Embryonic stem cells in genetics

Dr. Dalit Ben-Yosef

IVF Laboratory Manager, the Lis Maternity Hospital

Genetic diseases are caused by specific gene mutation, which in its turn causes damaged protein production or lack of this protein.

Genetic diseases are caused by specific gene mutation, which in its turn causes damaged protein production or lack of this protein. As a result, there is a disruption in cell, tissue or damage to normal activity of any other system of the body. In the process of competing with these hard genetic diseases a scientific community acts in two fields: the first one is the technology development for early genetic analysis that will prevent ill babies’ delivery, and the second one is the disease investigation in order to treat or to relieve the symptoms at least partially. So far, laboratory animals were the most acceptable model for genetic disease research by changing mouse DNA using the genetic engineering methods in order to include a gene responsible for the human disease. However, there are so many genetic diseases that it is still impossible to produce a typical human mutation in mouse and disease does not express itself in mouse in the same way. That is why investigation is impossible using this model. By the way, this fact is caused by gender differences. Another model for inherited diseases investigation is a cells lab growing taken from sick people. However, in most cases it is impossible to produce cells culture from the damaged cells group, like in cases when a disease damages nerve cells or diseases themselves are expressed by mental retardation, and others.

Embryo stem cells producing for genetic human diseases research
During the innovative project that has been launched in IVF (in vitro fertilization) laboratory of the Lis Maternity Hospital the embryo stem cells are being produced by natural mutation, which characterizes a typical genetic disease, in order to use them as a research model for the specific genetic disease. Stem cells are produced from 5-6 days old embryos (blast cysts) genetic disorders carriers, which were taken from couples that in the process of combined treatment of the in vitro fertilization (IVF) and the preimplantation genetic diagnosis (PGD).

1) Preimplantation genetic diagnosis
PGD enables genetic diagnosis of embryos that were taken from IVF before pregnancy. In this method embryo genetic test is being carried out before its implantation into the womb for pregnancy development. The method is called Preimplantation Genetic Diagnosis or PGD. It is used for couples who are inherited genetic diseases carriers with high risk of offspring with disease or syndrome. In order to prevent such birth the IVF will be done to the couple. Within three days after fertilization, when embryo consists of 6-8 cells, we take one embryo cell and perform its genetic diagnosis in order to confirm that embryo is healthy and it is possible to put it back into womb or it is ill and will not be returned into women’s womb. Genetic analysis is performed on a single cell and presents the whole embryo, because of the same genetic charge in all cells. In early stage of embryo development, every embryo cell is capable to produce the whole embryo. Therefore, even after taking out a single cell, embryo continues dividing and developing in normal way. The genetic test result is ready within approx. 24-hour period, so afterwards it is possible to return healthy embryos to women’s womb and thereby to increase her chances to deliver a healthy child. Embryos that were diagnosed as disease carriers are not intended to be returned back to the womb in order to prevent contaminated offspring delivery. Embryo is growing in the lab for stem cells producing purpose during about two-day additional period; during this period it is accumulating a number of cells. In this stage, the internal embryo cells will be taken for a disease carrier cells culture producing.
The PGD treatment method is designated for every disease with known mutation reason or for every other disease that may be diagnosed also with amniotic fluid test or CVS (chorionic villus sampling). Dr. Mira Malkov, responsible for PGD field in IVF Department, and Prof. Yuval Yaron, Prenatal Diagnosis Department Manager in the Genetic Institute, have established a PGD-based system in the Department, which is really capable to diagnose every disease with known mutation reason. These embryo genetic tests have been carried out at the Center since 2002, more than 100 couples have been treated and over 60 different mutations have been diagnosed with single cell; some of them are very complicated from the genetic aspect. 55 women became pregnant in the Department after PGD and 40 of them have already delivered healthy children; this fact places us as a field-leading Department in Israel.

2) Embryo stem cells producing for the purpose of inherited diseases research
Embryo stem cells are pluripotential cells, in other words, they have a potential for differentiation of every known cell type such as: nerve cells, muscle, blood cells, etc. This feature characterizes embryo cells in their first days after fertilization, and in embryo stem cells producing we “preserve” this feature during cells growth in unique conditions in the laboratory. Meaning, embryo stem cells imitate cells at the beginning of embryo development, as well as that they have an unlimited dividing feature that makes it possible their growth to culture for a long period of time. But, from the other hand, by changing their growth conditions in the laboratory it might cause their differentiation to different cell types and also to our experimental disease damaged tissues. These sorted cells carry the same genetic ingredient as the embryo they were produced from.
For the first time human embryo stem cells were produced 10 years ago. Since then, many researches have been published testifying about the big hidden potential for research and treatment in cells. In fact, the advantage of embryo stem cells producing from disease carrier embryos is that cells are natural carriers of diseases typical mutations. Additionally, cell lines may also include mutations that impossible to produce by genetic engineering techniques, these cells constitute a model for the genetic disease they represent, and hereby they allow disease research advancing in order to understand mechanisms causing that. As well as that they constitute a model for medications development, which will help in finding treatment methods and/or disease therapy. In most cases, couples who were treated with PGD for specific genetic diseases diagnosis already have got a sick child in close or extended family, that’s why they have a strong desire to donate to research of the disease they are carrying. About 3 years ago we received for the first time an approval from the National Ethic Commission to produce embryo stem cells from embryos that were diagnosed as mutation carriers. Later, we built a system and asked the couples that were under PGD process at the Department to donate sick embryos for the research; as an alternative for donation was stopping of sick embryos growth. It is worthwhile to say that response from patients for donation of embryos diagnosed in PGD process as sick ones in order to produce embryo stem cells that will be used for research of disease they carry was striking. Almost all patients we had applied agreed with great desire to donate for the disease research they carry. Till now, 13 embryo stem cell lines have been produced that carry a mutation with characteristics of different genetic diseases. At the same time, we are working diligently to produce embryo stem cells that carry additional genetic diseases in order to extend the bank that was built and constitutes reserve of cells for different diseases. Our embryo stem cells are dedicated to research in cooperation with scientists and companies that investigate different genetic diseases or who are interested to scan potential medications for disease treatment or therapy.

Breakthrough in X-linked disorder research
One of our first produced embryo stem cells is carrying a mutation, which is known as common X-linked disorder. This fact allows us to investigate a complicated genetic basis, which causes the disease expression. X-linked disorder is a hard disease that includes the most common genetic reason for mental retardation and autism. There are a number of models in mouse that used for X-linked disorder research, but any of them is not suitable enough for the disease molecular mechanism investigation. Such innovative research has been made in cooperation with Prof. Nisim Benbenisti and Dr. Rachel Aygs from the Hebrew University of Jerusalem. The breakthrough, in fact, this is a model developed for the first time ever and allows researching the mechanism that leads to gene silencing and disorder expression. Since embryo stem cells have been used as unique model for research of processes that occur in first days of embryo development, we succeeded to demonstrate that embryo with X-linked mutation is not expressing disorder symptoms during its early development, but only during later stages after differentiation to separate cells. Unique stem cells we have produced allow investigation of the epigenetic mechanism that leads to gene silencing and disorder appearance. Results of this innovative research were published in the scientific exclusive periodical magazine “Cell Stem Cell”.

This research is a wonderful example of significant importance in producing of embryo stem cells with mutations of known genetic diseases in order to advance research of diseases themselves, which will help in appropriate medications development.

24.2.2009

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