Now in noise

The institute's scientists plan to capture cells of the immune system, and "listen" to the cytokine conversations they have between them. In the first stage they will focus on helper T cells

When learning a new language, it is difficult to follow a conversation between the two speakers of the language. The situation can be doubly difficult when trying to follow what is being said in a room where a conversation is going on between many people, who all speak the same language as their mother tongue. Dr. Nir Friedman, from the Department of Immunology at the Weizmann Institute of Science, knows this difficulty intimately because he is trying to understand the molecular "language" of the cells of the immune system.

When the body is faced with an immune challenge such as infection or cancer, the immune system's army of cells is mobilized, and all cells work together to fight back in a coordinated manner. "Instructions" pass from one "level" of cells to another "level", and each type of cells carries out certain "commands" that lead to a coordinated and appropriate immune response to the situation. These action instructions are transmitted between the cells using different molecules, including small proteins called cytokines, which carry relevant and defined information, just like words in a human language.

Because of background noise (many molecules "moving around in the field"), it is very difficult to understand what exactly is happening - that is, which cell is "talking" to which other cell, and how the molecular instructions are translated into the reactions of the cells. Therefore, in order to understand this basic process that occurs during the immune response, it is advisable to study the system at the level of individual cells and not be satisfied with reviewing entire populations of cells. In other words, it is advisable to "listen" to only one cell at a time.

The existing scientific tools are quite limited in their sensitivity and in their ability to monitor the activity of individual cells. For example, scientists often use "reporter" genes, such as green fluorescent protein (GFP), because it "broadcasts" its reports through light when it is expressed together with the protein being studied. But if the protein is produced in the cell in relatively small amounts, the glow of the reported protein will be too weak to be detected under a normal microscope.

Dr. Friedman, who is a physicist by training, decided to use tools that are usually used for research in physics, to study biological systems. While doing post-doctoral research at Harvard University, he developed, together with other researchers, a new method that makes it possible to discover proteins produced in a cell (in the E.Coli bacterium) even when it is a single molecule.

To detect such tiny amounts of protein, the scientists used the enzyme beta-galactosidase for reporting. In this case, the source of the measured signal is not in the enzyme itself, but in another target substance, which is broken down by it. As soon as the target substance is broken down, it glows, thus reporting the presence of the enzyme that breaks it down. Since one enzyme molecule can break down many target molecules in a second, a strong amplification of the signal is created, which makes it possible to detect tiny amounts of the reporter protein (the enzyme) using standard microscopy systems. That, at least, was the theory. In practice, the scientists were unable to receive the signals, because the decomposition products of the target substance were removed from the cell quickly, immediately after they were created - which led to a significant decrease in the strength of the signals. To overcome this problem, the scientists used tiny and sophisticated devices that are divided into closed spaces (using a technology called micro-fluidics), within which individual cells can be captured, thus preventing the bright signals from escaping from the spaces.

The newly developed method allowed the researchers to notice for the first time the "pulses" of protein production - short periods of time during which several protein molecules are formed, in between longer periods of time in which there is a break in production. The findings show that this basic process of protein production is random and disordered: the length of time between one "pulse" and the next, as well as the number of protein molecules formed in each such "pulse" change each time. Thanks to the new method it is now possible to characterize them experimentally.

In his current research at the Weizmann Institute of Science, Dr. Friedman plans to develop and modify these micro-devices to capture cells of the immune system, and finally "listen" to the cytokine conversations they conduct between them. In the first stage, he intends to focus on helper T cells - a type of white blood cells that secrete cytokines and are involved in the activation and direction of other immune cells during the immune response. Because these T cells also have receptors for certain cytokines, they are able to respond to the cytokines they themselves secrete. But why would the T cells do this? How will such a phenomenon benefit the system? Does it make the response more selective and accurate? Does this lead to an all-or-nothing response? Understanding these processes may shed light on various biological activities that are important in the activation and differentiation of T cells.

In addition, if "listening" to individual cells allows scientists to understand the basic "words" of the cytokine "language", they can be more daring and open some of the passages in the miniature devices, to create more complex cellular encounters, where many more cells talk to each other . This way it will be possible to decipher the meaning of more extensive parts of the entire conversation.

Combining these new methods with mathematical models and analytical analyzes may allow scientists to predict how the cells will react under different conditions, and test these predictions in experiments to substantiate the theories. Dr. Friedman: "Due to their great influence on the immune system, cytokines may be used as effective means of healing. A better understanding of intercellular communication may allow, in the future, a more extensive realization of the medical potential of these molecules."

Dr. Nir Friedman was born in Tel Aviv. In 1989, he received a bachelor's degree in physics and mathematics from the Hebrew University, as part of the "Talfiot" program, and during his military service he studied for a master's degree in physics at Tel Aviv University. He did his doctorate at the Weizmann Institute of Science under the guidance of Prof. Nir Dodzon in the Department of Physics of Complex Systems. He received his degree in 2001, and stayed at the post-doctoral research institute for two years in the laboratory of Prof. Yoel Stevens. So he became interested in cells and living organisms. He then did post-doctoral research at Harvard University, where he stayed and worked for four years. In 2007 he joined the Department of Immunology at the Weizmann Institute of Science.

Dr. Friedman has received several prestigious scholarships and awards, including a career advancement grant from the European Human Frontier Science Program. At the Weizmann Institute of Science, in 2007, he was awarded the Sir Charles Clore Research Award. He is married and has three children. His hobbies include photography, listening to jazz and playing drums in a jazz band.