Tiny tissues, which Israeli researchers grow outside the patient's body, may help restore organs
What directs the development process in the fetus? How does the embryo turn from a collection of uniform cells into a creature with different tissues and organs, where cells work with each other in precise timing?
Already in the 70s, they knew that the process of embryonic development is directed by chemical signals, but then they had no idea what those signals were. In 1990, the research group, headed by Prof. Eduardo Mitrani from the Institute of Life Sciences at the Hebrew University, characterized a gene that encodes one of the key molecules that induces the beginning of tissue differentiation in a chicken embryo. Today it is known that a similar process also occurs in mammals. This was his first breakthrough.
The second breakthrough is emerging these days. Mitrani developed a technology that enables the growth of cells in tiny tissues outside and inside the body, which function similarly to organs in the body. This technology opens the door to diverse applications such as using these tissues as artificial organs or as a biological pump that secretes proteins inside the body to cure diseases. Last week Mitrani won the first prize in the competition for innovative developments named after Kay at the Hebrew University.
"The whole story started after our first discovery," says Mitrani. "We said: 'How is it possible that we understand what causes an embryo to differentiate and do not know what regulates differentiation and division of cells in adult tissues?'" To find the chemical signals that induce differentiation in an adult, Miterani looked for ways to grow the cells in culture under conditions similar to their natural state: "From looking at In embryos, we saw that there are two important rules for the construction and function of tissues: maintenance of mutual relations between different types of cells, and proximity to the source of supply of food and gases. I wanted to maintain the structure of the tissue because it was clear to me that what determines the proper functioning of cells is their environment. We found that the minimum thickness of micro-organs that maintain the architecture of the tissue must be greater than a few tenths of a millimeter. Beyond that, they cannot function, because the nutrients are not able to reach all the cells in them. This is how we created micro-organs that are able to maintain themselves in culture, and in them is the 'program' that guides the cells in their function and differentiation."
The micro-organs will function better than expected. Lung microorgans, for example, can be grown for months in culture. The tiny block of cells secretes everything it needs and a self-reinforcing system is created. "We thought that if the tiny tissues do work independently, we will try to transplant them into the body, and maybe they will continue to work independently there as well," says Mitrani. "To our surprise, not only did they continue to live inside the body, but also 'connected to the network.' No matter where we implanted them, everywhere a network of blood vessels was formed around them and a new small organ was obtained in the body, like a small fetus."
This finding opens the door to new treatment options. One possibility is to use the micro-organs to restore damaged organs - for example, to build an extracorporeal liver system. So far, they have not been able to successfully grow liver cells outside the body and maintain most of their vital functions. Mitrani and his team showed that liver microorgans function outside the body similarly to the whole liver; This is the first system that manages to maintain certain liver functions outside the body.
The artificial liver consists of micro-organs of human liver or pig liver connected to rows of synthetic membranes, between which blood is transferred from the patient. These micro-organs produce the array of liver proteins and secrete them into the blood that is returned to the patient at the end of the "round".
The researchers successfully completed a series of experiments with the artificial liver in animals that were in a state of liver failure, and managed to extend their lives considerably. In another experiment, the micro-organs were transplanted into animals after 92% of their original liver was removed. 35% of the animals survived. The eight percent of the original liver that remained underwent complete reconstruction in a short time, and the liver returned to its normal size. All animals that did not undergo transplantation died.
In collaboration with liver experts from Hadassah, professors Danny Shovel and Ilan Ilan, is building the company "Epigenesis", which was established to develop the artificial liver, a system that, according to Mitrani, will be possible to connect to humans within a few months. This system will be able to benefit patients suffering from acute liver failure, and also patients waiting for a liver transplant. The latter will be able to extend the waiting time through a temporary connection to the artificial liver and in some cases restore what is left of the original liver and prevent the transplant.
Another treatment option is the use of micro-organs as biological pumps to create proteins needed to restore tissues and organs in cases of illness. In many diseases, the only treatment option is with drugs that consist of proteins. Proteins cannot be swallowed because they break down in the digestive system. They must be given by injection, which makes treatment and dose control difficult. A high dose is toxic, and sometimes by the time it reaches the needed organ, it is digested and ineffective. The micro-organs are used in this case as a "biological pump". "A patient will come to the clinic, the doctor will remove a piece of tissue from his liver, insert the appropriate genes into the tissue and implant it back into the patient. The micro-organs will connect to the blood network and start producing the necessary proteins in the appropriate doses and for extended periods," says Mitrani. "This is a platform that makes it possible to produce and inject any material that allows the correction of specific problems in the body." Experiments in collaboration with Prof. Amos Pent, from the School of Medicine in Jerusalem, showed that the biological pumps are capable of producing the genes, and for the purpose of the application, the "Biogenics" company was established.
