Rehovot, Israel
July 10, 2007
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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