Prof. Yoram Gruner from the Weizmann Institute of Science will receive the Rothschild Prize in Life Sciences on Thursday

The Rothschild Prize in the Life Sciences will be awarded on Thursday this week to Prof. Yoram Gruner from the Weizmann Institute of Science, for his original research and groundbreaking discoveries in the molecular biology of Down syndrome, along with four other scientists from the fields of social sciences and mathematics.

The Rothschild Prize in the Life Sciences will be awarded on Thursday this week to Prof. Yoram Groner of the Weizmann Institute of Science, for his original research and groundbreaking discoveries in the molecular biology of Down syndrome, which indicated a direct link between excess genes from chromosome 21 and the appearance of clinical symptoms of the disease, and proved the excess gene dosage theory as a cause for the development of Down syndrome.

The prize in engineering will be awarded to Prof. Avraham Lampel, from the Technion. The prize in agriculture to Prof. Shalom Applebaum from the Hebrew University, the prize in social sciences to Prof. Ariel Rubinstein from Tel Aviv University, and the prize in mathematics to Prof. David Kashdan, from the Hebrew University.

The prizes will be awarded in the presence of representatives of the Israeli government and a representative of the Rothschild family.

Prof. Yoram Gruner: Following the molecular basis for Down's syndrome

In the days when genetics took its first molecular steps, it was relatively easy to adopt the concept that a defective gene could cause disorders in the body's biological function, and even disease. But what happens when there are too many normal copies of a certain gene in the genetic load? Can an excess of normal genes cause negative effects? The answer to this question was not clear, since too many copies of the same gene do not necessarily result in the production of an excess amount of the protein encoded in the gene. And in the end, the proteins are the real players in the field of the living cells. The genes "only" encode the information necessary for their construction. In addition to the lack of clarity on this question, the geneticists were faced with many examples from the world of plants, where multiple copies of normal genes is a widespread phenomenon (and important in development), which does not cause any disorders.

This is the context in which the pioneering work of Prof. Yoram Gruner, who founded the department of molecular genetics at the Weizmann Institute of Science (as a merger of the department of genetics with the department of virology), and who later served as vice president of the institute, should be seen.

What is the dose-excess genes theory, the proof of which won Prof. Gruner the prestigious prize? Why was it important to prove her? And when do three copies of chromosome 21 appear in the cells of the human body?

In 1866, the English doctor John Langdon Down described a disease that was later named after him - Down syndrome. About 50 years ago it became clear that it is related to the appearance of three copies of chromosome 21 (instead of the two copies that exist in the cells of normal humans). Contrary to popular belief, Down syndrome is a fairly common genetic disease. Despite widespread use of prenatal diagnosis methods, one out of every 800 babies born in the Western world suffers from Down syndrome. In addition to intellectual-developmental retardation, patients with this disease suffer from a series of defects, some of which appear in other diseases that are common in the normal population. Among other things, these are deficiencies in muscle function, diabetes, leukemia and a relatively high frequency of Alzheimer's disease.

The scientists who sought to understand how an additional, third copy of chromosome 21 causes Down syndrome, examined two possibilities in this regard. One theory, called Developmental Instability, postulated that Down's symptoms are caused by the disruption of the physiological balance as a result of the increase in the number of chromosomes. This concept reconciled with the great similarity between Down syndrome patients and with the fact that most of the defects from which they suffer, also appear in the general population, although with lower frequency and severity. Another theory called the Gene dosage effect proposed that each of the symptoms is directly caused by an excess dosage of one gene or several genes from the extra chromosome, which is accompanied by an increase in the amount of protein produced by that gene.

Prof. Gruner, being a molecular biologist, tended to support the "excess gene dose" theory and set himself the goal of proving it. His findings not only proved the theory but also laid the foundations for studying the molecular genetics of Down syndrome. He set himself a challenge: to isolate one particular gene from chromosome 21, and prove that an excess dose of that gene causes the symptoms known in Down syndrome - and in this way prove the correctness of the "excess gene dosage" theory. This approach was at the time (1979) bold and innovative. The information regarding the genes found on chromosome 21 was extremely incomplete, molecular tests that allow monitoring of gene expression were not available, and gene cloning technology was in its infancy. As in many other cases, in this case too, in order to reach new areas of knowledge, the scientists had to invent new wheels. Test results showed that in the blood of those suffering from Down syndrome there is a relatively large amount of an enzyme called SOD1. But is the gene encoding SOD1 located on chromosome 21? And if so, what is the role of SOD1 in the disease? Is an excess of this enzyme related in one way or another to the unique symptoms in the syndrome? Questions of this type, which are now routinely asked in many studies in the field of genetics, were then, in the early 80s, almost beyond the reach of science.

But Prof. Gruner and the members of his research group did not give up. They set out on a hunting trip for the "suspicious" gene with which they hoped to prove the "excess dose of genes" theory. The hunting trip resulted in the cloning of the first gene from chromosome 21 and the determination of its base sequence, and was an important milestone on the way to achieving the goal. But do the genes that create an excess amount of SOD1 really play a role in causing the defects of Down syndrome?

In the first step, the members of Prof. Gruner's group created transgenic cells with several copies of the gene that contained an excess amount of SOD1, similar to cells from Down syndrome patients. These transgenic cells showed abnormal physiological properties as a result of creating an excess amount of hydrogen peroxide which is the reaction product of SOD1. One of the defects that resulted from this was damage to the absorption process of nerve mediators (neurotransmitters) which are normally absorbed and stored inside the cell. Later, Prof. Gruner and the members of his group deciphered the molecular mechanism that causes the defect and showed that the focus of the damage is a special pump whose function is to pump the neurotransmitters into the cell. This finding provided a molecular mechanistic explanation of how excess gene dosage of a gene from chromosome 21 causes a physiologically significant defect in cell function.

But what is the connection between this injury in the process of pumping the neurotransmitters and the symptoms of Down syndrome? To answer this question, Prof. Gruner and the members of his group set out on another pioneering adventure. They inserted the gene encoding SOD1 into mice and created for the first time a transgenic mouse model with a gene from chromosome 21. These mice, which carried SOD1 genes in excess and produced large amounts of SOD1, contained in their blood a very low level of the neurotransmitter serotonin - similar to what is found in babies with Down syndrome . This finding practically proved the "excess gene dosage" theory as the mechanism that causes Down syndrome.

But how exactly does an excess of SOD1 cause a decrease in serotonin in the blood? Later in the study, it was discovered that, similar to the findings in transgenic cells, in mice too, excess SOD1 causes an excess of hydrogen peroxide, which damages the special pump that draws serotonin from the blood into the platelet cells, where it is supposed to accumulate. The failure of this pumping mechanism causes serotonin to remain in the bloodstream and break down. As a result, a low level of serotonin is created in the platelets and later also in the brain of the transgenic mice, similar to the situation that exists in people with Down syndrome (a similar phenomenon occurs in diabetes, where, as a result of a lack of insulin, or a failure of its effectiveness, the sugar dissolved in the blood does not penetrate into the cells where it is needed, but remains in the bloodstream and causes negative effects).

Thus, a classic cycle of scientific research was completed, beginning with a hypothesis that tries to explain a biological phenomenon at the level of the whole organism, continuing with the identification of the molecular cause of the phenomenon, isolating it, proactively recreating the phenomenon using the identified factor, and finally, deciphering the mechanism of action in which the factor exerts its action - and proving the hypothesis.

About the Rothschild Prize:

Rothschild Prize Awarded since 1959 to outstanding researchers in various fields, and its purpose is to assist, encourage, and promote science and culture in Israel.
This is the 50th year that the award has been given by the Rothschild family, and this year, the National Library was chosen to host the ceremony. This, as a token of appreciation for the role of the National Library of Israel in collecting, preserving, distributing, bequeathing and promoting the research of the cultural and historical heritage of the people and the state.
The National Library, which is in the process of renewal, has served as a center for researchers from Israel and the world for over a century.
With the government's decision on its renewal, operations will begin to access and digitize the next abundant material, so that the treasures of manuscripts and books will be accessible to anyone who wishes to consult them.

The chairman of the National Library, David Bloomberg, said: "In this year, when the library begins on a new path, I am happy and proud to host the recipients of the Rothschild Prize, who are an example of vigorous research activity, non-stop innovation and a true spirit of passion for knowledge. I congratulate the winners, thank the Rothschild family and the benefactor for giving the library the honor of hosting, and believe that there is nothing like the National Library to host lovers of knowledge and wisdom."