Enhancing and expanding the utility of Target 5000 - Q&A with Adrian Dockery

Can you tell us a little more about your research project?

Our study is called Target 5000. We combine medicine and genetics to best help our participants, who have genetic conditions that cause visual impairment. There are lots of different teams involved in the project and Fighting Blindness are the glue that sticks them all together. There is a genetic counselling team, three medical teams and a scientific team. I am part of the science team led by Prof. Jane Farrar, based in Trinity College Dublin. Our team consists of two parts, we have a gene therapy group and the Target 5000 group. Both teams work very closely together to inform and enhance each other’s work.

The Target 5000 pathway starts in the hospitals when people go to see their ophthalmologist, because they suspect there may be an issue with their sight. After a couple of tests and a chat about family history of vision issues, our ophthalmologist might start to consider that the issue is genetic. This is where the science team comes in. We receive a blood sample from this person and we register it in our biobank (a biobank is just a fancy term for a very well organised set of freezers). We then filter the blood to just keep the genetic material (DNA).

Once we have the DNA we can decide what the best way to analyse the sample is. This is usually decided by the type of condition that that person has. Some conditions are associated with very specific regions of DNA and we can start our search there, however other conditions can be caused by many different types of change in their DNA and so we have to take a different approach for those. If there is a known genetic change in that person’s family, then we can just test for that very specific change. Sometimes it’s not very clear what the condition may be, so we test for everything we can.

Interpreting the genetic test results is probably the most challenging part of the job. If we have to search “everywhere” in the DNA, we can expect to find well over 20,000 changes per person. Even though we know that we get half of our DNA from each parent, almost 200 of these DNA changes (or variants) will be completely new and not from your parents at all. Almost all of the changes that happen in your DNA will never impact your health or quality of life, but in some cases, one or two changes are enough to cause a genetic condition.

Each time we assess one of these changes we essentially put that variant on trial, to determine if it is likely to be innocent (benign) or guilty (pathogenic). To do so, we have to look at what evidence we have about that variant. We have a couple of sources of information that we use to determine this. We can use computer programs to predict if the changes is likely to cause a harmful effect. We also know that the conditions we work with are very rare, therefore the variants that cause them must also be very rare.

If we have samples from the participant’s family, we can use them to see if the affected people have the change, and if the unaffected people don’t. We call this “segregation analysis” and it is one of the most powerful lines of evidence we can use. When we combine all of this evidence, we can decide if we think the change is pathogenic or benign. We have analysed over 700 families now and in 70% of these, we have found variants that we believe are pathogenic. In the other 30%, it is now a matter of expanding our search to check for other possible variants.

What attracted you to retinal research?

I have been interested in genetics from a young age. Once I started studying genetics in university, I knew a role in medical genetics was my dream job. I found it so fascinating, everything from the diagnostics to the potential for therapies. So after my bachelor’s degree, I did a Master’s degree in Molecular Medicine. During my Masters I went to a lecture on retinal research and gene therapy that was given from a member of Prof. Farrar’s lab.

Once again, I knew that was exactly the kind of work that I wanted to do. I was able to secure a research placement in Prof. Farrar’s lab for a few months as part of my Master’s degree, and at the end of the placement I was offered a PhD position. I completed my PhD two years ago and have been working as a postdoctoral researcher ever since.

The eye is such a magnificent achievement of biomechanical design. The combination of light refraction with cell signalling still seems like a work of wizardry to me sometimes. From a genetics point of view, the retina is really interesting. So far, we know of at least 300 genes that the eye needs to develop and function correctly.

It has been captivating to learn how many of genes work and interact with each other. The fact that the eye is also quite a contained organ is a huge advantage in terms of treatment potential. That is made particularly clear by the number of clinical trials for gene therapies currently ongoing for conditions of the eye.

Within the next five years, where do you expect great advances to be made in vision research?

I have no doubt that there will be lots of progress made in the field of gene therapies, it is a very exciting time to be in retinal research. There have been some really promising therapies in development for quite some time now and for a range of conditions. My hope is that now that one therapy, Luxturna, has received EU approval, many promising treatments will follow close behind it. Therapies that are designed to treat other conditions where there are currently no other treatments available for.

I am also optimistic that genetic diagnostic rates for rare conditions will improve in the next few years. There are lots of brilliant people currently working in this area and I would love to see our own detection rates move from 70% up closer to 100%, because at the end of the day, these are not just percentages, but real people and real families. We may never achieve 100% but that certainly won’t stop us trying.

Lastly, many of our European neighbours have far superior national investment in genetics services. I am quietly optimistic that Ireland’s genetic diagnostic service will start to catch up in the next few years. I think there needs to be more attention brought to this issue, not only to develop the necessary infrastructure, but also to identify and train the people that would be required for such a service.

What are your other interests?

I like to think that I am constantly learning new things, even outside of my role as a scientist. I love fixing things and finding out how things work. I have an old racer bike that I constantly take apart and put back together. I have also spent a lot of time on Coursera lately, it is a website that allows you to take online courses from some of the best universities around the world. I have recently got certificates for courses in areas of medicine, computer programming, and clinical trials. I am currently learning about cataract surgery which is very interesting.