The method may be used in biomedical research, and in the future in
gene therapy and in genetic engineering of plants
Our bodies could not maintain their existence without thousands of
proteins performing myriad vital tasks within cells. Since malfunctioning
proteins can cause disease, the study of protein structure and function can
lead to the development of drugs and treatments for numerous disorders. For
example, the discovery of insulin's role in diabetes paved the way for the
development of a treatment based on insulin injections. Yet, despite
enormous research efforts led by scientists worldwide, the cellular function
of numerous proteins is still unknown. To reveal this function, scientists
perform various genetic manipulations to increase or, conversely, decrease
the production of a certain protein, but existing manipulations of this sort
are complicated and do not fully meet the researchers' needs.

Prof. Moti Liscovitch and graduate student Oran Erster of the Weizmann
Institute's Biological Regulation Department, together with Dr. Miri
Eisenstein of Chemical Research Support, have recently developed a unique
"switch" that can control the activity of any protein, raising it
several-fold, or stopping it almost completely. The method provides
researchers with a simple and effective tool for exploring the function of
unknown proteins, and in the future the new technique may find many
additional uses.

The "switch" has a genetic component and a chemical component: using
genetic engineering, the scientists insert a short segment of amino acids
into the amino acid sequence making up the protein. This segment is capable
of binding strongly and selectively to a particular chemical drug, which
affects the activity level of the engineered protein - increasing or
reducing it. When the drug is no longer applied, or when it is removed from
the system, the protein returns to its natural activity level.

As reported recently in the journal Nature Methods, the first stage of
the method consists of preparing a set of genetically engineered proteins
(called a "library" in scientific language) with the amino acid segment
inserted in different places. In the second stage, the engineered proteins
are screened to identify the ones that respond to the drug in a desired
manner. The researchers have discovered that in some of the engineered
proteins, the drug increased the activity level, while in others this
activity was reduced. Says Prof. Liscovitch: "We were surprised by the
effectiveness of the method - it turns out that a small set of engineered
proteins is needed to find the ones that respond to the drug. With their
greater resources, biotechnology companies will be able to create much
larger sets of engineered proteins in order to find one that best meets
their needs."

The method developed by the Weizmann Institute scientists is ready for
immediate use, both in basic biomedical research and in the pharmaceutical
industry, in the search for proteins that can serve as targets for new
drugs. Beyond offering a potent tool that can be applied to any protein, the
method has an important advantage compared with other techniques: It allows
the total and precise control over the activity of an engineered protein.
Such activity can be brought to a desired level or returned to its natural
level, at specific locations in the body and at specific times - all this by
giving exact and well-timed doses of the same simple drug.

In addition, the method could be used one day in gene therapy. It may
be possible to replace damaged proteins that cause severe diseases with
genetically engineered proteins, and to control these proteins' activity
levels in a precise manner - by giving appropriate doses of the drug.
Another potential future application is in agricultural genetic engineering.
The method might make it possible, for example, to create genetically
engineered plants in which the precise timing of fruit ripening would be
controlled using a substance that increases the activity of proteins
responsible for ripening. Moreover, numerous proteins are used in industrial
processes, as biological sensors and in other applications. The possibility
of controlling these applications - strengthening or slowing the rate of
protein activity in an immediate and reversible manner - can be of great
value.

Prof. Mordechai Liscovitch's research is supported by the Nella and
Leon Benoziyo Center for Neurological Diseases; La Fondation Raphael et
Regina Levy; and the Estate of Simon Pupko, Mexico.
Prof. Liscovitch is the incumbent of the Harold L. Korda Professorial
Chair of Biology.

The Weizmann Institute of Science in Rehovot, Israel, is one of the
world's top-ranking multidisciplinary research institutions. Noted for its
wide-ranging exploration of the natural and exact sciences, the Institute is
home to 2,600 scientists, students, technicians and supporting staff.
Institute research efforts include the search for new ways of fighting
disease and hunger, examining leading questions in mathematics and computer
science, probing the physics of matter and the universe, creating novel
materials and developing new strategies for protecting the environment.
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