Genetic Pursuits

Mark McCarthy became a scientist by accident. He arrived at university with plans to become a physician and didn’t give much thought to research until many years later, when a laboratory experience he considered just a rite of passage kicked off a long and fruitful career in science.

As part of his training as a junior doctor in the United Kingdom (UK), he was required to rotate through various specialties and discovered he enjoyed endocrinology – the study of hormones.

“Endocrinology and the associated diseases of the endocrine system provided an intellectual challenge. But at the same time, I appreciated that these were conditions where you could generally do quite a lot for the people who came your way,” says Mark, Executive Director of Human Genetics at Genentech.

Over the years, Mark realized that he would eventually need research experience to reach the top of his field. At the time, physicians in the UK had to have research experience and credentials in order to advance to the rank of consultant, or attending physician.

“At first, I was dragged kicking and screaming into the lab run by my mentor, which studied the genetics of Type 2 diabetes,” he says. “We'd call it imposter syndrome now, but initially it was incredibly painful. I was thrown into a lab and had to start from the bottom up. Having to go into research felt like an unnecessary distraction to me at the time. As if I had become a pretty good 100-meter runner and somebody told me to stop doing that and start throwing the hammer instead.”

Rite of Passage

At first, research was just a box to check so he could advance in his career. Once he got that lab experience, Mark thought, he could go back to being a physician. But something changed during his third year in the lab.

“Over time, I found my feet. I published some papers, gave a few talks, and I realized I was quite enjoying research, particularly the more computational aspects,” he says. “To my surprise, I found myself wanting to continue in the lab.”

His next stop was the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, where he spent a year studying the genetics of more common diseases, which typically involve multiple genes. This transformative time gave Mark the opportunity to truly be at the forefront of cutting-edge genetics research and discovery, which would begin to shape the path for his career researching human genetics. It also boosted Mark’s confidence, showing him he had the skills and a perspective necessary to contribute to this rapidly evolving field.

When Mark returned to the UK, he split his time between the lab and clinic. He took a role at the Imperial College School of Medicine, and then as Professor of Diabetic Medicine at the University of Oxford. As the years went by, he did more research and less clinical medicine until he found himself a full-time scientist.

New Challenge

At Oxford, he was leading a global group working on the genetics of Type 2 diabetes. The team focused on genetic variants that influence a person’s risk of developing Type 2 diabetes to better understand the cellular and molecular underpinnings of the disease. The hope was these findings could help pave the way to new diabetes treatments. But by 2018, Mark was ready for a change.

“It had been a tremendously fulfilling and productive effort. But having accomplished many of my goals, I felt ready for a new challenge.”

He started considering opportunities elsewhere, including at pharmaceutical companies, but nothing seemed to be the right fit until he visited Genentech in August 2018 to give a research lecture on the approaches his team had used to dissect the genetics of Type 2 diabetes.

“Genentech was the first place I visited where I could really imagine myself. Everybody I spoke with was energized, enthusiastic and open,” says Mark. Genentech wouldn’t just open the door to new professional opportunities, but also for his personal passions – such as exploring miles and miles of scenic Bay Area trails on his bicycle.

“I came back from that visit with a glimmer in my eye.”

Although this was his first position in industry, he noticed the company’s principles and approach to science didn’t seem so divorced from his experience in academia – a collaborative environment that values basic research, publishing and mentorship.

Mark notes that he is fortunate to have the opportunity to mentor post-doctoral trainees in his role. “Our postdoc program is an embodiment of Genentech’s curiosity-driven research ideal. While no two postdocs are the same, each with their own strengths, what unites them is their enthusiasm to do impactful research.”

Genetics at Genentech

As the Executive Director of Human Genetics, Mark leads Genentech’s efforts to use genetic data to improve our understanding of human disease and to support the development of potential medicines.

For someone who was initially quite reluctant to pursue research, his work has proven to be tremendously influential. Mark has been included on Clarivate’s list of Highly Cited Researchers, which recognizes scientists who have published multiple papers frequently cited by their peers during the last decade. Since joining Genentech in 2019, Mark has authored more than 60 papers.

Mark’s team studies naturally occurring genetic variants to understand how different versions of a given gene alter the risk of disease. These approaches show scientists what happens in the body when a particular gene works less well – or better – than normal.

“That’s the reason why human genetics are so relevant to what we do at Genentech, and it’s underscored by the observation that therapeutic targets supported by genetic evidence have a twofold chance of making it through the drug development process with the hopes of developing a safe and effective medicine.”

Besides using human genetics to prioritize Genentech’s most promising projects, Mark is working to connect his team with many others at Genentech in a cross functional effort called translational genomics.

Sometimes, scientists will find an obvious mechanistic link between a genetic variant and an increased risk of disease, but often, that biological relationship isn’t so clear. Translational genomics is a highly collaborative effort that brings together human genetics, cellular and tissue genomics, genetic screens, informatics, and computing to characterize the processes that underlie disease risk and progression, and improve our ability to decide which targets are worth pursuing.

Diversifying Genetic Data

Though human genetics can be immensely helpful in drug development, Mark acknowledges that the field still has some critical limitations.

“A disproportionate amount of the genetic data that we have comes from individuals of European descent because the investment to establish biobanks over the years was made in Europe and North America,” Mark says. “That’s not good for science or patients because we’re missing out on a lot of information about genetic variation in other parts of the world.”

Genetics don’t just play a role in a person’s risk of disease – they can also affect how medicines work in different people and what kinds of side effects they may experience. Genentech and Roche, with partners in Africa, Latin America, and Asia, are working to broaden the populations from which we get genetic information.

“If we’re only testing information from people of European descent, we may design a medicine that’s safe and effective in this population, but not so safe and effective in others. Or we might discard something because it has a safety issue in Europeans without knowing if it could benefit patients of other ethnicities.”

Genetics have revolutionized many aspects of medicine, but according to Mark, the field is still in its early days. “We are just scratching the surface of understanding how genetic variation relates to disease. Looking to the future, I am very optimistic that investments we are making now in diversifying our data will allow more people to benefit from important approaches, such as personalized therapies.”