Modern technology allows us to track movement invisible to the naked eye, from ships sailing beyond the horizon to orbiting satellites in outer space. Scientists at the Weizmann Institute have now introduced tracking to the frontiers of inner space as well. They have developed a molecular "radar" that, for the first time, makes it possible to track signaling enzymes inside a cell in real time.
Using this molecular "radar," the scientists have mapped the exact progress of an intercellular messenger that plays a key role in embryonic development.
The achievement, featured recently on the cover of Science, 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. It could also help resolve the mystery of how cells in an embryo manage to form the different types of tissues and organs of a human or animal body.
"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, head of 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 an 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," Shilo says. "Suddenly we can look at processes in a cell or an embryo as they are happening and we don't have to infer things from the consequences any more."
Shilo conducted the study with Dr. Rony Seger of the Biological Regulation Department and with doctoral student Limor Gabay of the Molecular Genetics Department.
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 which one molecule activates the next, 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 actually to observe phosphorylation -- the pathway of signal transmission -- in real time.
Shilo and his team worked with Drosophila fruit flies. These insects are used commonly 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 an 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.
The new molecular "radar" is also 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.
"Clearly, we can use this method to track the phosphorylation pattern in these diseases, and it could be a useful diagnostic tool for finding 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. This research was funded in part by the Dr. Josef Cohn Minerva Center for Biomembrane Research at the Weizmann Institute; the Tobacco Research Council of the United States; the U.S.-Israel Binational Science Foundation; the U.K.-Israel Science and Technology Research Fund; the Minerva Foundation, Germany; the Lynne and William Frankel Fund for the Diagnosis and Treatment of Ovarian and Breast Cancer, Philadelphia, Pennsylvania. Antibodies for this research were developed in collaboration with Sigma Israel Chemicals Ltd. Research facilities: The Ner Trust, Inc., Zurich, Switzerland.