REHOVOT, Israel - August 22, 1997 - A molecular "radar" that makes it possible to track signaling enzymes inside a cell in real time has been developed at the Weizmann Institute of Science. Using the "radar," the scientists mapped the exact progress of an intercellular messenger that plays a key role in embryonic development.
The achievement, reported in the August 22 issue of Science and featured on the journal's cover, is expected to prove valuable in gaining a better understanding of how signals are transferred inside a cell and how the signaling process goes awry in diseases, such as cancer.
"Previously, in studying message transmission inside the cells of a developing organism, we scientists were rather like people at an airport watching the planes take off and land," says research team leader Prof. Ben-Zion Shilo who heads the Institute's Molecular Genetics Department. "We could make some intelligent inferences about where the planes were going or where they had come from, but we couldn't see the course a plane was following.
"Our new method gives us the ability equivalent to that of an air traffic controller who looks at the dots on the radar screen and can thus follow the movements of each plane step by step.
"We can suddenly look at processes in a cell or an embryo as they are happening and don't have to infer things from the consequences any more," Shilo says.
Prof. Shilo conducted the study with Dr. Rony Seger of the Membrane Research and Biophysics Department and with doctoral student Limor Gabay of the Molecular Genetics Department.
Observing messengers in real time
The starting point for the study was the knowledge that many messages inside cells are passed on by means of phosphate atoms.
When a molecular messenger, such as a hormone, attaches itself to a receptor on the cell membrane, it sets off a chain reaction inside the cell. In its course, one molecule activates the next, and so on, through the addition of phosphate atoms, a process known as phosphorylation.
To track the activated, phosphate-containing molecules, the team developed antibodies that react only with molecules phosphorylated in a particular fashion. Since these antibodies can be easily traced, the system allowed the scientists to actually observe phosphorylation - hence, the pathway of signal transmission - in real time.
Shilo and his team worked with Drosophila fruit flies. These insects are commonly used in scientific research because they share many genetic and molecular characteristics with higher animals, develop rapidly and are easy to study. The researchers focused on a hormone-like messenger called epidermal growth factor (EGF), which becomes active during embryonic development and ensures the formation of a proper body pattern.
Using the new method, they followed the signal transmitted by EGF from the point at which EGF attaches to its receptor on the cell membrane up to the time it delivers the message to the genes in the cell nucleus. They were able to see precisely when and where the signal is passed on within individual cells, and also to observe which cells within the embryo are affected by EGF at different stages of embryonic development.
"We can trace signals in several cells simultaneously and chart an atlas of signal transmission for the entire embryo," says Shilo.
Preventing abnormal development
The new molecular "radar" also is a valuable tool for studying phosphorylation patterns set off by other receptors, and for investigating phosphorylation in other organisms, including humans. It can shed light on both normal development and abnormal tissue growth, such as in cancer.
"Phosphorylation is universal in living organisms and is part of normal growth and development. But in many types of cancer there is deregulated phosphorylation, causing uncontrolled cell growth," says Shilo.
"Clearly, we can use this method to track the phosphorylation pattern in these diseases, and it could be a useful diagnostic tool to find where things are going wrong," says Shilo. "And if you can see where things are going wrong you can set about finding specific ways to stop them."
Dr. Seger holds the Samuel and Isabelle Friedman Career Development Chair. Antibodies for this research were developed in collaboration with Sigma Israel Chemicals Ltd. The study was supported in part by the Dr. Josef Cohn Minerva Center for Biomembrane Research at the Weizmann Institute and by grants from the Tobacco Research Council of the United States, the US-Israel Binational Science Foundation, the UK-Israel Science and Technology Research Fund and the Minerva Foundation, Munich, Germany.
The Weizmann Institute of Science, in Rehovot, Israel, is one of the world's foremost centers of scientific research and graduate study. Its 2,400 scientists, students, technicians, and engineers pursue basic research in the quest for knowledge and the enhancement of the human condition. New ways of fighting disease and hunger, protecting the environment, and harnessing alternative sources of energy are high priorities.
###
Journal
Science