Daniel MacArthur

Daniel MacArthur grew up in a medical family. “My father was a clinician and my mother a physiotherapist, so I grew up with conversations about the human body and how it works at a mechanistic level.” But he didn’t decide on a scientific career until much later. “I had always loved      the process of distilling ideas into the written word, so I had assumed my career path would be something like journalism. It honestly wasn’t until the week before I submitted my university preferences that I fully realised that I was far more interested in a path in science or medicine.”

As a result, he did his undergraduate degree in biomedical science at the University of Sydney, Australia. Although this course was primarily designed as the first step for students planning to pursue a graduate medical course, he was still undecided about whether to go down the research or clinical path.

His first exposure to research made up his mind. “I did a summer student placement in the lab of Professor Kathryn North.  I was working on a set of patients who had the class of muscle disorders known as muscular dystrophy, but who did not yet have a genetic diagnosis. During my placement I was able to find a particular protein that was missing in the muscle of two of the patients, and then sequence their DNA and find the causal mutations. Both patients had been waiting for a diagnosis for over a decade, and this hooked me completely on research: the intoxicating idea that, with a particular set of experiments, it was possible to come up with an answer that was not just interesting scientifically but could deeply change patients’ lives.”

To come up with something so fulfilling so early in a career is quite unusual, and MacArthur gives full credit to Kathryn North. “Giving an undergraduate student the  chance to try something really important in such a short research project was remarkable,” he notes. He went on to complete an Honours research year and then a PhD with North, who remains an important mentor. “So much of what I’ve learned about research, collaboration, and leadership has come from Kathryn,” he says.

After a postdoc project at the Wellcome Trust Sanger Institute in the UK in 2012, MacArthur moved to the Broad Institute of MIT and Harvard, US, to build a new research team in a recently established department led by renowned statistical geneticist Mark Daly. Among other projects, MacArthur’s team began working with exome sequencing to improve the diagnosis of patients with very rare genetic disorders. But they quickly realised that what they were missing was the existence of good reference datasets to give a picture of normal genetic variation in the general population. “At that time we had a resource that contained just over six thousand individuals, was pretty outdated in terms of data quality, and just wasn’t large enough to allow accurate diagnoses.”

However, he was surrounded by a group of scientists at the Broad Institute who were involved in generating exome sequencing on a massive scale. “They had already sequenced tens of thousands of people, mostly as part of large case control studies of the genetics of common complex disorders, like type 2 diabetes and coronary heart disease     . And over the course of a few months I worked with leaders at the Broad – especially Mark Daly, David Altshuler, and Sek Kathiresan – on a really ambitious plan to collect all the human sequencing data being generated at the Institute, and to aggregate it into a single, unified resource of genetic variation that we could share with the world.”

That resource became the Exome Aggregation Consortium (ExAC), launched in 2014, which had an immediate impact on the diagnosis of rare disorders worldwide. It was renamed two years later as      the Genome Aggregation Database (gnomAD), and has continued to grow over time, now encompassing exomes and genomes from nearly a million people. “This work was both extremely challenging and deeply rewarding because the sheer scale required people with lots of different  backgrounds – data scientists, software engineers, computational biologists, project managers – to come together to solve fundamental problems in both genetics and computation,     ” he says. “But the impact has made it all worthwhile – millions of patients worldwide have now benefited from diagnostic tests that use the gnomAD resource.”

MacArthur credits the success of gnomAD to being in the right place, at the right time, with the right people. “I was so lucky to have an incredible series of postdocs, computational biologists, and engineers in my group who did a lot of the heavy lifting, but we could never have pulled it off without a much larger team including data scientists, engineers, project managers, and many other experts across the Broad Institute, and of course the many researchers and participants who donated their data to the programme.”

He left the Broad to come back to Australia in early 2020, and is now Director of the Centre for Population Genomics (CPG), a joint initiative of the Garvan institute of Medical Research in Sydney and the Murdoch Children’s Research Institute in Melbourne. The work of the CPG is focused on addressing challenges to the equitable, population-scale implementation of genomic medicine. The Centre’s major programmes include OurDNA, which is currently recruiting 10,000 Australians of diverse ancestry and collecting DNA and live cells, and a rare disease programme that has already provided diagnoses to over 450 families affected by severe genetic conditions.

The work of gnomAD continues to thrive under the leadership of Heidi Rehm and Mark Daly, and MacArthur is still an active contributor to the program. “It’s so common in academia for projects to die when a researcher moves on, and I’m really grateful that Heidi, Mark, and the broader team have not just kept gnomAD alive, but continued to massively grow and improve it.”

MacArthur’s time outside of work is largely focused on his family. “I have three young boys, and it’s such a privilege to spend my time with them as they grow and develop into increasingly awesome human beings.”

In his lecture, he will describe the origins of gnomAD and the power of open science, making data available early and as easily as possible, as well as the work he is currently leading in Australia. “I’ll be covering the need to build genomic resources that are designed from the outset to lay  the foundations for the next phase of genomic medicine, and to make sure its impact is equitable.”