Ace of Hearts: A Conversation with Developmental Biologist and Cardiologist Deepak Srivastava

Deepak Srivastava, MD, remembers his first broken heart. It came from a frog.

"It happened in my high school biology class. I had to dissect out a frog heart and when I did, it continued to beat in the petri dish. I couldn't believe it. I was totally enamored. So I took it home."

The heart finally gave out around midnight, some 12 hours later. "My parents kidded me about watching it until the end, but I thought it was the coolest thing. Ever since then, I have been fascinated by the heart."

No wonder, then, that the 40-year-old Srivastava is happy in his work. As director of the Gladstone Institute of Cardiovascular Disease, the LA- and Texas-reared and self-described "man in a hurry" is riding a wave of excitement about cardiac stem cells. It is a wave he helped generate with his earlier work at the University of Texas Southwestern Medical Center, and one he continues to build since returning to San Francisco in 2005. During his previous stint at UCSF as a pediatrics resident, Srivastava met his future wife, a pediatric clinical research nurse.

"I feel compelled to understand the causes of heart disease and create new interventions for them," says the man who once aspired to an investment banking career before "seeing the light." Millions have a stake in his success; heart disease remains the country's number one killer. And while Srivastava concentrates on how genetic defects arise — specifically the molecular events that instruct so-called progenitor cells to fashion a normal heart or, as in one out of 100 live births, a malformed version — he remains a basic scientist with a clinician's instincts.

"We approach heart problems from both sides of the equation, which is a little unusual," says Srivastava, who runs his own 20-person lab while overseeing another 80 or so institute scientists. "Most heart researchers are trained either as human geneticists — who work with patients to try to find their disease-causing genes — or they are trained as molecular or developmental biologists and they work with animal models. We do both. And we go back and forth interrogating people's DNA to try to understand the mechanisms underlying disease."

Interrogation and integration have worked well so far. Some examples: Over the last decade, Srivastava and his colleagues have come to understand a network of genes that compel an undifferentiated cell to become a heart cell. They also have teased out how to both direct a cell to its fate and keep the production line for future cells in operation. Moreover, he has found that some of the same genes that make a heart are the ones that directly cause human childhood and adult heart disease when mutated.

And in what might serve as a screaming headline for translational research — and a tribute to its serendipitous nature — Srivastava and his research team have also found a protein called thymosin beta-4 that has not one, not two, but three remarkable properties.

First, thymosin beta-4 is critically important to cell movement in a developing heart, which is why researchers in Srivastava's lab studying how congenital defects occur first found it interesting.

Second, thymosin beta-4 protects heart cells from dying when they don't get enough oxygen. And third, it stimulates the formation of new blood vessels.

You can almost hear the dots connecting. A number of animal tests later, Srivastava and his collaborators learned that thymosin beta-4, which is a small enough protein to be made synthetically, both protects and repairs cells damaged in a heart attack, at least in mice. Will the same prove true for humans? The answer could come sooner than we think. Phase I clinical trials in human heart attack patients will begin at UCSF and elsewhere around the country next year.

Of course, not every lead pursued in the lab can turn up something as promising as thymosin beta-4. But there is a confidence about Srivastava, the father of three, that is reassuring, even in a research area like stem cells, which is so fraught with hype.

"Once you get a cell to become what you want it to, and then get them in enough numbers, you have to figure out how to deliver them properly to the organ of choice, and then have them integrate appropriately with the cells already there and not get rejected," Srivastava says without hesitation. Daunting? Yes. But not insurmountable. "Each of them can be addressed," Srivastava adds cheerfully.

Indeed, if you had to name the vibe that most aptly describes a man who traded Wall Street for Owens Street, it is cheerfulness laced with self-awareness and certainty. Srivastava, who likes to read books about the nature of leadership (being genuinely caring is key), concedes that it was not always so.

"During the first week of school during my senior year at Rice [University], I met a freshman English major who ended up helping me paint my room. She kept asking me all these deep questions about my life and what I wanted to do with it. I was an economics major at the time, but by 4 a.m., it was crystal-clear in my mind that I should not become an investment banker - that I should become a scientist instead. The next morning, I changed all my classes, and I never debated or reconsidered my decision again."

Fortunately, Srivastava liked science [his father is a biochemist] and had taken enough courses to at least apply to medical school. He was only 19, but he was accepted.

Now, as he leads an internationally prominent institute across the street from UCSF's Mission Bay campus, does Srivastava ever think back to that night in Houston when his life changed forever? "Yes. I'm still close friends with the woman who asked me all those questions. She takes enormous credit for what I'm doing and she deserves it."

If Srivastava's research continues to go well, it seems she will not be the only one applauding.

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Related Links

Gladstone Institute of Cardiovascular Disease

The J. David Gladstone Institutes at UCSF

Srivastava lab

Congenital heart disease

iVillage Total Health

Cardiac development: Transcription and the broken heart

Nature, March 12, 1998

Potential of stem-cell-based therapies for heart disease

Nature, June 29, 2006

Making or breaking the heart: From lineage determination to morphogenesis

Cell, September 22, 2006