The Weak Link
When cancer cells metastasize or tissues become damaged through inflammation, it’s likely that enzymes called matrix metalloproteinases (MMPs) are involved. This family of enzymes cuts through various bodily materials, including the tough collagen fibers that hold our tissues together.
One member of the family in particular — MMP-9 — is often produced by migrating cancer cells and in certain autoimmune diseases, and scientists have long believed that finding a way to inhibit its activities might be useful for treating these diseases. A team led by Prof. Irit Sagi of the Structural Biology Department in the Faculty of Chemistry has now employed an unconventional combination of techniques to reveal the structure of the entire MMP-9 protein. The team included Gabriel Rosenblum of the Structural Biology Department, Drs. Phillippe Van den Steen and Ghislain Opdenakker of the University of Leuven, Belgium, and Dr. Sidney Cohen of the Institute’s Chemical Research Support.
Their findings revealed a linker whose extreme flexibility and contortions “would impress even a swami yogi,” in the words of a scientific reviewer. The distinctive MMP-9 linker may turn out to be its Achilles’ heel: The team has already designed a molecule that binds directly to this domain to neutralize its activity, and Yeda, the business arm of the Weizmann Institute, has applied for a patent for this molecule.
One Hundred Times Stronger
Natural interferon is widely used to treat a number of different cancers, but its effectiveness is rather modest. Weizmann Institute scientists have now succeeded in engineering a new version of interferon whose activity is 100 times stronger than that of the natural molecule.
Prof. Gideon Schreiber of the Institute’s Biological Chemistry Department was originally interested in a basic research question concerning interferons: How do these proteins produce two different kinds of effects inside the cell — either serving as the body’s first line of defense against viral infection or inducing programmed cell death, called apoptosis? Prof. Schreiber revealed that the different types of activity stem from the way interferon binds to its receptor. Moreover, his team identified the precise amino acids and structural features that affect the binding.
The scientists then created versions of interferon with different degrees of binding ability and different types of activity: They manipulated the interferon-receptor bond by replacing various amino acids in the interferon’s binding site and then testing the resulting interferon versions. Using this approach, they managed to create an interferon molecule, called YNS, that binds to cellular receptors much more strongly and, in a laboratory dish, is 100 times more effective than natural interferon at triggering the death of cancer cells. The scientists then found that the YNS molecule effectively eliminated human breast cancer cells in laboratory mice, while the natural interferon did not.
Yeda Research and Development Company, the Institute’s technology transfer arm, has patented the YNS molecule. If the new interferon proves successful at eliminating cancer cells in humans, it could be developed into an effective anti-cancer drug.
Deadly Repeats
Huntington’s disease is a genetic time bomb. Programmed in the genes, it appears at a predictable age in adulthood, causing a progressive decline in mental and neurological function, and finally death. There is, to date, no cure. Huntington’s, and a number of diseases like it, collectively known as trinucleotide repeat diseases, are caused by an unusual genetic mutation: A three-letter piece of gene code is repeated over and over in one gene. By the number of these DNA repeats, one can predict, like clockwork, both the age at which the disease will appear and how quickly it will progress. But what is the mechanism behind this remarkable precision?
Shai Kaplan in Prof. Ehud Shapiro’s lab in the Biological Chemistry, and Computer Science and Applied Mathematics Departments, realized the answer might lie in the buildup of mutations that occurs in our cells throughout our lives. The scientists realized that the longer the initial disease sequence, the greater the chance of additional mutations. In this manner, the genes carrying the disease code might accumulate more and more DNA repeats over time, until some critical threshold is crossed.
Shapiro, Kaplan, and Dr. Shalev Itzkovitz of the Computer Science and Applied Mathematics Department have created a computer simulation that predicts, from the given number of genetic repeats, both the age of onset and the disease progression. The new disease model appears to fit all of the facts and to provide a good explanation for the onset and progression of all of the known trinucleotide repeat diseases. This explanation may, in the future, point researchers in the direction of a possible prevention or cure.
Ancient Throwback: New Technology
Today the management “posts” in the cell are occupied by proteins; but eons ago, when single-celled organisms were beginning to make their mark on Earth and life was simple, the living world might have been an “RNA world.” Recent findings suggest that RNA molecules, single strands of nucleic acids that are far less sophisticated than proteins, are capable of performing many of the cell’s main regulatory functions.
Riboswitches, discovered several years ago in bacteria, are segments of RNA that can bind to certain substances, thereby regulating the levels of these substances in the cell. Only one riboswitch has so far been found in higher organisms: The thiamin (vitamin B1) riboswitch regulates thiamin biosynthesis in numerous organisms that produce this vitamin — from the most ancient bacteria to highly developed plants. Dr. Asaph Aharoni and Samuel Bocobza of the Plant Sciences Department investigated this lone plant riboswitch. The scientists revealed the mechanism by which the riboswitch senses the presence of thiamin in the cell nucleus and makes sure the levels of this essential vitamin are neither too high nor too low by turning its production on or off as needed.
They may be ancient mechanisms, but riboswitches could be the basis of sophisticated future biotechnologies. Dr. Aharoni and Bocobza engineered reporter genes — genes that glow in fluorescent colors under the microscope when activated — that responded to thiamin levels as the riboswitches did. When inserted into plants, these reporters lit up whenever thiamin levels fell. This sort of reporter gene-riboswitch combination could pave the way to the design of live biosensors for all sorts of applications.