With the decoding of the human genome, identifications of the approximately 20,000 genes in the human body were completed. Next to each of those genes is a short DNA sequence, which is a control segment
- From the right: Dr. Roni Belcher, Dr. Zohar Barnet Itzhaki, Hamotal Borenstein and Dr. Ido Amit. hierarchy
With the decoding of the human genome, identifications of the approximately 20,000 genes in the human body were completed. Next to each of those genes is a short DNA sequence, which is a control segment: it is protein binding to that segment that determines whether that gene will be expressed, when, and in what quantity. The importance of those short segments does not fall short of that of the "normal" genes, and perhaps even surpasses them: they are responsible for the correct development of the organs and tissues in the fetus; They are the ones who determine that the eye cells - and only they - will contain light-sensitive receptors, and that the pancreatic cells - and only they - will secrete insulin; And they guide the body's systems on how to deal with external threats. About 90% of the genetic changes (mutations) that cause diseases in humans are found in these control regions. Therefore, a thorough understanding of how they work, and of the disruptions they cause, will help in the development of targeted healing methods - personalized for each patient.
Despite their great importance, the mechanisms of activity of the control factors are still not understood. Now a team of scientists, led by Dr. Ido Amit from the Department of Immunology at the Weizmann Institute of Science, in collaboration with scientists from the Broad Institute in Massachusetts, including Manuel Gerber and Nir Yosef, as well as Aviv Regev and Nir Friedman from the Hebrew University, succeeded in developing an advanced method for scanning and mapping them. The research findings, published in the scientific journal Molecular Cell, reveal the operating principles of the "control code" of the genome: it turns out that the control factors work hierarchically, when they are divided into three levels. The researchers mapped the activity of 50 control factors, at different time points, in immune cells that were exposed to the virus, and thus, in fact, were able to get down to the details of the mechanisms that regulate this type of immune response.
"These days there is a race similar in importance and complexity to the mapping of the human genome - the effort to understand the genetic changes in the control regions, and their connection to diseases and variation between humans," says Dr. Amit. "This race has encountered a significant obstacle: the process by which control mechanisms have been mapped for 30 years is complex, complicated and slow, because it is done manually, example by example. That's why such studies were only done by huge teams of scientists. Using the new method, we - a handful of people - managed to carry out research on the same scale, but in a fraction of the time." The goal is to identify the proteins that bind to the control sequences (called "transcription factors"), and to determine which protein binds to which sequence, in which cell, and in which condition. For this purpose, the proteins are fixed to the DNA, and then the DNA undergoes decoding ("sequencing") in order to determine the exact position where the protein binds to the genome. The method developed by Dr. Amit combines advanced automation and computational methods, and simultaneously measures a large amount of proteins.
The scientists exposed certain cells of the immune system to the bacteria, and then monitored 50 regulatory proteins known to be important to the immune response, at four different time points. In this way, they were able to identify the binding sites to which the control proteins bind, to determine which genes they activate, at what level, and by what mechanisms. In addition, they discovered that there is a hierarchy in the activity of the 50 proteins, and that they can be classified into one of three levels: the first level of control factors determines the basic identity of the cell and its differentiation pathway. These factors alone are able to determine the properties of the cells that make up the muscle tissues, those that make up the nervous system, and so on. While the first level of control factors creates a rough division into basic cell identities, the second level determines sub-identities, by regulating the intensity of gene expression. This is how, for example, the differences between different cells of the immune system, or between smooth muscle cells and striated muscle cells are created. The third level of control is the most specific, and affects the expression of certain genes. At this level, the cells' response to external factors is determined: bacterial invasion, hormonal signaling, hunger, and more.
Understanding the hierarchical structure makes it possible to predict how diseases caused by defects in the control factors will manifest. Disruptions in control factors from the third level may harm, for example, the body's ability to deal with viral diseases. Disruptions in the control factors from the first level may cause leukemia, because in this disease the differentiation pathways of the blood cells are damaged. In addition, a deep understanding of the control program also has potential in the field of rehabilitation medicine, as it allows to induce a renewed differentiation of cells through the appropriate control factors. Patients who need a cell transplant of a certain type will be able to use their own cells after being rehydrated, thus overcoming the difficulty of finding a suitable donor.
Dr. Amit: "The new method for mapping the genetic control program opens up new avenues for measuring biological processes and for a deep understanding of them, thus helping to understand the disruptions that occur in various diseases. An example of this is leukemia, which is associated with such control factors. The processes of this disease are being researched by me these days, in collaboration with Prof. Shay Yazraeli from the medical center in Tel Hashomer".
Ido Amit grew up in Kibbutz Jezreel, and from childhood he was intrigued to know how biological machines work, and how they can be repaired and improved. This curiosity led him to study life sciences: he did his bachelor's and master's degrees at Bar-Ilan University, and his third degree at the Weizmann Institute of Science, under the guidance of Prof. Yosef Jordan, in the Department of Biological Control. He then embarked on post-doctoral research at the Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University. In 2011, he joined the faculty of the Department of Immunology at the Weizmann Institute of Science, where he studies the immune system from a genomic and systemic perspective.
Ido Amit lives in the institute with his wife Dana and his three children: Omri, 13, Yonatan, 9, and Alma, XNUMX year old. In his spare time he rides road and off-road bikes.
