Star Scientist - Dr Emma Rath
Emma Rath decided to take a big risk when she reached her 40s, ditching her career in IT for medical research
22 August 2023
It was a gamble, but this stunning change in direction has more than paid off.
She’s now Dr Rath and working in the Institute’s Computational Genomics facility where’s she uncovering the secrets of congenital heart disease and dilated cardiomyopathy.
What made you move from IT to medical research so late in your career?
I had worked for decades in the IT industry but started getting to the age where loved ones around me were getting sick. Then when a close family member got cancer, I decided I wanted to use my IT skills for medical research. I enrolled in a Masters by Coursework in Bioinformatics. Then did a Masters by Research in Bioinformatics. I loved doing research, so I undertook a PhD in Structural and Computational Biology at the University of Sydney which allowed me to also spend time at ANSTO and at the Asbestos Diseases Research Institute. I started off focusing on bioinformatics computational biology but when I got the chance to go into the wet lab, that was a real wow moment. I had the chance to figure out the structure of an anti-cancer compound. It was important for me to have the chance to be in a lab and find out where the data comes from and see the blood, sweat and tears that goes into research.
What attracted you to the field of bioinformatics?
I liken my work to that of being a data detective because I process and analyse DNA data using large computers to search for any problems that might be causing disease.
In each of our cells, we have chromosomes made up of DNA. Each cell has six billion 'letters', called nucleotides, of DNA. The different regions of DNA on the chromosome are different genes. DNA genes are used to create RNA, which is used to create proteins and enzymes.
At the beginning of my research studies, I was studying protein sequences. Now in my current work, I am studying DNA sequences.
How do you even begin to make sense of six billion different letters?
At the Institute, our team is looking into genetic causes of cardiac diseases congenital heart disease (CHD) and dilated cardiomyopathy (DCM). We sequence the genome – all six billion nucleotides of DNA – of patients whom we know that their cardiac problem is genetic, either because it runs in the family, or they were born with a defect.
To sequence, we can’t just start from the beginning of each chromosome and read to the end. It’s too long. The most accurate technology can read only around 150 nucleotides at a time.
So we break the chromosomes into hundreds of thousands of fragments and read chunks of 150 nucleotides. The technology has an error rate of one percent. So we don’t read each chromosome just once. We need to have dozens and dozens of copies, so that when there is an error – on average one error every 100 nucleotides – then we can see it is an error because the dozens of other copies don’t have that specific error. That’s how we get the error rate much lower than one percent. So now we have hundreds of millions of DNA sequencing reads, each 150 nucleotides long, and we assemble them into chromosomes, like a jigsaw puzzle. And when we do that, then we can see where this patient has a variation or mutation that is different to what most of the rest of the population has.
It must be heartening to deliver families answers – to finally solve the mysteries of their disease.
It’s really rewarding work. We recently helped a little boy’s family who had been searching for eight years for the gene causing his heart defect, doing test after test. We looked at all of his DNA data, using our cutting-edge analysis software, and we eventually found the gene mutation. At some point during embryonic development, a gene protein called NFE2L2 has to clip onto another gene protein called KEAP1. Because he had a gene mutation in this place, they couldn’t clip together properly and that caused a heart defect because development didn’t occur properly. Now that the family finally has a genetic diagnosis, they can do genetic counselling and plan more babies without worrying about having heart problems in their future kids. Also, now that they know what syndrome he has, they know what developmental support he will need as he grows up.
We also have patients where we know that there have been a few cases of DCM in the family. There must be a genetic mutation running through that family. If we can identify the genetic mutation, then we can cheaply screen all the members of the extended family. For those members who have the mutation, we can inform them that as they get older, in 10 or 20 years, they will likely develop a cardiomyopathy and we can start monitoring them. When they need it in the future, they will start treatment with heart drugs. This is instead of the first symptom we notice being a sudden cardiac arrest which is fatal in nine out 10 cases outside of hospital.
Is every mutation you find disease causing?
When we undertake genomic analysis for lots of patients, we end up with hundreds of Variants of Unknown Significance (VUS). A VUS is a mutation in a gene that is associated with the cardiomyopathy and one we think might be harmful, but because we don’t see this mutation in large population databases, we can’t be 100 percent sure.
But when we see this same VUS emerge in multiple patients and families, there is a good chance that it might the cause of the DCM. So, we pass these variants on to the 'functional genomics' researchers. They will test those specific variants in living cells in a petri dish, or even in mice and will then confirm whether this VUS really is causing the disease or not. It’s time consuming and costly, but patients and their families really need to know.
Why do some families have members who have the same mutation yet have different outcomes?
Even when we know the primary mutation causing the disease, there can still be 'variable penetrance' in cardiomyopathies. That is, two people in the same family have the same causal mutation and the same disease but one family member has the disease worse than the other. Some of that variable penetrance can be due to environmental factors. And some is due to genetics. There may be adults in the family who have reached adulthood, whereas a younger person, such as a child, has a cardiac problem.
One of the ways that we are trying to grapple with variable penetrance of mutations is by looking at hundreds of thousands of people and their health data, examining the differences in the millions of variants, and coming up with Polygenic Risk Scores (PRS). Bioinformaticians and statisticians identify the 10 or 100 variants that can be different and the difference seems to affect your risk of getting a disease. Then we test whether you have those specific mutations. It’s really cheap to test a few mutations instead of testing all six billion nucleotides. Then we calculate your PRS, as a guide for your risk of getting the disease. Analysing DNA data and generating new PRS scores for the population is currently a busy area of research.
How did you end up working at the Institute
I spent the first three years working at the Garvan Institute for Medical Research where I undertook whole genome sequencing of people who were healthy versus those who had developed cancer. I then got the chance to join Associate Professor Eleni Giannoulatou’s lab. She’s amazing to work with – she’s so good at building up the team’s spirit. Some people have to go off and do management courses but Eleni is a natural leader and also has an incredible technical background. I hope to stay in her team for many years to come.
What’s it like being able to collaborate with so many researchers at the Institute?
We are not siloed in our work. We get to work closely with Professor Sally Dunwoodie’s team as well as Professor Fatkin’s team, so I get an insight into different areas of expertise and biology. It’s very interesting work and I feel like I am also developing and learning new things all the time.
How do you juggle having a family and building your career?
Most of our team are able to work from home. We don’t need to be in the lab like many of the Institute’s researchers who can’t just press a pause button on their work. I can work hours that suit my job and my children. I can be there when they come home from school, and they can talk to me. I think this job allows me to be a better parent. It also means that I can undertake hobbies with my children too. I’ve just started doing archery with my daughter and we are also learning Chinese together. We haven’t got very far yet, but we are having a lot of fun learning together.
Acknowledgement of Country
The Victor Chang Cardiac Research Institute acknowledges Traditional Owners of Country throughout Australia and recognises the continuing connection to lands, waters and communities. We pay our respect to Aboriginal and Torres Strait Islander cultures; and to Elders past and present.
