Thursday, March 7, 2013

Born with half a heart but full of life and hope for the future

Joshua Goulart, playing Little League
I thought of Joshua when this week’s rainstorm walloped the Bay Area. He must have been thrilled. He loves big storms, strong winds and anything associated with the force of nature. Maybe that’s because he is a force of nature. Joshua was born without a left ventricle, essentially half a heart, due to a birth defect.

Just a newborn, he endured three open-heart surgeries and a massive stroke that killed 60% of his left brain. Despite very long odds of survival, and the prognosis that he’d never walk or talk, Joshua and his family never gave up. And through years of continuous therapy and true determination, Joshua now 11 is doing remarkably well. Yet, as pediatric cardiologist Deepak Srivastava pointed out during CIRM’s Spotlight on Stem Cell Advances in Pediatric Heart Disease seminar that Joshua:
“has a looming problem on the horizon where he will require a heart transplant if we're not able to find a better solution for him. And that's not a great solution for a 15- or 20-year-old. It may be good for a 70-year-old. But it's not a good solution because [heart transplants] don't last a lifetime.”
You can watch videos of those talks on our website.

Based on this reality, Joshua’s mom Mary Goulart, who also told Joshua's story at the Spotlight, expressed both her gratitude for how medical research has helped her son but also her hope for stem cell advances in the future:
“Only 30 years ago, the joy of loving our son and watching him grow and thrive today would not have been possible. But because of long-term funding and incredible research, our precious boy, along with hundreds and maybe even thousands of others, is here to show us there is always hope. So our hope now, today, is that regenerative medicine can find other options for our son, should his heart start to fail in the future. I'm very, very hopeful.”
Joshua after a heart surgery
 Dr. Srivastava has made great strides towards reaching the hopes of Joshua’s family through his roles as both a pediatric cardiologist and director of Roddenberry Center for Stem Cell Biology and Medicine at the Gladstone Institutes. He has done much of this work with funding from CIRM (you can read descriptions of his awards here.)

For the past fifteen years, his focus has been on understanding congenital heart disease, which basically arises from faulty genetic instructions for building the heart during early development. By using embryonic stem cells to recreate the various developmental stages of heart cells, Srivastava and his colleagues figured out which genes normally control how the heart forms. With that information in hand, they then identified that some of these genes, when mutated, were responsible for known human congenital heart defects.

But knowing the mutation doesn’t necessarily tell you the disease’s mechanism. After many years of trying to study mechanism in mouse models but hitting roadblocks, the breakthrough came with Shinya Yamanaka’s induced pluripotent stem cell technique. Now Srivastava has been able to make iPS cells from skin samples of patients with heart defects and then grow them into heart cells to uncover the disease behavior in a way they couldn’t have before:
“We have been able to figure out mechanisms by which these gene mutations are actually causing disease--what genes they're regulating, how it's disrupted, to the point that we're now beginning to screen for drugs that will alter or reverse the pathophysiology. We could not have done this without the use of stem cell technologies, and did not do it for five years even when we had discovered these gene mutations.”
For severe defects like Joshua’s, Srivastava believes they now have the knowledge and skill to grow stem cells into the necessary cell types that make up the various parts of the heart. The challenge is using regenerative medicine and bioengineering to build these cells into the correct three dimension structures, for example a ventricle or a heart valve that will provide a long-term solution. And so his next step is to build a team to help re-build the heart:
And so the very next person I'm trying to recruit to Gladstone, then, is a bioengineer to put he or she into the mix with the chemist, the computational biologist, the stem cell biologist, that we have on the same floor, and let those people go at it and do their magic in this multidisciplinary fashion. I think that's where the next breakthroughs will come from.
T.D.

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