, I made connections with colleagues I have never met before and expanded my network.”

The mentors’ perspective

Marc Sultan, Group Head of Next-Generation Sequencing in BMD and Carstens’ co-mentor, adds: “Nadia showed how to make an internship work. She was very motivated and passionate and was willing to ask questions and reach out to the right people to help. This was the key factor in making her project such a success.”