Why you should care

A disease that turns a crucial part of the heart to stone — or, more precisely, into bone — affects about 5 million Americans. 

With a newly minted Ph.D. and a coveted senior research biologist position with San Francisco Bay Area biotech firm Berkeley Lights, Mark White is something of a golden boy. During his doctoral studies at the Gladstone Institutes and UC-San Francisco, he earned a reputation as both a brilliant scientist and a generous soul. White was always first to volunteer time from his experiments to lead visitors on tours of his lab. No one would think of him and call to mind a heart of stone. But he’s on a path to just that — literally — unless advances in our understanding of a strange heart abnormality can reveal a solution.

When White was 7, a pediatrician heard a faint heart murmur. A test called an echocardiogram revealed the culprit: a bicuspid aortic valve. In other words, White was born with only two leaflets — rather than the usual three — in his aortic valve, a crucial channel that carries blood from the main pumping chamber of the heart, known as the ventricle, into a major blood vessel called the aorta. His twin brother also has a bicuspid aortic valve, as do roughly 5 million Americans, many of whom aren’t even aware of their condition.

Over time, a seemingly minor defect turns the otherwise delicate structures of the aortic valve into stone, or, more precisely, into bone.

Despite these astounding numbers, bicuspid aortic valve gets little press. It’s not disfiguring, and most affected individuals can lead normal lives for decades. But over time, this seemingly minor defect evokes a strange response from the otherwise delicate, almost translucent structures of the aortic valve: They turn into stone or, more precisely, into bone, a process known as aortic valve calcification. The cells that line the surface of the aortic valve sense that something is amiss and respond by activating molecular signals that normally occur only in cells that form and remodel our skeletons, or osteoblasts.

Bicuspid aortic valve can result in serious complications — from infection of the heart’s inner lining to dilation and even rupturing of the aorta. These typically strike at around age 55 to 75 and often require risky surgery to replace the aortic valve. Some families carry genetic mutations that accelerate bone formation, which can cause these symptoms to appear at an even younger age. An estimated 500,000 Americans have aortic valve calcification severe enough to cause symptoms. Without corrective surgery, half of these patients will die within two years.

White unearthed crucial features of the molecular signaling mechanisms that control the activity of the cells that line the aortic valve.

Even as a preteen, White brainstormed solutions to protect himself and his brother from these grim realities. He imagined ways to grow a new valve inside his own body as an alternative to conventional mechanical implants or pig heart valves. At the Gladstone Institutes, he applied cutting-edge molecular approaches to studying aortic valve disease in humans, as opposed to then-conventional studies in laboratory animals. He also used emerging DNA sequencing techniques to profile the activity of thousands of genes in aortic valve samples derived from patients undergoing heart transplantation.

And his perseverance paid off. White’s research unearthed several crucial features of the molecular signaling mechanisms that control normal versus abnormal activity in the cells that line the aortic valve, laying the foundation for new technologies to control their development and behavior.

Thanks to White and his colleagues, scientists can now begin to explore ways to prevent bone formation in bicuspid aortic valve patients. Meanwhile, White and other researchers at King’s College London have learned how to reprogram skin cells into endothelial cells, which form the inner lining of blood vessels and are related to the cells that line the valve structures — removing the need to surgically acquire cells from the heart itself. This technological tour de force opens the door to the discovery of small molecules, potentially useful as medicines, to prevent the activation of bone-forming pathways.

White and his colleagues hope to develop a simple preventive measure, like a daily pill, that would deflect heart cells otherwise intent on turning the valve into stone toward more normal behavior. If they succeed, they could finally transform White’s heart of stone into its true form: a heart of gold.

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