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The correct guess in genetics

The gene involved in diabetes, which was reported this week, is the first step in deciphering the genetic puzzle

Classic hereditary diseases such as Tay-Sachs, cystic fibrosis and types of deafness or mental retardation, are only a small percentage of the burden on the healthcare system. Many of the hospitalized patients come to the hospitals due to common ailments such as hypertension, heart disease, diabetes, asthma and more. While diseases of the first type are caused by a definite defect in a single gene, the latter are called multigenic diseases, and their roots lie in the combination of many genetic factors. Deciphering the basis of multigenic diseases is a first-rate challenge for modern medicine, and also a great hope that lies in the human genome project.

The ambitious project came to an end this year, and almost the entire human DNA sequence, approximately three billion "letters" (bases), will now be stored in the supercomputers of the genome centers in Israel and around the world. An immediate result of this achievement is that the genetic basis of many hundreds of the "simple", monogenic diseases has already been discovered, and some of them are already included in the basket of tests carried out in hospitals. But there are still thousands of single-gene diseases, whose genes need to be discovered. The process of identifying a gene of this kind still requires great skill, and close cooperation between medical researchers and genome and bioinformatics scientists is essential.

A beautiful example of this kind of success is the discovery published this week - the identification of the gene for the disease mucolipidosis 4. This is a hereditary disease whose symptoms are somewhat similar to those of Tay-Sachs, even though it mainly affects Ashkenazi Jews. The new gene was discovered by a team in the Department of Genetics at the Hadassah University Hospital in Jerusalem, headed by Prof. Gideon Bach, in collaboration with the Genome Center of the Weizmann Institute of Science. This is one of the few cases so far of identifying a new gene for a disease, which was done based on the purity of Israeli science. But the more distant horizon of the "harvest of the genome" is the expected victory over the multigenic diseases, guaranteeing an almost complete release from grief and suffering in the field of human health. Here the research picture is much more complicated: no more clear answers like "a defined change in gene X causes disease Y". The researchers are at a loss here in the face of a phenomenon where a dozen different genes may be responsible for a disease such as diabetes. To fully understand this situation, one must go down to the study of the genetic variation between humans.

If we compare the genomes of two people over their entire length, it will be found that on average they differ by only one letter out of a thousand. It is a wonder that such a small variation can account for all the human diversity in height, shape, color, character, health and disease. The secret of human uniqueness is that the tiny differences add up to each other, and together they create a rich fabric of possibilities. This phenomenon is not unique to humans; It also exists at the basis of the diversity of plants and farm animals.

The sites in the Bible where all humans differ from each other are revealed in fixed places. It is said that in a certain position in the passage D-NA, Reuven has a base T, while Shimon has a base C. If we examine many more men and women, there will be "agreement" between all of them on the entire sequence in the passage, and the differences will focus on the point of difference that distinguishes Reuven and Shimon. There will be a defined division: for example, 60% will have the letter T and 40% will have the letter C. These genetic differences are called single base polymorphisms, and are often indicated by the foreign acronym SNP (pronounced Snip). They are at the center of attention when it comes to multigenic diseases, and pharmaceutical companies are in fierce competition for their discoveries. It is possible to study them with the help of unique equipment, the like of which has now been incorporated into basic research in Israel, for example the D-NA chip reader device. In the future, similar equipment will be used by the entire community in hospitals or private medical services.

It is quite clear that the difference described above between C and T cannot alone cause any disease. Because if that were the case, 40% of all the inhabitants of the planet would be sick. There is a real difference here compared to the DNA differences called mutations, which are relatively rare, and usually appear only in one individual in a hundred or a thousand - and are the causes of monogenic diseases. How, then, does a multigenic disease appear?

When it comes to the lottery, no one expects that guessing one result will bring any prize: only certain combinations of X, 1, 2 will bring high winnings. By analogy, it seems that a defined composition of "branches" is the cause of phenomena such as blood pressure, osteoporosis (loss of calcium in the bones), autoimmune diseases (autoimmunity) and even mental illnesses. This is where a difficulty arises: one has to map hundreds of thousands of tiny differences all over the genome to discover the 10 or 15 critical sites included in the genetic "toto form" for a particular disease.

Furthermore - the genome scientists suspect that every multigenic disease has many forms; After all, there are more than 100 different ways to guess 13 out of 15 Toto games. This situation greatly increases the difficulty of making a connection between a combination of branches and a disease, but it also holds a unique promise: the chance to design a personal drug cocktail for each version of the disease. In this futuristic process, data on branches that determine a person's individual sensitivity to certain drugs will also be integrated.

The long road to solving the genetic puzzle must nevertheless be started with a first step. Something like this happened this week, when an important discovery was made about Gan's involvement in diabetes. The research was done by a team led by Prof. Eric Lander from the Massachusetts Institute of Technology in the USA. With the help of a rigorous statistical analysis, it was discovered that all those who have the letter C and not G in a certain "snip" in the gene called PPARG (which encodes a receptor for a hormone that oversees the breakdown of fats in the body) have a 25% greater chance of developing diabetes. At first glance, the discovery seems puzzling: the identified genetic characteristic is found in five out of six people in the world. But if we treat the finding as identifying one of the games participating in the Toto lottery, we will understand that this is an important step. It is likely that it will make it possible to identify additional genes, and within a few years the entire structure of the "form" will be deciphered.

Israel is rich in genetically defined populations and agricultural knowledge. Therefore, it serves as an excellent arena for research in human and plant genetics, including multigenic diseases. But in order to utilize these resources, it is necessary to equip yourself with sophisticated equipment and supercomputers, develop a broad knowledge base and train many scientists in a specific field. In this way, it will be possible to minimize the phenomenon of "genetic colonialism" - the use of Israel's genetic resources by foreign parties, who reap most of the scientific fame and economic benefit. Only a significant strengthening of the existing genomic infrastructures in universities and research institutes, with massive government investments, can create a fertile ground for biotechnology, medicine and future agriculture in Israel.

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