News: Winter 2017

Calum MacRae, MD, PhD: One Brave Heart

Musing over the proposal that netted him a $75 million “One Brave Idea” prize from the American Heart Association, Calum MacRae, MD, PhD recognizing the many applicants for the grant, credits good luck and strong collaborations over ingenuity. “I think the funders were brave to give us the money.”

Nevertheless, MacRae, chief of cardiovascular medicine at Brigham and Women’s Hospital, possesses a breadth of expertise and a big-picture outlook that seem ideally suited to the purpose of the award—to support a groundbreaking idea aimed at preventing or reversing coronary heart disease. The prize is jointly funded by the American Heart Association, Google’s Verily, and AstraZenica.

MacRae’s aim is to develop a more complete understanding of the phenotype of cardiac disease through a combination of technological innovation and a holistic approach that views nearly every aspect of an individual’s biology as potentially relevant to the disease process. To MacRae, who runs both clinical and basic research programs studying the genetics of heart disease, “at the end of the day, genetics is the easy part; there is a single way of understanding the genomes of bacteria, conifers, humans, and everything in between.”

The phenotype—the various forms in which a condition expresses itself during a person’s life, starting long before there is any outward sign of illness—has received too little attention. With new dynamic phenotypes, it will be possible to improve the utility of patients’ genotypes and, in many cases, to identify the biological pathways involved in disease. With better measurement of phenotypes and the environment , and new understanding of how these enormously complex interactions lead to disease, according to MacRae, will address the rate-limiting step in modern medicine.

If MacRae’s proposal challenges the current cardiovascular research paradigm, that’s because the creators of the One Brave Idea prize chose to break with traditional methods of funding. Attendees were informed of the prize and given a scant four weeks to respond. Fortunately, the first-round application consisted of only four questions, each of which had to be answered in 250 words or less.

MacRae’s winning idea—his one brave idea, if you will—was that for the first time it might be possible to describe the phenotype of cardiac disease in a way that is precise enough, and early enough, to allow for interventions that stop it before it causes serious damage. But to do so required looking at individuals much earlier in life, and in far greater depth, than had been done previously.

MacRae seeks a holistic understanding of cardiac disease. In addition to studying patients’ genomes, epigenomes, transcriptomes, and proteomes, the team will collect information on a broad range of characteristics, including features of skin, bone, behavior, and more. Though most may turn out not to be relevant to heart disease, chances are that some will, and the only way to find them is to look.

To illustrate where such an approach might lead, MacRae offers the example of obesity. Maybe the reason for obesity is the genetic variants that cause the disease also change the way you think about food. Or maybe they change the bacteria in your gut. We’re trying to be agnostic in the way we think about coronary heart disease. We need to think about it as a heart disease or a cholesterol disease but as a problem that we need to solve. Unless you understand the whole patient and the whole disease, it’s very difficult to understand how any individual piece of it might work.”

This approach would not be possible without a grant on the scale of the One Brave Idea prize. MacRae compares it to funding a startup company with its “fail-quickly” approach that supports risk-taking – “do fifty experiments, then pick the two that really work and take them across the finish line. I’m under no illusions as to how easy it will be.”
After decades of medicine dominated by specialists, MacRae sees a resurgence in the role of the generalist – “but a different type of generalist, one interested in learning the fundamental rules of how everything fits together, which is made possible by new technologies and new methods of analysis.

The end result won’t simply be a better understanding of heart disease or even better treatment and prevention. For one thing, MacRae sees this project as overturning the way science is done. For another, it has the potential to change the doctor-patient relationship. Patient visits are shorter than they used to be, and most of the time is spent collecting data. Technology should improve collection and analysis before, during and after the appointment, freeing up time for the doctor to get to know patients on a deeper level.