Clues in Our Cells & New Approaches to Heart Disease
Being able to look deep inside a cell, study its finely tuned recycling system and use that knowledge to test novel interventions for heart disease gives Roberta A. Gottlieb, MD, a tremendous sense of wonder and satisfaction.
"The cell is such a complicated network—it's amazing," said Gottlieb, director of Translational Research in the Barbra Streisand Women's Heart Center, director of Molecular Cardiobiology in the Smidt Heart Institute, and the Dorothy and E. Phillip Lyon Chair in Molecular Cardiology in honor of Clarence M. Agress, MD.
Now, researchers in the Gottlieb Laboratory have invented a powerful tool that enables them to see up close and in real time how cells process unwanted, unnecessary or damaged components. Of particular interest is the disposal of organelles, specialized structures within each cell that include the mitochondria, which serve as cells' energy factories. This tool paints the mitochondria in different colors based on how long they've been in the cell and reveals specialized regions that give rise to new mitochondria.
"For us, this breakthrough is like stepping onto the moon for the first time," said Gottlieb. "Nobody's been able to look at mitochondrial turnover this way before. We are seeing new things in tissue, and we're just at the beginning. It will take us a long time to plumb the depths of this discovery."
The Gottlieb Laboratory's emphasis on translational research, which seeks to advance groundbreaking ideas from the bench to patients' bedsides, is a top priority of the research program in the Barbra Streisand Women's Heart Center. Its overriding focus is to find ways to intervene as early as possible to treat or even prevent cardiovascular disease.
Other lines of inquiry include research into the impact of sex hormones on energy balance and metabolism, led by Deborah Clegg, PhD, a research scientist with the Diabetes and Obesity Wellness and Research Institute at Cedars-Sinai. She is collaborating with faculty in the Barbra Streisand Women's Heart Center to explore the connection between heart disease and hormones such as estrogen.
In addition, physiologist Michael D. Nelson, PhD, a project scientist at the center, uses advanced imaging techniques to pinpoint diastolic dysfunction, or problems in the heart's relaxation phase, in women with ischemia, a condition marked by decreased blood flow and oxygen to the heart muscle. The goal is to prevent a possible progression to heart failure.
Understanding life inside a cell—and how quickly the energy-producing mitochondria are recycled under normal conditions and in response to injury or illness—is critical to developing new treatments for heart disease.
"Faulty mitochondrial turnover is most likely at the root of many, many diseases," explains Gottlieb. That includes cardiovascular disease as well as neurodegenerative diseases and many cancers. One theory is that poor recycling leads to a build up of damaged mitochondria in the cell, resulting in permanent mutations in mitochondrial DNA.
The Gottlieb Laboratory recently developed a novel protein that glows when viewed with ultraviolet light, allowing the scientists to monitor and time mitochondrial turnover. They call this one-of-a-kind cellular tool the "Mito-Timer." In 2014, the researchers genetically engineered a mouse with the protein. This year, they began producing picture-perfect images of mitochrondrial turnover in action.
Their findings are yielding clues about the power of preventive care and lifestyle choices. It appears that the cell's recycling system—called autophagy—can be sped up or spurred on by regular fasting.
"It gives the cell a chance to tune up the system and return to baseline," Gottlieb said. Unfortunately, the opposite is also true. Intracellular recycling can be suppressed by "a life of excess, especially caloric excess, as in diabetes and obesity."
While examining the heart's mitochondrial landscape, the researchers are also gaining insights into how recycling happens at different rates in different types of tissues. Next up: The scientists want to explore how various cardiovascular conditions, as well as obesity, diabetes and advanced age, undermine the ability of cells to function optimally.
Equally important will be learning which interventions, from exercise to fasting, might accelerate intracellular turnover. Other studies have shown that fasting for relatively short periods might have benefits over a longer span of time. The Gottlieb researchers are planning to compare the impact of various periods of fasting on cell health. "If the theory holds, perhaps instead of taking medications for a heart condition, someone could fast once a week," Gottlieb said.
Also planned is a return to earlier experiments that suggest that heart cells in females may be more efficient at the recycling process. Finding out why females perform better at this task might lead to new therapeutic approaches.
Other research in the Gottlieb Laboratory focuses on a group of cardiac stem cells called c-kit positive cells, which are important for making capillaries and small blood vessels—key players in coronary microvascular disease, which primarily affects women.
As a young physician, before she found her calling in research, Gottlieb specialized in hematology/oncology. One patient, a young woman in the third trimester of her first pregnancy, had just been diagnosed with heart failure, the result of having had chemotherapy for cancer as a teenager.
Gottlieb never forgot the case. Recently, she and her team discovered that chemotherapy drugs can damage c-kit cardiac stem cells. But, the problem doesn't show up until the heart is under stress, as it is during pregnancy, and lacks the reserves to regenerate heart tissue or repair itself.
"Ultimately, if the heart continues to have a demand that the capillary network can't meet, it develops fibrosis and long-term damage, and eventually progresses to heart failure," Gottlieb said.
She is now collaborating with Puja K. Mehta, MD. Together, they are studying women who are being treated for breast cancer to find out whether c-kit positive cells are able to protect adult hearts or are injured by antitumor drugs.
And there is no shortage of cellular territory yet to explore. Since the human body is made up of about 37 trillion cells, a molecular biologist like Gottlieb has job security. For her, the joy comes not just in discovery but also in sharing her passion for research.
"If you light the candle of knowledge in someone else, that legacy keeps on going," she said. "This is why I moved to Cedars-Sinai—to do this kind of work. I'm an MD. I want the science we do to make a difference. That's the endgame."