Mutant Protein Holds Promise For Cell Growth Control

Leptin was discovered ten years ago and has attracted attention first because of its involvement in control of appetite and later by its effect on growth, puberty, digestion and immunological processes. Leptin can also have negative consequences, such as, for example, enhancing the spread of tumorous growths.

In his laboratory at the Hebrew University's Faculty of Agricultural Food and Environmental Quality Sciences in Rehovot, Arieh Gertler, the Karl Bach Professor of Agricultural Biochemistry, along with his students, has developed a technique for genetically engineering mutations of the leptin protein. Prof. Gertler has been assisted in this work by graduate students Dana Gonen-Berger and Leonora Niv-Spector and research assistant Gili Benyehuda.

In experimental work carried out cooperatively with researchers at the Agronomic Research Institute of France and the University of Paris VI, the scientists have developed a model showing which amino acids in leptin are responsible for activating leptin receptors in living cells. By replacing these amino acids with others, they were able to create a leptin variant that could bind with cell receptors, but would be unable to activate them, thereby providing a unique, novel research tool. In this way, the mutated leptin, with the substituted amino acids, acts as an "antagonist," competing with the normal leptin for the "attention" of the cell receptors to which both leptins are attracted. The result is a "standoff" situation in which the normal leptin is neutralized.

Since leptin is involved in several cell functions, the development of this mutated "antagonistic leptin" could have significant consequences not only for better understanding of leptin action in animals but also on halting undesirable leptin effects in humans, such as undesired cell proliferation in cancer, or in controlling other pathological phenomena in which leptin is a factor.

Thus far, the researchers have succeeded in creating antagonists of human, sheep, rat and mouse leptins.

A company, Protein Laboratories Rehovot (PLR), that was formed by Prof. Gertler and the Hebrew University's Yissum Research Development Company 18 months ago, was given the license to produce and market the mutated leptin products. Further development is currently being pursued towards testing whether leptin antagonists are capable of anti-cancer activity. This work is being pursued in cooperation with Prof. Nira Ben-Jonathan of the University of Cincinnati in the U.S., with the assistance of Prof. Gertler's graduate student, Gila Ben Avraham.

Prof. Gertler has presented his work at a symposium of the Israeli Endocrinology Society and most recently at an international biotechnological conference in Miami, Fla., sponsored by the scientific journal Nature.