Shaping the Future

 

 

Weizmann Institute scientists were the first to use cells from the amniotic fluid surrounding the human fetus, for diagnostic purposes. Early clinical applications of this procedure (amniocentesis), carried out in the 1950s, included detection of the sex of the fetus and additional evaluations. Today the technique is a common medical practice in prenatal tests for various genetic defects.

 

 

Some sufferers of Duchenne muscular dystrophy (DMD), the most commonly inherited form of muscular dystrophy, also experience severe learning difficulties. Weizmann Institute scientists discovered that the gene responsible for this fatal hereditary disease is also active in the brain. This may explain the connection between DMD and cognitive impairments. Weizmann scientists have made significant contributions to elucidating the complex structure and evolution of the huge gene responsible for DMD.

 

 

Weizmann Institute scientists developed transgenic mice that include human genes-encoding proteins which can cause the development of Down's syndrome symptoms. These genes originate on chromosome 21. (Down's syndrome is caused when an extra copy of chromosome 21 is present in the developing embryo.) The transgenic mice which carry human genes are an important research model and are central to studying the genetic basis of Down's syndrome as well as the relatively frequent development of Alzheimer's disease and leukemia in people with Down's syndrome.

 

 

Sufferers of smooth brain syndrome, or lissencephaly, are born with brains lacking any of the folds or crevices which characterize a healthy brain. The syndrome is expressed during embryonic development and most of its victims are severely retarded or die in the first decade of their life. Weizmann Institute researchers discovered and cloned the gene responsible for the occurrence of lissencephaly and are developing a variety of mice whose genome will include the defective gene. These mice will serve as a primary research model for studying the syndrome and attempting to cope with and prevent it.

 

 

Weizmann Institute researchers discovered a group of five genes, named DAP (death-associated protein), which are connected to cell death. One of these genes is responsible for the production of a specific enzyme (kinase), whose structural and compositional defects are associated with the development of cancerous growths. Proteins which are products of these genes- and their retardants- may provide important medical uses for treating many diseases such as cancer, autoimmune diseases (diseases that occur when the immune system mistakenly attacks and destroys healthy body tissue and substances essential for the body), and Alzheimer's and Parkinson's disease, as well as preventing the death of immune system cells in AIDS patients.

 

 

The production of an excess or shortage of different proteins can bring about the development of various health disorders and diseases. Weizmann Institute scientists uncovered important stages of gene expression processes that cause the synthesis of various proteins. These discoveries may represent an important aspect in the development of the new medical field of gene therapy.

 

 

Weizmann Institute scientists deciphered the molecular mechanism by which the hepatitis B virus is able to force certain human genes to become "expressed," causing protein synthesis according to the genetic data encoded in genes' DNA. This ability stems from a unique protein carried by the virus that disturbs the normal process of gene expression in cells.

 

The forced expression of these human genes enables viruses to make human cells produce viral proteins more efficiently. This finding may lead to the development of ways to stop viruses taking control of human cells.

 

 

Weizmann Institute scientists demonstrated that proto-oncogenes (genes whose mutations cause the development of cancer), play an important role in the healthy and vital processes of cell division and differentiation in higher animal species, and work similarly in lower animals.

 

Working on the drosophila fruit fly, the scientists at the Weizmann Institute and other institutes demonstrated that proteins synthesized according to information encoded in proto-oncogenes operate at different "stations" in the intercellular communication chain responsible for differentiation and specialization of the cells. These genes have a similar structure to those in higher animals, hinting that proto-oncogenes in higher animals actually evolved early on. The fact that these structures survived through evolution testifies that they play an essential role in life.

 

Based on these studies, scientists are building a detailed understanding of the stages of message transmission in the cell communication network. This may help doctors to select sites and "stations" at which it will be possible to intervene. For example, from studying a communication process that doesn't cause cancer in a worm-like nematode or in fruit flies, it may be possible to identify where and how the process can be altered to prevent the development of malignancies in humans.

 

 

DNA in the body's cells is damaged every day. The sun's rays, smoke and other pollutants can influence the sensitive and complex molecular structure of genetic material, sometimes disturbing the order of its components. Every disturbance, large or small, is actually a mutation, a genetic substitution that can cause disease.

 

A unique repair system operates in the body to prevent disease and mutations. However, this system is not 100 percent effective and, as a result, some genetic defects are not repaired. On one hand, this failure allows for evolution; at its worst, it allows for genetic diseases such as cancer.

 

The "worker" that implements the duplication of DNA in the cell division process is the enzyme DNA polymerase. When this enzyme encounters an injured DNA fragment, it "freezes on the spot" and stops the duplication process completely. This reaction (emanating from the polymerase's strict self-control system) is intended to prevent mutations but it can also halt the normal body tissue renewal process. So, to rescue the "frozen" polymerase, a special protein system called by-pass agents operates in the body.

 

Weizmann Institute scientists developed a method of investigating these by-pass agents. Only one other technique of this type exists in the world. The method uses a "sauce" of living cells (Escherichia coli bacteria) and activates various processes in it as if it were a large, living organism. The scientists then examine the polymerase's ability to overcome defects in the genetic material, and study the identity and mode of operation of the by-pass agents which assist it.

 

One of these proteins, called subunit beta, is responsible for keeping the polymerase progressing along the DNA strand. When the polymerase encounters a damaged DNA fragment, subunit beta frees itself and falls off. This makes the polymerase lose its grip on the DNA strand. The Institute scientists discovered that at this stage, the by-pass agents come to the rescue and produce an alternative to the lost subunit beta, allowing the stuck polymerase to move again along the DNA.

 

 

The international Human Genome Project, considered one of the most important scientific challenges of the twentieth century, is intended to determine the precise location and nature of each of approximately 40,000 genes constituting the human genome (our complete genetic make-up), and afterwards, to determine the exact order in which the chemical building blocks of DNA are arranged in each of these genes. The entire human genome contains some three billion of these building blocks.

 

Many people have compared the scientific significance of the project to landing a man on the moon.

 

Extensive research in this field is being conducted by the Weizmann Institute and its Genome Center. In light of this, the Israel Academy of Sciences and Humanities and the Ministry of Science decided to establish a national genome and bioinformatics infrastructure laboratory at the Weizmann Institute. Bioinformatics is a new computer-rich science that enables biologists to analyze the order of the chemical building blocks in the long chain molecules of DNA and proteins and to prepare international data banks for sharing the results of the world genome project.

 

 

Weizmann Institute scientists developed a new approach that helps researchers throughout the world identify hidden genes which suppress unwanted cell proliferation or kill them off when necessary. A disorder occurs in a gene of this type, disallowing it to fulfill its role. This may lead to cancerous growths, such as various carcinomas and lymphomas.

 

When this gene is not actively suppressing a cancer it is dormant and is therefore difficult to locate. The system developed by Weizmann scientists (called "technical knockout selection"), is based on a series of complex genetic engineering processes which cause random inactivation of different genes in the cells. When paralysis strikes the gene that suppresses cell proliferation or mediates cell death, it results in the cell proliferating, allowing it to be identified. Several genes have been isolated by this novel system.

 

 

The large quantity of genetic material found in every cell in the body necessitates an especially economical storage arrangement; nevertheless, this allows the DNA to function and be expressed (causing the synthesis of various proteins).

 

In the past it was found that when DNA reaches high concentrations, it behaves like a liquid crystal (an intermediate stage between a solid crystal with all its constituent molecules arranged in the same direction, and a liquid with its component molecules pointing in different and random directions). For example, Weizmann Institute scientists demonstrated that when the quantity of DNA increases in bacteria, it is organized into a liquid crystal-like matrix.

 

Preliminary evidence suggests that DNA in the male sperm cells is also arranged like a liquid crystal and scientists believe this organization is essential for male fertility. Weizmann Institute scientists demonstrated that chemotherapy retards or prevents the organization of DNA into a liquid crystal, and this may damage male fertility. Scientists are now examining the connection between DNA organization in sperm cells and fertility.

 

DNA in eukaryotic cells is wrapped around protein structures called nucleosomes. Weizmann scientists proposed an innovative theory that one of the functions of the nucleosome is to prevent DNA compacting into a particularly dense liquid crystal structure, which would make expression of the genetic material more difficult. This theory is based, among other things, on the fact that when cells lacking nucleosomes (for example, bacteria) are confronted by stressful conditions, the DNA collapses into a compacted liquid crystal structure. This process is apparently intended to slow cell activity until conditions improve, and to protect genetic material. If this theory is confirmed, it should create a new understanding of the principles by which genetic material is arranged in the cells, and of various processes related to chemotherapy.