Nov. 14, 2002 UCLA scientists coupled the protein that makes fireflies glow with a device similar to a home video camera to eavesdrop on cellular conversations in living mice. Reported in the Nov. 11 online edition of the Proceedings of the National Academy of Sciences, their findings may speed development of new drugs for cancer, cardiovascular diseases and neurological diseases.
Led by Dr. Sanjiv Gambhir, UCLA associate professor of molecular and medical pharmacology and director of the Crump Institute for Molecular Imaging, the team's research will allow scientists to study how cellular proteins talk to one another. These communications trigger changes that regulate a healthy body and cause disease when the signals go awry.
Gambhir and his colleagues used an optical camera equipped with the same kind of computer chip used in home video cameras to convert light into electrons. The team injected luciferase, the protein that makes fireflies glow, into cells, then injected the cells into the mouse.
They saw a remarkable sight. Each time two specific proteins spoke with each other, it activated the luciferase. The luciferase illuminated under the camera and produced brilliant flashes of light in the mouse.
"The mouse literally glowed under the camera," said Gambhir, a member of the UCLA Jonsson Cancer Center. "We 'heard' the proteins 'talk' by watching the communication pathways come to life."
"In the past, we had to extract an individual cell from an animal and use a microscope to study how cellular proteins communicated with each other," Gambhir said. "Now we can watch proteins in the same cell talking to each other in their natural setting."
"It's similar to when the switchboard operator used to eavesdrop on people's telephone conversations," he said. "Our technique enables us to listen in on multiple conversations in cells taking place deep within a living animal."
According to Gambhir, the discovery will enable researchers to create and evaluate new ways of treating human disease. "Human disease is often caused by a single misfiring during a series of intracellular communications," he said. "If we can understand and monitor what goes wrong, we may be able to develop drugs to block or improve cells' ability to process their proteins' internal conversations."
Cells rely on receptors that line their surfaces to communicate between the external world and their internal environment. Functioning like baseball catchers' mitts, the receptors continually grab and release different hormones and molecules that influence cellular communication activity.
"A cell receptor has no voice or vocal cord," Gambhir said. "It must plug into the cell's protein network to speak. One protein moves and acts on another, which sets off a chain reaction of conversations. Finally, the message reaches deep into the nucleus and tells the cells' genes what to do."
Gambhir said that the new system could be used to test drugs that target protein-to-protein interactions in mice or advance medical research with a new breed of mice that indicates when intracellular interactions take place. The method is non-invasive and does not harm or cause pain to the mouse.
"This technique can help us better understand the processes of many human diseases," Gambhir said. "For example, we can image new drugs for cancer that halt cell division and actually see whether or not they work in the living body. If the drugs don't stop cell growth, we can design better drugs and test them under the camera. The possibilities are endless."
The National Cancer Institute and Department of Energy funded the study. Gambhir's co-authors included R. Paulmurugan from UCLA and Y. Umezawa from the University of Tokyo.
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