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Cells, chips - and cancer research - the National Science Foundation

The ability of the cells of the immune system to inhibit the cancer cells depends to a large extent on the distance between the receptors by means of which they check and identify the "suspicious" cell

Electron microscope image of a lymphocyte cell on the surface of the chip. Photo: Estee Toledo and Dr. Guillaume Le Soux.
Electron microscope image of a lymphocyte cell on the surface of the chip. Photo: Estee Toledo and Dr. Guillaume Le Soux.

White blood cells (lymphocytes) are the gatekeepers of our immune system. Like patrol officers who occasionally stop suspects, the lymphocytes patrol the blood vessels in the body and know how to distinguish between healthy cells and diseased cells that may later develop and become cancerous cells. If the cell is identified as a diseased cell - for example a cell infected with a virus, or a cancerous cell - the body's "patrol officers" break it down and destroy it. If the cell signals that it is healthy, the white blood cells allow it to continue as normal.

For the purpose of the identification process, the cells of the immune system are equipped with receptors - molecules that know how to recognize and connect to other molecules ("ligands") displayed on the surface of suspect cells. There are receptors that, when attached to the ligand, signal the immune cell to attack the suspect cell, and there are those that signal to avoid attack and "protect" the tested cell. The delicate balance between the signs allows the immune system to make the diagnosis between the types of cells and prevent an attack on healthy cells. The discovery of the attack inhibitor receptors has led in recent years to the development of a treatment method against cancer, which helps the body's immune system identify and attack cancer cells. With this method, it is possible to block and neutralize the inhibitory receptors, and allow lymphocytes to attack the cancer cells impersonating healthy cells.

Despite the many studies carried out in this field so far, several questions remain open about the mechanism of action of the suppressor receptors, among them the question: does and how does the physical distance between the receptor that signals an attack and the suppressor receptor affect the inhibition of the attack? This is where Prof. Mark Schwartzman from the Department of Materials Engineering at Ben-Gurion University of the Negev came into the picture, who developed a silicon chip whose surface simulates the face of a cancer cell, so that the chip functions, in fact, as a kind of artificial cell, capable of binding the receptors to it - and arranging them in order a certain.

 

Using a nanolithography method, which originates from computer chip manufacturing technology, the researchers created a chip with tiny drawings of dots made of various metals 10 nanometers in size.

 

 

Using a nanolithography method, which originates from computer chip manufacturing technology, the researchers created a chip with tiny drawings of dots made of various metals 10 nanometers in size. Molecules of ligands that bind the receptors, both attack receptors and inhibition receptors, were chemically attached to the points. The tiny size of the dots allows only one molecule to attach to each dot. The chip was designed so that the molecules are arranged in different arrays (molecules adjacent or distant in a controlled manner).

The research team in the laboratory

In more detail: the researchers placed on the surface of the chip lymphocytes from a living person of the type "natural killer cells" that are responsible for the operation of the immune system. In this way, they were able to demonstrate that indeed the natural lymphocytes "thought" that they had met a cancer cell and secreted toxic substances in order to attack the target cells. The researchers also discovered that the response of the cells was and is dramatically different from array to array and depends on the distance between the receptors. As the receptors got further and further apart, on the chip, the secretion of the toxic substance was inhibited. This result was a real surprise since it is contrary to the belief prevalent in the scientific community, according to which the inhibition activity in the cell requires physical proximity between the two receptors. The researchers explained this result by the fact that the cell envelope, the membrane, has limited flexibility. Thus, when the receptors are adjacent, they cannot connect with each other.

The researchers say that this research has two innovative and important aspects - nanotechnological and biological. "Nanotechnological tools make it possible to create, see and control objects on the order of 10 nanometers or even less," says Prof. Schwartzman. "This is the order of magnitude of a molecule in the body. Using these tools, we achieved in the research - which won a research grant from the National Science Foundation, an unprecedented control over the arrangement of a molecule as a single cell and we even managed for the first time to 'turn off' or 'turn on' important processes occurring in the cell."

Research is also important in the field of biology and medicine. "We were able to understand how the size and physical arrangement of the receptors in the cell affects the way they 'talk to each other'." Explains the research partner, Prof. Angel Forgador, dean of the Faculty of Health Sciences at Ben-Gurion University of the Negev. "This understanding is therefore of far-reaching importance in the development of immunotherapy methods against cancer. Today, it is possible to direct the activity of the cells of the immune system, through the genetic engineering of receptors, so that they fight cancer cells more effectively. This innovative method is currently at the forefront of cancer treatment and has already been proven to be effective against certain types of blood cancer, but in order to be able to use it against other types of cancer, further development is still necessary."

The research was carried out by researchers in the laboratories of Prof. Mark Schwartzman and Prof. Angel Forgador, led by doctoral student Estee Toledo and post-doctoral researcher Dr. Guillaume Le Soux, as well as research groups from Germany and France. Photographs: Danny Machlis, Ben-Gurion University of the Negev.