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A micro-organ in a tiny piece of skin

A thin piece of skin that will be taken from a patient, genetically modified and returned to the body - may be used as a "biological pump" that secretes necessary proteins into the blood and saves the need for frequent injections

Merit Sloin

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For the past eight years, in the laboratory of Prof. Eduardo Materni, from the Institute of Life Sciences at the Hebrew University, a technology has been developed that makes it possible to grow tiny tissue parts outside and inside the body, which function similarly to organs in the body. Materani was able to create tiny pieces of tissue that manage to maintain the structure of a whole tissue and that thickness, about three-tenths of a millimeter, allows a good passage of gases and nutrients between the cells.
The pieces of tissue acted like micro-organs - they were able to maintain themselves in culture similar to a whole organ and to exist outside the body for long periods of time.

Materni created micro-organs from different tissues, and their function was better than expected. Lung micro-organs, for example, were grown in culture for months - the tiny block of cells absorbed everything it needed from the environment and a self-reinforcing system was created, which maintained a fixed structure and the expression of all the genes operating in the lung cells. This also happened with liver and skin micro-organs. Wherever the pieces of tissue were implanted in the body, a network of blood vessels was formed around them and a small organ was obtained that operated independently.

This technology has a wide application potential, starting with the use of micro-organs as artificial organs for limited periods of time until finding a suitable organ for transplantation, through using them to restore the damaged organ, and ending with their use as a biological pump that secretes proteins inside the body that will be used to cure diseases and restore tissues. Two weeks ago, at the Israeli biotechnology conference, Prof. Materani and his colleague Prof. Amos Fant from the Hebrew University School of Medicine showed how the potential inherent in these micro-organs can be applied.

In many diseases, the only treatment is drugs composed of proteins. Proteins cannot be swallowed: they break down in the digestive system. They must therefore be given by injection, which makes treatment and dose control difficult. A high dose may be toxic. In other cases, by the time the protein reaches the needed organ, it is digested and ineffective. "The successful experiments with the lung cells made us think that it might be possible to use our micro-organs as a biological pump," says Materni. "The idea was to inject into the cells in the piece of tissue genes that produce the proteins needed by the patient, and then transplant the engineered piece of tissue into the body in the hope that its cells will produce the necessary proteins. These cells will actually function as a natural 'factory' for the production of the protein."

The development of the biological pump was done in collaboration with Prof. Fant. "We decided to implement the technology in skin tissue for two reasons," says Fant. "First, the methods of working with skin tissue are known; Second, the accessibility to the skin tissue is easy, and if a problem arises, the tissue can be easily removed and the treatment stopped." A company called "MedGenics" was established in Gush Segev in the Galilee to implement the idea. The company's first project was to inject into skin tissue of human origin a gene encoding the hormone erythropoietin, which is involved in the maturation process of red blood cells. Erythropoietin is created in the kidney, and in patients suffering from kidney failure and waiting for a kidney transplant, it is lacking and needs to be supplied from the outside. Today, the human erythropoietin protein is produced using genetic engineering methods, and is delivered to patients by injection several times a week. Due to the rapid elimination of the protein from the body, it is necessary to inject patients with large amounts that may cause side effects.

Fant and his team inserted the human gene encoding the erythropoietin protein into a virus. Next, they prepared tiny pieces of skin and injected the transgenic virus, which carries the genes encoding the necessary human protein, into the skin cells. First they tested the pieces in tissue culture. The researchers expected that the protein would be produced inside the cells and that the cells would secrete it out into the culture fluid. Indeed, the presence of erythropoietin in the tissue culture indicated that the gene inserted into the cells of the skin patches worked. The pieces of skin will function as micro-organs - they maintained their normal function in tissue culture for many weeks and secreted erythropoietin into the culture liquid.

In the next step, the researchers checked whether the engineered pieces of skin also secrete erythropoietin inside the body. They implanted them under the skin of mice lacking an immune system, which do not reject tissues of human origin. The tests showed that the pieces of skin continued to secrete the hormone even inside the body and increased the production of red blood cells in the mice. In other experiments, additional genes were tested such as a gene that codes for growth hormone, or a gene that codes for a protein called interferon alpha, which acts against viruses and is used to treat hepatitis patients (viral jaundice). In all cases the new gene functioned properly and the skin cells in the mice secreted the necessary proteins for months, depending on the type of virus that was introduced. Medgenix is ​​now waiting for the approvals required to conduct clinical trials on humans.
"The technology allows us to direct the amount of protein that the skin tissue secretes by controlling the amount of virus that is introduced into the cells," says Fant. "The implementation of the method will be simple. The doctor will take a small sample from the patient's skin, from which tiny pieces of tissue about three tenths of a millimeter thick will be prepared. After the engineered virus, which will carry the gene coding for the necessary protein, is inserted into the skin cells, the doctor will make a thin cut in the patient's skin and insert the thin piece of skin. Such an engineered piece would be able to provide all the amount of erythropoietin needed by the patient, and it would be able to function in the body for a long time. The process is simple and can be repeated several times as long as the patient needs protein."

Prof. Metrani is now engaged in another development. "The fact that wherever we implanted the micro-organs in animals, a network of blood vessels formed around them, gave us the idea of ​​using micro-organs to stimulate the creation of new blood vessels. We tested and found that the micro-organs in culture secrete growth factors that stimulate the formation of blood vessels", he says.

The road to implementing the idea was short. The goal: to try to use micro-organs to stimulate the creation of new blood vessels in blocked areas - for example in diseases that arise as a result of abnormal blood supply to the heart or in cases of clogging of blood vessels in the limbs. The experiments focused on mice and rabbits, which suffered from a lack of blood supply to the legs. The researchers made micro-organs from pieces of skin taken from the animals and implanted them in the affected area. The result: a significant improvement in the function of the affected limbs and a significant increase in the formation of new blood vessels in the affected area. These days, the "Beit Israel" hospital in Boston is testing the effectiveness of the treatment of pigs suffering from heart failure. If the trials are successful, the researchers may receive approval to move to clinical trials in humans.

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