Left: a melanoma tumor with a pink biomarker marking gene regulation. Right: a melanoma tumor with a glutaminase inhibitor. Gradinaru and Kong showed that low glutamine leads to drug resistance.
Credit: Courtesy of M. Kong
Partners in Innovation
Since 2008, the Caltech–City of Hope Biomedical Research Initiative has brought together resources and expertise from the two institutions. Funded by Caltech, City of Hope, and private donors, the initiative provides seed grants to accelerate the development of basic scientific research and its translation into biomedical applications. On September 27, 2016, researchers, doctors, donors, and faculty gathered at the Argyros Auditorium at City of Hope to celebrate this partnership and hear about some of the latest discoveries to come from the collaboration.
“When institutions like ours [are] dedicated to a pursuit of knowledge, and to the practical application of that knowledge to the benefit of patients and families around the world, we can do profound things together,” said Robert Stone, president and chief executive officer of City of Hope, in his opening remarks.
“The partnership with City of Hope is very special. It’s one that’s deep and can have profound impact,” said Caltech president Thomas Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. “Contributing to the improvement of the human condition is something that a biologist or a chemist or a physicist or an engineer at the bench thinks about when they’re doing their experiments. If they find something that they can grab onto, and they have a partner who knows how to translate that, then the combination is formidable and will improve people’s lives for generations to come.”
The symposium featured speakers from two collaborations made possible by the 2014 round of funding.
Perfecting Personalized Therapy
Viviana Gradinaru: assistant professor of biology and Heritage Principal Investigator
Mei Kong: associate professor in the Department of Cancer Biology at the Beckman Research Institute of City of Hope
Cancerous cells are characterized by their rapid growth, and they need the nutrient glutamine to sustain this growth and survive. However, cancer cells that are buried in the center of tumors with very little access to nutrients are actually extremely difficult to kill. Kong theorized that, instead of starving in a low-glutamine environment, these core cells were actually mutating into “super-cells” with drug resistance. She proposed that glutamine plays a central role in gene regulation and that the lack of glutamine leads to more spontaneous mutations, and thus drug-resistant cancer cells.
Kong teamed up with Caltech assistant professor Viviana Gradinaru to find a way to see the distribution of glutamine molecules throughout a tumor and to see if decreased glutamine levels changes gene regulation.
Gradinaru had previously developed a technique to render opaque tissues, such as the brain, completely transparent (a process called clearing) while chemically labeling particular cells in order to create 3-D models of organs and bones. By applying this clearing technique to melanoma tumor samples, the team was able to show that low-glutamine environments did indeed lead to gene deregulation, which leads to drug resistance.
Your Future is Calling
Mory Gharib: director, Graduate Aerospace Laboratories, Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering
Saro Armenian: associate professor, Department of Population Sciences; director, Childhood Cancer Survivorship Program, Beckman Research Institute of City of Hope
Although the survival rates for patients with childhood cancer are increasing (80–90 percent of diagnosed patients survive), people who have had childhood cancer unfortunately are at greater risk for health complications later in life, such as heart failure. Former cancer patients must undergo regular screenings and monitoring for these additional health problems, which can be expensive and time-consuming.
One important measure of heart health is the so-called ejection fraction, the fraction of blood that is ejected from the heart with each heartbeat. A healthy heart will have an ejection fraction around 64 percent; too low or too high of an ejection fraction indicates health problems. Gharib, who is a faculty member in Caltech’s department of medical engineering within the Division of Engineering and Applied Science, wanted to find a way to measure the ejection fraction using the theory that the human body can be modeled as a “wave field”—with each pump of blood, the heart sends vibrations throughout the body that can be modeled as oscillating waves.
When the heart is pumping, the aortic valve (the valve that blood passes through on its way to the rest of the body) is either open or closed. When it is closed, the heart is sealed from the rest of the body (a “decoupled system”) and when the aortic valve is open, the heart and the body are one, “coupled” system. Gharib used mathematical models of these two systems to calculate a so-called intrinsic frequency characterizing each, which he then used to compute the ejection fraction.
The next step was to develop a way to measure these intrinsic frequencies in a noninvasive way that patients could do on their own in order to check their general heart health. Gharib, Armenian, and their groups designed a small piece of hardware that can connect to an iPhone and calculate a patient’s ejection fraction—for less than $8. The device, called Vivio, gives comparable results to a cardiac magnetic resonance imaging, the gold standard in the medical industry for measuring heart health.
Both Gradinaru and Gharib’s projects were part of the 2014 round of funding. Seven Biomedical Research Initiative teams, including Gharib’s and teams led by Mikhail Shapiro, Alexei Aravin, Joel Burdick, Andre Hoelz, Mitch Guttman, and Linda Hsieh-Wilson, received support in the 2016 round of funding.
Written by Lori Dajose
California Institute of Technology