Researcher on the rise: Alexander Blakes

Researcher and clinician Alexander Blakes talks about how health data from the 100,000 Genomes Project is helping him deliver new diagnoses to patients and discover new insights into genomics.

My aim as a researcher and clinician

As a clinician, I have always been interested in medical genetics. My work has focused on finding new diagnoses for people in the 100,000 Genomes Project, whose data sits in the National Genomic Research Library.

A key challenge in our field is that many patients with rare genetic conditions don't receive a diagnosis. For patients, receiving a diagnosis can be transformative.

With new technologies like whole genome sequencing, we can now read almost every letter of a person’s genome. However, our ability to understand and interpret that information is still quite limited.

Our research investigated a critical part of the genome – genetic changes that might disrupt the splicing process.

How does splicing work?

Most of our genes have a complex structure. The sections that code for proteins, known as exons, are often separated by large non-coding tracts, called introns. When cells manufacture proteins, genes are copied into a messenger molecule known as RNA.

During the copying process, introns are cut out in a process called splicing. The important coding sections are left intact and stitched together, and these will be used as the blueprint for the protein.

In our research, we focussed on genetic changes that might disrupt splicing. These changes are often at the interface of coding and noncoding parts of the genome.

We wanted to see if changes in these regions were causing rare conditions.

Getting new insights into the causes of rare conditions

There were 2 outcomes that I was really interested in.

The first was delivering new diagnoses to participants who might have been missed in the ordinary pipeline of interpreting results.

By collaborating with scientists, bioinformaticians, and clinicians, we were able to show that some of the splicing changes were causing rare conditions in several participants.

This work was done at the University of Southampton, led by Diana Baralle and Jenny Lord. The expertise of the Southampton team in splicing and RNA biology, particularly our ability to run detailed molecular tests, were essential to the success of the project.

The second outcome I was interested in was finding new mechanisms that cause disease. We were interested in mechanisms that were relevant not only to one gene, but to many different genes involved in a wide range of conditions.

One of the key messages from our work was that genetic changes could still disrupt splicing and cause rare conditions, even if they were far away from the coding sections.

Impact for participants

Having an answer as to what caused a condition is very powerful.

Often, it can unlock more information about a patient’s prognosis, and the chances of a relative having the same condition.

It can also reassure people that often these conditions are caused by random chance.

There is immediate help we can offer, such as genetic counselling and clinical genetic services. There are also exciting prospects for future treatments which could let us correct problems in the splicing process, addressing the root cause directly.

What I’m working on now

My work still centres around understanding the impact of genetic changes on the normal function of the genome.

Recently, my focus has moved away from splicing, and more towards genetic changes at the far end of genes. These genetic changes sometimes have unusual properties. From a scientific perspective, they are really interesting to study.

We are taking a broader approach than before by combining datasets from a variety of different sources. The National Genomic Research Library is still really important, but we are also using datasets from UK Biobank, gnomAD, and from other national and international collaborations.

I’m doing this research at the Manchester Centre for Genomic Medicine and the Manchester Rare Conditions Centre.

Manchester is an amazing environment; it brings together NHS and research facilities, scientists, clinicians, and clinical academics all in the same building. It’s a fantastic place to be an early career researcher.

What motivates me

Helping to give participants a diagnosis is the whole point of my research.

On the one hand, I want to discover new biology and answer interesting scientific questions about genomics. On the other hand, I want maximize benefits for patients. Luckily in our field, the 2 go hand-in-hand.

Advances in science often directly translate into clinical results, and patients we see in the clinic shape the scientific questions we ask. It is very much a positive a feedback loop.

Participants who have volunteered data to the National Genomic Research Library are enabling extensive new research, including my own. Their contributions are helping to provide diagnoses to so many other patients and families.

The value of the National Genomic Research Library

Having access to the library has been pivotal to my work. It was the resource we used to carry out all our research, and ultimately it allowed us to find new diagnoses for several patients.

It has also been very important for my academic development, as it exposed me to datasets and resources that I hadn't used before as an early career researcher.

Thanks to my work with the National Genomic Research Library, I was very fortunate to be awarded a PhD fellowship with the Wellcome Trust. This fellowship will be an important cornerstone of my academic career.

From my experience, I would say that participants can feel confident that their data is secure, private, and confidential. And for researchers, access to the data is relatively straightforward and really worthwhile.

My message to early career researchers

The National Genomic Research Library is incredible. The scale and breadth of the data is amazing, and there's so many interesting questions that you can explore.

What’s more, the library is continuing to grow. In time, more and more data from clinical genetics practice will be made available, providing extra opportunities for early career researchers.

Now is a great time to get involved, submit a project, and hopefully make a real difference to participants and their families.

And finally...

To hear more about my research, catch the latest Early Career Researcher Cancer Showcase, or check out other research in the upcoming Genomics England research seminars.

You can also apply to join the Genomics England academic research community if you are interested in accessing data from the National Genomic Research Library.

Feel free to check out my Twitter (@DrABlakes) or email me [email protected]